Results of a Double-Blind, Randomized Trial of Ceftobiprole Treatment of Complicated Skin and Skin Structure Infections Caused by Gram-Positive Bacteria

Abstract

Ceftobiprole is the first broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) to be assessed in late-stage clinical trials. As a pivotal step in the clinical development of ceftobiprole, a multicenter, global, randomized, double-blind trial was conducted to compare the efficacy of ceftobiprole to that of vancomycin in patients with complicated skin and skin structure infections (cSSSIs) caused by gram-positive bacteria. The primary objective was to assess noninferiority on the basis of the cure rates 7 to 14 days after the completion of therapy in patients administered ceftobiprole 500 mg every 12 h or vancomycin 1 g every 12 h. Of 784 patients randomized, 282 receiving ceftobiprole and 277 receiving vancomycin were clinically evaluable. Of these patients, 93.3% treated with ceftobiprole and 93.5% treated with vancomycin were cured (95% confidence interval of difference, ؊4.4%, 3.9%). The cure rates for patients with MRSA infections were 91.8% (56/61) with ceftobiprole treatment and 90.0% (54/60) with vancomycin treatment (95% confidence interval of difference, ؊8.4%, 12.1%). At least one adverse event (AE) was reported by 52% of the ceftobiprole-treated patients and 51% of the vancomycin-treated patients. The most common AEs reported by the ceftobiprole-treated patients were nausea (14%) and taste disturbance (8%). Discontinuation of the study drug because of treatment-emergent AEs occurred in 4% (n ‫؍‬ 17) of the ceftobiprole-treated patients and 6% (n ‫؍‬ 22) of the vancomycin-treated patients. The results of this trial support the use of ceftobiprole as an effective and well-tolerated treatment option for patients with cSSSIs caused by a spectrum of gram-positive bacteria.Complicated skin and skin structure infections (cSSSIs) in hospitalized patients are often caused by gram-positive bacteria (28). Because Staphylococcus aureus and Streptococcus pyogenes are the leading causes of cSSSIs, guidelines for the treatment of cSSSIs consistently recommend empirical antimicrobial therapy that provides activity against these bacteria.Over the last 20 years, the prevalence of methicillin-resistant S. aureus (MRSA) as a cause of cSSSIs has been increasing worldwide (15,18,19). Recent experience suggests that MRSA is now responsible for nearly 60% of purulent skin and soft tissue infections in patients presenting to emergency rooms in the United States (23). Community-origin MRSA with apparently enhanced virulence has emerged as the leading cause of serious skin infections arising in the community (23). The increasing importance of MRSA as a cause of cSSSIs has driven the need for the development of new agents with reliable activity against this pathogen. In particular, the development of a cephalosporin with a broad spectrum of activity that includes MRSA and that can be used to treat a range of serious polymicrobial infections began several years ago and has progressed to the point where one such agent, ceftobiprole, is now in late-stage clinical trials.Ceftobiprole, ...

Meta-analysis of Randomized Controlled Trials of Vancomycin for the Treatment of Patients With Gram-Positive Infections: Focus on the Study Design

“…a These numbers correspond to 2 different randomized controlled trials that were published as one in Clinical Infectious Diseases. 50 45 2005 Corey et al, 39 2010 D'Antonio et al, 55 2004 Florescu et al, 44 2008 Gilbert et al, 72 1991 Jaksic et al, 32 2006 Kureishi et al, 69 1991 Lin et al, 27 2008 Noel et al, 43 2008 Noel et al, 42 2008 Rolston et al, 66 1994 Rolston et al, 58 1999 Rubinstein et al, 38 2001 Rubinstein et al, 50 2011 (0015) …”

Pharmacodynamic Profiling of Ceftobiprole for Treatment of Complicated Skin and Skin Structure Infections

“…It has been assessed in clinical trials involving patients with complicated skin and skin structure infections (cSSSI), including those caused by methicillin-resistant Staphylococcus aureus (MRSA) (15,16). In one of these trials, which was conducted with patients with cSSSI due to gram-positive and/or gram-negative pathogens, ceftobiprole at 500 mg every 8 h administered as a 2-h infusion was statistically noninferior to a combination of vancomycin plus ceftazidime (15).…”

Vancomycin-Induced Nephrotoxicity

“…Finally, two 5 th generation cephalosporin prodrugs (ceftaroline fosamil and ceftobiprole medocaril) have been found to possess anti-MRSA activities. Ceftaroline has been shown to produce similar clinical cure rates as vancomycin in complicated skin and skin structure infections (Iizawa, Nagai et al 2004;Ge, Biek et al 2008), whereas ceftobiprole was found to show similar efficacy as vancomycin in suspected gram positive infections, diabetic foot and mixed bacterial complicated skin and skin structure infectons (Noel, Bush et al 2008 a;Noel, Strauss et al 2008;Noel, Strauss et al 2008 b). In summary, several newer antibiotics have been shown to provide a potential equally effective but less nephrotoxic alternative to vancomycin for deep-seated MRSA infections.…”