Antibiotic Myths E. Goodman

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 • 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; 25:584-99.) 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) 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 – 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! 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 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 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 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 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) 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 for Pseudomonas – Not always for Streptococcus pneumoniae 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. Pharmacodynamic Parameters of Fluoroquinolones Antibiotic serum concentration Cmax (peak) AUC MIC90 • For optimal antimicrobial effect: – Cmax/MIC should be > 8-10 or • – AUC/MIC should be > 125 for GNR, >30 for GPC AUC MIC Time above MIC Time (h) “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 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 (90%) Doxycycline/minocycline (93/95%) Clindamycin (90%) Linezolid (100%) 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 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 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 (non HIV patients) – 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 – Other enterococcal infections do not need „cidal therapy including bacteremia unassociated with IE When is Cidal Therapy Needed • Bacterial Endocarditis • Bacterial Meningitis • Maybe neutropenic or immunocompetent host • Maybe osteomyelitis • Not for almost all other bacterial infections • HIV therapy • Chemotherapy of active TB • ? Severe P. aeruginosa bacteremia/ pneumonia When are Multiple Drugs Needed to Prevent/Retard Development of Resistance? – No real data that dual Rx prevents emergent beta lactam resistance – Instead it provides a second drug in case beta lactam resistance emerges 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 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 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 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