Ceftobiprole Research Articles

Ceftobiprole medocaril (BAL5788) treatment of experimental Haemophilus influenzae, Enterobacter cloacae, and Klebsiella pneumoniae murine pneumonia

Ceftobiprole (BAL9141) is an investigational cephalosporin active against methicillin- and vancomycin-resistant staphylococci administered as a water-soluble prodrug, ceftobiprole medocaril (BAL5788). Using an immunocompetent murine pneumonia model of Haemophilus influenzae, Enterobacter cloacae, or extended-spectrum β-lactamase (ESBL) nonproducing or producing Klebsiella pneumoniae pneumonia, we compared results of treatment with ceftobiprole medocaril (71 mg/kg, sc, qid), ceftriaxone (50 mg/kg, im, bid), or cefepime (50 mg/kg, ip, q.i.d.). Results were expressed as median and 25th to 75th percentile log 10 colony forming units per gram of lung tissue. Ceftobiprole, ceftriaxone, and cefepime were each more active than was no treatment and were equally active for treatment of experimental H. influenzae, E. cloacae, or ESBL-nonproducing K. pneumoniae pneumonia. For ESBL-producing K. pneumoniae, no differences were detected between no treatment and treatment with ceftobiprole, ceftriaxone, or cefepime. Ceftobiprole is active against H. influenzae, E. cloacae, and ESBL-nonproducing K. pneumoniae in an immunocompetent experimental murine pneumonia model.

The cephalosporin ceftobiprole medocaril* is effective against Staphylococcus aureus infections and is non-inferior to vancomycin,

The cephalosporin ceftobiprole medocaril* is effective against Staphylococcus aureus infections and is non-inferior to vancomycin,

Ceftobiprole Medocaril

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 opt-in right on ceftobiprole medocaril. However, following Roche's decision not to exercise this right in May 2004, Basilea gained full global commercialisation rights for ceftobiprole medocaril. Roche retains its major shareholding in Basilea. Ceftobiprole medocaril is currently in phase III trials for complicated skin and skin structure infections due to MRSA, and nosocomial pneumonia (including ventilator-associated pneumonia) due to suspected or proven MRSA, and community-acquired pneumonia. The US FDA has granted fast-track status to the compound for these two indications. Phase III results are expected in 2006 and an NDA is expected to be submitted to the FDA in 2007. An additional pivotal phase III trial (STRAUSS 2, STudy of Resistant Staphyloccocus aureus in Skin and Skin structure infections) of ceftobiprole medocaril was initiated in October 2005 for complicated skin infections, including diabetic foot infections. This trial will be conducted in conjunction with Johnson & Johnson Pharmaceutical Research and Development.

Antistaphylococcal Activity of Ceftobiprole, a New Broad-Spectrum Cephalosporin

Ceftobiprole (formerly BAL9141), the active component of the prodrug BAL5788 (ceftobiprole medocaril), is a novel cephalosporin with expanded activity against gram-positive bacteria. Among 152 Staphylococcus aureus isolates, including 5 vancomycin-intermediate and 2 vancomycin-resistant strains, MIC(50) and MIC(90) values for ceftobiprole were each 0.5 microg/ml against methicillin-susceptible strains and 2 mug/ml against methicillin-resistant strains. Against 151 coagulase-negative staphylococci (including 4 vancomycin-intermediate strains), MIC(50) and MIC(90) values were, respectively, 0.125 microg/ml and 1 microg/ml against methicillin-susceptible and 1 microg/ml and 2 microg/ml against methicillin-resistant strains. Teicoplanin was less active than vancomycin against coagulase-negative strains. Linezolid, quinupristin-dalfopristin, and daptomycin were active against all strains, whereas increased MICs for amoxicillin-clavulanate, cefazolin, minocycline, gentamicin, trimethoprim-sulfamethoxazole, levofloxacin, rifampin, mupirocin, fusidic acid, and fosfomycin were sometimes observed. At 2x MIC, ceftobiprole was bactericidal against 11 of 12 test strains by 24 h. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to select for clones with MICs >4 times those of the parents; the maximum MIC achieved for ceftobiprole after 50 passages (in 1 of 10 strains) was 8 mug/ml. Single-passage selections showed very low frequencies of resistance to ceftobiprole irrespective of genotype or phenotype; the maximal ceftobiprole MIC of recovered clones was 8 mug/ml.

Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant Staphylococcus aureus

The therapeutic activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was compared to that of vancomycin in a rat tissue cage model of chronic methicillin-resistant Staphylococcus aureus (MRSA) foreign-body infection. The MICs and MBCs of ceftobiprole and vancomycin in Mueller-Hinton broth for strain MRGR3 were 1 and 4 and 1 and 2 microg/ml, respectively. In vitro elimination rates of strain MRGR3 of 4 and 8 microg/ml of ceftobiprole or vancomycin were equivalent. After 2 weeks of infection, mean +/- standard error of the mean viable counts of strain MRGR3 were 6.83 +/- 0.11 log CFU/ml of tissue cage fluid (n = 87). High-dose regimens of ceftobiprole medocaril (equivalent to 150 mg/kg of ceftobiprole) or 50 mg/kg vancomycin produced nearly identical average peak and trough levels of ceftobiprole and vancomycin in tissue cage fluid, which exceeded the MBC of either antibiotic towards strain MRGR3 for > or =75% of each dosing interval. After 7 days of therapy with ceftobiprole medocaril or vancomycin, average counts of MRGR3 decreased significantly (P < 0.02) by 0.68 +/- 0.28 (n = 29) and 0.88 +/- 0.22 (n = 28) log CFU/ml of tissue cage fluid, respectively, compared with cages of untreated animals, but were not significantly different from each other. No resistant mutants were detected on ceftobiprole-supplemented agar following therapy with this cephalosporin. The in vivo activity of ceftobiprole medocaril against chronic MRSA foreign-body infections was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations.

Ceftobiprole/Ceftobiprole medocaril

Over the past decade, resistance to antimicrobials has increased dramatically and is limiting the therapeutic options for the treatment and management of serious bacterial infections. Cephalosporins are commonly used to treat bacterial infections due to their broad spectrum of activity and low toxicity. However, the incidence of cephalosporin-resistant strains is increasing, thus decreasing the routine use of these agents. Researchers have focused on developing novel (3-lactam antibiotics which are active against resistant bacteria. One particular novel agent is ceftobiprole, which is the first of a new class of parenteral cephem antibiotics. This fourth-generation cephalosporin was designed to have strong affinity for penicillin-binding proteins conferring resistance in staphylococci, pneumococci and other Gram-positive and Gram-negative pathogens, and was shown to have broad-spectrum efficacy and a low propensity to induce resistance in vitro. Ceftobiprole is administered in vivo as the water-soluble prodrug ceftobiprole medocaril, which is rapidly cleaved in plasma to form ceftobiprole. Ceftobiprole medocaril exhibited potent efficacy in animal infection models and proved safe and effective in a phase II trial in patients with complicated skin and skin structure infections. Ceftobiprole medocaril has advanced to phase III development for the treatment of bacterial infections, particularly those caused by methicillin-resistant Staphylococcus aureus (MRSA).