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

Abstract

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin (meticillin)-resistant staphylococci, was statistically noninferior to a combination of vancomycin plus ceftazidime in patients with complicated skin and skin structure infections (cSSSI). This analysis used data from this clinical trial to determine the relationship between therapeutic outcome and the percentage of time that the unbound ceftobiprole concentration exceeds the MIC (percent T>MIC). From the trial of ceftobiprole (500 mg every 8 h, 2-h infusion) for cSSSI due to gram-positive and/or gram-negative bacteria, data from 309 patients in the microbiological intent-to-treat analysis set with measured ceftobiprole concentrations and baseline MICs were used to assess the relationship between percent T>MIC and therapeutic outcome. Individual pharmacokinetic (PK) profiles were obtained from a three-compartment population PK model. The relationship between percent T>MIC and a clinical cure was determined. For the clinical trial dosing regimen, individual percent T>MICs were used to calculate fractional target attainment rates (TARs) for >30 and >50% T>MIC targets at various MICs. There was a statistically significant relationship between achieving a >30 or >50% T>MIC and a clinical cure (P ‫؍‬ 0.003 and P ‫؍‬ 0.007, respectively; Pearson's 2 test). The fractional TAR was greater than 90% at a MIC of <4 mg/liter for patients with normal renal function. A relationship between percent T>MIC and a clinical cure with ceftobiprole was demonstrated. A ceftobiprole regimen of 500 mg every 8 h as a 2-h infusion has a high probability of achieving a target of >30 or >50% T>MIC for patients with cSSSI due to gram-positive and gram-negative pathogens.

Monte Carlo simulation analysis of ceftobiprole, dalbavancin, daptomycin, tigecycline, linezolid and vancomycin pharmacodynamics against intensive care unit‐isolated methicillin‐resistant Staphylococcus aureus

“…In contrast, ceftobiprole and dalbavancin were superior to all investigated agents and had 100% likelihood of target attainment. This corroborates the results of other clinical and pharmacodynamic studies that showed the therapeutic value of these two agents …”

Exposure to Ceftobiprole Is Associated with Microbiological Eradication and Clinical Cure in Patients with Nosocomial Pneumonia

“…Similar to the exposure-response relationship found for other antimicrobials (6,7,16,17), the relationship found here indicates that optimal exposure increases the likelihood of microbiological eradication. In patients with insufficient exposure to ceftobiprole, the probability of microbiological eradication is approximately 44%, whereas the probability of microbiological eradication in patients with an exposure of 100% is 91%.…”

Pharmacokinetics and Target Attainment of Ceftobiprole in Asian and Non‐Asian Subjects

“…Observed target attainment rates for Asian (n = 47) and non-Asian (n = 152) subjects for targets of concentrations above the MIC, ranging from 40%-100% of the dosing interval. 16 We therefore calculated the exposure for fT >MIC to be 30%-100% and concluded that for all these different targets, the exposure in the 2 subgroups was comparable. and in human data.…”