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The War on Drugs: The Mythology of Antibiotics

The War on Drugs: The Mythology of Antibiotics. Edward L. Goodman, MD, FACP, FIDSA, FSHEA May 9, 2005. An Epidemic of Drastic Proportions: demographics. Affects people of all ages Disproportionately involves the very young and very old Involves the more affluent and well insured

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The War on Drugs: The Mythology of Antibiotics

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  1. The War on Drugs:The Mythology of Antibiotics Edward L. Goodman, MD, FACP, FIDSA, FSHEA May 9, 2005

  2. An Epidemic of Drastic Proportions: demographics • Affects people of all ages • Disproportionately involves the very young and very old • Involves the more affluent and well insured • Costs in the billions • Producers reap huge profits • Pushers are among elite • Users are not addicted • Sometimes still demand a drug fix

  3. Effects of the Epidemic • Direct toxicity of the drugs • Diarrhea from most • Deafness from a few • Renal failure from quite a few • Skin rash from all • Secondary infections from all • IV phlebitis from all

  4. Indirect Effects: Secondary Infections • Pneumonia • Vent associated • Bacteremia/fungemia • Line associated • MDR Urinary tract infections • Catheter associated • Prolonged hospital stay • Excessive costs

  5. Description of “Pushers” • Well educated • Well intentioned • Extremely Defensive • Fearful of lawyers • Use that as an excuse • Forgetful • Forgotten lessons of graduate school • Addicted to the culture of cultures

  6. The Truth • Producers = PHARMA • Pushers = physicians • Victims = all of us • Drugs = antimicrobials • Root Causes = ignorance of microbiology, epidemiology, pharmacology • DRUGS OF FEAR

  7. More of the Truth • Antibiotic use (appropriate or not) leads to microbial resistance • Resistance results in increased morbidity, mortality, and cost of healthcare • Antibiotics are used as “drugs of fear” • (Kunin et al. Annals 1973;79:555) • Appropriate antimicrobial stewardship will prevent or slow the emergence of resistance among organisms (Clinical Infectious Diseases 1997; 25:584-99.)

  8. Antibiotic Misuse • Published surveys reveal that: • 25 - 33% of hospitalized patients receive antibiotics (Arch Intern Med 1997;157:1689-1694) • At PHD during 1999, 2000 and 2001, 50-60% of patients received antibiotics • 22 - 65% of antibiotic use in hospitalized patients is inappropriate (Infection Control 1985;6:226-230)

  9. Consequences of Misuse of Antibiotics • Contagious RESISTANCE • Nothing comparable for overuse of procedures, surgery, other drugs • Morbidity - drug toxicity • Mortality - MDR bacteria harder to treat • Cost

  10. Appropriate Use of Antibiotics • Need 8-10 lectures • Many useful reference sources • Sanford Guide (hard copy or electronic) • Epocrates (epocrates.com) • Hopkins abx-guide (hopkins-abx.guide.org) • ID Society – practice guidelines (idsociety.org)

  11. Inappropriate Use of Antibiotics • Asymptomatic UTI in non pregnant patients • “Acute sinusitis” before trial of 7-10 days of symptomatic treatment (NEJM 8/26/04) • Respiratory cultures when there is no clinical evidence of pneumonia • Positive catheter tip cultures when no bacteremia • Coagulase negative staph in single blood cultures • FUO with no clinical site of infection • Prophylaxis for surgery beyond 24 hours

  12. More Inappropriate Uses • Aseptic meningitis when already pretreated • Consider observe 6-8 hours, then retap • Abnormal CXR when no clinical symptoms for pneumonia • Swabs of open wounds growing potential pathogens • THE LIST COULD GO ON FOREVER!

  13. Antibiotic Myths • More is better • IV is better than oral • Longer duration is better • Multiple drugs are better • Vancomcyin: a whole mythology of its own • Miscellaneous

  14. Is More Better? • What does “more” (higher doses) accomplish? • Higher serum levels, and thus • Higher tissue levels • But when are higher levels needed? • Privileged sanctuary where drugs penetrate poorly • CSF/vitreous • Heart valve vegetations • Implants/prostheses/biofilms • Defenseless host

  15. Pharmacodynamics • MIC=lowest concentration to inhibit growth • MBC=the lowest concentration to kill • Peak=highest serum level after a dose • AUC=area under the concentration time curve • PAE=persistent suppression of growth following exposure to antimicrobial

  16. Parameters of antibacterial efficacy • Time above MIC - beta lactams, macrolides, clindamycin, glycopeptides • 24 hour AUC/MIC - aminoglycosides, fluoroquinolones, azalides, tetracyclines, glycopeptides, quinupristin/dalfopristin • Peak/MIC - aminoglycosides, fluoroquinolones

  17. Time over MIC associated with better killing • Should exceed MIC for at least 50% of dose interval for beta lactams and vancomycin • Higher doses may allow longer time over MIC • For most beta lactams, optimal time over MIC can be achieved by continuous infusion (except unstable drugs such as imipenem, ampicillin)

  18. Higher serum/tissue levels are associated with faster killing • Aminoglycosides • Peak/MIC ratio of >10-12 optimal • Achieved by “Once Daily Dosing” • PAE helps • Fluoroquinolones • 10-12 ratio achieved for enteric GNR • PAE helps • not achieved forPseudomonas • Not always for Streptococcus pneumoniae

  19. AUC/MIC = AUIC • For Streptococcus pneumoniae, FQ should have AUIC >= 30 • For gram negative rods where Peak/MIC ratio of 10-12 not possible, then AUIC should >= 125.

  20. AUC MIC90 Pharmacodynamic Parameters of Fluoroquinolones Cmax (peak) • For optimal antimicrobial effect: – Cmax/MIC should be > 8-10or • – AUC/MIC should be > 125 for GNR, >30 for GPC Antibiotic serum concentration AUC MIC Time above MIC Time (h)

  21. “More is Better” continued • Since beta lactams don’t kill any better at higher concentrations • Why give them IV? • Why increase dose? • Just give often enough • Confounding factor • Higher dose gives higher serum levels which may exceed MIC for longer time

  22. When is IV better than enteral? • Patient unable to take enteral meds/food • Patient unable to absorb enterally • Short bowel syndrome • Malabsorption • Vascular collapse • Ileus

  23. “Completely” BioavailableIV and enteral essentially identicalGIVE ENTERALLY IF POSSIBLE • Respiratory quinolones (90-98%) • Fluconazole (90%) • Trimethoprim sulfa (85%) • Metronidazole (90%) • Doxycycline/minocycline (93/95%) • Clindamycin (90%) • Linezolid (100%)

  24. Well Absorbed No IV formulation to compare • Cephalexin (90%) • Amoxycillin (75%) • Dicloxacillin (50%) • Clarithromycin (50%) • Since none of these are concentration dependent, enteral therapy should suffice if levels >MIC for >50% dosing interval • Easily achieved for these agents

  25. Is Longer Duration Better? • In every study comparing two lengths of therapy, shorter is as good • Two weeks Pen & Gent for viridans strept SBE = 4 weeks of Pen alone • Two weeks of PO Cipro and Rif for right sided OSSA endocarditis = 4 weeks of IV Nafcillin • Five days of Levaquin 750 for CAP = 10 days of 500 daily (CID 10/03) • Eight days Rx for HAP (non Pseudomonas) = 14 days (ATS/IDSA 1/05) • Three days of T/S or FQ for cystitis = 10 days

  26. Is Longer Worse? • Increases antibiotic resistance • Exposes patient to more toxicity • Increases cost • May actually increase the risk of some infections

  27. When are Multiple Antibiotics Indicated? • Empiric therapy when organism(s) not known • For mixed infections when one drug won’t cover • For synergy • To retard or prevent the development of resistance

  28. When is Synergy Needed? • If it allows reduction in dosage of toxic components of a combination • Flucytosince with AMB can shorten the course and lower the dose of AMB for Crypto meningitis (non HIV patients) • No other good example

  29. Synergy Needed • When monotherapy is not bactericidal • Enterococcal endocarditis • Neither penicillin nor aminoglycoside are ‘cidal by themselves • When combined ‘cidal activity produced • Other enterococcal infections do not need ‘cidal therapy including bacteremia unassociated with IE

  30. When is Cidal Therapy Needed • Bacterial Endocarditis • Bacterial Meningitis • Maybe neutropenic or immunocompetent host • Maybe osteomyelitis • Not for almost all other bacterial infections

  31. When are Multiple Drugs Needed to Prevent/Retard Development of Resistance? • HIV therapy • Chemotherapy of active TB • ? Severe P. aeruginosa bacteremia/ pneumonia • No real data that dual Rx prevents emergent beta lactam resistance • Instead it provides a second drug in case beta lactam resistance emerges

  32. Vancomycin Myths • “Ultimate drug for gram positive” • Clearly inferior to Nafcillin for sensitive staph • Slowly bactericidal • High failure rate in MRSA infections • Will likely be supplanted by Daptomycin/Linezolid • “Vancomycin is a toxic drug” • No clear evidence of renal or oto-toxicity in monoRx • When combined with aminoglycoside, 30-40% risk of toxicity

  33. More Vanco Myths • “Must do serum levels” (predicted on prior myth) • Non concentration dependent • So peaks unnecessary except for meningitis • No correlation with efficacy/toxicity ever demonstrated in literature • Cannot measure true peaks • Long alpha phase • Must do log decay curve • Troughs may allow less frequent dosing

  34. More Myths • Keflex is still a appropriate for outpatient SSI, respiratory infections • >50% of staph aureus are MRSA • Poor activity vs. pen resist pneumococcus, Hemophilus • Fluoroquinolones are superior for UTI, sinusitis, bronchitis, pneumonia • Not unless resistant organisms

  35. The Solution • Vaccinate against preventable infections • Reduction in promiscuous cultures • Lead to unnecessary Rx • Antimicrobial stewardship • Restriction of drugs by • Payors • Antimicrobial Management Programs • EDUCATION • Computerized Physician Order Entry

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