Antimicrobial Resistance in Antimicrobial Resistance in Streptococcus pneumoniaeStreptococcus pneumoniae

Implications for Prescription Implications for Prescription Drug LabelingDrug Labeling

John H. Powers, MDJohn H. Powers, MDLead Medical OfficerLead Medical Officer

Antimicrobial Drug Development and Resistance Antimicrobial Drug Development and Resistance InitiativesInitiatives

Office of Drug Evaluation IVOffice of Drug Evaluation IV

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

U.S. Food and Drug AdministrationU.S. Food and Drug Administration

IntroductionIntroduction

Historical background on antimicrobial Historical background on antimicrobial resistance labeling claimsresistance labeling claims

Rationale for labeling of antimicrobial Rationale for labeling of antimicrobial resistance labeling claimsresistance labeling claims

Data on cross-resistance of Data on cross-resistance of Streptococcus Streptococcus pneumoniaepneumoniae to various antimicrobials to various antimicrobials

Proposal for future labeling of antimicrobial Proposal for future labeling of antimicrobial resistance claims for resistance claims for S. pneumoniaeS. pneumoniae

Historical BackgroundHistorical Background

Most resistance claims deal with resistance to Most resistance claims deal with resistance to drugs within same class - “in class” resistancedrugs within same class - “in class” resistance

cephalosporins and beta-lactamase production in cephalosporins and beta-lactamase production in various infections with various infections with Haemophilus influenzaeHaemophilus influenzae and and Moraxella catarrhalisMoraxella catarrhalis

nafcillin and penicillinase-producing staphylococcinafcillin and penicillinase-producing staphylococci

Some “out of class” resistance claims not Some “out of class” resistance claims not approvedapproved

quinolones and penicillinase-producing quinolones and penicillinase-producing NeisseriaNeisseria gonorrhoeae gonorrhoeae (PPNG)(PPNG)

quinolones and beta-lactamase producing quinolones and beta-lactamase producing H. H. influenzaeinfluenzae and and M. catarrhalisM. catarrhalis

Historical BackgroundHistorical Background

Approved “out of class” resistance claimsApproved “out of class” resistance claims vancomycin and serious or severe methicillin-vancomycin and serious or severe methicillin-

resistant resistant Staphylococcus aureus Staphylococcus aureus (MRSA) infections(MRSA) infections

linezolid and hospital-acquired pneumonia and linezolid and hospital-acquired pneumonia and complicated skin and skin structure infections with complicated skin and skin structure infections with MRSA; vancomycin-resistant MRSA; vancomycin-resistant Enterococcus faeciumEnterococcus faecium

dalfopristin-quinupristin and vancomycin-resistant dalfopristin-quinupristin and vancomycin-resistant Enterococcus faeciumEnterococcus faecium bacteremia bacteremia

levofloxacin and community-acquired pneumonia levofloxacin and community-acquired pneumonia with penicillin-resistant with penicillin-resistant S.pneumoniaeS.pneumoniae (PRSP) (PRSP)

Rationale for LabelingRationale for Labeling

Information in labeling should aid clinicians in Information in labeling should aid clinicians in clinical decision makingclinical decision making

organism is unique and distinguishable - is cross-organism is unique and distinguishable - is cross-resistance across drugs linked?resistance across drugs linked?

drug to which organism is resistant is commonly used drug to which organism is resistant is commonly used to treat infection under studyto treat infection under study

few alternative therapiesfew alternative therapies

in vitroin vitro resistance correlates with increased clinical resistance correlates with increased clinical failuresfailures

incentive for drug sponsors to acquire data on efficacy incentive for drug sponsors to acquire data on efficacy and safety of drug in infections due to resistant and safety of drug in infections due to resistant organismorganism

Rationale for LabelingRationale for Labeling

Vancomycin and MRSAVancomycin and MRSA organism was unique with distinguishable organism was unique with distinguishable

characteristicscharacteristics methicillin resistance correlates with resistance to other methicillin resistance correlates with resistance to other

drugs which are not separately designated in label (e.g. drugs which are not separately designated in label (e.g. cephalosporins and quinolones)cephalosporins and quinolones)

at time of approval, methicillin and other anti-at time of approval, methicillin and other anti-staphylococcal penicillins were commonly used drug in staphylococcal penicillins were commonly used drug in treatment of staphylococcal infectionstreatment of staphylococcal infections

at time of vancomycin approval, few alternative at time of vancomycin approval, few alternative therapies for serious MRSA infectionstherapies for serious MRSA infections

some data indicated worse outcome with MRSA some data indicated worse outcome with MRSA compared to MSSA infectionscompared to MSSA infections

Rationale for LabelingRationale for Labeling

Levofloxacin and PRSPLevofloxacin and PRSP at time of approval, PRSP considered unique new at time of approval, PRSP considered unique new

organism for which clinicians desired treatment organism for which clinicians desired treatment informationinformation

penicillin previously commonly used to treat CAP penicillin previously commonly used to treat CAP and penicillin resistance used as marker for and penicillin resistance used as marker for resistance to other drug classesresistance to other drug classes

limited treatment options for cross-resistant limited treatment options for cross-resistant organismsorganisms

at time of levofloxacin approval, little data on at time of levofloxacin approval, little data on clinical outcomes with CAP and PRSPclinical outcomes with CAP and PRSP

Rationale for LabelingRationale for Labeling

Since that time……Since that time……

subsequent information on cross-resistance of subsequent information on cross-resistance of penicillin-resistant isolates and resistance to penicillin-resistant isolates and resistance to other drug classesother drug classes Doern GV et al. Antimicrob Agents Chemo Doern GV et al. Antimicrob Agents Chemo

2001;45:17212001;45:1721

accumulating clinical data of no worse treatment accumulating clinical data of no worse treatment outcomes in most cases of CAP with PRSP with outcomes in most cases of CAP with PRSP with MIC <4 mcg/mLMIC <4 mcg/mL Feikin DR et al. Am J Public Health 2000;90:223-9.Feikin DR et al. Am J Public Health 2000;90:223-9.

Rationale for LabelingRationale for Labeling

What degree of cross-resistance is clinically What degree of cross-resistance is clinically significant?significant?

little scientific data address this questionlittle scientific data address this question

IDSA guidelines for some infections (UTI) suggest that IDSA guidelines for some infections (UTI) suggest that clinicians should use alternate drugs when resistance clinicians should use alternate drugs when resistance is 10%-20% for a drug classis 10%-20% for a drug class Warren JW et al. Clin Infect Dis 1999;29:745-58Warren JW et al. Clin Infect Dis 1999;29:745-58

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

Data on Cross-ResistanceData on Cross-Resistance

FDA contract to obtain surveillance data from FDA contract to obtain surveillance data from Focus TechnologiesFocus Technologies

Purpose of identifying and tracking resistant Purpose of identifying and tracking resistant organisms of public health importance for organisms of public health importance for drug developmentdrug development

The Surveillance Network (TSN) of Focus The Surveillance Network (TSN) of Focus TechnologiesTechnologies 317 U.S. laboratories updated continuously317 U.S. laboratories updated continuously Community, government, university laboratoriesCommunity, government, university laboratories Bed size < 99 to > 500Bed size < 99 to > 500

Data on Cross-ResistanceData on Cross-Resistance

The Surveillance Network (TSN) of Focus The Surveillance Network (TSN) of Focus TechnologiesTechnologies

> 65 million antimicrobial susceptibility testing > 65 million antimicrobial susceptibility testing results based on cultures which clinicians orderresults based on cultures which clinicians order

> 500 microbial taxa and > 100 individual drugs> 500 microbial taxa and > 100 individual drugs

> 2.9 million patients; inpatient and outpatient data> 2.9 million patients; inpatient and outpatient data

access to estimated 2.6% of all isolates tested per access to estimated 2.6% of all isolates tested per year in U.S.year in U.S.

Drug Drug YY

Evaluating Cross-ResistanceEvaluating Cross-Resistance

Drug XDrug X

S, SS, S

S, IS, I

S, RS, R

I, SI, S

I, II, I

I, RI, R

R, SR, S

R, IR, I

R. RR. R

MIC MIC

Correlations in MIC Distributions between Correlations in MIC Distributions between Oxacillin and Ciprofloxacin Tested against Oxacillin and Ciprofloxacin Tested against S. S.

aureus aureus (1998 – 2002)(1998 – 2002)Total n = 9,779Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R

13

Total n = 234802Total n = 234802

* Each data point plotted represents 10 results*

Correlations in MIC Distributions between Correlations in MIC Distributions between Penicillin and Cefuroxime Tested against Penicillin and Cefuroxime Tested against S. S.

pneumoniae pneumoniae (2000 – 2002)(2000 – 2002)Total n = 9,779Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R

14

Total n = 5387Total n = 5387

Correlations in MIC Distributions between Correlations in MIC Distributions between Levofloxacin and Penicillin Tested against Levofloxacin and Penicillin Tested against S. S.

pneumoniae pneumoniae (2000-2002)(2000-2002)Total n = 9,779Levo R isolates: n = 87; 26.4% Pen S; 42.5% Pen I; 31.0% Pen R

15

Data on Cross-ResistanceData on Cross-ResistancePCN-R S. pneumoniae also R to other drug PCN-R S. pneumoniae also R to other drug

classclassDrug class(total N tested)

Rate of cross-resistance% (n)

2nd generationcephalosporins(5,580)

97.9% (1197/1223)

TMP-SMX (13,520) 87.5% (2575/2943)

Erythromycin (20,011) 82.4% (3550/4307)

Tetracyclines (10,351) 45.9% (1049/2284)

Clindamycin (13,168) 23.5% (733/3113)

3rd generationcephalosporins(32,369)

19.6% (1394/7107)

Levofloxacin (13,653) 1.4% (39/2847)

Data on Cross-ResistanceData on Cross-ResistanceS. pneumoniae resistant to other drug class S. pneumoniae resistant to other drug class

also PCN-Ralso PCN-RDrug class(total N tested)

Rate of cross-resistance% (n)

2nd generationcephalosporins(5,580)

60.4% (1197/1980)

TMP-SMX (13,520) 52.2% (2575/4937)

Erythromycin (20,011) 50.4% (3550/7050)

Tetracyclines (10,351) 49.9% (1049/2102)

Clindamycin (13,168) 50.7%% (733/1446)

3rd generationcephalosporins(32,369)

93.3% (1394/1494)

Levofloxacin (13,653) 32.5% (39/120)

Resistance Labeling for PRSPResistance Labeling for PRSP

Suggestion at Jan 2003 AIDAC meeting to label drugs Suggestion at Jan 2003 AIDAC meeting to label drugs for “susceptible pathogens” onlyfor “susceptible pathogens” only

Does not address labels which currently carry PRSP Does not address labels which currently carry PRSP claimclaim not granting claims to other drugs may place those not granting claims to other drugs may place those

drugs at unfair competitive disadvantagedrugs at unfair competitive disadvantage removing previously granted claims from labels removing previously granted claims from labels

difficult from regulatory perspectivedifficult from regulatory perspective

Does not address issues of conveying important Does not address issues of conveying important information to physiciansinformation to physicians

No incentive to drug sponsors to acquire clinical data No incentive to drug sponsors to acquire clinical data on treatment of resistant pathogenson treatment of resistant pathogens

Proposal for Future ClaimsProposal for Future Claims

High rate of cross-resistance among penicillin-High rate of cross-resistance among penicillin-resistant strains of resistant strains of S. pneumoniaeS. pneumoniae and other drug and other drug classesclasses 22ndnd generation cephalosporin, macrolide, generation cephalosporin, macrolide,

tetracycline and TMP-SMX resistance does not tetracycline and TMP-SMX resistance does not appear to be distinct from penicillin resistanceappear to be distinct from penicillin resistance

all are drugs used for respiratory tract infectionsall are drugs used for respiratory tract infections

Convey information about cross-resistance to Convey information about cross-resistance to clinicians in prescription drug labeling especially clinicians in prescription drug labeling especially when prescribing drug empiricallywhen prescribing drug empirically

Provide incentives to drug sponsors to obtain Provide incentives to drug sponsors to obtain clinical data on treatment of multi-resistant clinical data on treatment of multi-resistant organismsorganisms

Proposal for Future ClaimsProposal for Future Claims

Define term of Define term of multi-drug resistant S. multi-drug resistant S. pneumoniae pneumoniae (MDR-SP)(MDR-SP) resistance to penicillin, 2resistance to penicillin, 2ndnd generation cephalosporins, generation cephalosporins,

macrolides, tetracyclines and TMP-SMXmacrolides, tetracyclines and TMP-SMX maintain distinct nature of non-cross linked resistance maintain distinct nature of non-cross linked resistance

such as that to anti-pneumococcal quinolonessuch as that to anti-pneumococcal quinolones definition could change over time if other resistance definition could change over time if other resistance

becomes linkedbecomes linked

Informs clinicians that organism resistant to one Informs clinicians that organism resistant to one of these drug classes is likely resistant to allof these drug classes is likely resistant to all

Drug sponsor would still need to obtain clinical Drug sponsor would still need to obtain clinical data to garner resistance claimdata to garner resistance claim

Proposal for Future ClaimsProposal for Future Claims

Data for “in class” resistant strainsData for “in class” resistant strains example: a sponsor studying a tetracycline class drug example: a sponsor studying a tetracycline class drug

would need strongest supportive data on would need strongest supportive data on tetracycline-resistant organismstetracycline-resistant organisms

Data on “out of class” resistant strainsData on “out of class” resistant strains given high rate of cross-resistance many of these given high rate of cross-resistance many of these

organisms will be resistant to other drug classesorganisms will be resistant to other drug classes data on susceptible isolates for “out of class” data on susceptible isolates for “out of class”

resistance may support data on resistant organismsresistance may support data on resistant organisms example: data on treatment of penicillin-susceptible example: data on treatment of penicillin-susceptible

isolates would support data on penicillin-resistant isolates would support data on penicillin-resistant isolates for a tetracycline class drug isolates for a tetracycline class drug as long as no as long as no appreciable difference in MICs for penicillin appreciable difference in MICs for penicillin susceptible and resistant isolates for that drugsusceptible and resistant isolates for that drug

Proposal for Future ClaimsProposal for Future Claims

Quantity versus qualityQuantity versus quality drug sponsors desire “number to shoot for” when drug sponsors desire “number to shoot for” when

garnering resistance claimgarnering resistance claim

should resistance claim be based on quality of data should resistance claim be based on quality of data rather than quantity?rather than quantity?

characteristics of “high quality” cases:characteristics of “high quality” cases: disease unlikely to remit spontaneously e.g. acute disease unlikely to remit spontaneously e.g. acute

bacterial meningitis versus acute exacerbations of bacterial meningitis versus acute exacerbations of chronic bronchitischronic bronchitis

certainty of diagnosis e.g. isolates from normally sterile certainty of diagnosis e.g. isolates from normally sterile body sites (CSF versus sputum)body sites (CSF versus sputum)

little confounding in assessment of drug’s contribution little confounding in assessment of drug’s contribution to efficacy e.g. other antimicrobial therapiesto efficacy e.g. other antimicrobial therapies

efficacy rate in disease in questionefficacy rate in disease in question

ConclusionConclusion

Drug XDrug X is indicated in the treatment of is indicated in the treatment of community-acquired pneumonia due to community-acquired pneumonia due to Streptococcus pneumoniaeStreptococcus pneumoniae, including , including multi-drug resistant strains (resistant to multi-drug resistant strains (resistant to penicillin, 2penicillin, 2ndnd generation cephalosporins, generation cephalosporins, macrolides, tetracycline and TMP-SMX)macrolides, tetracycline and TMP-SMX)

List actual clinical trials data on which List actual clinical trials data on which resistance claim is based in Clinical resistance claim is based in Clinical Studies section of labelStudies section of label