Ceftobiprole is currently in Phase 3 clinical trials for the treatment of hospital-acquired pneumonia, community-acquired pneumonia requiring hospitalization, and neutropenia and fever associated with chemotherapy administration. A Phase 2 clinical trial involving S. aureus bacteremia is also underway. Two Phase 3, multicenter, randomized clinical trials have been completed with ceftobiprole for the treatment of cSSSI.[42,43] In the first study, patients greater than 18 years of age were eligible if they were diagnosed with a cSSSI caused by suspected or verified gram-positive bacteria. cSSSI was defined as an infection involving subcutaneous tissue or requiring significant surgical intervention and one or more of the following: (1) surgical site infection within 30 days of surgery or trauma with purulent drainage or 3 or more signs of infection; (2) abscess for less than 7 days with purulent drainage or aspirate and evidence of loculated fluid, and erythema and/or induration of 20 mm or more in diameter; or (3) cellulitis for less than 7 days with advancing edema, erythema, or induration and one other sign of infection.
Patients were excluded if they had a cephalosporin or vancomycin allergy, Cl cr less than 30mL/min or oliguria less than 20 mL/h in response to fluid challenge, or alanine aminotransferase/aspartate aminotransferase levels 3 times the upper limit of normal. In addition, patients could not be pregnant or lactating, neutropenic, or HIV-infected with a CD4+ count less than 0.2 x 10 9 /L; have diabetic foot infections or infections associated with bites; or have received antimicrobial therapy for more than 24 hours in the previous 7 days.
Patients were randomized to receive either ceftobiprole 500mg intravenously over 60 minutes every 12 hours or vancomycin 1 g intravenously over 60 minutes every 12 hours (serum concentrations were adjusted based on local practices) for 7–14 days. All abscesses were incised and drained within 48 hours. Empiric therapy with aztreonam or metronidazole was allowed for the first 48 hours pending organism identification. Patients were evaluated at baseline and followed up on days 4, 8, and 14. Additional evaluations included end-of-therapy or within 24 hours of last treatment dose, test-of-cure, or 7–14 days after end-of-therapy, and late follow-up, or 28–35 days after end-of-therapy in patients clinically cured at test-of-cure visit.
The primary endpoint of this noninferiority study was clinical cure rate at the test-of-cure visit, where cure was resolution of infection or improvement not needing antimicrobial therapy. Noninferiority was defined as less than a 10% difference in the clinical cure rate. Secondary endpoints were microbiologic efficacy and safety.
Demographics were comparable between treatment groups, with the most common diagnosis being abscesses (48%). Approximately 80% of gram-positive isolates in the modified intent-to-treat and microbiologically evaluable groups were S. aureus. Of these, approximately 35% were MRSA. The second most common gram-positive isolate identified was Streptococcus pyogenes (~6%). MICs for MSSA in the modified intent-to-treat group were 0.5 µg/mL for ceftobiprole and 1 µg/mL for vancomycin. MICs for MRSA in the modified intent-to-treat group were 2 µg/mL for ceftobiprole and 1 µg/mL for vancomycin.
Clinical cure rates are found in Table 4 . Overall, the ceftobiprole group was noninferior to the vancomycin group for all populations identified (intent-to-treat, modified intent-to-treat, clinically evaluable, microbiologically evaluable). Of patients with only gram-negative isolates identified at baseline, more patients were cured in the ceftobiprole group than in the vancomycin group (75% vs 50%). Clinical cure rates were also similar for the MSSA and MRSA groups; however, ceftobiprole had a higher cure rate compared with vancomycin in MRSA isolates positive for Panton-Valentine leukocidin (93.1% vs 84.6%; NS).
The second study also focused on cSSSIs, but inclusion criteria were broadened to include diabetic foot infections. In addition, ceftobiprole was compared with vancomycin plus ceftazidime for possible gram-negative pathogens. Patients were greater than 18 years of age with a diagnosis of a cSSSI, defined as an infection involving subcutaneous tissue or requiring significant surgical intervention, and one or more of the following: (1–3) infections as outlined in aforementioned study in addition to (4) a foot infection, in diabetic patients, consisting of a full-thickness skin ulcer, cellulitis, myositis, or tendonitis with 3 or more other signs of infection. Infections involving both gram-negative and gram-positive pathogens were included. Specific exclusion criteria were allergy to antimicrobials used in the study, severe hepatic and renal impairment, and infections requiring longer treatment duration (ie, foreign body infection and osteomyelitis).
Patients were randomized (2:1) to receive intravenous infusions of ceftobiprole 500mg over 120 minutes every 8 hours and placebo over 60 minutes every 12 hours, or vancomycin 1 g over 60 minutes every 12 hours plus ceftazidime 1 g over 120 minutes every 8 hours for 7–14 days. Vancomycin dose was adjusted based on serum concentrations according to local practices. In addition, metronidazole was allowed for up to 48 hours. Final assessment occurred 7–14 days after end-of-therapy.
The primary endpoint was noninferiority of the ceftobiprole group compared with the vancomycin–ceftazidime group on clinical cure rates at the test-of-cure visit of clinically evaluable and intent-to-treat populations. Secondary endpoints were microbiologic efficacy of the microbiologically evaluable population and safety utilizing the intent-to-treat group. Noninferiority was determined if the lower limit of the 95% confidence interval of the treatment difference was –10% or more.
Of the 828 patients enrolled, 547 were allocated to the ceftobiprole group and 281 to the vancomycin–ceftazidime group. Baseline characteristics were similar between groups. The most common infection types were diabetic foot (31%) and abscesses (30%), and S. aureus was the most common bacteria isolated, at approximately 63% of total isolates. Twenty-eight percent of the isolates were gram-negative pathogens. Of these isolates, E. coli was more common in the vancomycin–ceftazidime group (45% vs 36%), whereas P. aeruginosa was more common in the ceftobiprole group (29% vs 16%).
Results of this study are shown in Table 4 . In summary, clinical cure rates, microbiologic eradication rates, and adverse events were similar between ceftobiprole-treated patients compared with vancomycin plus ceftazidime–treated patients. Noninferiority of ceftobiprole was demonstrated in all endpoints. Although the results were nonsignificant, ceftobiprole-treated patients had higher clinical cure rates in diabetic foot infections and cellulitis, but lower cure rates for wound or abscesses compared with vancomycin plus ceftazidime–treated patients. In addition, the ceftobiprole group had nonsignificantly higher cure rates for MRSA infections, but lower cure rates for gram-negative infections compared with the vancomycin plus ceftazidime group.
In summary, ceftobiprole appears to be equivalent in efficacy and safety to vancomycin in treatment of cSSSI involving gram-positive pathogens or vancomycin plus ceftazidime when gram-positive and gram-negative organisms are the source of infection. Limitations of these studies include the exclusion of patients with renal and hepatic impairment and of those with more severe infections requiring longer treatment. We await the results of other Phase 3 clinical trials for the treatment of hospital-acquired pneumonia, community-acquired pneumonia, and chemotherapy-induced neutropenia and fever.
The Annals of Pharmacotherapy. 2008;42(6):806-816. © 2008 Harvey Whitney Books Company
Cite this: Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin - Medscape - Jun 01, 2008.