Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

Shawn D Anderson, PharmD; John G Gums, PharmD, FCCP

Disclosures

The Annals of Pharmacotherapy. 2008;42(6):806-816. 

In This Article

Unanswered Questions

Since ceftobiprole is not yet approved, questions remain. In pharmacokinetic studies, ceftobiprole medocaril was diluted to 200 mL in 5% dextrose.[33,34] It is unknown whether the drug will need to be reconstituted or whether diluents other than dextrose are compatible. In addition, stability after reconstitution or need for refrigeration is not known. As infusion was the only method of administration in clinical trials, options for other routes of administration (eg, intramuscular) have not been evaluated.

Two dosing regimens were used in clinical trials based on presumed pathogens in cSSSIs. In the latter clinical trial, a 2-hour infusion was utilized to maximize pharmacodynamic targets. A 2-hour infusion may complicate the administration of ceftobiprole with other intravenous medications. This may become problematic if Phase 3 clinical trials are positive for community-acquired and nosocomial pneumonia where combination therapy is the standard of care. In the Monte Carlo simulation by Mouton et al.,[40] estimated ceftobiprole serum concentrations for additional dose and interval combinations were analyzed and presented in figure format. Unfortunately, TARs were not calculated for these combinations. As administration of ceftobiprole may create confusion and complicate administration, additional dosing schemes need to be explored.

Because ceftobiprole is a broad-spectrum antimicrobial, resistance induction and "collateral damage" are of concern. Although ceftobiprole was not shown to induce resistance in clinical trials, numerous abstracts demonstrate that low- and high-level ceftobiprole resistance develops when isolates are exposed to sub-MIC concentrations.[44,45,46,47,48] No correlation has been identified between baseline MIC and development of resistance in staphylococci.[45] Clinical trial data indicate that cure rates against P. aeruginosa infections are lower than in ceftazidime-treated patients. Although MICs were not reported in the ceftazidime group, ceftobiprole was effective against P. aeruginosa infections, with MICs 4 µg/mL or less. This suggests that optimizing pharmacodynamic parameters for MICs 8 µg/mL or more may increase activity against P. aeruginosa; however, the safety and tolerability of these regimens have not been evaluated. Comparing efficacy between antipseudomonal agents other than ceftazidime is difficult, as these data include in vitro and animal models. If ceftobiprole is used as an antipseudomonal cephalosporin, concern for resistance induction is real and limitations on widespread use must be considered. Overuse of ceftobiprole may also increase resistance in Enterobacteriaceae, particularly E. coli and K. pneumoniae, and may increase the rate of VRE colonization and C. difficile infection. As such, judicious use and proper monitoring of ceftobiprole will be necessary.

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