Transcript Document 7268570

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
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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
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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
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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 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!
Antibiotic Myths
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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 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
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
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Short bowel syndrome
Malabsorption
Vascular collapse
Ileus
“Completely” Bioavailable
IV and enteral essentially identical
GIVE ENTERALLY IF POSSIBLE
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Respiratory quinolones (90-98%)
Fluconazole (90%)
Trimethoprim sulfa (85%)
Metronidazole
Doxycycline/minocycline
Clindamycin (90%)
Linezolid (100%)
Well Absorbed
No IV formulation to compare
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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?
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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
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Vaccinate against preventable infections
Reduction in promiscuous culturing
Antimicrobial stewardship
Education
Restriction of drugs
– Payors
– Hospitals