ceftobiprole-medocaril and Staphylococcal-Skin-Infections

Ceftobiprole medocaril is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received an approvable letter from the United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftobiprole exerts its antibacterial activity by inhibiting the penicillin-binding proteins (PBPs) involved in cell wall synthesis. It has an established stability against hydrolysis by many gram-positive beta-lactamases and a higher affinity for various PBPs (such as PBP2a of MRSA or PBP2x of Streptococcus pneumoniae), which leads to a wider spectrum of activity compared with older beta-lactams. Ceftobiprole activity does not cover extended-spectrum beta-lactamase-producing Enterobacteriaceae and some other pathogens, including Enterococcus faecium or Acinetobacter baumanii. Generally well tolerated, with nausea and taste disturbance being the most common adverse events, ceftobiprole appeared noninferior to empiric therapy in several clinical trials. Ceftobiprole is available only for intravenous administration; recommended dosage regimens have not been approved by the FDA as of this writing. However, based on the Canadian package insert, expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of complicated skin and skin structure infections caused by certain gram-positive pathogens, and 500 mg as a 2-hour infusion every 8 hours when susceptible gram-negative or both gram-positive and susceptible gram-negative pathogens are involved. Dosage adjustments are indicated for patients with moderate or severe renal impairment, and dosage recommendations are expected to be 500 or 250 mg, respectively, as a 2-hour infusion every 12 hours. Several precautions regarding hypersensitivity and drug incompatibility are reported. Ceftobiprole represents a promising option for the treatment of mono- and polymicrobial infections caused by multidrug-resistant gram-positive and susceptible gram-negative pathogens, but further toxicity and safety studies are warranted.

Topics: Animals; Cephalosporins; Clinical Trials as Topic; Disease Models, Animal; Drug Interactions; Drug Resistance, Bacterial; Drug Synergism; Humans; Methicillin-Resistant Staphylococcus aureus; Staphylococcal Skin Infections; Time Factors

Ceftobiprole medocaril [BAL 5788, RO 65-5788, JNJ 30982081] is a prodrug in phase III clinical development with Basilea Pharmaceutica and Cilag AG (Johnson & Johnson) for the potential treatment of serious bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole medocaril is the water-soluble prodrug of the pyrrolidinone cephalosporin, ceftobiprole [BAL 9141, RO 63-9141]. Because of the low water solubility of ceftobiprole, its clinical application was limited and Basilea began its investigations into ceftobiprole medocaril for further development. Ceftobiprole medocaril is being developed for IV administration and is currently undergoing phase III trials for complicated skin and skin structure infections (including MRSA) and hospital-acquired (nosocomial) pneumonia. Ceftobiprole medocaril has a broad spectrum of activity against Gram-positive bacteria (including methicillin-resistant staphylococci, penicillin-resistant pneumococci and Enterococcus faecalis) and Gram-negative bacteria. Ceftobiprole medocaril inhibits all transpeptidases, including the penicillin-binding protein (PBP) 2a, by a unique combination of features. PBP 2a is the primary enzyme responsible for beta-lactam drug resistance in MRSA; PBP 2a also acts as a key defense mechanism by interacting with the bacterial cell wall to form a chemical barricade that is impervious to antibiotics. Ceftobiprole medocaril has been designed specifically to bind to this penicillin-resistant target. Ceftobiprole medocaril is bactericidal and has not shown resistance development in vitro or in stringent animal models. Studies conducted by Basilea have demonstrated that ceftobiprole medocaril is readily converted to ceftobiprole, and shows markedly improved water solubility. In February 2005, Basilea Pharmaceutica AG entered into an exclusive worldwide agreement with Cilag AG International (Johnson & Johnson) to develop, manufacture and market ceftobiprole medocaril. Ortho-McNeil Pharmaceutical (Johnson & Johnson) will market ceftobiprole medocaril in the US, and its affiliate companies, known as Janssen-Cilag, will market the product outside the US (entered as World in the Licensee table). Basilea has retained an option to co-promote ceftobiprole medocaril in the US, major European countries, Japan and China. Johnson & Johnson Pharmaceutical Research and Development LLC will develop ceftobiprole medocaril in collaboration with Basilea. Roche previously retained an o

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Clinical Trials, Phase III as Topic; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Staphylococcal Skin Infections; Staphylococcus aureus