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.