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Review and Update of Antibacterial Drug Therapy

Review and Update of Antibacterial Drug Therapy. Daniel Streetman, PharmD, MS Pharmacotherapy Specialist Lexicomp | Wolters Kluwer Health. Objectives. Describe factors to consider when prescribing antibiotics

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Review and Update of Antibacterial Drug Therapy

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  1. Review and Update of Antibacterial Drug Therapy Daniel Streetman, PharmD, MS Pharmacotherapy Specialist Lexicomp | Wolters Kluwer Health

  2. Objectives • 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

  3. Antimicrobial SelectionSystematic Process • Confirm infection • Identify pathogen(s) • Begin presumptive therapy • Monitor

  4. Antimicrobial SelectionSystematic Process • Confirm infection • Identify pathogen(s) • Begin presumptive therapy • Monitor • Decreased antimicrobial use - particularly of broad-spectrum agents • Less resistance, cost, toxicity

  5. Risks of Antimicrobial UseResistance and Toxicity • CDC "Urgent Threats" • C. difficile • Carbapenem-resistant Enterobacteriaceae • N. gonorrheae • Limited pipeline http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf Cochrane Database Syst Rev 2013 Jan 31.

  6. Risks 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.

  7. Antibiotics Are Common Cause of ADE-Related ER Visits Clin Infect Dis 2008;47:735-43.

  8. Antimicrobial SelectionSystematic Process • Confirm infection • Identify pathogen(s) • Begin presumptive therapy • Monitor

  9. Confirm Infection and Identify 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

  10. Pharyngitis:Viruses S.pyogenes Acute Otitis Media:S.pneumoniae H.influenzae M.catarrhalis Viruses CABP:S.pneumoniae H.influenzae M.catarrhalis M.pneumoniae C.pneumoniae L.pneumophila Viruses UTI:E.coli (85%) S.saprophyticus Enterococcus spp. K.pneumoniae P.aeruginosa Proteus spp. Enterobacter spp. Aspiration Pneumonia:Oral anaerobes S.viridans Enteric gm(-) bacilli SSTI:S .aureus S.pyogenes S.agalactiae Hospital-Acquired:S.aureus (MRSA) ESBL gm(-)s

  11. Antimicrobial SelectionSystematic Process • Confirm infection • Identify pathogen(s) • Begin presumptive therapy • Monitor

  12. Initiate Presumptive Therapy • β-lactams • Penicillins • Cephalosporins • Carbapenems • Monobactams • Macrolides • Tetracyclines • Fluoroquinolones • Sulfonamides • Aminoglycosides • Vancomycin • Clindamycin • Metronidazole • Linezolid • Quinupristin/Dalfopristin • Daptomycin • Telavancin • Rifamycins • Urinary antiseptics

  13. Initiate Presumptive TherapyPatient Factors • Severity and acuity • Allergies • Age • Comorbidities (including pregnancy) • Genetics • Concurrent medications

  14. Initiate 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.

  15. Initiate 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.

  16. Monitoring Renal Function for Drug 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! Renal blood flow s from 120 mL/min at 30-40 years of age to 60 mL/min at 80 years of age.

  17. Initiate Presumptive TherapyAge Caution in children: • Tetracyclines • Chloramphenicol Caution in older pts: • β-lactams, vanco, etc. • Fluoroquinolones • Isoniazid Tetracycline tooth staining Incidence of INH Hepatotoxicity

  18. Initiate 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

  19. Initiate 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

  20. Initiate Presumptive TherapyDrug Factors • Local sensitivities/recommendations • Pharmacodynamics • Pharmacokinetics • Route • Distribution • Interactions • Toxicities • Cost

  21. AntibioticsLocal Sensitivities and Recommendations • SST: treat for 7-10 days (PO) or 10-14+ days (IV/PO) • If CA-MRSA is nota 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%

  22. Initiate 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

  23. Initiate 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

  24. Initiate Presumptive TherapyPharmacodynamics - Optimal dosing • Beta-lactams • Time > MIC • Aminoglycosides • Peak:MIC • Fluoroquinolones

  25. Initiate 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

  26. Initiate Presumptive TherapyDrug Factors • Local sensitivities/recommendations • Pharmacodynamics • Pharmacokinetics • Route • Distribution • Interactions • Toxicities • Cost

  27. Antimicrobial SelectionSystematic Process • Confirm infection • Identify pathogen(s) • Begin presumptive therapy • Monitor

  28. Monitor Therapy • Fever, WBC, Local signs and symptoms • Need for changing therapy • Failure • Streamlining, IV to PO • Antimicrobial serum concentrations • Toxicity-related testing

  29. Monitor TherapyRecommended Testing • Antimicrobial serum concentrations • Aminoglycosides • Vancomycin • Chloramphenicol • Toxicity-related testing • Renal function, hydration status

  30. Monitor TherapyFailure • Inadequate diagnosis • Poor initial drug selection • Poor source control • New infection • Resistant population • Secondary infection

  31. Supplemental Information and Case Discussions

  32. CABPPathogens 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'

  33. Macrolides • 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

  34. Macrolides • Abdominal pain, N/V/D • QTc prolongation • May increase GI motility ... motilin agonist • specific to erythromycin and azithromycin

  35. Macrolide Drug Interaction Concerns • 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

  36. Macrolides May Increase Risk of 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.

  37. Does Azithromycin Increase Risk of Cardiac-Related Deaths? N Engl J Med 2013;368:1704-12. N Engl J Med 2012;366:1881-90.

  38. Tetracyclines • 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

  39. Tetracyclines • 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

  40. Interactions with Tetracyclines and Fluoroquinolones • 84%  in doxycycline AUC with Al3+/Mg3+-based antacid • ≤ 51%  in doxy and TCN absorption with bismuth • FQs also inhibit CYP1A2  45-97% with Al3+/Mg3+  3-63% with Ca2+

  41. Fluoroquinolones • 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

  42. Fluoroquinolones • 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

  43. Fluoroquinolones • 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

  44. Fluoroquinolone Toxicities • Neuropsychiatric effects • CNS stimulation • Tendon rupture • Age > 60 yrs • Steroid use • Post-transplant • QT prolongation • Hyper-/hypoglycemia

  45. AOMPathogens 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"

  46. PharyngitisPathogens 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

  47. Beta-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)

  48. Beta-LactamsPenicillin “Classes” • Natural penicillins • Penicillin • Extended-spectrum • Ampicillin, amoxicillin • Antistaphylococcal penicillins (ß-lac resistant) • Methicillin, nafcillin, oxacillin, dicloxacillin • Antipseudomonal penicillins • Piperacillin, ticarcillin

  49. 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

  50. Beta-LactamsCephalosporins • Block cross-linking of bacterial cell wall by endopeptidases (“PBPs”) • on interior of cell wall • Resistance • Beta-lactamases • Alteration of PBPs

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