Synergistic Activity of Ceftobiprole and Vancomycin in a Rat Model of Infective Endocarditis Caused by Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus

Abstract

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 g/ml, respectively, for MRSA ATCC 43300 and 4, >64, and 8 g/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.

Combination Antibiotic Treatment of Serious Methicillin-Resistant Staphylococcus aureus Infections

“…At least 16 in vitro studies have explored synergy between vancomycin and β-lactams against MRSA isolates, [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] all but one of which found evidence of synergy in some or all of the tested strains (►Table 1). These studies varied in their methodology (checkerboard synergy testing or time-kill curves), types of strains tested (MRSA vs. hVISA vs. VISA) and the β-lactams used, but a consistent finding across nearly all the studies was synergistic bacterial killing in most but not all strains tested.…”

“…The few studies that have assessed combinations of vancomycin with β-lactams in animal models have all found evidence of synergy. 56,61,65 Climo et al found faster sterilization of infection with vancomycin plus nafcillin in MRSA rabbit endocarditis and renal abscess models. 56 Ribes et al tested various combinations of linezolid, vancomycin, and imipenem in a murine peritonitis VISA model using time-kill curves, and found faster bacterial killing with vancomycin plus imipenem compared with vancomycin alone, in both strains tested.…”

Pharmacokinetic and pharmacodynamics evaluation of ceftobiprole medocaril for the treatment of hospital-acquired pneumonia

“…The values for MIC 50/90 are generally one to two dilutions lower with most studies reporting MIC 90 of 0.5 µg/ml [2,13,14,36] and likelihood of target attainment is anticipated to be high with q12h dosing. Postantibiotic effect and synergy have not been formally studied, but they are likely to occur in MSSA, since they have been demonstrated with MRSA [49].…”

“…The clinical significance of the postantibiotic effect is not clear. Synergy with vancomycin for MRSA and VISA strains has been demonstrated both in vitro and in vivo, but the significance of these observations is also unclear [49].…”

Efficacy of Telavancin Alone and in Combination with Ampicillin in a Rat Model of Enterococcus faecalis Endocarditis

“…(42), (v) AMP (100 mg/kg, q8h, i.m.) plus CRO (10 mg/kg, q8h, s.c.) (41), and (vi) DAP (45.3 mg/kg, q24h, s.c.) (21,45) and VAN (120 mg/kg, q12h, s.c.) (47,48). A group of infected but untreated control animals was left along with the therapy group to show the end log 10 CFU per gram versus the baseline (t ϭ 0) untreated controls.…”