ceftobiprole and Pseudomonas-Infections

Current antibiotics available for the treatment of healthcare-associated pneumonia (HCAP) may result in clinical failure due to resistance development, side effect intolerance, or poor pharmacokinetic-pharmacodynamic profiles. New agents active against common HCAP pathogens are needed. The mechanism of action, spectrum of activity, pharmacokinetics, adverse effects, and clinical efficacy of seven new agents in clinical development or recently approved with either methicillin-resistant Staphylococcus aureus (MRSA) or pseudomonal activity are reviewed. They include doripenem, a new antipseudomonal carbapenem; ceftobiprole and ceftaroline, two anti-MRSA cephalosporins; iclaprim, a selective dihydrofolate reductase antagonist; and three glycopeptides, dalbavancin, telavancin, and oritavancin.

Topics: Aminoglycosides; Anti-Bacterial Agents; Carbapenems; Ceftaroline; Cephalosporins; Cross Infection; Doripenem; Glycopeptides; Lipoglycopeptides; Methicillin-Resistant Staphylococcus aureus; Pneumonia, Bacterial; Pseudomonas Infections; Pyrimidines; Staphylococcal Infections; Teicoplanin

Ceftobiprole, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) (P. Hebeisen et al., Antimicrob. Agents Chemother. 45:825-836, 2001), was evaluated in a subcutaneous skin infection model with Staphylococcus aureus Smith OC 4172 (methicillin-susceptible S. aureus [MSSA]), S. aureus OC 8525 (MRSA), Pseudomonas aeruginosa OC 4351 (having an inducible AmpC beta-lactamase), and P. aeruginosa OC 4354 (overproducing AmpC beta-lactamase). In the MSSA and MRSA infection models, ceftobiprole, administered as the prodrug ceftobiprole medocaril, was more effective in reducing CFU/g skin (P < 0.001) than were cefazolin, vancomycin, or linezolid based on the dose-response profiles. Skin lesion volumes in MSSA-infected animals treated with ceftobiprole were 19 to 29% lower than those for cefazolin-, vancomycin-, or linezolid-treated animals (P < 0.001). In MRSA infections, lesion size in ceftobiprole-treated mice was 34% less than that with cefazolin or linezolid treatment (P < 0.001). Against P. aeruginosa, ceftobiprole at similar doses was as effective as meropenem-cilastatin in reductions of CFU/g skin, despite 8- and 32-fold-lower MICs for meropenem; both treatments were more effective than was cefepime (P < 0.001) against the inducible and overproducing AmpC beta-lactamase strains of P. aeruginosa. Ceftobiprole was similar to meropenem-cilastatin and 47 to 54% more effective than cefepime (P < 0.01) in reducing the size of the lesion caused by either strain of P. aeruginosa in this study. These studies indicate that ceftobiprole is effective in reducing both bacterial load and lesion volume associated with infections due to MSSA, MRSA, and P. aeruginosa in this murine model of skin and soft tissue infection.

Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Bacterial Proteins; beta-Lactamases; Cephalosporins; Colony Count, Microbial; Dose-Response Relationship, Drug; Female; Gram-Negative Bacteria; Gram-Positive Bacteria; Half-Life; Immunocompromised Host; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Hairless; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections; Skin Diseases, Infectious; Staphylococcal Infections; Staphylococcus aureus

Topics: Anti-Bacterial Agents; Canada; Cephalosporins; Cross Infection; Humans; Intensive Care Units; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas Infections