Antimicrobial Resistance in Streptococcus pneumoniae Implications for Prescription Drug Labeling

1. Antimicrobial Resistance in Streptococcus pneumoniaeImplications for Prescription Drug Labeling 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

2. Introduction • Historical background on antimicrobial resistance labeling claims • Rationale for labeling of antimicrobial resistance labeling claims • Data on cross-resistance of Streptococcus pneumoniae to various antimicrobials • Proposal for future labeling of antimicrobial resistance claims for S. pneumoniae

3. Historical Background • Most resistance claims deal with resistance to drugs within same class - “in class” resistance • cephalosporins and beta-lactamase production in various infections with Haemophilus influenzae and Moraxella catarrhalis • nafcillin and penicillinase-producing staphylococci • Some “out of class” resistance claims not approved • quinolones and penicillinase-producing Neisseriagonorrhoeae (PPNG) • quinolones and beta-lactamase producing H. influenzae and M. catarrhalis

4. Historical Background • Approved “out of class” resistance claims • vancomycin and serious or severe methicillin-resistant Staphylococcus aureus (MRSA) infections • linezolid and hospital-acquired pneumonia and complicated skin and skin structure infections with MRSA; vancomycin-resistant Enterococcus faecium • dalfopristin-quinupristin and vancomycin-resistant Enterococcus faecium bacteremia • levofloxacin and community-acquired pneumonia with penicillin-resistant S.pneumoniae (PRSP)

5. Rationale for Labeling • Information in labeling should aid clinicians in clinical decision making • organism is unique and distinguishable - is cross-resistance across drugs linked? • drug to which organism is resistant is commonly used to treat infection under study • few alternative therapies • in vitro resistance correlates with increased clinical failures • incentive for drug sponsors to acquire data on efficacy and safety of drug in infections due to resistant organism

6. Rationale for Labeling • Vancomycin and MRSA • organism was unique with distinguishable characteristics • methicillin resistance correlates with resistance to other drugs which are not separately designated in label (e.g. cephalosporins and quinolones) • at time of approval, methicillin and other anti-staphylococcal penicillins were commonly used drug in treatment of staphylococcal infections • at time of vancomycin approval, few alternative therapies for serious MRSA infections • some data indicated worse outcome with MRSA compared to MSSA infections

7. Rationale for Labeling • Levofloxacin and PRSP • at time of approval, PRSP considered unique new organism for which clinicians desired treatment information • penicillin previously commonly used to treat CAP and penicillin resistance used as marker for resistance to other drug classes • limited treatment options for cross-resistant organisms • at time of levofloxacin approval, little data on clinical outcomes with CAP and PRSP

8. Rationale for Labeling • Since that time…… • subsequent information on cross-resistance of penicillin-resistant isolates and resistance to other drug classes • Doern GV et al. Antimicrob Agents Chemo 2001;45:1721 • accumulating clinical data of no worse treatment outcomes in most cases of CAP with PRSP with MIC <4 mcg/mL • Feikin DR et al. Am J Public Health 2000;90:223-9.

9. Rationale for Labeling • What degree of cross-resistance is clinically significant? • little scientific data address this question • IDSA guidelines for some infections (UTI) suggest that clinicians should use alternate drugs when resistance is 10%-20% for a drug class • Warren JW et al. Clin Infect Dis 1999;29:745-58 • one model based on costestimated clinically relevant degree of resistance for TMP-SMX in UTI as 22% • Le TP et al. Clin Infect Dis 2001:33;615-21.

10. Data on Cross-Resistance • 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

11. Data on Cross-Resistance • The Surveillance Network (TSN) of Focus Technologies • > 65 million antimicrobial susceptibility testing results based on cultures which clinicians order • > 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.

12. Evaluating Cross-Resistance S, R R. R I, R Drug Y I, I S, I R, I S, S I, S R, S MIC Drug X

13. Correlations in MIC Distributions between Oxacillin and Ciprofloxacin Tested against S. aureus (1998 – 2002) Total n = 9,779 Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R Total n = 234802 * Each data point plotted represents 10 results* 13

14. Correlations in MIC Distributions between Penicillin and Cefuroxime Tested against S. pneumoniae (2000 – 2002) Total n = 9,779 Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R Total n = 5387 14

15. Correlations in MIC Distributions between Levofloxacin and Penicillin Tested against S. pneumoniae (2000-2002) Total n = 9,779 Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R 15

16. Data on Cross-ResistancePCN-R S. pneumoniae also R to other drug class

17. Data on Cross-ResistanceS. pneumoniae resistant to other drug class also PCN-R

18. Resistance Labeling for PRSP • Suggestion at Jan 2003 AIDAC meeting to label drugs for “susceptible pathogens” only • Does not address labels which currently carry PRSP claim • not granting claims to other drugs may place those drugs at unfair competitive disadvantage • removing previously granted claims from labels difficult from regulatory perspective • Does not address issues of conveying important information to physicians • No incentive to drug sponsors to acquire clinical data on treatment of resistant pathogens

19. Proposal for Future Claims • High rate of cross-resistance among penicillin-resistant strains of S. pneumoniae and other drug classes • 2nd generation cephalosporin, macrolide, tetracycline and TMP-SMX resistance does not appear to be distinct from penicillin resistance • all are drugs used for respiratory tract infections • Convey information about cross-resistance to clinicians in prescription drug labeling especially when prescribing drug empirically • Provide incentives to drug sponsors to obtain clinical data on treatment of multi-resistant organisms

20. Proposal for Future Claims • Define term of multi-drug resistant S. pneumoniae (MDR-SP) • resistance to penicillin, 2nd generation cephalosporins, macrolides, tetracyclines and TMP-SMX • maintain distinct nature of non-cross linked resistance such as that to anti-pneumococcal quinolones • definition could change over time if other resistance becomes linked • Informs clinicians that organism resistant to one of these drug classes is likely resistant to all • Drug sponsor would still need to obtain clinical data to garner resistance claim

21. Proposal for Future Claims • Data for “in class” resistant strains • example: a sponsor studying a tetracycline class drug would need strongest supportive data on tetracycline-resistant organisms • Data on “out of class” resistant strains • given high rate of cross-resistance many of these organisms will be resistant to other drug classes • data on susceptible isolates for “out of class” resistance may support data on resistant organisms • example: data on treatment of penicillin-susceptible isolates would support data on penicillin-resistant isolates for a tetracycline class drug as long as no appreciable difference in MICs for penicillin susceptible and resistant isolates for that drug

22. Proposal for Future Claims • Quantity versus quality • drug sponsors desire “number to shoot for” when garnering resistance claim • should resistance claim be based on quality of data rather than quantity? • characteristics of “high quality” cases: • disease unlikely to remit spontaneously e.g. acute bacterial meningitis versus acute exacerbations of chronic bronchitis • certainty of diagnosis e.g. isolates from normally sterile body sites (CSF versus sputum) • little confounding in assessment of drug’s contribution to efficacy e.g. other antimicrobial therapies • efficacy rate in disease in question

23. Conclusion • Drug X is indicated in the treatment of community-acquired pneumonia due to Streptococcus pneumoniae, including multi-drug resistant strains (resistant to penicillin, 2nd generation cephalosporins, macrolides, tetracycline and TMP-SMX) • List actual clinical trials data on which resistance claim is based in Clinical Studies section of label