EXCELLENT ACTIVITY OF FK037, A NOVEL PARENTERAL BROAD-SPECTRUM CEPHALOSPORIN, AGAINST METHICILLIN-RESISTANT STAPHYLOCOCCI

FK037 exhibits potent in vitro and in vivo antibacterial activity against methicillin-resistant staphylococci. In in vitro studies, FK037 was the most active of the cephalosporins and imipenem tested against the highly methicillin-resistant staphylococci (MIC > 100 mug/ml). Only 2 of 57 strains of highly methicillin-resistant Staphylococcus aureus (H-MRSA) had a FK037 MIC value of 50 mug/ml. On the other hand, 55, 40 and 19 strains had MICs of 50 or greater-than-or-equal-to 100 mug/ml to cefpirome, flomoxef and imipenem, respectively. Against 13 strains of highly methicillin-resistant coagulase-negative staphylococci (H-MRCNS), FK037 inhibited all the strains at less-than-or-equal-to 50 mug/ml, but there were many strains highly resistant to the reference drugs with MICs of greater-than-or-equal-to 100 mug/ml. The influence of culture conditions such as low temperature, high inoculum and supplementation with 4% NaCl on the anti-MRSA activity of FK037 was less than those with cefpirome, flomoxef and imipenem. The in vitro frequency of spontaneous mutant cells highly resistant to FK037 in MRSA was lower than that to cefpirome and flomoxef. These findings were supported by lack of colonies inside the inhibition zone demarcated by FK037 in a disk sensitivity test, although many colonies proliferated inside the inhibition zone demarcated by flomoxef and imipenem. The increase in MIC of FK037 against a MRSA strain during subculture in the presence of the drug was smaller than that noted with the reference drugs. FK037 had higher affinity and faster binding for the PBP 2a of MRSA than that of the reference drugs. Moreover, the capacity to induce PBP 2a was lower for FK037 than that of cefpirome but higher than that of flomoxef. In an in vitro pharmacokinetic model simulating human plasma concentrations, FK037 showed potent bactericidal activity against H-MRSA in the plasma concentrations after intravenous infusion dosing with 1.0 g. FK037 was synergistically active against H-MRSA in combination with either imipenem of fosfomycin. The in vitro post-antibiotic effect (PAE) of FK037 against H-MRSA ranged from 1.2 to 1.7 hours at one to four times the MIC. FK037 had potent therapeutic effects against lethal systemic infections and experimental local infections in mice such as pneumonia, endocarditis, subcutaneous abscess, intrauterine infection and granuloma pouch infection due to MRSA or methicillin-resistant Staphylococcus epidermidis (MRSE). FK037 was about 4, 8 and 1.5 times more effective than cefpirome, flomoxef and imipenem, respectively, against lethal systemic infections with H-MRSA. Against imipenem-resistant H-MRSA, FK037 was 3 to 11 times more effective than imipenem. Although the in vitro activity of FK037 was inferior to that of vancomycin, the ED50 ratio to those of vancomycin ranged from 1.2 to 3.4, which were less than those anticipated from the difference in MICs. Moreover, the therapeutic effect of FK037 was little influenced by challenge doses, while those of cefpirome and flomoxef were markedly reduced by high challenge doses. Against local infections due to MRSA or MRSE, FK037 was the most effective of the beta-lactams tested. The therapeutic effect of FK037 was stronger than that anticipated based on its in vitro activity. Moreover, FK037 was as effective as vancomycin against MRSA in a subcutaneous abscess model. Against murine pneumonia with H-MRSA in an in vivo pharmacokinetic model simulating human plasma concentrations for intravenous infusion of 2.0g, FK037 was significantly more effective than cefpirome and flomoxef in reducing the number of viable bacteria in the lungs. In granuloma pouch infection due to H-MRSA, the in vivo frequency of cells highly resistant to methicillin after 5 treatments with FK037 was lower than that with cefpirome and flomoxef. FK037 showed synergistic effect with imipenem or fosfomycin against lethal systemic infection with MRSA. FK037 produced in vivo PAE of 4.1 hours against a thigh infection with H-MRSA in neutropenic mice. From these results, FK037 merits further clinical trials for infection with MRSA.