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Staphylococcus aureus Bacteremia and Endocarditis: A Bad Bug and A New Drug

G. Ralph Corey M.D.Professor of Internal Medicine and Infectious Diseases

Duke University Medical CenterDurham, North Carolina

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The Daptomycin TrialA Bad Bug

• Background

“Bad Bugs - No Drugs”*

S. aureus is no. 1 villain• Staphylococcus aureus

– Unique organism– Increasing in frequency– Increasing in complexity– Increasing resistance

• New options for therapy are badly needed*Talbot et al. CID. 2006.

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Lowy, NEJM 1998.

S. aureusA Unique Organism

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S. aureus Bacteremia Is a Bad Disease: Prospectively Identified

Patients at DUMC

• 12-week mortality: 24%• Metastatic infections: 34%• Endocarditis: 12.2% • Relapse: 10%

S. aureus = D. V.

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The Daptomycin TrialA Bad Bug

• Background• “Bad Bugs - No Drugs”*• Staphylococcus aureus

– Unique organism– Increasing in frequency– Increasing in complexity– Increasing resistance

• New options for therapy are badly needed

*Talbot et al. CID. 2006.

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The Daptomycin TrialA New Drug

• Approved for complicated skin infections

Despite this

• 25% of daptomycin use is off-label forS. aureus bacteremia!

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The Daptomycin TrialBacteremia and Endocarditis

• Daptomycin being “tested” in patients with S. aureus bacteremia by clinicians

• A structured bacteremia trial needed but there were difficulties

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The Daptomycin TrialBacteremia and Endocarditis

• Lack of indication for SAB

• FDA guidance focuses on catheter-related blood stream infections (1999) - multiple organisms

• No successful CR-BSI trial since this guidance Raad et al. CID 2005

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The Daptomycin TrialBacteremia and Endocarditis

Focus on catheter-related infection ignores:

– S. aureus is unique

– Infection category undefined on enrollment

– Origin of bacteremia NOT predictive of outcomeFowler et al. Archives 2003

– 40% of endocarditis is health care associated Fowler et al. JAMA 2005

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The Daptomycin TrialBacteremia and Endocarditis

• No randomized endocarditis trial for over 20 years: nafcillin vs nafcillin/gentamicin Korzeniowski et al Ann Int Med. 1982

• Imipenem approval for endocarditis based on 11 patientsMedical Reviewer, FDA 1985

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The Daptomycin TrialBacteremia and Endocarditis Challenges

• Design

• Enrollment

• Long f/u of difficult population in an open-label trial = lower than expected success rates

• Inter-observer variability in echo readings

• Consistency in outcome determination

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Daptomycin Trial Bacteremia and Endocarditis

• These trials require vigilant clinicians– Is back pain from the hospital bed

or new vertebral osteomyelitis?

• Experienced teams needed to address difficult surgical decisions– When should a heart valve be replaced?

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Daptomycin Trial Bacteremia and Endocarditis

• Given all these difficulties impressive that anyone would undertake a SAB/endocarditis trial

• Fortunately the FDA provided significant support and guidance

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Adjudication Committee Final Diagnoses (ITT)

LIE8% RIE

14%

cBAC53%

uBAC25%

LIE8% RIE

16%

cBAC50%

uBAC27%

Daptomycin GroupDaptomycin GroupN = 120N = 120

Comparator GroupComparator GroupN = 115N = 115

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Success at End of Therapy and Test of Cure (ITT)

61.761.7

44.244.2

60.960.9

41.741.7

74 120

70 115

53 120

48 115

End of TherapyEnd of Therapy Test of CureTest of Cure

DaptomycinDaptomycin

ComparatorComparator

00

1010

2020

3030

4040

5050

6060

7070

% S

uc

ces

s%

Su

cce

ss

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MRSA - Success at TOC by Final Diagnosis (IEAC, ITT)

44.4

60.0

45.550.0

32.6

45.5

27.3

50.0

0

20

40

60

80

100

MRSAOverall

uBAC cBAC RIE LIE

Daptomycin

Vancomycin

20

45

14

43

Su

cce

ss

Ra

te %

6

10

5

1110

22

6

22

4

8

3

60/5 0/4

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IEAC Reasons For Failure at TOC (ITT, > One Reason May Apply)

DaptomycinDaptomycinN = 120N = 120

ComparatorComparatorN = 115N = 115

Overall failureOverall failure 67 (55.8%)67 (55.8%) 67 (58.3%)67 (58.3%)

Persisting or relapsing Persisting or relapsing S. aureusS. aureus infection infection 19 (15.8%)19 (15.8%) 11 (9.6%)11 (9.6%)

Clinical failure without persisting or relapsing Clinical failure without persisting or relapsing S. aureusS. aureus infection infection 4 (3.3%)4 (3.3%) 4 (3.5%)4 (3.5%)

Discontinued due to adverse eventDiscontinued due to adverse event 8 (6.7%)8 (6.7%) 17 (14.8%)17 (14.8%)

Patient diedPatient died 13 (10.8%)13 (10.8%) 13 (11.3%)13 (11.3%)

Non-study antibiotics Non-study antibiotics 20 (16.7%)20 (16.7%) 16 (13.9%)16 (13.9%)

No blood culture drawn at TOCNo blood culture drawn at TOC 9 (7.5%)9 (7.5%) 12 (10.4%)12 (10.4%)

Non-evaluable (e.g., withdrew consent, left AMA)Non-evaluable (e.g., withdrew consent, left AMA) 9 (7.5%)9 (7.5%) 14 (12.2%)14 (12.2%)

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The Daptomycin Trial Strengths

• Well designed by the best endocarditis experts in the world in conjunction with the FDA

• Wisely ignored the source of bacteremia as inclusion criteria - S. aureus unique

12-week mortality: 24%

Metastatic complications: 34%

Endocarditis: 12.2%

Relapse: 10%

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The Daptomycin Trial Strengths

• Wide variety of patients – results generalizable – new antibiotic must take on all comers

• Combination therapy in comparator group sets the highest outcome bar

• Core echocardiography laboratory essential

• A blinded Independent External Adjudication Committee established

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Daptomycin Trial Outcome

• Daptomycin at 6 mg/kg daily is safe and effective in the treatment of S. aureus bacteremia and endocarditis

• Daptomycin is statistically non-inferior to comparator therapies and numerically better for MRSA

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The Daptomycin TrialOther Important Findings

• Persistent S. aureus bacteremia - inadequate “surgical” intervention

• Persistent infection can lead to decreased susceptibility

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The Daptomycin TrialMy Conclusions

• S. aureus infections are a serious and increasing problem

• Clinicians need a new treatment option

• Daptomycin provides us with that option