Ceftobiprole, a Broad-Spectrum Cephalosporin With Activity against Methicillin-Resistant Staphylococcus aureus (MRSA).

Abstract

The introduction of methicillin in 1959 was a ground-breaking achievement in the war against penicillin-resistant Staphylococcus aureus. Methicillin was developed to overcome the primary mode of resistance found with resistant strains of S. aureus, inactivation of penicillin by beta-lactamase. In 1961, this monumental achievement was overshadowed by the discovery of several strains of S. aureus in the United Kingdom, which had developed resistance to methicillin (methicillin-resistant S. aureus [MRSA]). MRSA was subsequently isolated throughout the world and, in addition to causing hospital-acquired infections, has now spread to the community. With this resistance mechanism, MRSA has proved to be resistant to all subsequent beta-lactam molecules developed over the past several decades. Ceftobiprole, a new-generation cephalosporin, is the first beta-lactam agent to demonstrate potent in vitro and in vivo activity against MRSA. MRSA is a major cause of hospital and community-acquired infections worldwide and a major cause of morbidity and mortality. Klein et al. determined that from 1999 to 2005, the estimated number of hospitalizations involving S. aureus infections increased by 62% (from 294,570 to 477,927), with MRSA-related infections more than doubling during this same period (from 127,036 to 278,203).1 In 2005, approximately 94,360 patients in the U.S. developed a serious MRSA infection, with 18,650 deaths (20%) related to the hospital stay.2 Of these severe MRSA infections, 85% were associated with health care exposure and one-third occurred during hospitalization. Methicillin resistance is conferred by a penicillin-binding protein (PBP) that is encoded by the mecA gene found in the staphylococcal cassette chromosome mec (SCCmec).3–5 These mobile genetic elements may carry additional genetic material that encode resistance to other classes of antimicrobials. Penicillin resistance in Streptococcus pneumoniae is mediated through a similar adaptive mechanism by the bacteria. Alterations of PBP 2 to PBP 2x by S. pneumoniae may lead to a decrease in activity of penicillin, necessitating higher doses to achieve adequate activity, or may prevent the binding altogether (penicillin-resistant S. pneumoniae [PRSP]). Ceftobiprole (BAL 9141) is the first of a new generation of extended-spectrum cephalosporins with activity against clinically important gram-positive bacteria, including MRSA, PRSP, and Enterococcus faecalis.6–10 If approved, ceftobiprole would become the only cephalosporin with established activity against E. faecalis and MRSA. The drug has shown activity against clinically important gram-negative pathogens, including Citrobacter spp., Escherichia coli, Enterobacter spp., Klebsiella spp., Serratia marcescens, and Pseudomonas aeruginosa. The limited number of approved drugs with activity against multidrug-resistant bacteria such as MRSA and P. aeruginosa has increased the demand for new agents with a novel mechanism of action or an ability to overcome bacterial resistance. Ceftobiprole is a broad-spectrum cephalosporin with additional properties that circumvent many of the mechanisms of resistance to beta-lactams. Ceftobiprole has been evaluated in phase 3 trials for treating complicated skin and soft-tissue infections (cSSSIs) caused by gram-positive and gram-negative bacteria. Recent studies examining the use of ceftobiprole for the treatment of community-associated and hospital-associated pneumonia have also been completed but have been published only in abstract form.