# Presentation: 242699

## 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 CenterDurham, North Carolina

##  The Daptomycin TrialA 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.**

## S. aureusA Unique Organism

**Lowy, NEJM 1998.**

*S. aureus*A Unique Organism

## 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.**

##  The Daptomycin TrialA 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.**

## The Daptomycin TrialA New Drug

**Approved for complicated skin infections**
**Despite this**
**25% of daptomycin use is off-label for*****S. aureus***** bacteremia! **

## The Daptomycin TrialBacteremia and Endocarditis

**Daptomycin being “tested” in patients with *****S. aureus***** bacteremia by clinicians**
**A structured bacteremia trial needed but there were difficulties**

## The Daptomycin TrialBacteremia 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**

## The Daptomycin TrialBacteremia and Endocarditis

**Focus on catheter-related infection ignores:                                          **
***S. aureus***** is unique                                             **
**Infection category undefined on enrollment             **
**Origin of bacteremia NOT predictive of outcome****Fowler et al. Archives 2003****               **
**40% of endocarditis is health care associated                                                      ****Fowler et al. JAMA 2005**

## The Daptomycin TrialBacteremia 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 patients****Medical Reviewer, FDA 1985**

## The Daptomycin TrialBacteremia 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**

## 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?**

## 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 **

## Adjudication Committee Final Diagnoses (ITT)

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

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

**20**
** ****45**

**14**
**43**

**Success Rate  %**

**6**
** ****10**

**5**
** ****11**

**10 **
**22**

**6 **
**22**

**4 **
**8**

**3 **
**6**

**0/5**

**0/4**

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

** **

|  | Daptomycin
N = 120 | Comparator
N = 115 |
| --- | --- | --- |
| Overall failure | 67 (55.8%) | 67 (58.3%) |
| Persisting or relapsing S. aureus infection | 19 (15.8%) | 11 (9.6%) |
| Clinical failure without persisting or relapsing S. aureus infection | 4 (3.3%) | 4 (3.5%) |
| Discontinued due to adverse event | 8 (6.7%) | 17 (14.8%) |
| Patient died | 13 (10.8%) | 13 (11.3%) |
| Non-study antibiotics   | 20 (16.7%) | 16 (13.9%) |
| No blood culture drawn at TOC |  9 (7.5%) | 12 (10.4%) |
| Non-evaluable (e.g., withdrew consent, left AMA) |  9 (7.5%) | 14 (12.2%) |

## 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%**

## 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**

## 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**

## The Daptomycin TrialOther Important Findings

**Persistent *****S. aureus***** bacteremia -  inadequate “surgical” intervention**
**Persistent infection can lead to decreased susceptibility**

## The Daptomycin TrialMy Conclusions

***S. aureus *****infections are a serious and increasing problem**
**Clinicians need a new treatment option**
**Daptomycin provides us with that option**