Review and Update of Review and Update of Antibacterial Drug TherapyAntibacterial Drug Therapy

Daniel Streetman, PharmD, MSPharmacotherapy Specialist

Lexicomp | Wolters Kluwer Health

ObjectivesObjectives

• Describe factors to consider when prescribing antibiotics

• Compare some of the antibiotic classes used to treat common infections among community-dwelling individuals

• Discuss the clinical application of this information for specific types of infections

Antimicrobial SelectionAntimicrobial SelectionSystematic Process

• Confirm infection

• Identify pathogen(s)

• Begin presumptive therapy

• Monitor

Antimicrobial SelectionAntimicrobial SelectionSystematic Process

• Confirm infection

• Identify pathogen(s)

• Begin presumptive therapy

• Monitor

• Decreased antimicrobial use - particularly of broad-spectrum agents

• Less resistance, cost, toxicity

Risks of Antimicrobial UseRisks of Antimicrobial UseResistance and Toxicity

• CDC "Urgent Threats"– C. difficile– Carbapenem-resistant

Enterobacteriaceae– N. gonorrheae http://www.cdc.gov/drugresistance/threat-

report-2013/pdf/ar-threats-2013-508.pdfCochrane Database Syst Rev 2013 Jan 31.

• Limited pipeline

Risks of Antimicrobial UseRisks of Antimicrobial UseResistance and Toxicity

• CDC "Urgent Threats"– C. difficile– Carbapenem-resistant

Enterobacteriaceae– N. gonorrheae

• Review of 11 RCTs, >3500 AOM episodes

• Per 100 abx tx's:– 5 fewer w/ pain at 2-3 d– 3 fewer perforations– 9 fewer infx of o/ear– no diff in other outcomes– no diff in future AOM risk– 7 toxicities (V/D, rash)

http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf

Cochrane Database Syst Rev 2013 Jan 31.

Antibiotics Are Common Cause Antibiotics Are Common Cause of ADE-Related ER Visitsof ADE-Related ER Visits

Clin Infect Dis 2008;47:735-43.

Antimicrobial SelectionAntimicrobial SelectionSystematic Process

• Confirm infection

• Identify pathogen(s)

• Begin presumptive therapy

• Monitor

Confirm Infection and Confirm Infection and Identify PathogenIdentify Pathogen• Fever, Leukocytosis, Local signs/symptoms

– Drug-induced fever– Antipyretic use– Steroid-induced leukocytosis

• Viral vs. Bacterial vs. Other– Sample infected tissue (Gm-stain, culture, etc.)– Contamination vs. Infection– Suspected pathogen(s) for specific site

Pharyngitis: Viruses

S.pyogenes

CABP: S.pneumoniae H.influenzae M.catarrhalis

M.pneumoniae C.pneumoniae L.pneumophila

Viruses

Hospital-Acquired: S.aureus (MRSA)

ESBL gm(-)s

Acute Otitis Media: S.pneumoniae H.influenzae M.catarrhalis

Viruses

SSTI: S .aureus

S.pyogenes S.agalactiae

Aspiration Pneumonia: Oral anaerobes

S.viridans Enteric gm(-) bacilli

UTI: E.coli (85%)

S.saprophyticus Enterococcus spp.

K.pneumoniae P.aeruginosa Proteus spp.

Enterobacter spp.

Antimicrobial SelectionAntimicrobial SelectionSystematic Process

• Confirm infection

• Identify pathogen(s)

• Begin presumptive therapy

• Monitor

Initiate Presumptive TherapyInitiate Presumptive Therapy• β-lactams

– Penicillins– Cephalosporins– Carbapenems– Monobactams

• Macrolides• Tetracyclines• Fluoroquinolones• Sulfonamides• Aminoglycosides

• Vancomycin• Clindamycin• Metronidazole• Linezolid• Quinupristin/Dalfopristin• Daptomycin• Telavancin• Rifamycins• Urinary antiseptics

Initiate Presumptive TherapyInitiate Presumptive TherapyPatient Factors

• Severity and acuity

• Allergies

• Age

• Comorbidities (including pregnancy)

• Genetics

• Concurrent medications

Initiate Presumptive TherapyInitiate Presumptive TherapyAllergy

• Is this rash an allergy?– "Ampicillin rash"

• up to 80-100% of pts with mononucleosis• 33% of amoxicillin recipients vs. 23% non-amox• cefalexin, cefaclor, cefadroxil most closely related

– 72% tolerated these vs. 97% of other cephalosporins

– Post-viral rash– Streptococcal rash

Pediatrics 2013;131(5):e1424-7. J Antimicrob Chemother 2007;60(1):107-11.

Initiate Presumptive TherapyInitiate Presumptive TherapyAllergy

• 80-90% of those with reported allergy to PCN have negative skin test– 97-99% can receive PCN without

immediate-type hypersensitivity reaction

Mayo Clin Proc 2005;80:405-10. N Engl J Med 2001;345:804-9.

Monitoring Renal Function for Monitoring Renal Function for Drug TherapyDrug Therapy• Glomerular filtration is likely

the most sensitive to age-related change (vs. secretion or reabsorption)

• Est Creatinine Clearance =

[140-age(yrs)] Weight (kg) (Serum Creatinine 72)

<Note: multiply above result by 0.85 for females!>

• This often overestimates GFR in older patients!

0

20

40

60

80

100

120

140

30s 40s 50s 60s 70s 80sAge (Decade)

Cre

atin

ine

Cle

aran

ce (

mL

/min

)

Renal blood flow s from 120 mL/min at 30-40 years of age to 60 mL/min at 80 years of age.

Initiate Presumptive TherapyInitiate Presumptive TherapyAge

Caution in children:•Tetracyclines•Chloramphenicol

Caution in older pts:•β-lactams, vanco, etc.•Fluoroquinolones•Isoniazid

0

1

2

3

4

5

6

7

8

9

21-35 35-49 50-64 65+

Patient Age (yrs)

Inci

den

ce (

%)

Tetracycline tooth staining

Incidence of INH Hepatotoxicity

Initiate Presumptive TherapyInitiate Presumptive TherapyComorbidities

• Renal, hepatic disease

• Cystic fibrosis, Diabetes, Burn patients, Neutropenic patients, HIV/AIDS, etc.

• Specific toxicity-related concerns– Ticarcillin, piperacillin: high Na+ content– Sulfonamides: crystalluria– Fluoroquinolones: myasthenia gravis

Initiate Presumptive TherapyInitiate Presumptive TherapyConcurrent Medications

• Macrolides: inhibit CYP3A4

• Fluoroquinolones: inhibit CYP1A2; binding to Al3+, Mg3+, Ca2+, Fe3+

• Tetracyclines: binding Al3+, Mg3+, Ca2+, Fe3+

• Linezolid: MAO inhibition

• β-lactams: increased conc's with probenecid

• Rifampin: major enzyme inducer

Initiate Presumptive TherapyInitiate Presumptive TherapyDrug Factors

• Local sensitivities/recommendations

• Pharmacodynamics

• Pharmacokinetics– Route– Distribution– Interactions

• Toxicities

• Cost

AntibioticsAntibioticsLocal Sensitivities and Recommendations

• SST: treat for 7-10 days (PO) or 10-14+ days (IV/PO)

– If CA-MRSA is not a concern: dicloxacillin or cephalexin– If CA-MRSA is concern: clindamycin, doxycycline, or

SMZ/TMP (± dicloxacillin or cephalexin)

Concern for MRSA increases with: Abscesses, Exudative lesions, Community prevalence of > 15%

Initiate Presumptive TherapyInitiate Presumptive TherapyPharmacodynamics - Mechanism(s) of Action

• Most abx work by only few general mechanisms:– Disrupt bacterial cell wall

• Beta-lactams, Vancomycin

– Interfere with bacterial protein/DNA/RNA synthesis• Macrolides/Azalides/Ketolides, Tetracyclines, Aminoglycosides,

Clindamycin, Linezolid, Quinupristin/Dalfopristin

– Block bacterial folic acid synthesis• Sulfonamides, Trimethoprim

– Disrupt DNA transcription/translation• Fluoroquinolones

– Other• Daptomycin, Metronidazole, most anti-TB drugs

Initiate Presumptive TherapyInitiate Presumptive TherapyPharmacodynamics - "cidal" vs. "static"

• Antibacterials that actually kill the bacteria in the body are classified as "bactericidal"– kill at least 99.9% of bacterial population– less than 3-log reduction = "bacteriostatic"

• Most drugs that inhibit protein synthesis are only bacteriostatic (exception: aminoglycosides)– Other "cidal" drugs include beta-lactams, vancomycin,

fluoroquinolones

Initiate Presumptive TherapyInitiate Presumptive TherapyPharmacodynamics - Optimal dosing

• Beta-lactams– Time > MIC

• Aminoglycosides– Peak:MIC

• Fluoroquinolones

Initiate Presumptive TherapyInitiate Presumptive TherapyPharmacokinetics

• Route of administration– Low/no oral bioavailability

• Vancomycin, Rifaximin, Fidaxomicin

– High/consistent oral bioavailability• Fluoroquinolones, Linezolid

• Distribution– Macrolides, Fluoroquinolones, Tetracyclines with

activity vs. Mycoplasma pneumoniae, Legionella pneumophila, Chlamydia pneumoniae

Initiate Presumptive TherapyInitiate Presumptive TherapyDrug Factors

• Local sensitivities/recommendations

• Pharmacodynamics

• Pharmacokinetics– Route– Distribution– Interactions

• Toxicities

• Cost

Antimicrobial SelectionAntimicrobial SelectionSystematic Process

• Confirm infection

• Identify pathogen(s)

• Begin presumptive therapy

• Monitor

Monitor TherapyMonitor Therapy

• Fever, WBC, Local signs and symptoms

• Need for changing therapy– Failure– Streamlining, IV to PO

• Antimicrobial serum concentrations

• Toxicity-related testing

Monitor TherapyMonitor TherapyRecommended Testing

• Antimicrobial serum concentrations– Aminoglycosides– Vancomycin– Chloramphenicol

• Toxicity-related testing– Renal function, hydration status

Monitor TherapyMonitor TherapyFailure

• Inadequate diagnosis

• Poor initial drug selection

• Poor source control

• New infection– Resistant population– Secondary infection

Supplemental Information Supplemental Information and Case Discussionsand Case Discussions

CABPCABPPathogens and Guidelines

• Likely pathogens:– S. pneumoniae, H. influenzae, M. catarrhalis,

M. pneumoniae, C. pneumoniae, L. pneumophila, viruses

• CABP: macrolide, doxycycline, respiratory quinolone, or β-lactam+macrolide*– ≥ 5 days, depending on clinical picture– 5 days: azithromycin or levofloxacin (750 mg dose)– 7-10 days: other oral agents

*Only if bacterial ... 20-25% of abx use 'inappropriate'

MacrolidesMacrolides• Erythromycin, Azithromycin (Zithromax),

Dirithromycin (Dynabac), Clarithromycin (Biaxin)

• Inhibit protein synthesis– Bind to 50S ribosomal subunit– Usually bacteriostatic, but can be bactericidal

• Spectrum: Gram + (staph, strep); Atypicals (Mycoplasma, Chlamydia, Legionella)

• Substrates and inhibitors of CYP3A4, Pgp– Azithromycin has unique kinetics

MacrolidesMacrolides• Abdominal pain, N/V/D

• QTc prolongation

• May increase GI motility ... motilin agonist– specific to erythromycin and azithromycin

Macrolide Drug Interaction Macrolide Drug Interaction ConcernsConcerns• Moderate to Strong CYP3A4 inhibitors

– Steroids, CCBs, statins, BZDs, AEDs, more

• Inhibit OATP1B1– Increase pravastatin AUC 2.1-fold, other

statins by up to 12-fold

• Inhibit P-glycoprotein– P-glycoprotein, newer anticoagulants

Macrolides May Increase Risk Macrolides May Increase Risk of Cardiac-Related Deathof Cardiac-Related Death• Erythromycin known to prolong QT interval

– Also inhibitor of CYP3A, OATP1B1, and p-glycoprotein

– >2-fold increase in SCD with eryth vs. o/abx– >5-fold increase with eryth and CYP3A inhibitor

• Clarithromycin also seems to share similar risks (QT effects, CYP3A, p-gp, etc.)

N Engl J Med 2004;351:1089-96. BMJ 2013;346:f1235.

Does Azithromycin Increase Does Azithromycin Increase Risk of Cardiac-Related Deaths?Risk of Cardiac-Related Deaths?

N Engl J Med 2013;368:1704-12. N Engl J Med 2012;366:1881-90.

TetracyclinesTetracyclines• Tetracycline, doxycycline (Vibramycin),

minocycline (Minocin), tigecycline (Tygacil)

• Inhibit protein synthesis– Inhibit 30S ribosomal subunit ... bacteriostatic

• Broad spectrum agents, including atypicals, H.pylori, Propionibacterium acnes– Including MRSA

• Variable lipid solubility and half-life (6 to >24 hrs)– TCN = 6-8 hrs– minocycline, doxycycline, tigecycline = ≥ 16 hrs

TetracyclinesTetracyclines

• Interactions: divalent chelation (GI interactions)

• GI burning, cramps, N/V/D

• Tooth discoloration, suppressed long bone growth– Avoid in later pregnancy and in children < 8 yrs of age

• Photosensitivity, hepatotoxicity– Special caution with expired meds

• 84% in doxycycline AUC with Al3+/Mg3+-based antacid

• ≤ 51% in doxy and TCN absorption with bismuth

• FQs also inhibit CYP1A2

0102030405060708090

100

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Al3+/Mg3+ Ca2+

Interactions with Tetracyclines Interactions with Tetracyclines and Fluoroquinolonesand Fluoroquinolones

45-97% with Al45-97% with Al3+3+/Mg/Mg3+3+

3-63% with Ca3-63% with Ca2+2+

FluoroquinolonesFluoroquinolones• Ciprofloxacin (Cipro), Levofloxacin (Levaquin),

Norfloxacin (Noroxin), Ofloxacin (Floxin), Lomefloxacin (Maxaquin), Sparfloxacin (Zagam), Moxifloxacin (Avelox), Gemifloxacin (Factive)

• Inhibits DNA gyrase (topoisomerase II) and toposiomerase IV; required for DNA uncoiling during replication and cell division– Bactericidal

• Active against many Gm(-) aerobes; many have good activity vs. many Gm(+) aerobes

FluoroquinolonesFluoroquinolones• By 'generation'

– 1st: nalidixic acid– 2nd: Ciprofloxacin (Cipro), Levofloxacin (Levaquin),

Norfloxacin (Noroxin), Ofloxacin (Floxin)– 3rd: Gemifloxacin (Factive)– 4th: Moxifloxacin (Avelox)

• "Respiratory" or not– "Respiratory" quinolone: levofloxacin, moxifloxacin,

gemifloxacin– Ophthalmic: gatifloxacin, besifloxacin, ciprofloxacin,

levofloxacin, moxifloxacin, ofloxacin

FluoroquinolonesFluoroquinolones

• Nearly 100% bioavailable (*chelation issues); hepatic metabolism, renal excretion

• Resistance: altered binding target and/or efflux mechanisms (high- vs. low-level); low frequency– Increased use frequently cause, thus need to restrict– Animal feed

• Polyvalent cations, CYP1A2 substrates

• GI effects, QTc prolongation, hyper/hypoglycemia, arthropathy and tendonitis (limits pediatric use), seizures

Fluoroquinolone ToxicitiesFluoroquinolone Toxicities

• Neuropsychiatric effects– CNS stimulation

• Tendon rupture– Age > 60 yrs– Steroid use– Post-transplant

• QT prolongation

• Hyper-/hypoglycemia

AOMAOMPathogens and Guidelines

• S. pneumoniae, H. influenzae, M. catarrhalis, viruses

• OM: amoxicillin (or amox/clavulanic acid or clindamycin or cephalosporin)**– Cephalosporins = cefuroxime, cefpodoxime, cefdinir,

ceftriaxone (IV/IM)– Alternatives: macrolide, sulfamethoxazole/trimethoprim– < 2 yrs old = 10 days– < 6 yrs old = 7-10 days– > 6 yrs old = 5-7 days

**Only recommended if bilateral, severe presentation, or failure to improve after 48-72 hrs of "watchful waiting"

PharyngitisPharyngitisPathogens and Guidelines

• Viral, S. pyogenes (20-30% kids, 5-15% adults)

• Pharyngitis: PCN VK, amoxicillin, or cephalosporin (or clindamycin)*– 10 days

*Only if Strep-positive ... otherwise, likely viral

• Amoxicillin higher-dose, given once daily is becoming preferred dose

• Treatment decreases infectious period from 10 days to approx 24 hrs, and decreases symptoms by 1-2 days

Beta-LactamsBeta-LactamsPenicillins

• Block cross-linking of bacterial cell wall by endopeptidases (“PBPs”)– on interior of cell wall

• Time-dependent killing

• Resistance– Beta-lactamases (H.flu)– Alteration of PBPs (MRSA)

Beta-LactamsBeta-LactamsPenicillin “Classes”

• Natural penicillins– Penicillin

• Extended-spectrum– Ampicillin, amoxicillin

• Antistaphylococcal penicillins (ß-lac resistant)– Methicillin, nafcillin, oxacillin, dicloxacillin

• Antipseudomonal penicillins– Piperacillin, ticarcillin

PenicillinsNotable Penicillins

• Amoxicillin vs. Ampicillin– Amoxicillin/Clavulanic acid (Augmentin)– Ampicillin/Sulbactam (Unasyn)– May cause non-allergic rash

• Piperacillin vs. Ticarcillin– Piperacillin/Tazobactam (Zosyn)– Ticarcillin/Sulbactam (Timentin)– HIGH sodium content

Beta-LactamsBeta-LactamsCephalosporins

• Block cross-linking of bacterial cell wall by endopeptidases (“PBPs”)– on interior of cell wall

• Resistance– Beta-lactamases– Alteration of PBPs

Beta-LactamsBeta-LactamsCephalosporins

• Organized into "generations" based on spectrum and year introduced

• Generally, with each generation:– Increased gm(-) and anaerobic activity– Greater resistance to -lactamase– Increased penetration of CNS

• Mostly renally eliminated– Ceftriaxone has hepatic/biliary elimination

• First Generation– cefazolin*, cephalexin, cefadroxil

• Second Generation– cefuroxime, cefoxitin*, cefotetan*, cefprozil, cefaclor

• Third Generation– ceftazidime*, ceftriaxone*, cefotaxime*, cefixime,

ceftibuten, cefdinir, cefditoren, cefpodoxime

• Fourth Generation: cefepime*

• Fifth Generation: ceftaroline*

Beta-LactamsBeta-LactamsCephalosporins

*Available as injectable product (IV and/or IM)

Amoxicillin in AOMAmoxicillin in AOM

• 80-90 mg/kg/day dosing is preferred over conventional 40-45 mg/kg/day– Effective vs. PRSP

• Alternatives only for treatment failure or allergy– Amoxicillin/clavulanate (prefer 14:1 ratio)– Cephalosporins– Macrolide, Clindamycin, SMZ/TMP

Cost ComparisonCost ComparisonPharyngitis Treatment Options

UTIUTI• UTI (lower): SMZ/TMP, nitrofurantoin, quinolone

Uncomplicated–SMZ/TMP or FQ = 3 days–nitrofurantoin = 5 days–amoxicillin/clavulanate = 3 days

Complicated–SMZ/TMP or FQ = 7-10 days–amoxicillin/clavulanate = 7-10 days

• UTI (upper): SMZ/TMP, ciproflox, levoflox–SMZ/TMP = 14 days–ciprofloxacin = 7-14 days–levofloxacin = 5-14 days

SSTISSTIPathogens and Guidelines

• S. aureus, S. pyogenes, S. agalactiae

• SST: treat for 7-10 days (PO) or 10-14+ days (IV/PO)

– If CA-MRSA is not a concern: dicloxacillin or cephalexin– If CA-MRSA is concern: clindamycin, doxycycline, or

SMZ/TMP (± dicloxacillin or cephalexin)

Other Unique AntibacterialsOther Unique Antibacterials• Telithromycin (Ketek)

– Related to macrolides; reserve for MDRSP– Serious liver toxicity risks; drug interaction risk

• Linezolid (Zyvox)– Active vs. VRE, MRSA– Weak MAO inhibition … interaction risks!

• Quinupristin/Dalfopristin (Synercid)– Active vs. VRE, MRSA, MRSE, MDRSP– Hepatotoxicity, phlebitis/local pain, arthralgia/myalgia

• Daptomycin (Cubicin)– Unique MOA (depolarizes cell membrane)– Active vs. MRSA– Myopathy, neuropathy

AntibioticsAntibioticsGuidelines for Common Infections

• CABP: macrolide, doxycycline, respiratory quinolone, or β-lactam+macrolide*– ≥ 5 days, depending on clinical picture

*Only if bacterial ... 20-25% of abx use 'inappropriate'

• OM: amoxicillin (or amox/clavulanic acid or clindamycin or cephalosporin)**– < 2 yrs old = 10 days– < 6 yrs old = 7-10 days– > 6 yrs old = 5-7 days

**Only recommended if bilateral, severe presentation, or failure to improve after 48-72 hrs of "watchful waiting"

AntibioticsAntibioticsGuidelines for Common Infections

• Pharyngitis: PCN VK, amoxicillin, or cephalosporin (or clindamycin)*– 10 days

*Only if Strep-positive ... otherwise, likely viral

• SST: treat for 7-10 days (PO) or 10-14+ days (IV/PO)

– If CA-MRSA is not a concern: dicloxacillin or cephalexin– If CA-MRSA is concern: clindamycin, doxycycline, or

SMZ/TMP (± dicloxacillin or cephalexin)

• UTI: SMZ/TMP, nitrofurantoin, quinolone– SMZ/TMP or FQ = 3 days– nitrofurantoin = 5 days

Spectrum of ActivitySpectrum of Activity

• Drugs vary widely regarding spectrum of activity, and detailed knowledge of this will require much study and/or experience– Even within same class, spectrum can be quite

different

• A few general notes about spectrum for each group of drugs follows in class-specific discussions ...

Methods of ResistanceMethods of Resistance

• Inactivating enzymes -lactamase, etc.

• Alteration of drug target– Changes in 50S, 30S subunits– Mutation in DNA gyrase– Altered penicillin binding proteins

• Expression of drug efflux transporter– TCNs, macrolides, fluoroquinolones

More About ResistanceMore About Resistance• Transferrable

– Person-to-person– Bacteria-to-bacteria– Plasmid-to-plasmid plasmid-

to-chromosome

• Strongly influenced by antibiotic use– Lower concentrations– Incomplete courses

• Increasingly limited antibiotic pipeline– Most current abx discovered pre-1970

AntibioticsAntibiotics

CephalosporinsCephalosporinsAdverse Effects

• Allergy - cross reaction up to 10% w/PCN– 1-2% w/o PCN allergy

• CNS - drug fever, seizures• Hematologic

– Hemolytic anemia, rare bone marrow suppression– N-methylthiotetrazole (NMTT) side chain: interferes with

vitamin-K dependent coagulation factor synthesis & possible disulfiram reaction ... cefotetan

• Diarrhea and C.difficile colitis• Interstitial nephritis

Beta-LactamsBeta-LactamsCarbapenems, Monobactams

• Imipenem, meropenem, ertapenem, doripenem– Severe polymicrobial infections, very broad spectrum– Cross-reactive with penicillins/cephalosporins– Cilastatin = dipeptidase inhibitor (used w/imipenem)– Seizure risk

• Aztreonam– Limited to gram negative rods – May include Pseudomonas– Occasionally used as alternative to AG– No cross-allergy to PCNs

• Concern with ceftazidime

VancomycinVancomycin• Inhibits bacterial peptidoglycan production

– Binds D-ala-D-ala component of peptidoglycan– Only effective vs. gm(+) organisms

• Critical "last resort" medication– Emerging resistance a concern

• Kinetics:– No oral absorption– ~90% renal elimination

• Phlebitis, “Red Man” syndrome, nephrotoxicity, ototoxicity

AminoglycosidesAminoglycosides

• Gentamicin, tobramycin, amikacin

• Inhibition of protein synthesis, altered protein synthesis (due to misreading)– binds to 30S ribosomal subunit– bactericidal (concentration-dependent)

• Spectrum: mostly aerobic Gm(-)– Syngery with ß-lactams (conc.-dependent instability)

• Renal excretion– Highly variable elimination– Can use serum concentrations to guide dosing

AminoglycosidesAminoglycosides

• Nephrotoxicity– High trough concentrations (Cmin > 2)– Cumulative exposure, elderly, other nephrotoxic drugs

• Ototoxicity, neuromuscular blockade (high dose)

SulfonamidesSulfonamides• Sulfamethoxazole, others

• Inhibits bacterial folic acid synthesis– p-aminobenzoic acid (PABA) analog that competes

as substrate for folic acid synthesis (required for DNA synthesis)

– Often given with trimethoprim (inhibitor of folic acid activation) to achieve synergy

• Broad spectrum (including MRSA)– Pneumocystis jiroveci (P. carinii)

SulfonamidesSulfonamides• Hepatic metabolism (acetylation), mostly renal

excretion

• Interactions: warfarin, sulfonylureas

• ADRs: allergy (cross-sensitive to other “sulfas”)– Can precipitate in acidic urine (drink water)– Hemolytic anemia (G6PD)– Photosensitivity– Severe skin reactions (SJS, TENs)– Megaloblastic anemia (rare)

Other Unique AntibacterialsOther Unique Antibacterials• Telithromycin (Ketek)

– Related to macrolides; reserve for MDRSP– Serious liver toxicity risks; drug interaction risk

• Linezolid (Zyvox)– Active vs. VRE, MRSA– Weak MAO inhibition … interaction risks!

• Quinupristin/Dalfopristin (Synercid)– Active vs. VRE, MRSA, MRSE, MDRSP– Hepatotoxicity, phlebitis/local pain, arthralgia/myalgia

• Daptomycin (Cubicin)– Unique MOA (depolarizes cell membrane)– Active vs. MRSA– Myopathy, neuropathy

Clindamycin (Cleocin)Clindamycin (Cleocin)• Inhibits protein synthesis (binds 50S)

• Spectrum: most anaerobes (except C. difficile), Gm(+) aerobes– Active against MRSA

• Widely distributed (except CNS)

• Largely metabolized, mixed elimination

• Diarrhea, pseudomembranous colitis

• Hepatotoxicity, rashes, blood dyscrasias

Metronidazole (Flagyl)Metronidazole (Flagyl)

• Classified as antiprotozoal• Spectrum: anaerobes including Bacteroides

and Clostridium• MOA:

– Accepts electrons (deprives fermentation chemistry)– Reduced molecule toxic to DNA

• Mixed anaerobic and colitis (GI), also CNS (abscess)

• ADR: disulfiram effect

Rifaximin (Xifaxan)Rifaximin (Xifaxan)• Rifamycin antibiotic indicated for (1)

traveler’s diarrhea due to E. coli and (2) hepatic encephalopathy– Use for C. difficile-associated diarrhea (CDAD)

is an unlabeled use (treatment, "chaser")– Inhibits RNA synthesis

• 200mg and 550mg tablets; given BID-TID

• Limited systemic absorption– Low side effect, interaction potential

Fidaxomicin (Dificid)Fidaxomicin (Dificid)

• Macrolide antibiotic indicated for treatment of C. difficile-associated diarrhea– Inhibits RNA synthesis (bactericidal)

• Available as 200 mg tablets, given BID

• Minimal systemic absorption (<10%) in healthy volunteers– Appears to be higher (2- to 6-fold) in patients