Transcript The War on Drugs: The Mythology of Antibiotics FIDSA, FSHEA

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
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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
– 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
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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
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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.
Antibiotic
serum concentration
Pharmacodynamic Parameters
of Fluoroquinolones
Cmax (peak)
AUC
MIC90
AUC
MIC
Time above MIC
Time (h)
• For optimal antimicrobial
effect:
– Cmax/MIC should be >
8-10
or
• – AUC/MIC should be >
125 for GNR, >30 for GPC
“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
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Short bowel syndrome
Malabsorption
Vascular collapse
Ileus
“Completely” Bioavailable
IV and enteral essentially identical
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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
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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?
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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 (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”
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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