misc antibiotics
DESCRIPTION
Antibiotics presentationTRANSCRIPT
MISCELLANEOUS ANTIBIOTICS
AARON DHANUKDHARRIESINGH
FLUOROQUINOLONES
FLUOROQUINOLONES • Novel group of synthetic antibiotics developed
in response to growing resistance• The fluorinated quinolones (FQs) represent a
major therapeutic advantages: Broad spectrum of activity Improved PK properties – excellent bioavailability,
tissue penetration, prolonged half-lives Overall safety
• Disadvantages: resistance, expense
MECHANISM OF ACTION: QUINOLONES
• Quinolone antibiotics inhibit bacterial DNA gyrase (Gram negative bacteria) or Topoisomerase IV (Gram positive bacteria) This blocks bacterial DNA synthesis
USES OF THE QUINOLONE ANTIBIOTICS
• Urinary Tract Infections: fluoroquinolones are more effective than trimethoprim-sulfamethoxazole
• Prostatitis• Respiratory tract infections• Gastrointestinal and Abdominal Infections
CLINICAL USES
Gram-positive – newer FQs with enhanced potency
• Methicillin-susceptible Staphylococcus aureus
• Streptococcus pneumoniae (including PRSP)
• Group A/B/C/G and viridans streptococci – limited activity
• Enterococcus sp. – limited activity
Gram-Negative – all FQs have excellent activity Enterobacteriaceae Including - E. coli, Klebsiella sp, Enterobacter sp,
Proteus sp, Salmonella, Shigella, Serratia marcescens, etc.• H. influenzae, M. catarrhalis, Neisseria sp.• Pseudomonas aeruginosa – significant resistance has
emerged; ciprofloxacin and levofloxacin with best activity
Atypical Bacteria – all FQs have excellent activity against atypical bacteria including:
• Legionella pneumophila - DOC• Chlamydia sp.• Mycoplasma sp.• Ureaplasma urealyticum
Other Bacteria – Mycobacterium tuberculosis, Bacillus anthracis
FLUOROQUINOLONESADVERSE EFFECTS
• Gastrointestinal – 5 % Nausea, vomiting, diarrhea, dyspepsia
• Central Nervous SystemHeadache, agitation, insomnia, dizziness, rarely,
hallucinations and seizures (elderly)• Hepatotoxicity
LFT elevation (led to withdrawal of trovafloxacin) • Phototoxicity (uncommon with current FQs)
More common with older FQs• Cardiac
Variable prolongation in QTc interval Led to withdrawal of grepafloxacin, sparfloxacin
FLUOROQUINOLONESADVERSE EFFECTS
• Articular Damage Arthopathy including articular cartilage damage,
arthralgias, and joint swelling Observed in toxicology studies in immature dogs Lead to contraindication in pediatric patients and
pregnant or breastfeeding women
• Other adverse reactions: tendon rupture, dysglycemias, hypersensitivity
VANCOMYCIN
Vancomycin is called a ‘glycopeptide’, meaning that it is a cyclic peptide, with sugar residues attached to it.
DISCOVERY
Vancomycin was discovered in a soil sample sent to the pharmaceutical company Eli Lilly by a missionary in Borneo in the 1950’s.
VANCOMYCINMECHANISM OF ACTION
• Inhibits bacterial cell wall synthesis at a site different than beta-lactams
• Inhibits synthesis and assembly of the second stage of peptidoglycan polymers
• Binds firmly to D-alanyl-D-alanine portion of cell wall precursors
MECHANISM OF ACTION OF VANCOMYCIN
Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin.
VANCOMYCINSPECTRUM OF ACTIVITY
Gram-positive bacteria• Methicillin-Susceptible AND Methicillin-Resistant
S. aureus and coagulase-negative staphylococci• Streptococcus pneumoniae (including PRSP),
viridans streptococcus, Group A/B/C/G streptococcus
• Enterococcus sp.• Corynebacterium, Bacillus. Listeria,
Actinomyces• Clostridium sp. (including C. difficile),
Peptococcus, PeptostreptococcusNo activity against gram-negative aerobes or
anaerobes
CLINICAL USES
• Infections due to methicillin-resistant staph including bacteremia, empyema, endocarditis, peritonitis, pneumonia, skin and soft tissue infections, osteomyelitis
• Serious gram-positive infections in -lactam allergic patients
• Infections caused by multidrug resistant bacteria
• Endocarditis or surgical prophylaxis in select cases
• Oral vancomycin for refractory C. difficile colitis
VANCOMYCINADVERSE EFFECTS
Red-Man Syndrome • flushing, pruritus, erythematous rash on face and upper
torso• related to RATE of intravenous infusion; should be infused
over at least 60 minutes• resolves spontaneously after discontinuation• may lengthen infusion (over 2 to 3 hours) or pretreat with
antihistamines in some cases
VANCOMYCINADVERSE EFFECTS
• Nephrotoxicity and Ototoxicity• rare with monotherapy, more common when administered
with other nephro- or ototoxins• risk factors include renal impairment, prolonged therapy,
high doses, ? high serum concentrations, other toxic meds• Hematologic - neutropenia and thrombocytopenia
with prolonged therapy• Thrombophlebitis
DAPTOMYCIN
• Daptomycin is called a lipopeptide antibiotic • Approved for use in 2003• Lipid portion inserts into the bacterial cytoplasmic membrane
where it forms an ion-conducting channel.• Marketed under the trade name Cubicin
Lipophilic Tail
DAPTOMYCIN
Mechanism of ActionDaptomycin binds to components of the
cell membrane of susceptible organisms and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein.
Step 1: Daptomycin binds to the cytoplasmic membrane in a calcium-dependent manner
Step 2: Daptomycin oligomerizes, disrupting the membrane
Step 3: The release of intracellular ions and rapid death
USES OF DAPTOMYCIN (CUBICIN)• Daptomycin is active against many aerobic Gram-
positive bacteria
• Includes activity against MRSA, penicillin-resistant Streptococcus pneumoniae, and some vancomycin-resistant Enterococci (VRE)
• Daptomycin is not active against Gram negative strains, since it cannot penetrate the outer membrane.
• IV only• Primarily been used to treat skin and soft tissue infections
(complicated skin and skin structure infections, including MRSA).
• Also approved for S. aureus bloodstream infections (bacteremia), including those with right-sided infective endocarditis
• Poor activity in the lung, thus not used for pneumonia
DAPTOMYCINADVERSE EFFECTS
• Hematologic: Anemia (2% to 13%) • Gastrointestinal:
• Diarrhea (5% to 12%) • vomiting (3% to 12%) • constipation (6% to 11%)
TRIMETHOPRIM/SULFAMETHOXAZOLE
OCH3
OCH3
OCH3
H2C
N
N
NH2
H2N
Sulfamethoxazole Trimethoprim
•LINK•Most commonly used as a mixture of the sulfa drug Sulfamethoxazole and Trimethoprim•These two drugs work in synergy, with the combination being superior to either drug alone.•
• This combination is known as co-trimoxazole, TMP-sulfa, or TMP-SMX. Usually oral administration.
MECHANISM OF ACTION• Trimethoprim-sulfamethoxazole works by preventing the synthesis of tetrahydrofolate (THF), an essential cofactor in the synthesis of nucleic acid precursors.
Tetrahydrofolic Acid Biosynthetic Pathway
• In the first step of the pathway, the sulfonamides are mistaken for the natural substrate, p-aminobenzoic acid (PABA) and the drug acts as a competitive inhibitor of this enzyme
• In a later step, the trimethoprim acts as a structural analog of dihydrofolate and therefore inhibits dihydrofolate reductase
CLINICAL USES• Trimethoprim/sulfamethoxazole is an agent with
activity against both gram-positive and gram-negative organisms including:
• Infections caused by Listeria monocytogenes• Staphylococcus saprophyticus infections presenting
as urinary tract infection or cystitis• Staphylococcus aureus, including some methicillin-
resistant strains[6]
• Susceptible strains of Escherichia coli• Shigellosis• Traveler's diarrhea• P. jeroveci pneumonia – IV treatment in severe cases
ADVERSE EFFECTS
• Skin rashes
• Nausea and vomiting
• Megaloblastic anemia, leukopenia, thrombocytopenia. (reversed with simultaneous administration of folinic acid )
RESOURCES
• Lipincott’s ilustrated review of Pharmacology
• Lange/ Levinson Review of Medical Microbiology and Immunlogy