BAL9141, a Novel Extended-Spectrum Cephalosporin Active against Methicillin-Resistant Staphylococcus aureus in Treatment of Experimental Endocarditis

Abstract

The therapeutic efficacy of BAL9141 (formerly Ro 63-9141), a novel cephalosporin with broad in vitro activity that also has activity against methicillin-resistant Staphylococcus aureus (MRSA), was investigated in rats with experimental endocarditis. The test organisms were homogeneously methicillin-resistant S. aureus strain COL transformed with the penicillinase-encoding plasmid pI524 (COL Bla؉) and homogeneously methicillin-resistant, penicillinase-producing isolate P8-Hom, selected by serial exposure of parent strain P8 to methicillin. The MICs of BAL9141 for these organisms (2 mg/liter) were low, and BAL9141was bactericidal in time-kill curve studies after 24 h of exposure to either two, four, or eight times the MIC. Rats with experimental endocarditis were treated in a three-arm study with a continuous infusion of BAL5788 (formerly Ro 65-5788), a carbamate prodrug of BAL9141, or with amoxicillin-clavulanate or vancomycin. The rats were administered BAL9141 to obtain steady-state target levels of 20, 10, and 5 mg of per liter or were administered either 1.2 g of amoxicillin-clavulanate (ratio 5:1) every 6 h or 1 g of vancomycin every 12 h at changing flow rates to simulate the pharmacokinetics produced in humans by intermittent intravenous treatment. Treatment was started 12 h after bacterial challenge and lasted for 3 days. BAL9141 was successful in the treatment of experimental endocarditis due to either MRSA isolate COL Bla؉ or MRSA isolate P8-Hom at the three targeted steady-state concentrations and sterilized >90% of cardiac vegetations (P < 0.005 versus controls; P < 0.05 versus amoxicillin-clavulanate and vancomycin treatment groups). These promising in vivo results with BAL9141 correlated with the high affinity of the drug for PBP 2a and its stability to penicillinase hydrolysis observed in vitro.

Quality Control Guidelines for BAL9141 (Ro 63-9141), an Investigational Cephalosporin, When Reference MIC and Standardized Disk Diffusion Susceptibility Test Methods Are Used

“…BAL9141 has demonstrated excellent activity against MRSA, with MICs at which 50% and 90% of the isolates tested are inhibited in the range of 2 to 4 g/ml (5, 7). BAL9141 also has notable activity against Streptococcus spp., Haemophilus influenzae, Moraxella catarrhalis, Neisseria spp., enterobacteriaceae, nonfermentative gramnegative bacilli, and anaerobes (2,5,7). This broad spectrum of activity plus the potency against MRSA makes BAL9141 a promising antimicrobial agent that has been advanced into human clinical trials.…”

“…BAL9141 (formerly Ro 63-9141) is a pyrrolidinone-3-ylidenemethyl cephalosporin which has a broad spectrum of antimicrobial activity; most notable is the potent activity against methicillin-resistant staphylococci (2,5,7). BAL9141 activity against MRSA is due to the inhibition of PBP 2a and stability with respect to ␤-lactamase hydrolysis.…”

Emerging agents to combat complicated and resistant infections: focus on ceftobiprole

“…The predominant pathogen was S. aureus (37% of which were MRSA). The Gram-negative isolates included Enterobacteriaceae (37), Pseudomonas species (6) and A. baumannii (2). Overall cure rates in the ceftobiproletreated (n = 282) and vancomycin-treated (n = 277) subjects in the clinically evaluable population were similar (93.3% and 93.5%, respectively).…”

“…Ceftobiprole medocaril was more active than vancomycin or amoxicillinclavulanic acid against MRSA in a rat experimental endocarditis model. 37 Ceftobiprole medocaril and vancomycin were equally active in a rabbit model of aortic valve endocarditis against MRSA, whereas ceftobiprole medocaril was more active than vancomycin against a VISA strain. 39 No difference was found between animals treated with ceftobiprole medocaril and those treated with vancomycin in a rat tissue cage model of chronic MRSA foreign-body infection.…”

“…36 Experiments involving prolonged serial transfer of staphylococci in the presence of subinhibitory concentrations of ceftobiprole or comparators and assessing single-step mutation frequencies suggest that staphylococci are relatively refractory to development of endogenous resistance to ceftobiprole. 37 Serial passage with increasing concentrations of ceftobiprole performed with 3 MRSA isolates and 1 MSSA isolate suggests that development of resistance to ceftobiprole due to chromosomal mutations occurs with low frequency, if ever, in MRSA. 15 However, a recent study 38 demonstrated that MRSA can develop highlevel ceftobiprole resistance in vitro mediated by mutations in PBP2a.…”