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

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

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

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

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

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

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: )

Antibiotic Misuse Published surveys reveal that: – % of hospitalized patients receive antibiotics (Arch Intern Med 1997;157: ) –At PHD during 1999, 2000 and 2001, 50-60% of patients received antibiotics – % of antibiotic use in hospitalized patients is inappropriate (Infection Control 1985;6: )

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

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)

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

More Inappropriate Uses Aseptic meningitis when already pretreated –Watch for six hours and retap, versus –Treat for days empirically Abnormal CXR when no clinical symptoms for pneumonia Swabs of open wounds growing potential pathogens THE LIST COULD GO ON FOREVER!

Antibiotic Myths More is better IV is better than po Longer duration is better Multiple drugs are better Vancomcyin mythology Miscellaneous

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

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)

Concentration Dependent Need peak level/MIC of –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

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

“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

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

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

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

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

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

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

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

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

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

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

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

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

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