listing antimicrobial resistant pathogens of public health importance implications for drug...

Listing Antimicrobial Listing Antimicrobial Resistant Pathogens of Resistant Pathogens of

Public Health ImportancePublic Health Importance

Implications for Drug Implications for Drug DevelopmentDevelopmentJohn H. Powers, MDJohn H. Powers, MD

Lead 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

Background on requests to list resistant Background on requests to list resistant pathogens of public health importancepathogens of public health importance

Criteria for listing pathogens of public health Criteria for listing pathogens of public health importanceimportance

Obtaining data on pathogens to examine Obtaining data on pathogens to examine criteriacriteria

Future plans for populating list of pathogens Future plans for populating list of pathogens of public health importanceof public health importance

Historical BackgroundHistorical Background

Continuation of previous discussions on Continuation of previous discussions on development of drugs for pathogens development of drugs for pathogens resistant to antimicrobialsresistant to antimicrobials late 1990’slate 1990’s February 2002 advisory committeeFebruary 2002 advisory committee November 2002 IDSA/PhRMA/ FDA workshopNovember 2002 IDSA/PhRMA/ FDA workshop

increasing increasing in vitro in vitro resistance among resistance among many pathogensmany pathogens in some cases translates into clinical failuresin some cases translates into clinical failures may signal future clinical problemmay signal future clinical problem


November 2002 workshopNovember 2002 workshop discussions on shift of resources in discussions on shift of resources in

pharmaceutical industry to treatment of more pharmaceutical industry to treatment of more chronic diseaseschronic diseases http://www.fda.gov/cder/present/idsaphrmahttp://www.fda.gov/cder/present/idsaphrma

List of best selling drugs does not include List of best selling drugs does not include any antimicrobialsany antimicrobials antidepressantsantidepressants anti-ulcer medicationsanti-ulcer medications cholesterol lowering drugscholesterol lowering drugs

Wall Street JournalWall Street Journal


February 2002February 2002 representative of pharmaceutical industry requested representative of pharmaceutical industry requested

FDA to develop list of pathogens for which drug FDA to develop list of pathogens for which drug development deemed of public health importancedevelopment deemed of public health importance http://www.fda.gov/ohrms/dockets/ac/02/slides/3837s2.htmhttp://www.fda.gov/ohrms/dockets/ac/02/slides/3837s2.htm

November 2002November 2002 representatives of IDSA, pharmaceutical industry, and representatives of IDSA, pharmaceutical industry, and

FDA discussed criteria for developing a listFDA discussed criteria for developing a list altered list slightly to combine several similar pointsaltered list slightly to combine several similar points

criteria considered important as list would likely criteria considered important as list would likely change over timechange over time example of penicillinase-producing staphylococci in 1950s example of penicillinase-producing staphylococci in 1950s

versus todayversus today

How to Use the ListHow to Use the List

Pathogen would not need to fulfill all of criteria Pathogen would not need to fulfill all of criteria to be placed on listto be placed on list

Drug sponsors would need clinical data on Drug sponsors would need clinical data on treatment of resistant pathogenstreatment of resistant pathogens differences in patient characteristics of those with differences in patient characteristics of those with

resistant organisms vs. susceptible organismsresistant organisms vs. susceptible organisms

Priority review designated based on results of Priority review designated based on results of clinical trialsclinical trials

Drug may still be approved but not be garner Drug may still be approved but not be garner resistance claim until sufficient clinical dataresistance claim until sufficient clinical data

Organism not on list does not mean that drug Organism not on list does not mean that drug cannot be developed - list is for cannot be developed - list is for prioritizationprioritization

Criteria for Developing ListCriteria for Developing List

1. Organism of sufficient prevalence in population 1. Organism of sufficient prevalence in population with disease under studywith disease under study

2. Organism causes serious and severe disease2. Organism causes serious and severe disease

3. Drug to which organism is resistant is 3. Drug to which organism is resistant is commonly used in disease under studycommonly used in disease under study

4. Limited available therapies due to multi-drug 4. Limited available therapies due to multi-drug resistanceresistance

5. Drug used to control spread of disease in 5. Drug used to control spread of disease in populationpopulation

6. Clinical correlation of 6. Clinical correlation of in vitro in vitro resistance with resistance with poor clinical outcomespoor clinical outcomes


1. Organism of sufficient prevalence in population 1. Organism of sufficient prevalence in population with disease under studywith disease under study speaks to current burden of public health problemspeaks to current burden of public health problem

ease with which clinical cases may be studiedease with which clinical cases may be studied

less prevalent organisms may still be important or may less prevalent organisms may still be important or may become more prevalent over timebecome more prevalent over time

linkage between disease under study and organismlinkage between disease under study and organism most resistance labeling claims relate to efficacy in a most resistance labeling claims relate to efficacy in a

particular diseaseparticular disease provides most helpful information to cliniciansprovides most helpful information to clinicians further discussion this afternoonfurther discussion this afternoon

Data on Resistant PathogensData on Resistant Pathogens

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 Resistant PathogensData on Resistant Pathogens

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

> 65 million antimicrobial susceptibility testing results > 65 million antimicrobial susceptibility testing results based on cultures which clinicians orderbased on cultures which clinicians order per patient analysis, one isolate per patientper patient analysis, one isolate per patient

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

Prevalence of Clinically Relevant Prevalence of Clinically Relevant SpeciesSpecies

(Based on Commonly Cultured (Based on Commonly Cultured Organisms)Organisms)Only 27 taxa account for 95% of clinically encountered bacterial species Only 27 taxa account for 95% of clinically encountered bacterial species

… … S. pneumoniae accounts for 1.3%S. pneumoniae accounts for 1.3%

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95.0% of the total isolates represented by 27 taxa

90.4% of the total isolates represented by 16 taxa

16.1% S. aureus; 9.0% inpatients, 6.5% outpatients

1.3% S. pneumoniae; 0.7% inpatients, 0.6% outpatients

0

10

20

30

40

50

60

70

80

90

100

0 25 50 75 100 534

Number of taxa

% o

f to

tal

iso

late

s

Prevalence of Clinically Relevant Species from All Prevalence of Clinically Relevant Species from All Specimen SourcesSpecimen Sources

0.40.040.50.6

0.10.50.80.81.3

0.10.61.00.9

3.57.2

9.416.4

0.60.70.91.01.11.2

2.13.9

6.228.9

46.6

0 10 20 30 40 50Percent of Patients

Top 10 Enterobacteriaceae Escherichia coli Klebsiella pneumoniae Proteus mirabilis Enterobacter cloacae Serratia marcescens Enterobacter aerogenes Citrobacter freundii Klebsiella oxytoca Citrobacter koseri Morganella morganiiStaphylococcus aureusCoagulase-negative staphylococciPseudomonas aeruginosaEnterococcus faecalisEnterococcus faeciumAcinetobacter baumanniiStenotrophomonas maltophiliaBurkholderia cepaciaStreptococcus pneumoniaeViridans streptococciBeta-hemolytic streptococci Streptococcus agalactiae Streptococcus pyogenesHaemophilus spp. Haemophilus influenzae Haemophilus parainfluenzaeAnaerobic bacteria

12

Limited Susceptibility Testing is PerformedLimited Susceptibility Testing is Performed

Year Number of results1998 5611999 3292000 3552001 2092002 45Total 1,499

Antimicrobial Total n % S % I % RPenicillin 941 85.4 9.5 5.1Ceftriaxone 170 100 0 0Tetracycline 142 43.7 35.9 20.4Spectinomycin 83 98.8 1.2 0Ciprofloxacin 73 97.3 0 2.7

Phenotype Total n % of totalPenicillin / tetracycline 128 (7.0)Penicillin / ciprofloxacin 34 (2.9)Tetracyclin / ciprofloxacin 25 (4.0)Penicillin / tetracycline / ciprofloxacin 23 (4.3)

Relatively low volume of testing currently done in clinical laboratories …

Antimicrobial susceptibility profiles (1998-2002) indicateseveral alternative therapies still exist…

…and multiple drug resistance typically involves only two drugs;

……current availability of data may be limited by laboratory current availability of data may be limited by laboratory testing protocols …example, N. gonorrhoeae …testing protocols …example, N. gonorrhoeae …

Increasing Proportion of Increasing Proportion of S. aureusS. aureus Bacteremia Caused by MRSABacteremia Caused by MRSA

0

5

10

15

20

25

1998 1999 2000 2001 2002

Year

Perc

ent o

f All

Patie

nts

with

B

acte

rem

ia

All S. aureus MSSA MRSAAll S. aureus

14

0

10

20

30

40

50

60

70

Individual Institution

% M

RS

APrevalence of MRSA among All PatientsPrevalence of MRSA among All Patients

MRSA range by institution: 7.3-60.8%Total institutions = 111

National average MRSA = 41.3%

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2. Organisms causes serious and severe disease2. Organisms causes serious and severe disease

resistance claims usually linked to disease under studyresistance claims usually linked to disease under study

range of organisms across various diseases e.g. S.pneumoniae range of organisms across various diseases e.g. S.pneumoniae common cause of respiratory tract disease but uncommon cause common cause of respiratory tract disease but uncommon cause of UTIof UTI

range of severity of disease from fatal to self-resolvingrange of severity of disease from fatal to self-resolving

impact of resistance most likely to be important and relevant to impact of resistance most likely to be important and relevant to public health in diseases which as not likely to resolve public health in diseases which as not likely to resolve spontaneouslyspontaneously issue of public health decisions versus decisions in individual patientsissue of public health decisions versus decisions in individual patients

Incidence of MSSA and MRSA by Incidence of MSSA and MRSA by SourceSource

0

5

10

15

20

25

30

35

40

45

50

Allsources

Blood CNS LRTI URTI UTI Wound

Specimen source

Per

cen

t of

Pat

ien

ts

S. aureus MSSA MRSAAll S. aureus

17

Bacteremia and Methicillin Resistance Bacteremia and Methicillin Resistance StatusStatus

7.3 6.6

10.712.2

Percent of Wound Infections withBacteremia

Percent of Respiratory Infectionswith Bacteremia

MSSA MRSA

18


3. Drug to which organism is resistant is 3. Drug to which organism is resistant is commonly used in disease under studycommonly used in disease under study

speaks to clinical relevance of drug resistancespeaks to clinical relevance of drug resistance example: TMP-SMX commonly used in treatment of UTI example: TMP-SMX commonly used in treatment of UTI

but streptomycin is notbut streptomycin is not

FDA attempting to gather information on drug usage FDA attempting to gather information on drug usage for various diseasesfor various diseases medical literaturemedical literature IMS databaseIMS database other sources of informationother sources of information

variations in medical practice and resistance patterns in variations in medical practice and resistance patterns in various geographic areas and patient populationsvarious geographic areas and patient populations


4. Limited available therapies due to multi-4. Limited available therapies due to multi-drug resistancedrug resistance use surveillance data to examine relationships use surveillance data to examine relationships

of cross-resistance within a given bacterial of cross-resistance within a given bacterial taxataxa

plans to look at similar analyses for other plans to look at similar analyses for other organisms e.g. fungiorganisms e.g. fungi

organisms which are resistant to multiple organisms which are resistant to multiple drugs are more likely to have fewer available drugs are more likely to have fewer available drugs for treatmentdrugs for treatment

Evaluating Multi-Drug Resistant Evaluating Multi-Drug Resistant PathogensPathogens

Number of agents to which isolates were resistantNumber of agents to which isolates were resistantNu

mbe

r o f

ag e

n ts

to w

h ich

i so l

ates

wer

e su

scep

tib l

eN

um

b er

o f a

g en t

s to

whi

ch is

olat

es w

ere

s us c

e pt i

b le

00

11

22

33

44

55

66

00 11 22 33 44 55 66

S, SS, S

S, R,S, R,

II

77

77

R.RR.R

Evaluating MDR Trends among SpeciesEvaluating MDR Trends among Species(2000-2002)(2000-2002)

Acinetobacter baumannii (n = 7,914) Streptococcus pyogenes (n = 701)Antimicrobials = Gentamicin, Ceftazidime, Imipenem,

Ciprofloxacin, Cefepime, Ampicillin-sulbactam, PiperacillinAntimicrobials = Penicillin, Vancomycin, Erythromycin,

Clindamycin, Ceftriaxone, Levofloxacin

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Detailed Analysis of Resistance PhenotypesDetailed Analysis of Resistance Phenotypes

Phenotype Gentamicin Ceftazidime Imipenem Ciprofloxacin Cefepime Ampicillin-sulbactam Piperacillin1 drug resistance 18.1 2.3 1 43.8 15.0 13.4 6.52 drug resistance 75.5 7.7 1.9 80.4 20.9 6.1 7.53 drug resistance 79.7 30.1 1.3 96.4 34.9 6.8 50.74 drug resistance 79.2 63.7 3.3 97.0 55.7 14.4 86.75 drug resistance 92.6 83.0 7.5 99.5 85.9 34.2 97.46 drug resistance 98.0 91.1 28.3 99.2 97.8 86.2 99.57 drug resistance 100 100 100 100 100 100 100

Percent of isolates resistant

A. baumanii (n = 7,914)

23

Multidrug Resistance among Multidrug Resistance among S. S. pneumoniae pneumoniae 2000-20022000-2002

Penicillin-susceptible (n = 1,627) Penicillin-resistant (n = 576)

Antimicrobials = Erythromycin, Ceftriaxone/Cefotaxime, Clindamycin, Levofloxacin, SXT

24

Antimicrobials = Erythromycin, Ceftriaxone/Cefotaxime, Clindamycin, Levofloxacin, SXT

25

Multidrug Resistance among Multidrug Resistance among S. S. pneumoniaepneumoniae

Penicillin-resistant (n = 576)

Percent of isolates resistant

Phenotype Total n Erythromycin Trimeth/sulfa Clindamycin Levofloxacin 3rd Gen Ceph

0 drug resistance 26 0.0 0.0 0.0 0.0 0.0

1 drug resistance 99 29.3 60.6 0.0 0.0 10.1

2 drug resistance 324 94.8 95.4 4.0 0.3 5.6

3 drug resistance 114 100.0 100.0 78.1 2.6 19.3

4 drug resistance 13 100.0 100.0 100.0 0.0 100.0


5. Drug used to control spread of disease 5. Drug used to control spread of disease in populationin population

drugs more important for limiting drugs more important for limiting disease when no vaccine availabledisease when no vaccine available

disease like STDs and tuberculosis disease like STDs and tuberculosis utilize drug therapy as major public utilize drug therapy as major public health intervention to prevent spread of health intervention to prevent spread of disease disease


6. Clinical correlation of 6. Clinical correlation of in vitro in vitro resistance with resistance with poor clinical outcomespoor clinical outcomes is is in vitroin vitro resistance clinically relevant? resistance clinically relevant? recent examples of where recent examples of where in vitroin vitro resistance did not resistance did not

correlate with poor outcomes in majority of casescorrelate with poor outcomes in majority of cases penicillin resistance in penicillin resistance in S.pneumoniaeS.pneumoniae in CAP in CAP

Pallares et al. NEJM 1995;474-480.Pallares et al. NEJM 1995;474-480. Feikin et al. Am J Pub Health 2000;90:223-229.Feikin et al. Am J Pub Health 2000;90:223-229.

macrolide resistance in macrolide resistance in S. pyogenesS. pyogenes pharyngitis pharyngitis Varaldo et al. Clin Infect Dis 1999;29:869-73.Varaldo et al. Clin Infect Dis 1999;29:869-73.

Clinical impact of resistance may be more important Clinical impact of resistance may be more important and more apparent in more serious disease which is and more apparent in more serious disease which is less likely to resolve spontaneouslyless likely to resolve spontaneously



often difficult to obtain data on clinical treatment often difficult to obtain data on clinical treatment outcomesoutcomes

organism must be prevalent enough to studyorganism must be prevalent enough to study takes time to accumulate datatakes time to accumulate data

Pallares et al. NEJM 1995;474-480.Pallares et al. NEJM 1995;474-480.

some drugs not used to treat severe disease where some drugs not used to treat severe disease where difference between susceptible and resistant isolates difference between susceptible and resistant isolates may be more likely (although overall cure rate lower)may be more likely (although overall cure rate lower) mortality in PORT class 1 CAP is 0.1%mortality in PORT class 1 CAP is 0.1%

Fine MJ et al. NEJM 1997;336:243-50Fine MJ et al. NEJM 1997;336:243-50



Are increasing case reports really “mounting clinical Are increasing case reports really “mounting clinical evidence”?evidence”?

publication biaspublication bias natural history in diseases such as CAP where severe natural history in diseases such as CAP where severe

disease carries mortality of ~30% regardless of therapydisease carries mortality of ~30% regardless of therapy Fine MJ et al. NEJM 1997;336:243-50Fine MJ et al. NEJM 1997;336:243-50

data showing no effect of antimicrobial therapy on data showing no effect of antimicrobial therapy on mortality in first 5 days of pneumococcal pneumoniamortality in first 5 days of pneumococcal pneumonia

Austrian R et al. Ann Intern Med 1964;60:759-76Austrian R et al. Ann Intern Med 1964;60:759-76 all case reports lack comparative data showing higher all case reports lack comparative data showing higher

rate of failure in resistant isolates versus susceptible rate of failure in resistant isolates versus susceptible isolatesisolates


Group A streptococcal (Group A streptococcal (S.S. pyogenespyogenes) ) pharyngitispharyngitis 3,227 patients under age 143,227 patients under age 14 throat swabs prior to treatment and at end of throat swabs prior to treatment and at end of

therapytherapy looked at clinical resolution and bacteriologic looked at clinical resolution and bacteriologic

eradicationeradication 1048 (32.5%) had positive test for GABHS1048 (32.5%) had positive test for GABHS 934 tested for susceptibility and clinical cure934 tested for susceptibility and clinical cure 668 follow-up cultures and bacteriologic cure668 follow-up cultures and bacteriologic cure macrolide resistance at baseline 46.3% of isolatesmacrolide resistance at baseline 46.3% of isolates penicillin resistance at baseline 0%penicillin resistance at baseline 0%

Varaldo et al. Clin Infect Dis 1999;29:869-73.Varaldo et al. Clin Infect Dis 1999;29:869-73.

Relating Resistance to Relating Resistance to OutcomesOutcomes

Group A Strep PharyngitisGroup A Strep PharyngitisResistance pattern Bacteriologic cure

Macrolidesusceptible(57.2%, 534/934)

80.2% (150/187)

Macrolide resistant(42.8%, 400/934)

59.7% (80/134)

Penicillin susceptible(100%, 934/934)

84.1% (175/208)

*no difference in clinical cure rates across drugs with <2% failures at day 3-5*no difference in clinical cure rates across drugs with <2% failures at day 3-5

Varaldo PE et al. Clin Infect Dis 1999;869-73.Varaldo PE et al. Clin Infect Dis 1999;869-73.

Previously Granted Resistance Previously Granted Resistance ClaimsClaims

Methicillin resistant Methicillin resistant S. aureus S. aureus (MRSA)(MRSA) vancomycin in serious infectionsvancomycin in serious infections linezolid in HAP and cSSSIlinezolid in HAP and cSSSI

Vancomycin resistant Vancomycin resistant E. faecium E. faecium (VRE)(VRE) linezolidlinezolid dalfopristin-quinupristin in bacteremiadalfopristin-quinupristin in bacteremia

Penicillinase-producing staphylococciPenicillinase-producing staphylococci nafcillin in serious and severe infectionsnafcillin in serious and severe infections

Beta-lactamase producing Beta-lactamase producing H. influenzaeH. influenzae and and Moraxella catarrhalisMoraxella catarrhalis number of infections with cephalosporinsnumber of infections with cephalosporins

Penicillin resistant Penicillin resistant S. pneumoniaeS. pneumoniae (PRSP) (PRSP) levofloxacin and moxifloxacin in CAPlevofloxacin and moxifloxacin in CAP

Future PlansFuture Plans

Examine epidemiology of organisms in causing Examine epidemiology of organisms in causing various diseasesvarious diseases

Obtain data on drug usage for various Obtain data on drug usage for various indicationsindications

Look at cross-resistance in various organisms Look at cross-resistance in various organisms among 27 taxa and other pathogens which among 27 taxa and other pathogens which committee may recommendcommittee may recommend

Obtain data on clinical correlations with clinical Obtain data on clinical correlations with clinical outcomes and resistance wherever possibleoutcomes and resistance wherever possible

ConclusionConclusion

Populate list based on today’s discussionsPopulate list based on today’s discussions

This afternoon’s discussions on other aspects This afternoon’s discussions on other aspects of drug development for resistant pathogensof drug development for resistant pathogens

Discussion on granting claims for “multi-drug Discussion on granting claims for “multi-drug resistant” organisms discussed yesterdayresistant” organisms discussed yesterday

Formulate guidance for drug development for Formulate guidance for drug development for resistant pathogensresistant pathogens

listing antimicrobial resistant pathogens of public health importance implications for drug...

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