Ranking of Antimicrobial Drugs According to Importance in Human Medicine
John H. Powers, M.D.
Lead Medical Officer
Antimicrobial Drug Development and Resistance Initiatives
Office of Drug Evaluation IV
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Introduction
Define problem of antimicrobial use in animals and relationship to antimicrobial resistance in human pathogens
Background on ranking process
Factors used in ranking drugs
factors based on drug efficacy
factors based on resistance
factors of low importance
The Problem
Antimicrobial drug use in food-producing animals:
may result is bacteria in animals resistant to drugs used to treat human illness
resistant bacteria in food-producing animals may be transmitted to humans
non-pathogenic bacteria originating in food-producing animals may transmit resistance traits to human pathogenic bacteria
Background
Desire to preserve usefulness of antimicrobials of greatest importance in treatment of human disease
Framework document includes categorization of drugs based on relative importance in human medicine
drugs ranked as high, medium or low importance in human medicine based on several factors
considered in hazard identification and consequence assessments
Joint CVM-CDER team developed guidelines for categorization of drugs
Background
Ranking of drugs not a regular part of CDER review and approval process for antimicrobials.
Approval process entails showing drug product must be safe and effective; demonstrating specific level of importance in human medicine is not required.
Regulatory initiatives do recognize some products may be of greater importance in human medicine.
Subparts E & H: serious and life-threatening disease
Background
Qualitative rather than a quantitative system
multiple factors may apply to some drugs
Degree of subjectivity in these determinations
Does not necessarily include all antimicrobial drugs and classes
Ranking expected to evolve over time
new drugs
emergence of diseases
changes in prescribing patterns
Factors in Ranking
Factors related to drug efficacy
sole therapy/limited available therapies
therapy of choice
spectrum of activity of particular importance
importance for oral therapy
importance in treating food-borne infections
unique mechanism of antimicrobial action
Factors related to development of antimicrobial resistance
cross-resistance within drug class
cross-resistance across drug classes
ease of transmissibility of resistance determinants
Factors in Ranking: Drug Efficacy
Sole or limited available therapy
“high” importance until widespread resistance in humans precludes use or other therapy available
vancomycin or linezolid for MRSA infections
Therapy of choice
not sole therapy but preferred for various reasons
cefazolin for pre-operative prophylaxis
important when treating high mortality/ morbidity infections
ceftriaxone or cefotaxime for acute bacterial meningitis
Factors in Ranking: Drug Efficacy
Spectrum of activity of particular importance
drugs used in treatment of infections due to resistant pathogens
dalfopristin/quinupristin for vancomycin resistant enterococcal infections
Importance in oral therapy
use of drug in cases where patient would have required parenteral therapy
fluoroquinolones or trimethoprim-sulfamethoxazole for variety of Gram negative infections
Importance in treating food-borne infections
most direct link between infections or colonization in animals and infections in humans
potential for transmission of resistance elements from animals to humans
includes drugs used for treatment of disease which may be severe/ resistant to other therapies
fluoroquinolones for treatment of multi-drug resistant Salmonella infections
Drugs with unique mechanism of action
especially valuable to human medicine if no widespread resistance to drug in environment
linezolid for resistant Gram positive infections
limitation of use of drug beyond treatment of human disease may limit emergence of resistance
what is considered “unique” may change over time
more drugs marketed within a given class
norfloxacin compared to newer quinolones
emergence of resistance to members of a given class
Cross resistance within drug class
importance of drugs within same class which have activity against organisms resistant to older members of class
organisms resistant to cefazolin may still be susceptible to ceftriaxone/cefotaxime
may vary with organism/drug class
Gram negative organisms resistant to gentamicin may be susceptible to amikacin
Cross resistance across drug classes
plasmid-mediated resistance may transmit multiple resistance genes at once
plasmids in Gram negatives carrying resistance genes for beta-lactamases may also carry genes for sulfa drugs and chloramphenicol resistance
if linked cross resistance, drugs ranked according to class considered of highest importance
drugs which do not have “linked” resistance to other antimicrobials of particular importance
chromosomally mediated resistance to fluoroquinolones
Ease of transmissibility of resistance
low = intrinsic resistance or change in target site that is not transmissible
chromosomal mutations and resistance to fluoroquinolones
high = single or multi-drug resistance that is transmissible
mobile resistance elements on plasmids and transposons such as plasmid mediated beta-lactamases
drugs with “low” transmissibility of resistance more likely ranked as more important in human medicine
Cross-resistance between drugs used in animals and drugs used in humans
actual drug proposed for use in animals different from drug used in humans
resistance to animal drug can result in resistance to human drug
avoparcin use in animals could predict vancomycin resistance in humans
animal drug assigned importance of human drug
Drugs of lesser importance
Little or no use in human medicine
Neither the first choice nor an important alternative for human infections
ionophores
polymyxins
Ranking of drugs according to human importance one part of overall framework document
Open for comments about ranking process
Evolving process based on changes in diseases, drugs and epidemiology of resistance