We investigated the effect of cefotaxime and chloramphenicol on endotoxin concentrations in cerebrospinal fluid (CSF) and on the development of brain edema in rabbits with Escherichia coli meningitis. Both antibiotics were similarly effective in reducing bacterial titers. Cefotaxime, but not chloramphenicol, induced a marked increase of endotoxin in CSF, from log., 1.5 ± 0.8 to log., 2.8 ± 0.7 ng/ml (P < .01). This result was associated with an increase in brain water content (405 ± 12 g of water/loo g of dry weight compared with 389 ± 8 g in untreated controls; P < .01), whereas in animals treated with chloramphenicol, brain water content was identical to controls. The cefotaxime-induced increase in endotoxin concentration and brain edema were both neutralized by polymyxin B, which binds to the lipid A moiety of endotoxin, or by a monoclonal antibody to lipid A. These results indicate that treating gram-negative bacillary meningitis with selected antibiotics induces increased endotoxin concentrations in CSF that are associated with brain edema.

The therapeutic efficacy of the fluoroquinolone pefloxacin mesylate was compared with those of cefotaxime and chloramphenicol in a rabbit model of Escherichia coli meningitis. The mean percent penetration (± the standard deviation) of pefloxacin (range, 1 to 30 mg/kg per h) into cerebrospinal fluid of infected rabbits was 51.3 + 14.0 compared with 11.1 + 1.0 for cefotaxime (100 mg/kg per h) and 22.3 + 1.5 for chloramphenicol (60 mg/kg per h). The rate of bacterial killing (Aloglo CFU/ml per h) did not change over a dosage range of 1 to 15 mg/kg per h (-0.37 + 0.15, 20% sterile). At 30 mg/kg per h, the rate achieved (-0.77 + 0.18, 100% sterile) was comparable to that of cefotaxime (-0.88 0.23, 100% sterile) and superior to that of chloramphenicol (-0.10 0.14, 0% sterile).Pefloxacin mesylate, a new fluoroquinolone, has been shown to have a wide spectrum of activity both in vitro and in vivo (4,8, 12, 13). Because of its excellent activity against members of the family Enterobacteriaceae and because in vitro tests may not reliably predict the bactericidal activity of a drug against meningitis (9), we evaluated the therapeutic efficacy of pefloxacin with a well-standardized rabbit model of Escherichia coli meningitis. The specific purposes of this investigation were to determine the percent penetration of pefloxacin into the cerebrospinal fluid (CSF) and to compare the in vivo efficacy of the drug with those of cefotaxime and chloramphenicol.MATERIALS AND METHODS Experimental strain. E. coli 492 was kindly supplied by George McCracken. It was originally isolated from the CSF of a patient with meningitis and is serum resistant. Stock cultures were stored frozen on glass beads at -70°C until the beginning of each experiment. At that time, a single bead was removed and incubated overnight in tryptic soy broth at 35°C. The inocula were prepared from these overnight cultures.Antimicrobial agents. Pefloxacin was supplied by RhonePoulenc Sante, Paris, France. Commercially available cefotaxime (Hoechst-Roussel Pharmaceuticals, Somerville, N.J.) and chloramphenicol (Parke, Davis & Co., Morris Plains, N.J.) were also used.Susceptibilities. MICs and MBCs were measured in Mueller-Hinton broth according to standard macrotube dilution methods (7), against an inoculum of 2 x 105 to 4 x 105 CFU/ml. The MIC was defined as the lowest concentration of drug that prevented visible turbidity. The MBC, defined as the concentration that killed .99.9% of the original inoculum, was measured by streaking 0.01 ml from each tube not showing turbidity onto a blood agar plate, incubating the plates overnight at 35°C, and counting the colonies thereon at that time.Time-kill curves. The in vitro bactericidal activity in Mueller-Hinton broth or in CSF of normal rabbits was examined over time in tubes containing pefloxacin (0.125, ,ug/ml). Tubes were inoculated with 1 x 106 to 2 x 106 CFU and incubated at 35°C. Samples were quantitatively cultured at 0, 2, 6, and 24 h.In vivo experiments. To determine the percent penetration of pefloxacin into the ...

Ciprofloxacin, pefloxacin, norfloxacin, and ofloxacin were investigated for immunomodulatory activity on humoral and cell-mediated immune responses. Ciprofloxacin and pefloxacin altered the humoral immune responses of mice to sheep red blood cells. This effect was not exhibited by norfloxacin or ofloxacin. All four quinolones did not alter cell-mediated responses. When these antimicrobial agents were tested for their interaction with human polymorphonuclear phagocytic activity, all agents suppressed this activity. In addition, all except norfloxacin showed anti-inflammatory activity.