Pharmacy & Therapeutics - November 2008 - (Page 639)

DRUG FORECAST continued from page 634 Infections of the fascial plane or muscle (36%) and the number of patients undergoing surgical debridement (39%) as part of initial therapy were similar in both groups. Ninety-two percent of the ceftobiprole patients and 90% of the vancomycin/ceftazidime patients completed the trial. The clinically evaluable population consisted of 729 patients. Clinical outcomes were evaluated at the TOC visit for 485 (89%) patients receiving ceftobiprole group and 244 (87%) receiving vancomycin/ceftazidime. For the primary outcome of clinical cure rates in the ITT and CE populations, ceftobiprole was considered non-inferior to vancomycin/ceftazidime at the TOC visit (7 to 14 days after therapy). Clinical cure rates in the ceftobiprole and vancomycin/ceftazidime groups were similar in the ITT group (81.9% vs. 80.8%; CI, –4.5% to 6.7%) and in the clinically evaluable group (90.5% vs. 90.2%; CI –4.2% to 4.9%). There were no significant differences in clinical cure rate or microbiologic eradication based on the type of infection. Diabetic foot infection was the most common diagnosis in 31% of patients in the ceftobiprole group and in 32% of those receiving vancomycin/ ceftazidime. Response rates were 86.2% for the ceftobiprole patients and 81.8% for the other group (CI, –5.4% to 15.7%). For the secondary outcome, the microbiologically evaluable population consisted of 590 patients in the clinically evaluable group with microbiologic data available—391 patients (71%) received ceftobiprole, and 199 (71%) received vancomycin/ceftazidime. Clinical cure and microbiological eradication rates at the TOC visit were similar in the microbiologically evaluable population for both gram-positive and gram-negative infections. In most patients (53%), infections had been caused by gram-positive pathogens, and more than 64% of pathogens in the microbiologically evaluable population were S. aureus. Of those, only 32.8% of the isolates were methicillin-resistant. Of the 12 patients in the ceftobiprole group with P. aeruginosa isolated as the only pathogen, three patients (25%) failed to respond to therapy; all of the isolates from these three patients demonstrated an MIC of 8 mcg/mL or more. All nine vancomycin/ceftazidime patients with P. aeruginosa infection achieved clinical cure at the TOC visit. Pneumonia Trials27–30 Phase 3 trials demonstrating the clinical efficacy of ceftobiprole for the treatment of community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) have been completed. Preliminary data from one randomized, double-blind, multicenter study demonstrated the noninferiority of ceftobiprole when compared with ceftriaxone (Rocephin, Roche) with or without the addition of linezolid, for hospitalized patients with CAP.27,28 Investigators enrolled 666 patients into the study (328 patients in the ceftobiprole arm and 338 patients in the comparator arm). Patients were stratified before randomization according to Pneumonia Outcomes Research Team (PORT) Severity Index scores and the need for linezolid in patients with proven or suspected MRSA or ceftriaxone-resistant S. pneumoniae. Non-inferiority was defined in both the clinically evaluable and ITT populations as a difference of 10% in the cure rate between treatment groups. The primar y outcome clinical cure rate at the TOC visit (7 to 14 days after therapy) for the clinically evaluable population was 86.7% for ceftobiprole and 87.6% for the comparator drug. Clinical cure rates in the ITT population were 77.4% with ceftobiprole and 80.2% with the comparator agent. Microbiologic eradication rates in both groups were also similar: 88% with ceftobiprole and 92% with the comparator drug. Patients with S. pneumoniae infection had comparable cure rates in each arm: 90% with ceftobiprole and 89% with the comparator drug; however, the authors did not report rates of penicillinresistant S. pneumoniae (PRSP). In patients with baseline PORT scores above 90, clinical cure rates were 90.2% for the clinically evaluable ceftobiprole patients and 84.5% for the comparator arm (95% CI, –6.7 to 18.1). Details of the study, including inclusion and exclusion criteria, dose, length of therapy, and differences between the groups, have not yet been published. The preliminary results of a phase 3 trial in patients with hospital-acquired pneumonia showed the non-inferiority of ceftobiprole versus ceftazidime/linezolid for the primary outcome;29,30 primary outcome clinical cure rates at the TOC visit (7 to 14 days after therapy) for the clinically evaluable population were 69% and 72%, respectively. In the subgroup of patients with ventilator-associated pneumonia (25% of patients), non-inferiority could not be established, because clinical cure rates were lower with ceftobiprole than with the comparator drug. Details of the study, including inclusion and exclusion criteria, dose, duration of therapy, and differences between the groups, have not been published. A subgroup analysis will probably be performed to determine potential differences in the patients with ventilator-associated pneumonia that might have led to the decreased response. ADVERSE DRUG REACTIONS Ceftobiprole is as tolerable and safe as other agents used for the treatment of cSSSIs, including vancomycin and ceftazidime.24,26 The pooled analysis from STRAUSS 1 and 2 showed similar adverse events reported for both ceftobiprole and the comparator. At least one adverse event was reported in more than 50% of patients in both studies, and most events were considered mild or moderate in intensity. Adverse events leading to discontinuation of the study drugs were similar in both trials. The most common adverse reactions in clinical trials included gastrointestinal effects (nausea, vomiting, diarrhea), dysgeusia (sense of distor ted taste), headache, and infusion-site reactions (Table 2). These events occurred with similar frequency in both treatment groups. DRUG INTERACTIONS The potential for clinically significant drug interactions with ceftobiprole is considered low because of its favorable pharmacokinetic profile. To date, no published studies have indicated a clinically significant drug interaction that would call for dose adjustments or discontinuation of therapy. Like all antimicrobial agents, ceftobiprole has the potential to decrease the effectiveness of oral contraceptives. Coadministration of warfarin (Coumadin, Bristol-Myers Squibb) with ceftobiprole sometimes causes an increased prothrombin time and an International Normalized Ratio (INR). Compatibility data for the coadministration of other medications with ceftobiprole, however, have not been published. Vol. 33 No. 11 • November 2008 • P&T® 639

Table of Contents Feed for the Digital Edition of Pharmacy & Therapeutics - November 2008

Pharmacy & Therapeutics - November 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Heparin-Induced Thrombocytopenia Medication Utilization Patterns and Hypertension-Related Expenditures among Patients Who Were Switched From Fixed-Dose to Free-Combination Antihypertensive Therapy European Society for Medical Oncology and Association for the Study of Bone and Mineral Research Pharmaceutical Approval Update

Pharmacy & Therapeutics - November 2008

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