In vivo activity of ceftobiprole in murine skin infections due to Staphylococcus aureus and Pseudomonas aeruginosa.
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.
Fernandez
Jeffrey
J
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 1000 Route 202 South, Raritan, NJ 08869, USA. jfernan5@its.jnj.com
Hilliard
Jamese J
JJ
Abbanat
Darren
D
Zhang
Wenyan
W
Melton
John L
JL
Santoro
Colleen M
CM
Flamm
Robert K
RK
Bush
Karen
K
D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001426:Bacterial Proteins / Q000378:metabolism; D002511:Cephalosporins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006207:Half-Life; D016867:Immunocompromised Host; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008812:Mice, Hairless; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D012874:Skin Diseases, Infectious / Q000188:drug therapy* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects; D001618:beta-Lactamases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D002511:Cephalosporins; C443755:ceftobiprole; C048795:AmpC beta-lactamases; D001618:beta-Lactamases