Catheter-Related Blood Stream Infections A Phase 2 Randomized, Controlled Trial of Dalbavancin vs. Vancomycin Tim Henkel, MD, PhD Executive VP and Chief Medical Officer Vicuron Pharmaceuticals

CR-BSI: Regulatory History 1993AIDAC recommended elimination of bacteremic sepsis indication 1998AIDAC discussion of CR-BSI 1999Draft Guidance for CR-BSI 2004No drug approved for CR-BSI

Review of Controlled Trials Raad et al, Quinupristin/Dalfopristin vs. Vancomycin –Eur J Clin Microbiol Infect Dis (1999) 18  199

Study Design Phase 2 Randomized, controlled, open label Clinical and microbiological entry criteria Gram-positive CR-BSI Primary endpoint  global response at FU Sample size planned  60/group Descriptive statistics with 95  CIs

Inclusion criteria Documented Gram-positive bacteremia or Empiric enrollment allowed pending cultures if  2 signs –core temperature  38.0  C or  36.0  C –WBC count  12,000,  4,000 or  10  bands –tachycardia –tachypnea –transient hypotension

Exclusion criteria  24 hrs of prior antibiotic therapy (Gram  ) Alternate focus of infection identified Recent S. aureus bacteremia from a source other than a CVC  2 weeks antibiotic therapy anticipated Creatinine clearance  50 ml/min, Neutropenia (ANC  100/mm3 for  72 hours) Use of chronic immunosuppressive drugs Documented resistance to either study drug

Microbiological Methods Catheter cultures Time to positivity of catheter vs. peripheral cultures Insertion site exudate cultures Identity of paired cultures confirmed by –Antibiograms –PFGE

Outcome Definitions Clinical: –Success  improvement in signs/ symptoms and no additional therapy required –Failure: persistence of signs and symptoms and additional therapy required. Microbiological  –success –Failure

Categories of Infection Definite CR-BSI: one of the following: –  1 positive peripheral blood culture, plus one of: positive semi quantitative (catheter tip,  15 CFU) quantitative (lumen wash,  10 2 CFU/mL) catheter culture positive hub or tunnel exudate culture –  5-fold increase in CFU/mL of identical pathogen from central vs. peripheral blood culture –  2 hour longer time to positivity for the peripheral culture relative to the central culture

Categories of Infection Probable CR-BSI: –S. aureus:  1 positive peripheral blood culture (in absence of other source of infection) –All other organisms:  2 blood cultures positive for identical species, at least 1 peripheral

Phase 2 CRBSI – Enrollment 34 centers in North America Enrollment period of 17 months 2639 patients screened 75 patients enrolled

Reasons for Screening Failures Reason  Inadequate culture data30 Prior antibiotic usage20 Renal insufficiency20 Additional focus of infection13 Mixed G  /G- infection 9 Neutropenia6

Conclusions A common disease, but challenging to study –Heterogeneous population –Inclusion/Exclusion criteria may result in population not representative of true disease spectrum –Microbiological methods not standard of care –No approved comparator Phase 3 study with current CRBSI design not feasible Alternate approaches to bacteremia indications and study design needed