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Pharmacokinetic differences between ampicillin and carbenicillin in the cerebrospinal fluid (CSF) were evaluated in experimental staphylococcal meningitis in rabbits after a single intravenous administration of 100 mg/kg dose of each drug. Half-lives (T 1/2) in CSF and CSF/serum ratios of T 1/2 were 52 minutes and 2.1 for ampicillin and 23 minutes and 1.3 for carbenicillin, respectively. These findings indicate that ampicillin is eliminated from CSF more slowly than carbenicillin. Penetration rates were calculated from CSF/serum ratios of area under the curve (AUC) and were 16.8% for ampicillin and 11.6% for carbenicillin, although the maximum concentration (Cmax) of carbenicillin in CSF was twice as high as that of ampicillin. Thus the penetration rate appeared to be influenced more by T 1/2 in CSF than by Cmax. Cmax in CSF was obtained at 15 minutes for carbenicillin and 30 minutes for ampicillin. As to carbenicillin there were considerable individual variations in CSF levels. The above observations suggest that T 1/2 and AUC in CSF are important parameters when evaluating the usefulness of an antibiotic in the treatment of bacterial meningitis.

Pharmacokinetic differences between a bolus and a 60 minutes continuous intravenous administration of 100 mg/kg dose of ampicillin in the cerebrospinal fluid (CSF) were evaluated in the rabbits with experimental staphylococcal meningitis. The maximum concentrations in CSF were 19.3 micrograms/ml for bolus injection and 7.24 micrograms/ml for 60 minutes continuous infusion. Half-lives (T1/2) in CSF and CSF/serum ratios of T1/2 were 29.9 minutes and 1.3 minutes for bolus injection and 48.1 minutes and 1.9 minutes for 60 minutes continuous infusion, respectively. These findings indicate that extremely high concentrations of short duration in serum are required to elevate the concentrations in CSF and the maintenance of certain concentrations in serum are required to keep concentrations above the therapeutic concentrations in CSF. The mean penetration rate derived from the CSF/serum ratios of AUC were 11.1% for bolus injection and 5.5% for 60 minutes continuous infusion. Thus bolus injection is considered to be superior to 60 minutes continuous infusion pharmacokinetically. Bacterial meningitis is one of the diseases in which therapeutic concentrations of antibiotics are difficult to attain at the the site of infections. Therefore, when an intravenous ampicillin is going to be used in the treatment of bacterial meningitis, bolus injection is preferred to 60 minutes continuous infusion.

Two patients with purulent meningitis, of which causative organism was presumed to be E. coli, were treated with intravenous administration of cefmetazole, 300 approximately 400 mg/kg/day in 4 approximately 6 divided doses, and the following conclusions were obtained. 1) Clinical response was favorable and a complete cure was obtained without sequelae in both patients. There were no adverse reactions noted except for a mild and transient eosinophilia (12%) in one case. 2) Of two strains of E. coli recovered from CSF, one was sensitive to ampicillin, cefazolin and cefmetazole, among which cefmetazole had the highest bacterial activity. Although another strain was sensitive to cefmetazole, it showed resistance to cefazolin (greater than 12.5 microgram/ml) and to ampicillin (greater than 100 microgram/ml). 3) Concentrations of cefmetazole in CSF following 1 approximately 2 hours of its intravenous administration were either equal to or higher than those of ampicillin, which was given to the same patient for a short period of time. The concentrations in CSF were higher than 3.1 microgram/ml on each occasion except for in some specimens during the convalescent phase and exceeded well the MIC of the causative organism. 4) Based on the above results, cefmetazole is considered to be a potent antibiotic in the treatment of E. coli meningitis. Although further studies are needed as to the dosage, an intravenous administration at 4-hour interval appears to be warranted based on the studies that the half-life of the drug is short in CSF in animal experiments.

A study was done on cefodizime (THR-221, CDZM) in combination with ampicillin (ABPC) for its transferability to cerebrospinal fluid (CSF) of rabbits with experimental meningitis caused by Staphylococcus aureus. Blood and CSF were collected at 15, 30, 45, 60, 90, 120 and 180 minutes after intravenous administration of CDZM at 100 mg/kg to 6 rabbits, ABPC at 100 mg/kg to 4 rabbits and simultaneous administration of both drugs at 100 mg/kg each to 5 rabbits. Drug concentrations were assayed with an high performance liquid chromatography method, and pharmacokinetic parameters were calculated. The comparison revealed no significant difference in concentrations achieved among different groups. Therefore, the mutual transferability of these drugs to CSF was not considered to interact adversely due to the simultaneous administration of both drugs. Accordingly, CDZM may be a candidate of chemotherapeutics in the therapy of purulent meningitis, and it is worthy of further investigations.

Aztreonam (AZT) and ampicillin (ABPC) were independently administered to 6 and 7 rabbits respectively, with S. aureus meningitis. Additionally, AZT and ABPC were concomitantly given to 6 rabbits with S. aureus meningitis. Concentrations of AZT and ABPC in cerebrospinal fluid (CSF) and serum were determined by HPLC method, and the results in concomitant treatment were compared with those for single treatment of each agent. Results were as follows: Maximum serum concentrations of AZT in concomitant treatment of AZT and ABPC were higher than those in single treatment of AZT. However, there was no significant difference between the 2 treatment groups with regard to maximum CSF concentration, percentage of AUC of CSF to serum, and T1/2 of the CSF and serum concentrations of AZT. ABPC in the concomitant treatment did not influence the CSF concentration of AZT. There was no significant difference in serum concentration of ABPC between concomitant treatment and the single one. However, the values of maximum CSF concentration, percentage of maximum CSF to serum concentration and percentage of AUC of CSF to serum in the concomitant treatment were lower than those in the single treatment of ABPC. With regard to T1/2 of CSF concentration of ABPC, there was no remarkable difference between the 2 treatment groups. The above results suggest that the distribution of ABPC into CSF is suppressed in the concomitant treatment of AZT and ABPC. AZT has no antimicrobial activity against Gram-positive bacteria. The CSF concentration of ABPC is suppressed in the concomitant treatment. Those facts suggest that AZT should be administered for meningitis cases after the identification of causative pathogens.

Concentrations of sulbactam (SBT) and ampicillin (ABPC) in the blood and cerebrospinal fluid (CSF) following an intravenous administration of SBT/ABPC at a dose of 150 mg/kg (SBT/ABPC = 1:2) were determined in 12 rabbits with staphylococcal meningitis. Drug concentrations were measured 9 times, 6 times each with intervals of 15 minutes and thereafter with intervals of 30 minutes. The results were compared with those of a group of 9 rabbits given 100 mg/kg of ABPC alone. 1. The maximum concentration of SBT in the CSF and the percentages of both the maximum concentration and the area under the concentration-time curve (AUC) of SBT in CSF vs. those in serum of the SBT/ABPC group were higher than those of ABPC and the half-life of SBT in the CSF was also longer than that of ABPC, all with significant difference. When these parameters for SBT of SBT/ABPC groups were compared with those of ABPC of the ABPC group, not much differences existed between the 2 groups except that the CSF half-life of SBT was much longer than that of ABPC. 2. The percentages of both the maximum concentration and AUC of ABPC in CSF vs. those in serum of the SBT/ABPC group were significantly lower than those of ABPC of the ABPC group. The CSF half-life of ABPC of the former group was longer than that of the latter. 3. The above results suggest that when SBT and ABPC are administered simultaneously, the penetration of ABPC into the CSF is inhibited.