The War on Drugs The Mythology of Antibiotics

1. The War on DrugsThe Mythology of Antibiotics Edward L. Goodman, MD August 17, 2009

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 • Watch for six hours and retap, versus • Treat for 10-14 days empirically • 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 po • Longer duration is better • Multiple drugs are better • Vancomcyin mythology • 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. Parameters of Killing • Concentration dependent pharmacodynamics • Quinolones • Aminoglycosides • Lipopeptide = Daptomycin • Non concentration dependent • All the others • Various parameters of efficacy • Area under curve dependent (stay tuned)

16. Concentration Dependent • Need peak level/MIC of 10-12 • Easily achieved with most enteric pathogens with FQ • Less easily achieved for FQ with Pseudomonas • Easily achieved with “once daily aminoglycoside” • Can’t push levels much higher • Narrow therapeutic index

17. Non Concentration Dependent:Time Dependent Killing • Beta lactams, glycopeptides, macrolides and most others • Parameters of efficacy • For beta lactams, time above MIC >50% of dosing interval • Unless significant post antibiotic effect (PAE) • AUC/MIC (AUIC) above a certain threshold

18. “More is Better” continued • If 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 perior of time

19. 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

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

21. Well Absorbed No IV formulation to compare • Cephalexin (90%) • Amoxicillin (75%) • Dicloxacillin (50%) • Clarithromycin (50%) • Since none of these are concentration dependent, enteral therapy should suffice if achieve level >MIC for >50% dosing interval

22. 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 Staph endocarditis = 4 weeks of IV Nafcillin • Five days of Levaquin 750 for CAP = 10 days of 500 daily. • Three days of T/S or FQ for cystitis = 10 days

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

25. 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

26. 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 • No other good example

27. Synergy Needed • When monotherapy is not bactericidal • Enterococcal endocarditis • Neither penicillin nor aminoglycoside are ‘cidal by themselves • When combined ‘cidal activity produced

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

29. When are Multiple Drugs Needed to Prevent/Retard Development of Resistance? • HIV therapy • Chemotherapy of active TB • ??Pseudomonas pneumonia

30. Vancomycin Myths • Vancomycin is the “Ultimate drug for gram positive” • Clearly inferior to Nafcillin for sensitive staph • Slowly bactericidal • High failure rate in MRSA infections • Vancomycin is a highly toxic drug • No clear evidence of renal or otic toxicity at standard doses - e.g, 1 gm Q12h • Evidence of toxicity as doses are pushed higher

31. More Myths • Keflex is still a appropriate for outpatient SSI, respiratory infections • 50% of staph aureus are MRSA • Poor activity vs. PRSP, Hemophilus • Fluoroquinolones are superior for UTI, sinusitis, bronchitis, pneumonia • Not unless resistant organisms • May allow short therapy for CAP • Once daily dosing is convenient

32. The Solution • Vaccinate against preventable infections • Reduction in promiscuous culturing • Antimicrobial stewardship • Education • Restriction of drugs • Payors • Hospitals