antibiotici beta lattamici
TRANSCRIPT
ANTIBIOTICI BETA LATTAMICI
Schematic of the monoderm Gram-positive cell envelope LTA lipoteichoic acid polymers WTA wall teichoic acid polymers M N-acetyl-muramic acid G N-acetyl glucosamine Refer to text for further details
Schematic structure of PG and target sites of different enzymes (pointed by color arrows) The synthetic enzyme (PBP) is highlighted in red while the lytic enzymes (NagZ AmpD and LT) are highlighted in blue Notably NagZ and AmpD catalyze the liberated muropeptides instead of intact PG Hexagons denote sugars while rectangles denote stem amino acids The cross-linkage between the top and bottom glycan strands is D-Ala rarr meso-A2pm LT lytic transglycosylase PBP penicillin-binding protein m-A2pm meso-diaminopimelic acid AnhMurNAc 16-anhydro-MurNAc β1 rarr 4 β-(14)-glycosidic bond
Colorazione di Gram
Distingue gram positivi da gram negativi
Nata per distinguere la polmonite da streptococco (gram +) e quella da klebsiella (bacillo gram -)
Hans Christian Gram used light microscopy to detect microbes that were stained with crystal violetiodine Microbes that cannot retain this dye following treatment with ethanol were counterstained with safranin (or fuchsin) thereby distinguishing Gram-positive from Gram-negative bacteria
The differential staining property is based on the peptidoglycan layer which is considerably thicker in Gram-positive microbes
Another difference is that Gram-positive bacteria elaborate a single membrane whereas Gram-negative microbes harbour a plasma membrane and an additional outer membrane with lipopolysaccharides
Staphylococcus aureus causes a broad spectrum of diseaseHumans are colonized by this organism mainly inthe nasopharynx and on the skin
Staphylococcus aureus has the unique propensity to infect and destroy normal healthy tissue causing skin and wound infections bloodstream infection (BSI) pneumonia osteomyelitis endocarditis lung abscess and pyomyositis
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Schematic of the monoderm Gram-positive cell envelope LTA lipoteichoic acid polymers WTA wall teichoic acid polymers M N-acetyl-muramic acid G N-acetyl glucosamine Refer to text for further details
Schematic structure of PG and target sites of different enzymes (pointed by color arrows) The synthetic enzyme (PBP) is highlighted in red while the lytic enzymes (NagZ AmpD and LT) are highlighted in blue Notably NagZ and AmpD catalyze the liberated muropeptides instead of intact PG Hexagons denote sugars while rectangles denote stem amino acids The cross-linkage between the top and bottom glycan strands is D-Ala rarr meso-A2pm LT lytic transglycosylase PBP penicillin-binding protein m-A2pm meso-diaminopimelic acid AnhMurNAc 16-anhydro-MurNAc β1 rarr 4 β-(14)-glycosidic bond
Colorazione di Gram
Distingue gram positivi da gram negativi
Nata per distinguere la polmonite da streptococco (gram +) e quella da klebsiella (bacillo gram -)
Hans Christian Gram used light microscopy to detect microbes that were stained with crystal violetiodine Microbes that cannot retain this dye following treatment with ethanol were counterstained with safranin (or fuchsin) thereby distinguishing Gram-positive from Gram-negative bacteria
The differential staining property is based on the peptidoglycan layer which is considerably thicker in Gram-positive microbes
Another difference is that Gram-positive bacteria elaborate a single membrane whereas Gram-negative microbes harbour a plasma membrane and an additional outer membrane with lipopolysaccharides
Staphylococcus aureus causes a broad spectrum of diseaseHumans are colonized by this organism mainly inthe nasopharynx and on the skin
Staphylococcus aureus has the unique propensity to infect and destroy normal healthy tissue causing skin and wound infections bloodstream infection (BSI) pneumonia osteomyelitis endocarditis lung abscess and pyomyositis
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Schematic structure of PG and target sites of different enzymes (pointed by color arrows) The synthetic enzyme (PBP) is highlighted in red while the lytic enzymes (NagZ AmpD and LT) are highlighted in blue Notably NagZ and AmpD catalyze the liberated muropeptides instead of intact PG Hexagons denote sugars while rectangles denote stem amino acids The cross-linkage between the top and bottom glycan strands is D-Ala rarr meso-A2pm LT lytic transglycosylase PBP penicillin-binding protein m-A2pm meso-diaminopimelic acid AnhMurNAc 16-anhydro-MurNAc β1 rarr 4 β-(14)-glycosidic bond
Colorazione di Gram
Distingue gram positivi da gram negativi
Nata per distinguere la polmonite da streptococco (gram +) e quella da klebsiella (bacillo gram -)
Hans Christian Gram used light microscopy to detect microbes that were stained with crystal violetiodine Microbes that cannot retain this dye following treatment with ethanol were counterstained with safranin (or fuchsin) thereby distinguishing Gram-positive from Gram-negative bacteria
The differential staining property is based on the peptidoglycan layer which is considerably thicker in Gram-positive microbes
Another difference is that Gram-positive bacteria elaborate a single membrane whereas Gram-negative microbes harbour a plasma membrane and an additional outer membrane with lipopolysaccharides
Staphylococcus aureus causes a broad spectrum of diseaseHumans are colonized by this organism mainly inthe nasopharynx and on the skin
Staphylococcus aureus has the unique propensity to infect and destroy normal healthy tissue causing skin and wound infections bloodstream infection (BSI) pneumonia osteomyelitis endocarditis lung abscess and pyomyositis
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Colorazione di Gram
Distingue gram positivi da gram negativi
Nata per distinguere la polmonite da streptococco (gram +) e quella da klebsiella (bacillo gram -)
Hans Christian Gram used light microscopy to detect microbes that were stained with crystal violetiodine Microbes that cannot retain this dye following treatment with ethanol were counterstained with safranin (or fuchsin) thereby distinguishing Gram-positive from Gram-negative bacteria
The differential staining property is based on the peptidoglycan layer which is considerably thicker in Gram-positive microbes
Another difference is that Gram-positive bacteria elaborate a single membrane whereas Gram-negative microbes harbour a plasma membrane and an additional outer membrane with lipopolysaccharides
Staphylococcus aureus causes a broad spectrum of diseaseHumans are colonized by this organism mainly inthe nasopharynx and on the skin
Staphylococcus aureus has the unique propensity to infect and destroy normal healthy tissue causing skin and wound infections bloodstream infection (BSI) pneumonia osteomyelitis endocarditis lung abscess and pyomyositis
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Hans Christian Gram used light microscopy to detect microbes that were stained with crystal violetiodine Microbes that cannot retain this dye following treatment with ethanol were counterstained with safranin (or fuchsin) thereby distinguishing Gram-positive from Gram-negative bacteria
The differential staining property is based on the peptidoglycan layer which is considerably thicker in Gram-positive microbes
Another difference is that Gram-positive bacteria elaborate a single membrane whereas Gram-negative microbes harbour a plasma membrane and an additional outer membrane with lipopolysaccharides
Staphylococcus aureus causes a broad spectrum of diseaseHumans are colonized by this organism mainly inthe nasopharynx and on the skin
Staphylococcus aureus has the unique propensity to infect and destroy normal healthy tissue causing skin and wound infections bloodstream infection (BSI) pneumonia osteomyelitis endocarditis lung abscess and pyomyositis
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Staphylococcus aureus causes a broad spectrum of diseaseHumans are colonized by this organism mainly inthe nasopharynx and on the skin
Staphylococcus aureus has the unique propensity to infect and destroy normal healthy tissue causing skin and wound infections bloodstream infection (BSI) pneumonia osteomyelitis endocarditis lung abscess and pyomyositis
Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Classi di Antibiotici beta-lattamici
1) Penicilline
2) Cefalosporine
3) Monobactami
4) Carbapenemi
Amoxicillina Ampicillina Azlocillina Bacampacillina Carbenicillina Cloxacillina Dicloxacillina Flucoxacillina Piperacillina Ticarcillina
1a Cefalessina2a Cefamandolo3a Cefotaxima4a cefepime5a Ceftobiprolo
Aztreonam
Imipenem Carbapenem Meropenem
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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-
Inibitori beta-lattamasi
Acido clavulanico
Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Meticillina
Farmaco di riferimento nel determinare la sensibilitagrave batterica
Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Aztreonam
Monobactami
Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Imipenem
Carbapenemi
Porzione in comune
Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Penicillinasi
Amidasi 6-aminopenicillanico
Acido penicilloico
Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Spettro di azione delle Penicilline
Staphylococcus Streptococcus Enterococcus
ActinobacteriaNocardia
Polmoniti Endocarditi Meningiti
Faringite Scarlattina Polmonite
Endocardite Infezione tratto urinario
Lesioni toraciche
Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Meccanismo di azione beta lattamici
Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Inibitori beta lattamasi
TazobactamSulbactamAcido Clavulanico
Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Spettro di azione delle Penicilline
Bacillus anthracis (G+)
Pseudomonas (G-)
Neisseria gonorrhoeae (G-)
Listeria (G+) Treponema pallidum Sifilide
Polmonite
Infezioni Tratto Urinario
Gonorrea
Meningite Endocardite Batteriemia
Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Farmacocinetica
Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Lo stafilococco aureus puograve causare intossicazione da cibo polmoniti batteriemia impetigo (acuta piogenica che colpisce soprattutto in etagrave pediatrica riguardante gli strati superficiali della cute la cui comparsa di solito si limita al volto e agli arti) follicoliti e osteomieliti nellrsquouomo mastiti artriti e infezioni del tratto urinario negli animali Lo stafilococco egrave la principale causa di infezioni nosocomiali del sistema nervoso centrale e lrsquoaureus egrave il piugrave comune agente della batteriemia
Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes
La resistenza allo streptococco pneumonie da parte delle penicilline egrave dovuta ad una minor affinitagrave di queste alla parete cellulare di questo batterio in particolare alle penicillin binding proteins Crsquoegrave una progressiva riduzione della sensibilitagrave alla penicillina ed altri beta lattamici che causa il bisogno di aumentare le dosi per inibire la crescita batterica
Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Treponema pallidum
Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Pseudomonas aeruginosa (gram negativo)
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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- Slide 53
- Slide 54
-
Lo Pseudomonas aeruginosa (PA)egrave un batterio gram negativo di cui egrave nota la sua la sua versatilitagrave ambientale lrsquoabilitagrave di causare la malattia in particolari individui suscettibili e di resistere agli antibiotici La complicazione piugrave seria in cui egrave coinvolto egrave la fibrosi cistica e porta ad infezione respiratoria diffusa
Lo P A puograve produrre un numero considerevole di proteine tossiche le quali non solo causano un esteso danno tissutale ma anche interferiscono con il sistema immunitario Queste proteine possono uccidere le cellule entrandovici o portare danni al tessuto connettivo
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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-
Penicilline antipseudomonas
AntibioticoMIC (microgrammiml)
Pseudomonas EColi
Carbenicillina32 8
Piperacillina4 2
Ticarcillina32 8
Mezlocillina32 2
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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-
Sintomi della Gonorrea
La gonorrea egrave causata dal batterio Neisseria gonorrhoeaeIl periodo di incubazione egrave di 1020 giorni con comparsa dei sintomi tra il 15 e il 20 giorno dopo lrsquoinfezione Un piccolo numero di persone sono asintomatici per tutta la vita Tra il 30 e il 60 delle persone con gonorrea hanno la malattia in uno stato subclinico Nelle donne questa malattia si puograve manifestare con perdite uterine difficoltagrave di urinare alterazione del ciclo mestruale o sanguinamento dopo rapporto sessuale La cervice pu apparire in varie forme da normale ad stremamente infiammata con pus Infezioni dellrsquouretra e della cervice sono frequenti Lrsquoinfezione si trasmette per via vaginale orale e anale Gli uomini hanno solo un 20 di probabilitagrave di infettarsi per via sessuale mentre le donne per il 50 Una madre affetta da gonorrea puograve trasferirla al nascituro durante il parto producendogli oftalmia neonatale
Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Antibiotici che possono essere usati in caso di gonorrea
Amoxicillina 2 g piugrave probenecid 1 g orale Ampicillina 2 to 3 g piugrave probenecid 1 g orale
Azitromicina 2 g orale
Cefixime 400 mg orale Cefotaxime 500 mg per iniezione muscolare
Cefoxitin 2 g per iniezione muscolare plus probenecid 1 g orale Cefpodoxime (Vantin) 400 mg orale
Ceftriaxone (Rocephin) 125 to 250 mg per iniezione muscolare
Ciprofloxacina 500 mg orale Levofloxacina 250 mg orale
Ofloxacina 400 mg orale
Spectinomicina 2 g per iniezione muscolare
Penicilline
Macrolidi
Cefalosporine
Chinolonici
Aminociclitolo
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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- Slide 52
- Slide 53
- Slide 54
-
Indicazioni Terapeutiche per le Penicilline
Endocarditi battericheGonorreaMeningitePolmoniti
Ascessi polmonariSifilide
Setticemia
Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Antibiotic-induced liver toxicity mechanisms clinical features and causality assessmentRobles M Toscano E Cotta J Lucena MI Andrade RJSourceLiver Unit Gastroenterology Service and Department of Medicine Viacutergen de Victoria University Hospital University of Maacutelaga SpainAbstractAntibiotics are the therapeutic agents most often associated with hepatotoxicity However this is mainly due to the widespread prescription of these drugs The relative risk of antibiotic-related hepatotoxicity is low Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be difficult particularly because some cases occur long after the drug has been stopped Among the penicillins amoxicillin clavulanate is the most associated with hepatotoxicity and is the most frequent cause of DILI-related hospitalisations Flucloxacillin ranks as the second highest cause of DILI in many countries The severity of antibiotic-induced DILI varies widely with the hepatitis-like (hepatocellular) damage tending to be more severe that than cholestaticmixed type The pattern is strongly influenced by age Recently telithromycin (a new generation macrolide) has been linked with DILI with a typical pattern which includes abrupt commencement of fever abdominal pain jaundice and in some cases ascites Antibiotic-induced DILI appears in most instances to be idiosyncratic Genetic-association studies have recently identified genotypes related to flucloxacillin and possibly to amoxicillin-clavulanate hepatotoxicity
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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-
Imipenem
Carbapenemi
Porzione in comune
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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-
CarbapenemiA questa classe appartengono lrsquoimipenem il meropenem lrsquoertapenem e il doripenemQuesti agenti hanno il piugrave vasto spettro antibatterico rispetto agli altri beta lattamici Sono resistenti alle beta lattamasiSono attivi contro i gram positivi e negativi con lrsquoeccezione di quelli intracellulari come le clamidie
Essi provvedono ad una maggiore copertura nei confronti dei batteri gram negativi rispetto agli altri beta lattamici e sono stabili nei confronti delle beta lattamasi e nei confronti di batteri multiresistenti
Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Carbapenems versus other beta-lactams in treating severe infections in intensive care a systematic review of randomised controlled trialsEdwards SJ Clarke MJ Wordsworth S Emmas CE
Carbapenems have not been comprehensively compared in clinical trials with fourth-generation cephalosporins (4GC) and antipseudomonal penicillins (APP) in the treatment of severe infections (SI) and febrile neutropenia (FN)
Of the 265 papers identified 12 were appropriate for meta-analysis (four 4GC and eight APP) The results showed that carbapenems are associated with a significant reduction in all-cause mortality compared to APP in the treatment of SI and withdrawals due to adverse events (RR 065 95 CI 045 to 096 p=003) are also less common When compared in the treatment of FN carbapenems are associated with a significant increase in clinical response during the initial 72 h of treatment (RR 137 95 CI 109 to 174 p=0008) and bacteriologic response (RR 173 95 CI 103 to 289 p=004) For all other outcomes including all comparisons with 4GC there were no significant differences between treatments The use of carbapenems rather than APP could reduce mortality and by simplifying treatment decisions reduce the time before patients receive appropriate antibiotic treatment
Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Un esempio
Nella esacerbazione acuta della bronchite cronica
First-Line Amoxicillin ampicillinpivampicillin TMPSMX and doxycycline were considered tobe first-line antibiotics for the management of patients with AECB (acute exacerbations of chronic bronchitis)
and Second-Line AntibioticsAmoxicillinclavulanic acid macrolides (ieroxithromycin clarithromycin and azithromycin) second-generation or third-generation cephalosporins (ie cefaclor) and quinolones were considered to be advanced or second-line antibiotics for this indication according to published guidelines
Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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- Slide 54
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Monobactami
Aztreonam possiede una forte attivitagrave nei confronti dei batteri gram-negativi compreso lo Pseudomonas aeruginosa
Non egrave attivo nei confronti dei gram positivi o gli anaerobi
Ersquo efficace nei confronti di un gran numero di batteri tra I quali IlCitrobacter lrsquoEnterobacter lrsquoE coli lrsquoHaemophilus la Klebsiella il Proteus e le specie di Serratia
Attualmente si sta studianto la somministrazione di aztreonam per via inalatoria come lisinato nel trattamento della fibrosi cistica polmonare
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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-
KlebsiellaPolmonitiInfezioni del tratto urinarioSetticemiaSpondilite anchilosante
Serratia
Responsabile delle infezioni nosocomiali (S marcescens)
Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Proteus
Ersquo un batterio a forma di bastoncino ed ha alte capacitagrave di produrre ureasi che rappresenta il modo di riconoscerlo
Lrsquoureasi idrolizza lrsquourea in ammoniaca e perciograve alcalinizza maggiormente le urine
Lrsquoalcalinizzazione puograve portare a formazione di cristalli che possono precipitare nei tubuli
Questo batterio puograve essere trovato nei calcoli renali e questi possono ricominciare lrsquoinfezione se non eliminati Questi calcoli possono portare anche a morte renaleIl proteus puograve anche causare infezioni nelle ferite setticemia e polmoniti sopratutto nei pazienti ospedalizzati
Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Cephalosporin use in treatment of patients with penicillin allergiesDePestel DD Benninger MS Danziger L LaPlante KL May C Luskin A Pichichero M Hadley JADepartment of Clinical Sciences College of Pharmacy University of Michigan Hospitals and Health Centers University of Michigan Ann Arbor 48109 USA
OBJECTIVE To review the evidence that supports the use of certain cephalosporins in penicillin-allergic patients DATA SYNTHESIS Physicians may now prescribe certain cephalosporins in patients with a history of a nonserious non-life-threatening penicillin reaction Exclusions include type I anaphylaxis Stevens-Johnson syndrome toxic epidermal necrolysis angioedema and other potentially life-threatening responses to medication Recent reports demonstrate that a considerable body of literature describing the cross-reactivity between cephalosporins and penicillin was established based on nonallergic adverse reactions or in vitro studies rather than on clinically relevant immune-mediated reactions Oral rechallenge and skin testing data support the relationship of the beta-lactam side-chain structures of these drugs as a predictor of cross-reactivity CONCLUSION Recent data suggest that the incidence of cross-reactivity among penicillins and cephalosporins is lower than historically reported Pharmacists should be aware that cephalosporin cross-reactivity in a penicillin-allergic patient is not necessarily a class effect Dispensing should be evaluated based on the type of allergic manifestations and the drug prescribed
Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Tossicitagrave da beta lattamici
Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Tossicitagrave da beta lattamici
Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Acc Chem Res 2008 Jan41(1)11-20Inhibitors of FabI an enzyme drug target in the bacterial fatty acid biosynthesis pathwayLu H Tonge PJSourceDepartment of Chemistry and Institute for Chemical Biology amp Drug Discovery Stony Brook University Stony Brook New York 11794-3400 USAAbstractThe modern age of drug discovery which had been slowly gathering momentum during the early part of the twentieth century exploded into life in the 1940s with the isolation ofpenicillin and streptomycin The immense success of these early drug discovery efforts prompted the general view that many infectious diseases would now be effectively controlled and even eradicated However this initial optimism was misplaced and pathogens such as multidrug-resistant Mycobacterium tuberculosis and methicillin-resistant Staphylococcus aureus present a major current threat to human health Drug resistance arises through the unrelenting pressure of natural selection and there is thus a continuing need to identify novel drug targets and develop chemotherapeutics that circumvent existing drug resistance mechanisms In this Account we summarize current progress in developing inhibitors of FabI the NADH-dependent enoyl reductase from the type II bacterial fatty acid biosynthesis pathway (FAS-II) a validated but currently underexploited target for drug discovery The FabI inhibitors have been divided into two groups based on whether they form a covalent adduct with the NAD (+) cofactor Inhibitors that form a covalent adduct include the diazaborines as well as the front-line tuberculosis drug isoniazid The NAD adducts formed with these compounds are formally bisubstrate enzyme inhibitors and we summarize progress in developing novel leads based on these pharmacophores Inhibitors that do not form covalent adducts form a much larger group although generally these compounds also require the cofactor to be bound to the enzyme Using structure-based approaches we have developed a series of alkyl diphenyl ethers that are nanomolar inhibitors of InhA the FabI from M tuberculosis and that are active against INH-resistant strains of M tuberculosis This rational approach to inhibitor development is based on the proposal that high-affinity inhibition of the FabI enzymes is coupled to the ordering of a loop of amino acids close to the active site Compounds that promote loop ordering are slow onset FabI inhibitors with increased residence time on the enzyme The diphenyl ether skeleton has also been used as a framework by us and others to develop potent inhibitors of the FabI enzymes from other pathogens such as Escherichia coli S aureus and Plasmodium falciparum Meanwhile chemical optimization of compounds identified in high-throughput screening programs has resulted in the identification of several classes of heteroaromatic FabI inhibitors with potent activity both in vitro and in vivo Finally screening of natural product libraries may provide useful chemical entities for the development of novel agents with low toxicity While the discovery that not all pathogens contain FabI homologues has led to reduced industrial interest in FabI as a broad spectrumtarget there is substantial optimism that FabI inhibitors can be developed for disease-specific applications In addition the availability of genome sequencing data improved methods for target identification and validation and the development of novel approaches for determining the mode of action of current drugs will all play critical roles in the road ahead and in exploiting other components of the FAS-II pathway
Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Recent Pat Antiinfect Drug Discov 2007 Jan2(1)73-7Linezolid in children recent patents and advancesVelissariou IMSourceResearch Fellow in Pediatric Infectious Diseases and Pulmonology P and A Kyriakou Childrens Hospital Athens Greece jane_velhotmailcomAbstractLinezolid is the first approved member of a new generation of antibiotics the synthetic oxazolidinones to become available with a broad spectrum of in vitro activity against Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) vancomycin-resistant Enterococcus faecalis and vancomycin-resistant Enterococcus faecium It has an excellent bioavailability both intravenously and orally and a very good safety profile both in adults and in children With regards to its antimicrobial action linezolid has a predominantly bacteriostatic action rather than a bacteriocidal effect and is active against Gram-positive bacteria that are resistant to other antibiotics Linezolid is currently showing great promise for the treatment of multi-resistant Gram-positive infections both in the community and in a hospital setting Clinical indications so far include skin and soft tissue infections community-acquired or nosocomial pneumonia due to MRSA VRE bacteremia and community-acquired pneumonia due to penicillin-resistant Streptococcus pneumoniae We anticipate that this new generation of antimicrobial agents will provide adequate cover in the future for infections that cause significant treatment failures so far such as VRE- associated endocarditis bone and joint multi-drug resistant infections and possibly central nervous system infections both in adult and children populations Some patents on linezolid are also discussed in this review
Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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Pharmacotherapy 2008 Apr28(4)458-68Telavancin an antimicrobial with a multifunctional mechanism of action for the treatment of serious gram-positive infectionsLeonard SN Rybak MJSourceAnti-Infective Research Laboratory Pharmacy Practice 4148 Eugene Applebaum College of Pharmacy and Health Sciences Wayne State University Detroit MI 48201 USAAbstractTelavancin is a once-daily lipoglycopeptide antibiotic structurally derived from vancomycin It has broad-spectrum activity against gram-positive bacteria including strains with reduced susceptibility to vancomycin Telavancins multifunctional mechanism of action including inhibition of peptidoglycan synthesis and disruption of membrane potential account for this enhanced activity as well as rapid bactericidal properties In vitro activity has been demonstrated against a wide range of gram-positive pathogens such as multidrug-resistant Streptococcus pneumoniae as well as methicillin-resistant glycopeptide-intermediate and vancomycin-resistant Staphylococcus aureus The agent also displays activity against many gram-positive anaerobic organisms Predictable linear pharmacokinetics have been demonstrated over a wide range of doses with the most common adverse effects being taste disturbance and nausea Clinical experience with telavancin in phase II and III studies for complicated skin and skin structure infections has shown it to have similar efficacy and tolerability compared with vancomycin and antistaphylococcal penicillins and recently telavancin received an approvable letter from the United States Food and Drug Administration for this indication Telavancin appears to be a promising agent for the treatment of serious infections caused by gram-positive pathogens including drug-resistant pathogens Further clinical experience will clarify its role in therapy
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