The recent emergence of methicillin-resistant Staphylococcus aureus (MRSA) with decreased susceptibility to vancomycin has intensified the search for alternative therapies for the treatment of infections caused by this organism. One approach has been to identify a ␤-lactam with improved affinity for PBP 2a, the target enzyme responsible for methicillin resistance in staphylococci. BMS-247243 is such a candidate, with MICs that inhibit 90% of isolates tested (MIC 90 s) of 4, 2, and 8 g/ml for methicillin-resistant strains of S. aureus, S. epidermidis, and S. haemolyticus, respectively, as determined on plates with Mueller-Hinton agar and 2% NaCl. The BMS-247243 MICs for MRSA were minimally affected by the susceptibility testing conditions (inoculum size, prolonged incubation, addition of salt to the test medium) or by staphylococcal ␤-lactamases. BMS-247243 MIC 90 s for methicillin-susceptible staphylococcal species ranged from <0.25 to 1 g/ml. The BMS-247243 MIC 90 for ␤-lactamase-producing S. aureus strains was fourfold higher than that for ␤-lactamase-nonproducing strains. BMS-247243 is hydrolyzed by staphylococccal ␤-lactamases at 4.5 to 26.2% of the rates measured for cephaloridine. The affinity of BMS-247243 for PBP 2a was >100-fold better than that of methicillin or cefotaxime. BMS-247243 is bactericidal for MRSA, killing the bacteria twice as fast as vancomycin. These in vitro activities of BMS-247243 correlated with its in vivo efficacy against infections in animals, including the neutropenic murine thigh and rabbit endocarditis models involving MRSA strains. In conclusion, BMS-247243 has in vitro and in vivo activities against methicillin-resistant staphylococci and thus may prove to be useful in the treatment of infections caused by these multidrug-resistant organisms.

Cefepime (BMY 28142) is a new aminothiazolyl methoximinocephalosporin whose antibacterial spectrum (1, 6,8,16,18,20) has been established. Therapeutic efficacy in systemically infected mice (8, 12), effectiveness in treating meningitis caused by Streptococcus pneumoniae in rabbits (19), and S. agalactiae and Escherichia coli infections in newborn rats (9) have also been studied. This report compares the efficacies of cefepime, ceftazidime, cefotaxime, and moxalactam in experimental bacterial meningitis. Infections were established intracranially in mice, using S. pneumoniae, S. agalactiae, Staphylococcus aureus, E. coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. In neonatal rats, S. pneumoniae, S. agalactiae, and Haemophilus influenzae were introduced intracisternally.MATERIALS AND METHODS Antibiotics. Cefepime sulfate salt was prepared at BristolMyers Co., Syracuse, N.Y. Ceftazidime pentahydrate, cefotaxime sodium, and moxalactam disodium were provided by

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A technique for inducing pneumococcal meningitis in mice and a description of the histopathologic changes that accompany this experimentally produced disease are provided in the present report. This infection of mice was investigated to determine whether it could serve as a suitable model for detecting agents that have potential therapeutic utility in bacterial meningitis in man. 21 antibiotics, belonging to six major classes were evaluated for efficacy in the experimental infection. The three most active agents proved to be amoxicillin, cephaloridine, and chlortetracycline. Up to this time, amoxicillin has not been commercially available as an injectable dosage form. However, in view of the compound’s outstanding efficacy in the present experiments, it would be desirable to investigate its effectiveness in the naturally occurring disease in man.

The synthesis and structure-activity relationships of a series of orally absorbed O-2-isocephems are described. These compounds possessed a D-[(p-hydroxyphenyl)glycyl]amino substituent at the 7-position while the substituent at the 3-position was varied. Relative to the analogous cephems, the O-2-isocephems exhibited comparable to better activity against Gram-positive organisms. Against Gram-negative organisms, their activity was variable but did indicate a lower beta-lactamase stability. Following oral administration, the O-2-isocephems generally exhibited longer half-lives but lower Cmax's and urinary recoveries.