Ceftobiprole non-inferior to daptomycin in treating Staphylococcus aureus bacteremia

1. In this randomized controlled trial, treatment of patients with complicated Staphylococcus aureus (S. aureus) bacteremia with ceftobiprole was non-inferior to treatment with daptomycin.

2. Secondary outcomes were consistent between the ceftobiprole and daptomycin treatment groups, including mortality, relapse, and microbiologic eradication.

Evidence Rating Level: 1 (Excellent)

Study Rundown: S. aureus is a leading cause of bacteremia and is associated with several complications, including infective endocarditis. Treatment options are somewhat limited, especially for those infected with methicillin-resistant S. aureus (MRSA), and there have been few randomized controlled trials to inform treatment of S. aureus bacteremia. One such trial occurred more than 15 years ago and led to the approval of daptomycin for this indication. This phase III non-inferiority trial aimed to compare the efficacy of ceftobiprole, a fifth-generation cephalosporin with bactericidal activity against methicillin-susceptible S. aureus (MSSA) and MRSA, to daptomycin in the treatment of complicated S. aureus bacteremia. Overall, it demonstrated that the treatment success rate in patients who received ceftobiprole was non-inferior to that in patients who received daptomycin. Both ceftobiprole and daptomycin treatment groups exhibited similar rates of mortality, relapse, bacteremia-associated complications, and microbiologic eradication. Ceftobiprole was also associated with increased gastrointestinal adverse events and hypokalemia. Moreover, definitive conclusions regarding the efficacy of ceftobiprole against the treatment of MRSA bacteremia are limited given the small sample size of the subgroup used in this study.

Click to read the study in NEJM

Relevant Reading: Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus

In-Depth [randomized controlled trial]: ERADICATE is a phase III, double-blinded, randomized, non-inferiority trial comparing the efficacy of ceftobiprole to daptomycin in the treatment of complicated S. aureus bacteremia. Patients who were at least 18 years of age and had clinical evidence of complicated bacteremia with at least one positive blood culture within 72 hours prior to assignment to a treatment group were selected for the study. These patients were assigned in a 1:1 ratio to receive 500 mg of ceftobiprole intravenously every six hours for eight days and then every eight hours thereafter versus daptomycin intravenously at a dose of 6 mg/kg every 24 hours with the option to up-titrate to 10 mg/kg. The primary outcome was “treatment success” at 70 days after randomization, defined as survival, symptomatic improvement, microbiologic eradiation, and symptomatic improvement without the use of other potentially effective antibiotics, with a non-inferiority margin of 15%. At the end of the study, 69.8% of patients in the ceftobiprole group exhibited treatment success versus 68.7% of those in the daptomycin group (adjusted difference, 2.0 percentage points; 95% Confidence Interval, -7.1 to 11.1). More specifically, the lower boundary of -7.1% was greater than that of the pre-specified non-inferiority margin, suggesting that ceftobiprole was non-inferior to daptomycin. Rates of secondary outcomes were consistent across both ceftobiprole and daptomycin treatment groups, including mortality (9.0% vs 9.1%), bacteremia-associated complications (5.8% vs 5.6%), and microbiologic eradication (82.0% vs 77.3%). Adverse events thought to be related to the treatment drug were more common in the ceftobiprole group (13.1% vs 5.6%) with higher incidences of gastrointestinal symptoms and hypokalemia in these patients. In summary, this trial demonstrated that ceftobiprole was non-inferior to daptomycin in the treatment of complicated S. aureus bacteremia.

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