ceftobiprole-medocaril and Disease-Models--Animal

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

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

Ceftobiprole medocaril, a new cephalosporin, is highly active against a broad spectrum of Gram-positive and Gram-negative clinical pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant pneumococci. In this study, we tested ceftobiprole against various Gram-negative pathogens in a rabbit meningitis model and determined its penetration into the cerebrospinal fluid (CSF). In this animal model, ceftobiprole produced an antibacterial activity similar to that of cefepime against an Escherichia coli strain, a Klebsiella pneumoniae strain, and a β-lactamase-negative Haemophilus influenzae strain. Against a β-lactamase-positive H. influenzae strain, ceftobiprole was significantly superior. The penetration of ceftobiprole through inflamed meninges reached about 16% of serum levels compared to about 2% of serum levels through uninflamed meninges.

Topics: Animals; Anti-Bacterial Agents; beta-Lactamases; Cephalosporins; Disease Models, Animal; Escherichia coli; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Haemophilus influenzae; Klebsiella pneumoniae; Meningitis, Bacterial; Microbial Sensitivity Tests; Rabbits; Treatment Outcome

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