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: )

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 –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 – 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 not possible, then AUIC should >= 125.

C max (peak) Time above MIC AUC MIC 90 Time (h) Antibiotic serum concentration MIC Pharmacodynamic Parameters of Fluoroquinolones AUC For optimal antimicrobial effect: – C max /MIC should be > 8-10 or For optimal antimicrobial effect: – C max /MIC should be > 8-10 or – AUC/MIC should be > 125 for GNR, >30 for GPC– AUC/MIC should be > 125 for GNR, >30 for GPC

Parameters of Killing Concentration dependent pharmacodynamics –Quinolones –Aminoglycosides –Telithromycin Non concentration dependent –All the others –Various parameters of efficacy

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 –Time above MIC 50% of dose interval Unless significant post antibiotic effect (PAE) –AUC/MIC above a certain threshold

“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

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

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