For rufloxacin MF961, ofloxacin and fleroxacin the inhibition of DNA synthesis, intracellular accumulation, optimum bactericidal concentration (OBC) and killing kinetics at the OBC for ...Enterobacteriaceae, Pseudomonas aeruginosa and staphylococci and induction of recA in Escherichia coli were determined. All agents had good activity against all the strains and inhibited DNA synthesis by 50% at concentrations correlating with the MIC. The maximum recA inducing concentrations after 60 min exposure to the quinolones in E. coli were 0.5 mg/L of rufloxacin, MF961, ofloxacin and 0.05 mg/L of fleroxacin. Accumulation of all quinolones was rapid; however, higher concentrations of all agents were accumulated within staphylococci than in Gram-negative bacteria. Rufloxacin was accumulated to higher concentrations in all bacteria than the other three agents. Laboratory mutants with decreased susceptibility to the four drugs were selected from each strain. All agents selected mutants with decreased susceptibility to quinolones alone, with phenotypes suggesting mutations in gyrA. Multiply-resistant mutants were also selected; however, as few had decreased expression of OmpF, the mutated gene is unlikely to be an allele of marA. All mutants had MICs > or = 2 mg/L, a typical breakpoint concentration for most quinolones.
The activity of six cephalosporins, six penicillins and one monobactam combined with BRL 42715, clavulanic acid, sulbactam or tazobactam at 0.1, 0.5, 1, 2, 5 and 10 mg/L was determined for 45 ...beta-lactamase producing Gram-negative bacteria. The combination of BRL 42715 with any of the agents was more active than any of the other inhibitor and beta-lactam combinations. Unlike the other beta-lactamase inhibitors, BRL 42715 enhanced the activity of the beta-lactams for strains that constitutively expressed Richmond & Sykes Class I beta-lactamase and against strains expressing extended-spectrum plasmid-mediated beta-lactamases.
Twenty-five strains of Enterobacteriaceae (five each of Enterobacter cloacae, Citrobacter freundii, Serratia marcescens, Morganella morganii, and Providencia stuartii) were exposed to FCE 22101 in ...agar containing 3, 5, or 10 x the MIC. Any putative mutant with a greater than or equal to four-fold increase in the MIC was examined for beta-lactamase expression and outer membrane protein (OMP) profile. Mutant colonies were selected at a frequency of 10(-7)-10(-11) with decreased susceptibility to FCE 22101 and other beta-lactams, but after one subculture on antibiotic-free agar the mutants from 13 of the 25 strains reverted to wild-type. Only 19 stable mutants were selected from the other 12 wild-type strains, of which 15 lacked an OMP of similar molecular size to OmpF, and/or a low size OMP of approximately 18 kDa. None of the mutants had a significant alteration in expression of Richmond & Sykes class I beta-lactamase. In a separate section of the study in which 50 strains of Pseudomonas aeruginosa were examined, it was found that FCE 22101, at a concentration of 4 mg/L, induced beta-lactamase expression such that, after 24 h exposure, 24 of the 50 strains had a greater than or equal to four-fold rise in the MIC of several anti-pseudomonal beta-lactams.
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