Efficacy of cefmenoxime in experimental Escherichia coli bacteremia and meningitis

Abstract

Cefmenoxime, a new semisynthetic cephalosporin structurally similar to cefotaxime, was evaluated for its activities in vitro and in vivo against a Kl Escherichia coli strain in comparison with activities of cefotaxime and ampicillin. In vitro the MICs and MBCs of both cefmenoxime and cefotaxime were the same, 1/16th and 1/32nd those of ampicillin, respectively. The efficacies of cefmenoxime and cefotaxime against experimentally induced E. coli bacteremia and meningitis in newborn rats were similar and significantly better than that of ampicillin as judged by bactericidal titers of blood and cerebrospinal fluid, rapidity of clearance of bacteria from blood and cerebrospinal fluid, and incidence of meningitis in animals with bacteremias. The efficacy of cefmenoxime or cefotaxime measured by impact on mortality was influenced by the size of bacterial populations. The mortality was significantly greater in rats with bacterial counts before therapy of .106 CFU/ml of blood than in animals with lower counts. Overall, the in vivo efficacy of cefmenoxime was similar to that of cefotaxime; thus it could be useful in the therapy of neonatal E. coli infection.It has been shown previously that experimental Escherichia coli bacteremia and meningitis induced in the newborn rat is suitable for evaluating in vivo efficacies of various antimicrobial agents, particular in terms of rates of bacterial clearance from blood and cerebrospinal fluid (CSF) and of mortality (4-6). In these studies, it has been shown the activity of armpicillin against E. coli Kl is limited (4, 5), but that of cefotaxime is excellent. Results of recent studies, however, have shown that the outcome of E. coli infections in this model treated with cefotaxime is not significantly better than that of a conventional therapeutic regimen, ampicillin-gentamicin (K. S. Kim, submitted for publication). Recently, Tsuchiya et al. (12) have shown that cefmenoxime, a new cephalosporin structurally similar to cefotaxime, has greater protective and therapeutic activities than cefotaxime against members of the family Enterobacteriaceae in mice despite their similar activities in vitro. The present study was therefore performed to examine the activity of cefmenoxime in vitro and in vivo against E. coli and to compare the results with those of cefotaxime and ampicillin. MATERIALS AND METHODSOrganisms. A serum-resistant E. coli Kl strain (C5) isolated from the CSF ofa newborn infant with meningitis was used in this study.In vitro studies. The MICs and MBCs were measured in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) by a macrobroth dilution mpethQd (13). Antimicrobial agents tested were cefmenoxime hydrochloride (Abbott Laboratories, TAP Pharmaceuticals, North Chicago, Ill.), ampicillin trihydrate (Bristol Laboratories, Syracuse, N.Y.) and cefotaxime sodium (Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.). All antibiotic solutions were serially twofold diluted from 16 to 0.03 ,ug/ml in Mueller-Hinton broth. Late logarithmic-phase cultures of strain C5 c...

Efficacy of Gatifloxacin in Experimental Escherichia coli Meningitis

“…Our time-kill studies confirmed that the BKR of cefotaxime was reduced when the initial bacterial concentrations were large whereas the BKR of gatifloxacin was independent of the initial bacterial concentration. Similarly, in experimental E. coli meningitis, a reduction in the effectiveness of cefotaxime therapy in the presence of high bacterial concentrations has been shown (12)(13)(14) and was confirmed in this study. In contrast to its BKR in vitro, the BKR of cefotaxime was not affected by bacterial concentrations in the meningitis model.…”

“…In experimental meningitis, persistence of E. coli in the CSF eventually results in much greater endotoxin release than that induced by effective antibacterial therapy (7). In the present and previous experimental studies (13), lower BKRs were associated with increased mortality. In children with Haemophilus influenzae or enteric gram-negative meningitis, failure to sterilize the CSF within 24 h of antibacterial therapy is associated with a poorer outcome (15,18,25).…”

The K1 capsule is the critical determinant in the development of Escherichia coli meningitis in the rat.

“…Briefly, outbred, pathogen-free, pregnant Sprague-Dawley rats with timed conception were purchased from Charles River Breeding Laboratories (Wilmington, MA); the rats delivered in our vivarium 5-7 d after arrival. Each adult rat and her pups (average litter size of 10 with range of [8][9][10][11][12][13][14][15][16] for the unencapsulated mutant and 5.0 x 106 to 1.0 X I0' CFU for the rough mutants (strains XYL and 2513). 24 h after inoculation, blood and CSF specimens were obtained as described previously (4,(12)(13)(14)(15)(16)(17) for quantitative cultures.…”

“…Hematogenous infection of meninges can be reliably established without the need for administration ofadjuvant or direct inoculation ofbacteria into CSF (4,(12)(13)(14)(15)(16)(17). With development of techniques for atraumatic collection of blood and CSF specimens, we have used this model to determine whether or not the K1 capsule and/or 0-LPS antigen are critical determinants in the development of E. coli meningitis.…”

Murine Hybridoma Antibodies Enhance Bactericidal Activity of Human Cord Blood against K1 Escherichia coli Strains

“…Frozen bacteria were thawed, diluted (l:20) in fresh prewarmed brain heart infusion broth, and grown at 37°C for approximately 4 h to match the turbidity of a MacFarland no. 0.5 standard (14). This late logarithmic culture was washed and resuspended in a concentration of 1 x 10' CFU/mL.…”