# Presentation: 781286

## Staphylococcus aureus Bacteremia and Endocarditis

**Francis P. Tally, M.D.**
**Senior Vice President and Chief Scientific Officer**
**Cubist Pharmaceuticals, Inc****.**

## Summary: Staphylococcus aureus Bacteremia

**Significant unmet medical need**
**Heterogeneous population including endocarditis with different outcomes**
**Lack of a placebo effect**
**Difficult to study but possible**
**Traditional non-inferiority assessment may not be the best or only assessment of efficacy**

## High Unmet Medical Need

***Staphylococcus aureus***** is a leading cause of bacteremia**
**Virulence leads to a high proportion of endocarditis (including on normal heart valves), metastatic infections, and/or death**
***Staphylococcus aureus***** bacteremia is both a cause and a result of endocarditis**
**Changing epidemiology is a therapeutic challenge**
- Growing resistance to beta-lactam antibiotics
- Increasing tolerance to vancomycin

## Proportion and Mortality of Coagulase-negative Staphylococcal and S. aureus Bacteremias (SCOPE Surveillance System)

**Proportion of BSI***

**crude mortality**

**Coagulase-negative staphylococci**

**(n~6566)**

***S. aureus *****

**(n~4237)**

- *  Total 20,978 monomicrobial bacteremias
- ** 41% resistant to Methicillin
- Wisplinghoff et al. *CID* 29:309-317, 2004

## Case Fatality of Staphylococcus aureus Bacteremia (n=122) in the Pre-Antibiotic Era 

**total cases**

**recovered**

**13**

**33**

**20**

**16**

**15**

**14**

**9**

**3**

**4**

**9**

**4**

**0        0**

**1**

**0**

- Number of patients

**Case Fatality = 82%**

- Age strata

**4**

- Skinner & Keefer. *Arch Int. Med * 68:851-75, 1941

## Mortality of MSSA vs. MRSA BacteremiaMeta-Analysis

**Mortality of MSSA vs. MRSA Bacteremia****Meta-Analysis**

**N=3963**

**RR=1.42**
**p<.001**

- Cosgrove SE et al. *Clin Infect Dis* 36:53-59, 2003

## Vancomycin Resistance: An Emerging Problem

- 1 Murray. *NEJM* 342:710, 2000
- 2 Hiramatsu, K et al.  *J. Antim. Chemo.* 40:135-136, 1997
- 3 Fridkin SK. *CID* 32:108, 2001
- 4 *MMWR* 51:565-567, 2002

## Vancomycin: Efficacy and Heteroresistance

_**EFFICACY IN MSSA/MRSA**_
**Vancomycin less effective versus nafcillin in MSSA bacteremia**
- Chang et al. *Medicine* 82, 2003
**Vancomycin failure with MRSA endocarditis**
- Small & Chambers. *AAC** *34:1227-1231, 1990
_**HETERORESISTANCE/TOLERANCE**_
**Vancomycin heteroresistance associated with increased failure**
- Fridkin SK. *CID* 32:108, 2001
- Lin & Chambers. *AAC* 47:3040, 2003
**Increased vancomycin failures with MICs ≥ 1 μg/ml and/or tolerance**
- Sakoulas. *JCM*, 2004

## Retrospective Analysis of Vancomycin Failure Associated with Vancomycin MIC in Patients with MRSA Bacteremia

| Overall Clinical Success Rate | 23% (n=30) |  |  |
| --- | --- | --- | --- |
| Vancomycin MIC | <0.5 | 1 - 2 | p value |
| Clinical Success by MIC | 55.6% (n=9) | 9.5%          (n=21) | 0.02 |

- MIC = Minimum Inhibitory Concentration
- Source: Sakoulas et al. *JCM*, June 2004

## Phase 3 study of Daptomycin in Infective Endocarditis/Bacteremia due to Staphylococcus aureus

**Multi-center (US & Western Europe)**
**Randomized**
**Open Label**
**Blinded external adjudication committee**
**Comparator-controlled**
- Semi-synthetic penicillins or vancomycin
**Protocol Amendment of April 1, 2004 to include LIE**

## Challenges to Studying Staphylococcus aureus Bacteremia/Endocarditis

| Challenges | Study Design |
| --- | --- |
| Heterogeneous population | Determine diagnosis at baseline using Modified Duke Criteria (definite/possible/not IE)
Blinded, centralized echo interpretation
Determine overall response and responses in each subgroup: LIE, RIE (complicated/uncomplicated), bacteremia (complicated/uncomplicated) |
| Difficult to enroll eligible patients | Numerous sites US and Europe |
| Ethical considerations | Open-label design with data safety monitoring committee review |
| Bias due to open-label design | Blinded independent, external adjudication committee of IE experts determines diagnosis and outcome |
| High rate of relapse | Long follow-up: 
Test of cure visit at 6 weeks post treatment
Post-study visit at 3 months post treatment |

## Diagnosis of enrolled patients by modified Duke criteria at baseline

## Overall Screening and Enrollment(as of October 8, 2004) 

## Summary: Staphylococcus aureus Bacteremia

**Significant unmet medical need**
**Heterogeneous population including endocarditis with different outcomes**
**Lack of a placebo effect**
**Difficult to study but possible**
**Traditional non-inferiority assessment may not be the best or only assessment of efficacy**