A Randomized, Multicenter Trial of Daptomycin Versus Vancomycin in the Treatment of Nosocomial or Healthcare-associated Methicillin-resistant Staphylococcus Aureus Bacteremia

Introduction: Nosocomial and/or healthcare-associated Staphylococcus aureus infections are common, serious conditions. S. aureus accounts for about 20% of cases of nosocomial bacteremia, and is associated with a mortality of 20-40%. This severity is due to the virulence of the bacterium, and the age and comorbidity of the patients in whom the infection occurs. First-line therapy is based on vancomycin, because the prevalence of methicillin resistance in S. aureus (~20%) is still high in the hospital environment. However the bactericidal activity of this drug is slow and it causes dose-dependent nephrotoxicity. The persistence of positive blood cultures after 72 hours, a parameter which in itself is predictive of the infection having a complicated clinical course, is seen in about 35% of patients receiving vancomycin therapy.

Hypothesis: The use of daptomycin to treat nosocomial or healthcare-associated bacteremia due to methicillin-resistant S. aureus (MRSA) would increase the proportion of patients whose blood cultures are sterilized after 72 hours by 15% relative to vancomycin and would improve treatment safety.

Primary objective: To study the efficacy of daptomycin compared to vancomycin on the sterilization of blood cultures after 72 hours of therapy.

Secondary objectives: Clinical cure at D14 and D28; relapse-free clinical and bacteriological cure at D90; mortality at D14, D28 and D90; treatment duration (in days) before sterilization of blood cultures; side effects occurrence during treatment, renal insufficiency; peripheral vein toxicity requiring placement of a central venous catheter; side effects requiring changes to the study treatment ; duration of hospitalization for bacteremia; increase of at least 2 dilutions in the minimal inhibitory concentration (MIC) of daptomycin and/or vancomycin between the first and last clinical isolates of S. aureus.

Methodology: A prospective, multicenter, randomized, open-label study to compare daptomycin monotherapy to vancomycin monotherapy. Patients will be randomized if they have a nosocomial or healthcare-associated infection, a blood culture positive for Gram-positive cocci in clusters, and a rapid molecular diagnostic test(GENEXPERT) that confirm the presence of methicillin-resistant S. aureus. Daptomycin will be given once daily in monotherapy (10 mg/kg as a single infusion over 30 minutes into a peripheral vein). Standard therapy is vancomycin in monotherapy given by intermittent or continuous infusion so as to obtain trough concentrations of 15-20 mg/L or plateau concentrations of 20-25 mg/L, respectively. The treatment duration for bacteremia in both arms is 14 days of intravenous therapy for uncomplicated bacteremias and 28 days of intravenous therapy for complicated bacteremias, defined by persistent fever or positive blood cultures after 72 h of the study treatment, secondary septic localizations existing at enrollment, or presence of foreign material without signs of infection.