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Infant rats with bacteremia and meningitis induced by ampicillin-resistant Haemophilus influenzae type b were treated with ampicillin and nafcillin, alone or in combination. Neither ampicillin alone (in 19 animals) nor nafcillin alone (in 20 animals) sterilized the blood or cerebrospinal fluid of any treated infant rat. When the combination of ampicillin and nafcillin was used, blood cultures were negative in 18 of 19 infant rats, and cerebrospinal fluid cultures were sterile in 15 of 19 when cultured 30 h after initiation of treatment. In vitro results demonstrated definite synergism between ampicillin and nafcillin against ampicillin-resistant H. influenzae type b. The study suggests that such synergism also exists in vivo.

Cerebrospinal fluid (CSF) sterilization after greater than 24 h of intravenous antibiotic therapy (delayed CSF sterilization) was noted in two infants treated with ceftizoxime and ceftazidime for bacterial meningitis. A case-control study was conducted of children between 6 w and 6 y of age treated between 1975 and 1985 at one institution for bacterial meningitis to determine risk factors for delayed CSF sterilization. Hemophilus influenzae type b was isolated from all children (n = 5) with delayed CSF sterilization, compared with only 78% of all children in the study (n = 83). In children with H. influenzae type b disease, children less than 6 mo of age were at higher risk than older children for delayed CSF sterilization (odds ratio = 7.5, 95% confidence limits = 1.4, 40.0). Factors not associated with delayed CSF sterilization included time of follow-up lumbar puncture, CSF total or differential white blood cell count, and CSF protein and glucose concentrations. Despite the in vitro antimicrobial susceptibility of H. influenzae type b to ceftizoxime and ceftazidime, delayed CSF sterilization may occur in infants receiving these antibiotics for bacterial meningitis.

To evaluate cotrimoxazole in the treatment of bacterial meningitis, we compared its action with that of ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis. Both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of infected rabbits, reaching 40 and 26%, respectively, of their simultaneous serum levels. Levels measured 30 and 60 min after intravenous injection exceeded the minimum inhibitory concentration of this combination for H. influenzae by 10- to 100-fold. The mean ratio of trimethoprim to sulfamethoxazole in cerebrospinal fluid was 1:22. Cotrimoxazole was as effective as ampicillin in therapy of beta-lactamase-negative H. influenzae meningitis and as effective as chloramphenicol for a beta-lactamase positive strain. These findings corroborate favorable preliminary clinical experience reported by others and indicate that cotrimoxazole deserves further study in the therapy of bacterial meningitis.

Sixty-two children with Haemophilus meningitis were treated with ampicillin sodium, 200 mg/kg/day for ten days. Thirty-one received the drug intravenously (IV) for ten days; the other 31 patients received ampicillin IV for five days (except for one test dose given intramuscularly [IM] on day 2) followed by IM administration of ampicillin the last five days. Ampicillin concentrations in cerebrospinal fluid (SCF) were higher one hour after IV administration, but at two and four hours, concentrations were greater after IM doses. Responses to therapy and rates of complications were similar in the two groups. Fourteen patients had positive CSF cultures on day 2. Ten of these were isolated only on Levinthal medium and would have been overlooked with routine culture methods. All organisms were ampicillin-susceptible and all CSF cultures were negative by 48 hours. More patients with delayed sterilization had neurologic sequelae (78%) than patients with prompt CSF sterilization (13%). The schedule of five days of IV treatment followed by five days of IM therapy was pharmacologically and clinically as effective as ten days of IV therapy and has practical advantages.

A new methoxymethyl ester of hetacillin is highly lipid-soluble, a property which was expected to enhance its penetration into the central nervous system (CNS). We compared the penetration of the ester and ampicillin into the cerebrospinal fluid (CSF) of normal rabbits and those with experimental Hemophilus influenzae meningitis. In normal rabbits treated by constant intravenous infusion, mean per cent penetration (see article) of the ester was four times as great as that of ampicillin (6.6 +/- 3.7% against 1.6 +/- 1.9%), and the difference in CSF drug levels attained was accentuated when bolus IV infusion was used. Drug concentration in brain tissue was three times as great in a rabbit treated with the ester (0.79 mug/gm against 0.26 mug/gm). In rabbits with meningitis, the ester again achieved higher CSF concentrations. Per cent penetration into CSF in infected rabbits was 23% for the ester and 13% for ampicillin. Bactericidal activity of the drugs was comparable; over 8 hr of treatment both drugs significantly reduced the CSF bacterial titers of infected animals. Our data demonstrated that the ester enters the CSF and CNS in higher concentration than ampicillin, with no loss in bactericidal activity.

Cefamandole and ampicillin were compared in the therapy of experimental Haemophilus influenzae meningitis in rabbits. Three dosages of each drug were administered as a continuous intravenous infusion for 8 hr to 24 infected animals. Samples of serum and cerebrospinal fluid (CSF) were obtained at 0, 4, and 8 hr for determination of antibiotic concentrations and bacterial titers in CSF. Serum levels of cefamandole were higher, but CSF concentrations of both antibiotics were similar. With the 60-mg/kg per hr dose, the mean serum level was 106 +/- 61 mug/ml for cefamandole and 58 +/- 32 mug/ml for ampicillin (P less than 0.05). With this dosage the mean level in CSF was 7.3 +/- 8.4 mug/ml for cefamandole and 9.5 +/- 5.4 mug/ml for ampicillin (P = 0.26). The percentage penetration ([concentration in CSF/concentration in serum] X 100%) was higher for ampicillin (mean, 18.8% +/- 8.9%) than for cefamandole (mean, 5.6% +/- 3.8%) with all dosages tested (P less than 0.001). The rate of bacterial killing in vivo during therapy was similar with both drugs. The efficacy of cefamandole and ampicillin given intramuscularly for five days (250 mg every 8 hr) was examined in 42 rabbits. Twelve of 14 untreated control rabbits died within 24-72 hr of inoculation. In contrast, 11 of 14 rabbits treated with cafamandole and 10 of 14 rabbits treated with ampicillin were cured of their infections. Cefamandole compared favorably with ampicillin in the therapy of experimental H. influenzae meningitis.