ceftobiprole-medocaril and Staphylococcal-Infections

Methicillin-resistant Staphylococcus aureus (MRSA), both hospital-acquired and community-acquired, is a dangerous pathogen that is involved in an increasing number of serious infections with high risk for morbidity and mortality. Community-acquired MRSA strains have epidemic potential and can be particularly virulent. Vancomycin has been the standard hospital treatment for the past 40 years, but vancomycin-resistant isolates of S. aureus have emerged in the USA, and vancomycin-intermediate isolates are increasingly being reported worldwide. New antimicrobial agents with activity against multidrug-resistant S. aureus and other resistant pathogens are urgently needed. Despite great strides, further advances in our understanding of the molecular and biochemical mechanisms responsible for antimicrobial resistance are still required. Several agents have been recently approved for the treatment of serious Gram-positive infections, including linezolid, daptomycin, and tigecycline. The novel investigational cephalosporin, ceftobiprole, is one of the first penicillinase-resistant agents to target penicillin-binding protein 2a (or PBP2a), an acquired PBP with low beta-lactam-affinity that confers intrinsic beta-lactam resistance to S. aureus and other staphylococci. This mechanism of PBP binding, including inhibition of PBP2a, confers broad-spectrum activity against clinically important Gram-negative and Gram-positive pathogens, including MRSA. Phase III clinical trials comparing ceftobiprole with vancomycin alone and in combination with ceftazidime for the treatment of complicated skin and skin structure infections showed ceftobiprole to have efficacy similar to the efficacy of these comparators as evidenced by non-inferior clinical cure and microbiological eradication rates.

Topics: Adult; Anti-Bacterial Agents; Cephalosporins; Clinical Trials, Phase III as Topic; Cross Infection; Humans; Methicillin Resistance; Microbial Sensitivity Tests; Penicillin-Binding Proteins; Staphylococcal Infections; Staphylococcus aureus

Methicillin-resistant Staphylococcus aureus (MRSA) mediastinitis after median sternotomy is a major complication of cardiac surgery with significant morbidity and mortality rates. We evaluated the efficacy of ceftobiprole medocaril in a new rat model of mediastinitis and compared it to vancomycin. The model was induced in 92 rats. Infection was induced immediately after median sternotomy by the injection of MRSA (strain 3020, 1 × 10(7) cfu/rat) into the sternal bone. After 24 h, rats (groups of 6-8) were treated intraperitoneally for 5 days or 14 days by either: (i) saline (control, q8h), (ii) ceftobiprole medocaril (70 or 100 mg/kg, q8h), or (iii) vancomycin (50 mg/kg, q12h). Efficacy was determined by a reduction in bacterial cfu in the sternum and spleen tissues. Comparisons were performed using the Mann-Whitney test. A 5-day treatment course of ceftobiprole at both doses tested lead to a significant reduction in MRSA load in the sternum (p < 0.01) as compared to the control group and compared to 5-day vancomycin treatment, which lead to a non-significant reduction (p = 0.07). Longer treatment (14 days) with ceftobiprole lead to a complete clearance of MRSA from the sternum, similarly to vancomycin. Ceftobiprole also showed a significant effect on eliminating MRSA dissemination to the spleen compared to saline-treated rats. Ceftobiprole was effective in treating MRSA mediastinitis in the rat model. In the 5-day course, ceftobiprole showed a significant reduction in sternal MRSA counts and was superior to vancomycin. After 14 days, both ceftobiprole and vancomycin showed clearance of MRSA from the sternum in more than 50 % of rats and almost complete clearance in the remainder.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Disease Models, Animal; Male; Mediastinitis; Methicillin-Resistant Staphylococcus aureus; Rats; Staphylococcal Infections; Sternum

The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, >64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log(10) CFU/g MRSA or 6 log(10) CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Daptomycin; Drug Dosage Calculations; Drug Synergism; Endocarditis, Bacterial; Female; Humans; Injections, Intravenous; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

The pharmacokinetics and distribution into bone tissue of ceftobiprole in uninfected New Zealand White rabbits were determined after subcutaneous administration of the prodrug ceftobiprole medocaril. Serum exposure (maximum concentration of the drug in serum, trough concentration, area under the concentration-time curve) to ceftobiprole at 20 and 80 mg/kg was dose proportional, and there was no accumulation of ceftobiprole following repeated (every 6 h [q6h]) injections of the antibiotic. Ceftobiprole titers in the tibial matrix and marrow were 3.2 +/- 1.3 microg/g and 11.2 +/- 6.5 microg/g, respectively, in uninfected animals treated with 20 mg/kg of the antibiotic and 13.4 +/- 7.3 microg/g and 66.3 +/- 43.2 microg/g, respectively, in uninfected animals treated with 80 mg/kg of the antibiotic. No differences in ceftobiprole titers were observed between right and left tibiae for either bone matrix or marrow. The efficacies of 4 weeks of treatment with ceftobiprole (40 mg/kg administered subcutaneously [s.c.] q6h), vancomycin (30 mg/kg administered s.c. q12h), or linezolid (60 mg/kg administered orally q8h) were compared, using a rabbit model of methicillin-resistant Staphylococcus aureus tibial osteomyelitis. After treatment with ceftobiprole, the bacterial titers in all infected left tibiae from evaluable rabbits were below the level of detection, whereas only 73% of infected left tibiae from vancomycin- or linezolid-treated animals had bacterial titers below the level of detection; the mean titers of ceftobiprole were 3 to 5 times higher in infected left tibiae than in uninfected right tibiae. These results indicate that ceftobiprole provided effective parenteral treatment of osteomyelitis in this rabbit model.

Topics: Animals; Body Weight; Cephalosporins; Disease Models, Animal; Methicillin Resistance; Microbial Sensitivity Tests; Osteomyelitis; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Tibia

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.

Topics: Animals; Cephalosporins; Foreign Bodies; Methicillin Resistance; Microbial Sensitivity Tests; Mutation; Rats; Rats, Wistar; Staphylococcal Infections; Staphylococcus aureus; Vancomycin