center for drug evaluation and research anti-infective drug advisory committee march 6, 2006 1 new...

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Center for Drug Evaluation and ResearchCenter for Drug Evaluation and ResearchAnti-Infective Drug Advisory Committee Anti-Infective Drug Advisory Committee March 6, 2006March 6, 2006

New Drug Application NDA 21-572/S-008 New Drug Application NDA 21-572/S-008 CubicinCubicin® (daptomycin for injection)® (daptomycin for injection)New Drug Application NDA 21-572/S-008 New Drug Application NDA 21-572/S-008 CubicinCubicin® (daptomycin for injection)® (daptomycin for injection)

Microbiology: Increased Daptomycin MICs Microbiology: Increased Daptomycin MICs During TherapyDuring Therapy

Peter Coderre, PhD, MBAPeter Coderre, PhD, MBACDER, DAIOPCDER, DAIOPAnti-Infective Drugs Advisory Committee MeetingAnti-Infective Drugs Advisory Committee MeetingRockville, MarylandRockville, MarylandMarch 6, 2006March 6, 2006

Microbiology: Increased Daptomycin MICs Microbiology: Increased Daptomycin MICs During TherapyDuring Therapy

Peter Coderre, PhD, MBAPeter Coderre, PhD, MBACDER, DAIOPCDER, DAIOPAnti-Infective Drugs Advisory Committee MeetingAnti-Infective Drugs Advisory Committee MeetingRockville, MarylandRockville, MarylandMarch 6, 2006March 6, 2006

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Increased Daptomycin MICsIncreased Daptomycin MICsIncreased Daptomycin MICsIncreased Daptomycin MICs

• Increasing daptomycin MICs documented in vitro, in vivo, in the literature and during this clinical trial

• Currently: S. aureus isolates with a MIC ≤ 1 g/ml are considered susceptible to daptomycin

• Breakpoints for intermediate and resistant isolates have yet to be established

• Increasing daptomycin MICs documented in vitro, in vivo, in the literature and during this clinical trial

• Currently: S. aureus isolates with a MIC ≤ 1 g/ml are considered susceptible to daptomycin

• Breakpoints for intermediate and resistant isolates have yet to be established

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Increased Daptomycin MICsIncreased Daptomycin MICsIncreased Daptomycin MICsIncreased Daptomycin MICs

What are the implications of increasing daptomycin MICs during treatment with daptomycin for infective endocarditis and bacteremia?

In patients with persistent or relapsing bacteremia, S. aureus demonstrated increasing daptomycin MICs (≥ 1 g/ml) during or after therapy with the drug.

What are the implications of increasing daptomycin MICs during treatment with daptomycin for infective endocarditis and bacteremia?

In patients with persistent or relapsing bacteremia, S. aureus demonstrated increasing daptomycin MICs (≥ 1 g/ml) during or after therapy with the drug.

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Changes in MICs for Relapsing or Persistent Bacteremia Patients#

Changes in MICs for Relapsing or Persistent Bacteremia Patients#

MIC >1> 2

steps MRSA MSSA

daptomycin arm (N=20)

9/20 (45.0%)

9/20 (45.0%)

12/20 (60.0%)*

11/20 (55.0%)*

comparator arm (N=10)

1/10 (10.0%)

0/10 (0%)

8/10 (80.0%)

2/10 (20.0%)

3 patients had both MSSA and MRSA # FDA Analysis

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Distribution of Terminal MICs for Daptomycin Treated Patients (ITT) by

Clinical Outcome

Distribution of Terminal MICs for Daptomycin Treated Patients (ITT) by

Clinical Outcome

MIC (g/ml)

0.12 0.25 0.5 1 2 4

clinical success (N=53)

1 (1.9%)

36 (67.9%)

14 (26.4%)

2 (3.8%)

0 (0%)

0 (0%)

clinical failure (N=59)

1 (1.7%)

34 (57.6%)

15 (25.4%)

3 (5.1%)

5 (8.5%)

1 (1.7%)

total (N=112)2

(1.8%)70

(62.5%)29

(25.9%)5

(4.4%)5

(4.5%)1

(0.9%)

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Clinical Failures in Daptomycin Arm with Increased Daptomycin MICs

Clinical Failures in Daptomycin Arm with Increased Daptomycin MICs

Case # Final Diagnosis Organism Baseline High MIC Step

MIC MIC Increase

009-212complicated bacteremia MRSA 0.25 2 3

010-152 complicated RIE MSSA 0.25 4 4

015-105complicated bacteremia Both 0.25 2 -

017-037 left IE Both 0.25 2 -

027-183 left IE MRSA 0.5 2 2

324-136complicated bacteremia MRSA 0.5 2 2

300-111 left IE MRSA 0.25 1 2

300-246 left IE MRSA 0.25 1 2

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Frequency of Increased MICs and Non-Susceptibility/Resistance to Daptomycin or

Vancomycin in Patients during Therapy^

Frequency of Increased MICs and Non-Susceptibility/Resistance to Daptomycin or

Vancomycin in Patients during Therapy^

N, % ↑ N, % ↑ N, %

developed N, %

developed

Dapto MIC Vanco MIC DaptoNS VancoR

IEAC successes

daptomycin (N=53) 17 (32.1%)* 12 (22.6%)* 0 (0%)* 0 (0%)*

comparator (N=48) 11 (22.9%) 13 (27.1%) 1 (2.1%) 0 (0%)

IEAC failures

daptomycin (N=67) 23 (34.3%) 16 (24.2%)* 6 (9.0%) 0 (0.0%)*

comparator (N=65) 12 (18.5%)* 17 (26.2%)* 0 (0.0%)** 0 (0.0%)**

*determination of MICs not done for one patient; **determination of MICs not done for two patients; *** one or more dilution increase; ^ contains non-evaluable patients as failures

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Overview of Isolates with Treatment Associated Decreases in Daptomycin Susceptibility Following

Commercial Availability

Overview of Isolates with Treatment Associated Decreases in Daptomycin Susceptibility Following

Commercial Availability

Isolate/N Source Daptomycin MIC (g/ml)

S.aureus blood 0.25 1

S.aureus * 0.25 4

S.aureus--5 blood 0.5 4

S.aureus ** 0.5 4

S.aureus blood 1 2--4

S.aureus 0.5 8

MRSA 0.25 1.5

E. faecium urine/blood 4 32

E. faecium blood 4 > 32

VRE*** blood 4

VRE*** 8

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Recent Literature Reporting Clinical Failures with Daptomycin TreatmentRecent Literature Reporting Clinical Failures with Daptomycin Treatment

Organism Condition Source Dose Highest Reference

(mg/kg) MIC (g/ml)

MRSA bacteremia blood 4 2 Mangili et al., 2005

MRSA osteomyelitis blood 6 4 Hayden et al., 2005

MRSA bacteremia blood 8 4 Skiest, 2006

MRSA bacteremia blood 6 4 Marty et al., 2006

E. faecium bacteremia blood 6 >32 Sabol et al., 2005

E. faecium fever blood none 4 Lesho et al., 2006

E. faecalis (VRE) bacteremia blood * 16 Munoz-Price, et al., 2005

E. faecalis (VRE) febrile neutropenia blood ?? ?? Long et al., 2005

*400 mg q48h

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Surveillance DataSurveillance Data

Species Study/Year

N Daptomycin MIC Distribution n (%) MIC (g/ml)

≤ 0.12 0.25 0.5 1 2

MSSA 2000-1 1601 304 (18.9%) 1165 (72.7%) 131 (8.2%) 1 (0.1%) 0 (0%)

2002 1547 83 (5.4%) 1140 (73.7%) 319 (20.6%) 3 (0.2%) 2 (0.1%)

2003 2894 229 (7.9%) 2371 (81.9%) 285 (9.9%) 8 (0.3%) 1 (<0.1%)

2003-4 3284 70 (2.1%) 1891 (57.6%) 1297 (39.5%) 25 (0.8%) 1 (<0.1%)

MRSA 2000-1 639 51 (7.9%) 396 (61.9%) 187 (29.3%) 5 (0.8%) 0 (0%)

2002 1076 20 (1.9%) 655 (60.9%) 388 (36.1%) 13 (1.2%) 0 (0%)

2003 1468 40 (2.7%) 963 (65.6%) 452 (30.8%) 13 (0.9%) 0 (0%)

2003-4 1976 10 (0.5%) 878 (44.4%) 1047 (52.9%) 40 (2.0%) 1 (<0.1%)

Source: Table 2.7.2-24, NDA 21-572 SN008

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S. aureus S. aureus MIC Distributions: 2004-2005 MIC Distributions: 2004-2005 (2004: n = 317; 2005: n = 359)(2004: n = 317; 2005: n = 359)

S. aureus S. aureus MIC Distributions: 2004-2005 MIC Distributions: 2004-2005 (2004: n = 317; 2005: n = 359)(2004: n = 317; 2005: n = 359)

0.9% 3.3%

0102030405060708090

100

< 1 (g/ml) > 1 (g/ml)MIC Group

% o

f T

ota

l

99.1% 96.7%

Source: Focus Technologies

2004 2005 2004 2005

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In VivoIn Vivo Evidence EvidenceIn VivoIn Vivo Evidence Evidence

• Sponsor data from rabbits, mice, rats for bacteremia, endocarditis, fibrin clot, etc.

• In rabbit model, daptomycin more efficacious than vancomycin, however, diminished susceptibility developed during therapy —due to selection by sub-inhibitory concentrations of daptomycin in vegetations

• Silverman et al. (2001): extensive clinical use required to establish if resistance will be a major clinical problem

• Sponsor data from rabbits, mice, rats for bacteremia, endocarditis, fibrin clot, etc.

• In rabbit model, daptomycin more efficacious than vancomycin, however, diminished susceptibility developed during therapy —due to selection by sub-inhibitory concentrations of daptomycin in vegetations

• Silverman et al. (2001): extensive clinical use required to establish if resistance will be a major clinical problem

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In VitroIn Vitro Evidence EvidenceIn VitroIn Vitro Evidence Evidence

• Spontaneous mutations rare; no known transferable elements

• Liebowitz et al. (1988): stable resistant organisms after multiple passages in increasing [daptomycin] and after chemical mutagenesis— isolates 16X higher than parental isolates

• Kaatz et al. (1990): DaptoR mutants were VanS, AmpS but cross-resistance to Nisin

• Spontaneous mutations rare; no known transferable elements

• Liebowitz et al. (1988): stable resistant organisms after multiple passages in increasing [daptomycin] and after chemical mutagenesis— isolates 16X higher than parental isolates

• Kaatz et al. (1990): DaptoR mutants were VanS, AmpS but cross-resistance to Nisin

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In VivoIn Vivo Evidence--Biofilms Evidence--BiofilmsIn VivoIn Vivo Evidence--Biofilms Evidence--Biofilms

• Evidence for pathogenesis of biofilms in IE is strong

• 60% of daptomycin penetrates vegetation but 90% is protein bound; therefore, expect < 60% penetration

• Vegetations manifest biofilm-like antibiotic resistance that cannot be completely explained by poor penetration of antimicrobials

• Composition of the valve biofilm has direct bearing on clinical outcomes

• Results demonstrate association between biofilm composition and clinical manifestations—IE can be manipulated by targeting biofilm development

• Evidence for pathogenesis of biofilms in IE is strong

• 60% of daptomycin penetrates vegetation but 90% is protein bound; therefore, expect < 60% penetration

• Vegetations manifest biofilm-like antibiotic resistance that cannot be completely explained by poor penetration of antimicrobials

• Composition of the valve biofilm has direct bearing on clinical outcomes

• Results demonstrate association between biofilm composition and clinical manifestations—IE can be manipulated by targeting biofilm development

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SummarySummarySummarySummary

• On therapy (endocarditis): increasing daptomycin MICs particularly among persisting or relapsing bacteremia

• On therapy (all-comers): increasing daptomycin MICs among clinical failures

• Surveillance data: increasing daptomycin MICs over time; more reports in literature (2005-6) showing daptomycin resistance

• In vivo: rabbit model, daptomycin more efficacious than vancomycin but diminished daptomycin susceptibility during therapy

• In vitro: bacteria develop resistance at sub-inhibitory concentrations; cross-resistance to nisin, but not vancomycin or ampicillin; biofilms—subinhibitory concentrations?

• On therapy (endocarditis): increasing daptomycin MICs particularly among persisting or relapsing bacteremia

• On therapy (all-comers): increasing daptomycin MICs among clinical failures

• Surveillance data: increasing daptomycin MICs over time; more reports in literature (2005-6) showing daptomycin resistance

• In vivo: rabbit model, daptomycin more efficacious than vancomycin but diminished daptomycin susceptibility during therapy

• In vitro: bacteria develop resistance at sub-inhibitory concentrations; cross-resistance to nisin, but not vancomycin or ampicillin; biofilms—subinhibitory concentrations?

center for drug evaluation and research anti-infective drug advisory committee march 6, 2006 1 new...

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