linezolid and ceftobiprole

In phase 3 clinical trials for ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of

Topics: Anti-Bacterial Agents; Cephalosporins; Enterobacteriaceae; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Skin Diseases, Bacterial; Staphylococcus

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

Beta lactam agents are the most active drugs for the treatment of streptococci and methicillin-susceptible Staphylococcus aureus endocarditis. However, methicillin-resistant S. aureus (MRSA) is resistant to all beta lactam agents licensed to date, and alternative treatments are limited. Ceftobiprole is a novel broad-spectrum cephalosporin that binds with high affinity to PBP 2a, the penicillin binding protein that mediates the methicillin resistance of staphylococci and is active against MRSA. Ceftobiprole was compared to vancomycin, daptomycin, and linezolid in a rabbit model of MRSA aortic valve endocarditis caused by the homogeneously methicillin-resistant laboratory strain COL. Residual organisms in vegetations were significantly fewer in ceftobiprole-treated rabbits than in any other treatment group (P<0.05 for each comparison). In addition, the numbers of organisms in spleens and in kidneys were significantly lower in ceftobiprole-treated rabbits than in linezolid- and vancomycin-treated animals (P<0.05 for each comparison). Anti-MRSA beta lactam agents such as ceftobiprole may represent a significant therapeutic advance over currently available agents for the treatment of MRSA endocarditis.

Topics: Acetamides; Animals; Anti-Bacterial Agents; Cephalosporins; Chromatography, High Pressure Liquid; Daptomycin; Disease Models, Animal; Endocarditis, Bacterial; Linezolid; Methicillin-Resistant Staphylococcus aureus; Oxazolidinones; Rabbits; Random Allocation; Vancomycin

Synergy time-kill studies of 47 methicillin-resistant Staphylococcus aureus strains with differing resistance phenotypes showed that combinations of subinhibitory concentrations of ACHN-490 and daptomycin yielded synergy against 43/47 strains at 24 h, while the combination was indifferent against the remaining 4 strains. ACHN-490 and ceftobiprole showed synergy in 17/47 strains tested at 24 h, while 6/47 strains showed synergy for subinhibitory combinations of ACHN-490 and linezolid.

Topics: Acetamides; Aminoglycosides; Anti-Bacterial Agents; Cephalosporins; Daptomycin; Drug Resistance, Bacterial; Drug Synergism; Linezolid; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Oxazolidinones; Sisomicin; Time Factors

Ceftobiprole (BPR) is an investigational cephalosporin with activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains. The pharmacodynamic (PD) profile of BPR against S. aureus strains with a variety of susceptibility phenotypes in an immunocompromised murine pneumonia model was characterized. The BPR MICs of the test isolates ranged from 0.25 to 2 mug/ml. Pharmacokinetic (PK) studies were conducted with infected neutropenic BALB/c mice; and the BPR concentrations were measured in plasma, epithelial lining fluid (ELF), and lung tissue. PD studies with these mice were undertaken with eight S. aureus isolates (two methicillin-susceptible S. aureus strains, three hospital-acquired MRSA strains, and three community-acquired MRSA strains). Subcutaneous BPR doses of 2 to 125 mg/kg of body weight/day were administered, and the change in the number of log(10) CFU/ml in lungs was evaluated after 24 h of therapy. The PD profile was characterized by using the free drug exposures (f) determined from the following parameters: the percentage of time that the concentration was greater than the MIC (T > MIC), the maximum concentration in serum/MIC, and the area under the concentration-time curve/MIC. The BPR PK parameters were linear over the dose range studied in plasma, and the ELF concentrations ranged from 60 to 94% of the free plasma concentration. fT > MIC was the parameter that best correlated with efficacy against a diverse array of S. aureus isolates in this murine pneumonia model. The 80% effective dose (ED(80)), ED(50), and stasis exposures appeared to be similar among the isolates studied. BPR exerted maximal antibacterial effects when fT > MIC ranged from 6 to 22%, regardless of the phenotypic profile of resistance to beta-lactam, fluoroquinolone, erythromycin, clindamycin, or tetracycline antibiotics.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Disease Models, Animal; Drug Resistance, Bacterial; Female; Humans; Methicillin Resistance; Mice; Mice, Inbred BALB C; Phenotype; Pneumonia, Staphylococcal; Staphylococcus aureus

We evaluated the activity of ceftobiprole against 100 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) and 100 hospital-associated MRSA (HA-MRSA) isolates. Eight isolates were evaluated by time-kill studies for kill rate and potential for synergy with tobramycin. Ceftobiprole MIC(50) and MIC(90) values were 1 and 2 microg/ml, respectively, against CA-MRSA and HA-MRSA. In time-kill analysis, ceftobiprole was bactericidal at all concentrations tested.

Topics: Acetamides; Anti-Bacterial Agents; Cephalosporins; Community-Acquired Infections; Cross Infection; Daptomycin; Drug Synergism; Humans; Linezolid; Methicillin Resistance; Microbial Sensitivity Tests; Oxazolidinones; Staphylococcal Infections; Staphylococcus aureus; Vancomycin