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Single, intravenously administered doses of cefoxitin and cefamandole did not penetrate into cerebrospinal fluid of normal humans. Multiple-dose administration with or without probenecid facilitated penetration of both antibiotics into the cerebrospinal fluid. Preliminary data showed that cefoxitin penetrated into cerebrospinal fluid of patients with inflamed meninges even when administered in a single dose without probenecid. However, the concentrations of cefoxitin in the cerebrospinal fluid of the individuals studied were not within the therapeutic range.

The activities of cefamandole, cephalothin, ampicillin, and chloramphenicol were compared in fulminant and temperate Escherichia coli meningitis in rabbits. Intensive dosing schedules were employed to achieve maximal therapeutic benefits with short-term treatment. In an 8-h schedule chloramphenicol was significantly more effective in sterilizing the cerebrospinal fluid and curing both fulminant and temperate infections than cefamandole or ampicillin. Cephalothin was without effect in fulminant meningitis. Cefamandole and ampicillin were equivalent in activity in this and longer (12- and 24-hr) treatment schedules. The therapeutic benefits of chloramphenicol were purchased via use of doses above those generally regarded as safe for human use. The mean serum, cerebrospinal fluid, and brain concentrations of chloramphenicol, cefamandole, and ampicillin were significantly greater in rabbits with fulminant meningitis than in those with temperate meningitis. The difference was of such magnitude as to support the need to monitor drug concentrations.

Because cerebrospinal fluid (CSF) antibiotic levels fail to predict either clinical success or relapse in the treatment of bacterial meningitis, we examined simultaneous antibiotic concentrations in the blood, brain, and CSF of control rabbits and of animals with experimental pneumococcal meningitis. Cefamandole pharmacokinetics were analyzed in detail and compared with those of cephalothin, ampicillin, penicillin G, and tobramycin. After 4 h of continuous intravenous infusion, cefamandole reached concentrations in both brain and CSF in excess of the minimal bactericidal concentration for the test organism and compared favorably with ampicillin and penicillin in achieving bacteriological cure. Cephalothin levels in the central nervous system remained undetectable in both control and infected animals during this time. Tobramycin concentrations were measurable in the CSF, but not in brain tissue in association with an inflammatory stimulus.

The penetration of cefamandole and ampicillin into the cerebrospinal fluid of rabbits with and without pneumococcal meningitis was evaluated. In normal animals, a mean maximum concentration of 0.22 +/- 0.13 microgram of cefamandole per ml was measured in the spinal fluid after a dose of 150 mg/kg given intramuscularly; with 25 and 50 mg/kg doses, no antibiotic was detected in the cerebrospinal fluid. With ampicillin, in intramuscular doses of 200 and 300 mg/kg, the mean maximum concentrations encountered in the cerebrospinal fluid were 1.59 +/- 0.4 and 1.47 +/- 0.44 microgram/ml, respectively. Penetration of cefamandole, and to a lesser extent ampicillin, was increased after 24 h of experimental meningitis. With cefamandole, the concentration of drug in the cerebrospinal fluid exceeded the usual inhibitory concentration for Haemophilus influenzae only with the 150 mg/kg dose. After 48 h of meningitis, there was a trend toward higher levels of antibiotic in the cerebrospinal fluid, but the difference between animals infected 24 versus 48 h was not statistically significant. In animals with meningitis, serum concentrations after 150 mg of cefamandole per kg and both ampicillin doses studied were 32 to 38% lower than the serum levels achieved in normal rabbits after identical doses of antibiotic.

In 20 test persons spinal fluid was taken at intervals of 15, 30, 60 and 90 minutes after a single injection of 40 mg cefamandole/kg body weight in order to determine the levels of the active substance. Whereas in serum an average peak value of 248 mcg/ml was determined after ten minutes, there was no trace at all of cefamandole in the spinal fluid.