review and update of antibacterial drug therapy daniel streetman, pharmd, ms pharmacotherapy...
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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
ciproflox levoflox norflox
Bio
av
ail
ab
ilit
y (
%)
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