Penetration of cefoxitin into cerebrospinal fluid of infants and children with bacterial meningitis.

Three consecutive doses of 75 mg of cefoxitin per kg were given intravenously every 6 h (225 mg/kg), in addition to penicillin or ampicillin, to 24 patients on days 4 and 5 and 9 and 10 of therapy for meningitis. Haemophilus influenzae b was isolated from cerebrospinal fluid (CSF) of 21 patients, Streptococcus pneumoniae from 2 patients, and Neisseria meningitidis from 1 patient. The median minimal inhibitory and bactericidal concentrations of cefoxitin for 16 isolates of H. influenzae b were 0.312 and 0.625 micrograms/ml, respectively. Sixteen of 18 isolates of H. influenzae b and S. pneumoniae were killed by 2.5 micrograms of cefoxitin per ml. Mean levels in CSF peaked at 1 h at 6 and 4.9 micrograms/ml on days 5 and 10, respectively. CSF levels on days 5 and 10 were greater than or equal to twice the median minimal inhibitory and bactericidal concentration in 20 and 18 patients, respectively. However, bacterial levels in CSF were greater than or equal to 2.5 micrograms/ml in only 11 of 23 patients on days 5 and 10. No significant adverse effects were found. These data indicate that at this dosage, cefoxitin may not reach levels in the CSF required for killing all susceptible strains of H. influenzae b and S. pneumoniae.

Cefoxitin penetration into cerebrospinal fluid in patients with purulent meningitis.

The penetration of cefoxitin into cerebrospinal fluid (CSF) was studied in 25 patients with purulent meningitis treated with antibiotics other than cefoxitin. Each patient received three 2-g doses of cefoxitin at 6-h intervals. Blood and CSF samples were obtained before and at 2, 4, or 6 h after the first and third doses. CSF cefoxitin concentrations were found in all patients and varied between 1.2 and 22.0 microgram/ml, with a majority of the concentrations falling within a range from 1.2 to 6.2 microgram/ml. The concentrations tended to be higher in CSF samples drawn after the third cefoxitin dose than in those drawn after the first cefoxitin dose, indicating an accumulation of cefoxitin in CSF with repeated doses. Peak cefoxitin concentrations in CSF seemed to occur between 2 and 6 h after intravenous administration of the drug since the highest concentrations were found in patients from whom CSF samples were taken 4 h after the doses. In patients with bacterial meningitis, it should be possible to achieve therapeutic cefoxitin levels in CSF by using nontoxic doses of the antibiotic.

Cefoxitin concentrations in the cerebrospinal fluids of patients with meningitis.

The concentrations of cefoxitin in serum and cerebrospinal fluid (CSF) were measured simultaneously in three groups of patients, 12 with aseptic meningitis (group 1) and 17 and 14 with bacterial meningitis (groups 2 and 3). The patients in group 1 received a single intravenous dose of 2 g of cefoxitin without other antimicrobial therapy. In addition to conventional doses of ampicillin or benzyl penicillin, patients in groups 2 and 3 received repeated infusions of 2 g of cefoxitin every 4 h for the first 3 or 4 days of the study and again on day 10. Additionally, group 3 received probenecid in a loading dose of 1 g followed by 0.5 g every 6 or 8 h. Concentrations of cefoxitin in CSF and serum were determined 1 or 2 h after infusion in group 2 and 2 h after infusion in group 3. The concentrations of cefoxitin in CSF did not reach detectable levels (1.56 microgram/ml) in 11 of the 12 patients in group 1. A level of 2.8 microgram of cefoxitin per ml of CSF was found, with an accompanying level of 30 microgram/ml of serum, in patient 12. In the group 2 patients with bacterial meningitis, the mean CSF concentrations were 3.3, 4.7, and 2.9 microgram/ ml on days 1, 3, and 10 of treatment, with simultaneous serum levels of 8, 9, and 8 microgram/ml. At similar times periods, the mean levels of cefoxitin in group 3 patients (with concomitant probenecid) were 8.6, 12.3, and 4.3 microgram/ml of CSF and 57, 35, 27 microgram/ml of serum.

Penetration of cefoxitin into cerebrospinal fluid of dogs with and without experimental meningitis.

The penetration of cefoxitin into the cerebrospinal fluid (CSF) after slow intravenous infusion of 50-100 mg/kg over 1 hr was studied in normal dogs and in dogs with meningitis experimentally induced by intrathecal injection of 10(9) Staphylococcus aureus. With healthy dogs the peak CSF concentration of 1 microgram of cefoxitin/ml was found to correspond with a serum level of 120 micrograms/ml. With administration of probenecid the CSF level was 1.5 micrograms of cefoxitin/ml. Doubling the dose from 50 to 100 mg/kg resulted in a CSF concentration of 2 micrograms of cefoxitin/ml. In the CSF of animals with meningitis, a peak concentration of 10 micrograms of cefoxitin/ml was obtained 90 min after the start of the infusion, and 5 micrograms/ml was still present at 240 min. The peak level in CSF of animals with meningitis was about 10% of the simultaneous level in serum.

Penetration of cefoxitin into human cerebrospinal fluid: comparison with cefamandole, ampicillin, and penicillin.

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.

Penetration of cefoxitin into cerebrospinal fluid and treatment of meningitis caused by gram-negative bacteria.

Two patients with meningitis caused by antibiotic-resistant Escherichia coli and Klebsiella pneumoniae were treated successfully with intravenous cefoxitin plus oral probenecid. A total of 25 patients with central nervous system disorders that required a diagnostic spinal tap were also given cefoxitin, with or without probenecid, for determination of the degree of penetration into cerebrospinal fluid. In patients with uninflamed meninges, little or no cefoxitin entered after a single dose of 4-6 g. After three doses of 4 g each over a 6-8-hr period, penetration was considerable (average, 7% of the simultaneous serum level). In patients with inflamed meninges, a similar concentration was achieved rapidly after a single 2-g dose. After a day of therapy, cerebrospinal fluid levels equivalent to 30%-70% of the simultaneous serum levels were found; as the inflammation subsided, cerebrospinal fluid levels fell to around 15% of those in serum. Probenecid did not appear to influence greatly the degree of penetration.