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In vivo antibacterial activity of FK037, a novel parenteral broad-spectrum cephalosporin.

FK037 has potent therapeutic activity against lethal systemic infections and experimental local infections due to a wide variety of Gram-positive and Gram-negative bacteria such as staphylococci, Streptococcus pneumoniae, Enterobacteriaceae and Pseudomonas aeruginosa in mice. In murine systemic infections, FK037 was the most effective of the cephalosporins and imipenem tested against highly methicillin-resistant Staphylococcus aureus (H-MRSA). It was more effective than ceftazidime against selected strains of S. aureus and Enterobacteriaceae, except Serratia marcescens and P. aeruginosa against which FK037 was as effective as ceftazidime and was as effective as cefpirome against all organisms tested, except MRSA and P. aeruginosa against which FK037 was more effective than cefpirome. These results correlated well with its in vitro activity. In murine local infections, with few exceptions, FK037 was more effective than ceftazidime and cefpirome against Klebsiella pneumonia in ED50 values and against methicillin-sensitive S. aureus (MSSA) subcutaneous abscess, pyelonephritis with Staphylococcus epidermidis, E. coli and P. aeruginosa, intrauterine infections with S. aureus and E. coli in reducing the number of viable bacteria in the abscess, kidneys and uterus. It is noteworthy that the therapeutic effects of FK037 were more potent than had been anticipated from its in vitro activity against local infections with staphylococci and P. aeruginosa when compared with ceftazidime or cefpirome. In addition, the therapeutic effects of FK037 were equipotent or superior to those of cefpirome and ceftazidime against pneumonia due to MSSA, K. pneumoniae and P. aeruginosa in reducing the number of viable bacteria in the lungs in mice using an in vivo pharmacokinetic model simulating human plasma concentrations after drip infusion of usual clinical doses (0.25 to 1.0 g for MSSA, 0.063 to 0.125 g for K. pneumoniae and 1.0 to 2.0 g for P. aeruginosa). FK037 induced an in vivo post-antibiotic effect (PAE) of 3.4 hours against a thigh infection with MSSA in neutropenic mice. These results strongly suggest that it has potential for clinical use against various infections due to bacteria which include staphylococci and P. aeruginosa.