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

2 Introduction u Define problem of antimicrobial use in animals and relationship to antimicrobial resistance in human pathogens u Background on ranking process u Factors used in ranking drugs –factors based on drug efficacy –factors based on resistance –factors of low importance

3 The Problem u 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

4 The Problem u Antimicrobial use in humans may contribute to most of resistance in man u Antimicrobial use in animals may also contribute u Several authors debate how large a problem this is –How large does it have to be to pose significant risk to human health? –Because is it difficult to measure does it mean it does not exist? u Avoparcin and vancomycin resistance example

5 Examples u Transmission of resistant bacteria from animals to humans –enteric bacteria in animals causing food-borne disease in man most direct link »Salmonella outbreak traced back pigs u Molbak N Engl J Med 1999;341: –Nonenteric bacteria in animals to non-enteric bacteria in man »ROB-1 beta-lactamase in Actinobacillus pleuropneumoniae from pigs transfer via plasmid to H. influenzae in man u Medeiros 1986Antimicrob Agents Chemo 1986;29: –possibility for gene transfer from enteric bacteria in animals to non-enteric bacteria in man »van A gene in enterococci to MRSA?

6 The Problem u Transmission of resistance genes within species or from one species to another –animal specific strains of bacteria can transmit genes to like organisms in humans »transfer between non-isogenic strains of enterococci in Denmark u DANMAP 2000 u Some authors postulate cycle of transmission –man may transmit resistant pathogens to animals via sewage –resistance amplified in animals –transmitted back to man »Teale J Appl Micro 2002;92:85S-89S.

7 Background u Desire to preserve usefulness of antimicrobials of greatest importance in treatment of human disease u 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 »ranking of human drugs not only or overall driver of categorization for drug use in animals u Joint CVM-CDER team developed guidelines for categorization of drugs

8 Background u Ranking includes all drugs, not just those used in treatment of food-borne pathogens u Drugs used in human medicine for food-borne illness also used to treat other non-food-borne diseases u Drugs used to treat non-enteric disease can affect enteric bacteria u Transmission of resistance elements can occur from enteric bacteria to other pathogens which do not cause enteric disease –transmission of resistant determinants from VRE to S. aureus

9 Background u Ranking of drugs not a regular part of CDER review and approval process for antimicrobials. u Approval process entails showing drug product must be safe and effective; demonstrating specific level of importance in human medicine is not required. u Regulatory initiatives do recognize some products may be of greater importance in human medicine. –Subparts E & H: serious and life-threatening disease

10 Background u Qualitative rather than a quantitative system –multiple factors may apply to some drugs u Degree of subjectivity in these determinations –application of general scientific and infectious disease principles u Does not necessarily include all antimicrobial drugs and classes u Ranking expected to evolve over time –new drugs, emergence of diseases, changes in prescribing patterns –review ranking every few years

11 Factors in Ranking u Factors related to drug efficacy 1) sole therapy/limited available therapies 2) therapy of choice 3) spectrum of activity of particular importance 4) importance for oral therapy 5) importance in treating food-borne infections 6) unique mechanism of antimicrobial action u Factors related to development of antimicrobial resistance 7) cross-resistance within drug class 8) cross-resistance across drug classes 9) ease of transmissibility of resistance determinants 10) cross resistance between animal/human drugs

12 Factors in Ranking: Drug Efficacy u Sole or limited available therapy –“high” importance until widespread resistance in humans precludes use or other therapy available »vancomycin or linezolid for MRSA infections u 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

13 Factors in Ranking: Drug Efficacy u Spectrum of activity of particular importance –drugs used in treatment of infections due to resistant pathogens »dalfopristin/quinupristin for vancomycin resistant enterococcal infections u 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

14 Factors in Ranking: Drug Efficacy u Importance in treating food-borne infections –most direct link between infection 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

15 Factors in Ranking: Drug Efficacy u 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 u norfloxacin compared to newer quinolones »emergence of resistance to members of a given class

16 Factors in Ranking: Drug Resistance u 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 »Gram positive organisms resistant to gentamicin usually resistant to amikacin

17 Factors in Ranking: Drug Resistance u 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

18 Factors in Ranking: Drug Resistance u 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

19 Factors in Ranking: Drug Resistance u 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

20 Factors in Ranking u Drugs of lesser importance –Little or no use in human medicine –Neither the first choice nor an important alternative for human infections »ionophores »polymyxins

21 Summary u Ranking of drugs according to human importance one part of overall framework document u Open for comments about ranking process u Evolving process based on changes in diseases, drugs and epidemiology of resistance