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Outline

Listing Antimicrobial Resistant Pathogens of Public Health Importance Implications for Drug Development John H. Powers, MD 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 Background on requests to list resistant pathogens of public health importance Criteria for listing pathogens of public health importance Obtaining data on pathogens to examine criteria Future plans for populating list of pathogens of public health importance

Historical Background Continuation of previous discussions on development of drugs for pathogens resistant to antimicrobials late 1990’s February 2002 advisory committee November 2002 IDSA/PhRMA/ FDA workshop increasing in vitro resistance among many pathogens in some cases translates into clinical failures may signal future clinical problem

Historical Background November 2002 workshop discussions on shift of resources in pharmaceutical industry to treatment of more chronic diseases http://www.fda.gov/cder/present/idsaphrma List of best selling drugs does not include any antimicrobials antidepressants anti-ulcer medications cholesterol lowering drugs Wall Street Journal

Historical Background February 2002 representative of pharmaceutical industry requested FDA to develop list of pathogens for which drug development deemed of public health importance http://www.fda.gov/ohrms/dockets/ac/02/slides/3837s2.htm November 2002 representatives of IDSA, pharmaceutical industry, and FDA discussed criteria for developing a list altered list slightly to combine several similar points criteria considered important as list would likely change over time example of penicillinase-producing staphylococci in 1950s versus today

How to Use the List Pathogen would not need to fulfill all of criteria to be placed on list Drug sponsors would need clinical data on treatment of resistant pathogens differences in patient characteristics of those with resistant organisms vs. susceptible organisms Priority review designated based on results of clinical trials Drug may still be approved but not be garner resistance claim until sufficient clinical data Organism not on list does not mean that drug cannot be developed - list is for prioritization

Criteria for Developing List 1. Organism of sufficient prevalence in population with disease under study 2. Organism causes serious and severe disease 3. Drug to which organism is resistant is commonly used in disease under study 4. Limited available therapies due to multi-drug resistance 5. Drug used to control spread of disease in population 6. Clinical correlation of in vitro resistance with poor clinical outcomes

Criteria for Developing List 1. Organism of sufficient prevalence in population with disease under study speaks to current burden of public health problem ease with which clinical cases may be studied less prevalent organisms may still be important or may become more prevalent over time linkage between disease under study and organism most resistance labeling claims relate to efficacy in a particular disease provides most helpful information to clinicians further discussion this afternoon

Data on Resistant Pathogens FDA contract to obtain surveillance data from Focus Technologies Purpose of identifying and tracking resistant organisms of public health importance for drug development The Surveillance Network (TSN) of Focus Technologies 317 U.S. laboratories updated continuously Community, government, university laboratories Bed size < 99 to > 500

Data on Resistant Pathogens The Surveillance Network (TSN) of Focus Technologies > 65 million antimicrobial susceptibility testing results based on cultures which clinicians order per patient analysis, one  isolate per patient > 500 microbial taxa and > 100 individual drugs > 2.9 million patients; inpatient and outpatient data access to estimated 2.6% of all isolates tested per year in U.S.

Prevalence of Clinically Relevant Species (Based on Commonly Cultured Organisms)

Prevalence of Clinically Relevant Species from All Specimen Sources

Limited Susceptibility Testing is Performed

Increasing Proportion of S. aureus Bacteremia Caused by MRSA

Prevalence of MRSA among All Patients

Criteria for Developing List 2. Organisms causes serious and severe disease resistance claims usually linked to disease under study range of organisms across various diseases e.g. S.pneumoniae common cause of respiratory tract disease but uncommon cause of UTI range of severity of disease from fatal to self-resolving impact of resistance most likely to be important and relevant to public health in diseases which as not likely to resolve spontaneously issue of public health decisions versus decisions in individual patients

Incidence of MSSA and MRSA by Source

Bacteremia and Methicillin Resistance Status

Criteria for Developing List 3. Drug to which organism is resistant is commonly used in disease under study speaks to clinical relevance of drug resistance example: TMP-SMX commonly used in treatment of UTI but streptomycin is not FDA attempting to gather information on drug usage for various diseases medical literature IMS database other sources of information variations in medical practice and resistance patterns in various geographic areas and patient populations

Criteria for Developing List 4. Limited available therapies due to multi-drug resistance use surveillance data to examine relationships of cross-resistance within a given bacterial taxa plans to look at similar analyses for other organisms e.g. fungi organisms which are resistant to multiple drugs are more likely to have fewer available drugs for treatment

Evaluating Multi-Drug Resistant Pathogens

Evaluating MDR Trends among Species (2000-2002)

Detailed Analysis of Resistance Phenotypes

Multidrug Resistance among S. pneumoniae 2000-2002

Multidrug Resistance among S. pneumoniae

Criteria for Developing List 5. Drug used to control spread of disease in population drugs more important for limiting disease when no vaccine available disease like STDs and tuberculosis utilize drug therapy as major public health intervention to prevent spread of disease

Criteria for Developing List 6. Clinical correlation of in vitro resistance with poor clinical outcomes is in vitro resistance clinically relevant? recent examples of where in vitro resistance did not correlate with poor outcomes in majority of cases penicillin resistance in S.pneumoniae  in CAP Pallares et al. NEJM 1995;474-480. Feikin et al. Am J Pub Health 2000;90:223-229. macrolide resistance in S. pyogenes pharyngitis Varaldo et al. Clin Infect Dis 1999;29:869-73. Clinical impact of resistance may be more important and more apparent in more serious disease which is less likely to resolve spontaneously

Criteria for Developing List 6. Clinical correlation of in vitro resistance with poor clinical outcomes often difficult to obtain data on clinical treatment outcomes organism must be prevalent enough to study takes time to accumulate data  Pallares et al. NEJM 1995;474-480. some drugs not used to treat severe disease where difference between susceptible and resistant isolates may be more likely (although overall cure rate lower) mortality in PORT class 1 CAP is 0.1% Fine MJ et al. NEJM 1997;336:243-50

Criteria for Developing List 6. Clinical correlation of in vitro resistance with poor clinical outcomes Are increasing case reports really “mounting clinical evidence”? publication bias natural history in diseases such as CAP where severe disease carries mortality of ~30% regardless of therapy Fine MJ et al. NEJM 1997;336:243-50 data showing no effect of antimicrobial therapy on mortality in first 5 days of pneumococcal pneumonia Austrian R et al. Ann Intern Med 1964;60:759-76 all case reports lack comparative data showing higher rate of failure in resistant isolates versus susceptible isolates

Criteria for Developing List Group A streptococcal (S. pyogenes) pharyngitis 3,227 patients under age 14 throat swabs prior to treatment and at end of therapy looked at clinical resolution and bacteriologic eradication 1048 (32.5%) had positive test for GABHS 934 tested for susceptibility and clinical cure 668  follow-up cultures and bacteriologic cure macrolide resistance at baseline 46.3% of isolates penicillin resistance at baseline 0% Varaldo et al. Clin Infect Dis 1999;29:869-73.

Relating Resistance to Outcomes Group A Strep Pharyngitis

Previously Granted Resistance Claims Methicillin resistant S. aureus (MRSA) vancomycin in serious infections linezolid in HAP and cSSSI Vancomycin resistant E. faecium (VRE) linezolid dalfopristin-quinupristin in bacteremia Penicillinase-producing staphylococci nafcillin in serious and severe infections Beta-lactamase producing H. influenzae and Moraxella catarrhalis number of infections with cephalosporins Penicillin resistant S. pneumoniae (PRSP) levofloxacin and moxifloxacin in CAP

Future Plans Examine epidemiology of organisms in causing various diseases Obtain data on drug usage for various indications Look at cross-resistance in various organisms among 27 taxa and other pathogens which committee may recommend Obtain data on clinical correlations with clinical outcomes and resistance wherever possible

Conclusion Populate list based on today’s discussions This afternoon’s discussions on other aspects of drug development for resistant pathogens Discussion on granting claims for “multi-drug resistant” organisms discussed yesterday Formulate guidance for drug development for resistant pathogens