# Presentation: 065881

## 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 **

## The Problem

**Antimicrobial use in humans may contribute to most of resistance in man**
**Antimicrobial use in animals may also contribute**
**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?
**Avoparcin and vancomycin resistance example**

## Examples

**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**
- Molbak N Engl J Med 1999;341:1420-25.
**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**
- Medeiros 1986Antimicrob Agents Chemo 1986;29:212-215.
- possibility for gene transfer from enteric bacteria in animals to non-enteric bacteria in man
*van A* gene in enterococci to MRSA?

## The Problem

**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**
**DANMAP 2000**
**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.**

## 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**
**ranking of human drugs not only or overall driver of categorization for drug use in animals**
**Joint CVM-CDER team developed guidelines for categorization of drugs**

## Background

**Ranking includes all drugs, not just those used in treatment of food-borne pathogens**
**Drugs used in human medicine for food-borne illness also used to treat other non-food-borne diseases**
**Drugs used to treat non-enteric disease can affect enteric bacteria**
**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***

## 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**
**application of general scientific and infectious disease principles**
**Does not necessarily include all antimicrobial drugs and classes**
**Ranking expected to evolve over time**
**new drugs, emergence of diseases, changes in prescribing patterns**
**review ranking every few years**

## Factors in Ranking

**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**
**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**

## 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**

## Factors in Ranking: Drug Efficacy

**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**

## Factors in Ranking: Drug Efficacy

**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**

## Factors in Ranking: Drug Resistance

**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**

## Factors in Ranking: Drug Resistance

**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**

## Factors in Ranking: Drug Resistance

**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**

## Factors in Ranking: Drug Resistance

**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**

## Factors in Ranking

**Drugs of lesser importance**
**Little or no use in human medicine**
**Neither the first choice nor an important alternative for human infections**
**ionophores**
**polymyxins**

## Summary

**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**