# Presentation: 772059

## Antimicrobial Resistance in Streptococcus pneumoniaeImplications 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*

## 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***

## 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 *****Neisseria***** *****gonorrhoeae *****(PPNG)**
**quinolones and beta-lactamase producing *****H. influenzae***** and *****M. catarrhalis***

## 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)**

## 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**

## 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**

## 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**

## 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.**

## 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 cost**** ****estimated clinically relevant degree of resistance for TMP-SMX in UTI as 22%**
**Le TP et al. Clin Infect Dis 2001:33;615-21.**

## 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**

## 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.**

## Evaluating Cross-Resistance

**Drug Y**

**Drug X**

**S, S**

**S, I**

**S, R**

**I, S**

**I, I**

**I, R**

**R, S**

**R, I**

**R. R**

**MIC **

## 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***

## 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**

## 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**

## Data on Cross-ResistancePCN-R S. pneumoniae also R to other drug class

## Data on Cross-ResistanceS. pneumoniae resistant to other drug class also PCN-R

## 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

## Proposal for Future Claims

- High rate of cross-resistance among penicillin-resistant strains of *S. pneumoniae* and other drug classes
**2****nd**** 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

## Proposal for Future Claims

**Define term of *****multi-drug resistant S. pneumoniae *****(MDR-SP)**
**resistance to penicillin, 2****nd**** 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**

## 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***

## 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**

## Conclusion

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