Comparison of the pharmacokinetics of imipenem after intravenous and intrathecal administration in rabbits.

BACKGROUND: Intrathecal administration of antibiotics has potentially high effectiveness for the treatment for severe intracranial infections, particularly nosocomial meningitis. The use of intrathecal injection of antibiotics has been reported mostly in case reports. However, there is sparse data regarding the pharmacokinetics of antibiotics after intrathecal administration. AIM: This study investigated whether intrathecal injection is an effective method for the administration of imipenem. MATERIALS AND METHODS: The pharmacokinetics of imipenem after intrathecal and intravenous administration of 1:1 imipenem: cilastatin (IMI/CIL) to rabbits were compared. RESULTS: The AUC0-t in the cerebrospinal fluid for intrathecal administration was approximately twice that of an equal dose of intravenous administration at doses of 0.35, 0.7, and 1.4 mg/kg. Brain concentrations of imipenem after intrathecal injection were three times greater than observed after intravenous injection and remained high for at least 8 hours post-injection. Elimination of imipenem after administration by either route was primarily via urine, but a transient surge of imipenem in bile and intestinal tissue was observed. CONCLUSIONS: Results indicate that there is a clinical potential for intrathecally administered IMI/CIL. Further studies are warranted to investigate the potential for seizure and to assess the translatability of the rabbit model to human treatment.

Comparative cerebrospinal fluid diffusion of imipenem and meropenem in rats.

The main objective of this study was to compare the cerebrospinal fluid (CSF) diffusion of imipenem and meropenem at steady state, following intravenous infusions at various rates in rats. A preliminary experiment was conducted to estimate the elimination half-lives of these two carbapenem antibiotics, and then to evaluate the infusion duration necessary to reach steady state. CSF diffusion of imipenem was essentially linear over the wide range of infusion rates (66-1,320microg min(-1)) and corresponding steady-state plasma concentrations (11.7-443.0 microg mL(-1)). Conversely the CSF diffusion of meropenem was saturable, with a predicted maximum CSF concentration equal to 1.3 microg mL(-1). Extrapolation of these data to the clinical situation may not be possible since the rats had normal blood-brain and blood-CSF barriers whereas patients with diseases such as meningitis may not. However, it is suggested that the observed differences in the diffusion characteristics of imipenem and meropenem may be partly responsible for their differences in toxicity and efficacy at the central level.

Imipenem but not meropenem induces convulsions in DBA/2 mice, unrelated to cerebrospinal fluid concentrations.

Imipenem and meropenem CSF diffusion was comparable in DBA/2 mice but only imipenem induced convulsions, not related to CSF concentration.

Comparative in vitro killing activities of meropenem, imipenem, ceftriaxone, and ceftriaxone plus vancomycin at clinically achievable cerebrospinal fluid concentrations against penicillin-resistant Streptococcus pneumoniae isolates from children with meningitis.

The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively. Against penicillin-resistant strains, the best killing activity at cerebrospinal fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin. However, while the killing activity of imipenem was significantly greater than that of meropenem, no significant difference was observed between the activities of meropenem and ceftriaxone-vancomycin.

Imipenem/cilastatin treatment of bacterial meningitis in children.

The safety and efficacy of imipenem/cilastatin were evaluated in 21 children, ages 3 to 48 months, with bacterial meningitis. Eradication of bacteria from the cerebrospinal fluid was demonstrated within 24 hours of antibiotic therapy in all but 2 patients who had Haemophilus influenzae type b meningitis and ultimately achieved bacteriologic cure after 2 to 3 days of imipenem/cilastatin therapy. Cerebrospinal fluid penetrations of imipenem and cilastatin were determined at various times after drug administration with mean cerebrospinal fluid: serum ratios of 14 and 10% for imipenem and cilastatin, respectively. The study was terminated when 7 (33%) patients developed seizure activity after antibiotic therapy was administered. The usefulness of imipenem/cilastatin for the treatment of bacterial meningitis in children may be limited by a possible increased incidence of drug-related seizure activity.

Transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system.

The transport of imipenem, a novel carbapenem antibiotic, in the rat central nervous system (CNS) was studied using in vivo, in situ and in vitro experimental techniques. After i.v. bolus administration, the imipenem concentration in the cerebrospinal fluid (CSF) rose to a peak within 30 min and declined with time. The CSF/serum unbound concentration ratio of imipenem was 0.22 at 2 hr after i.v. administration, substantially higher than that reported for benzylpenicillin. By using an in situ brain perfusion technique, we found that imipenem was transported through the blood-brain barrier principally via passive diffusion with a permeability-surface area product comparable to that of mannitol. In vitro, imipenem was accumulated by the isolated choroid plexus via an active organic anion transport system, although much less rapidly than benzylpenicillin. In vivo, after i.c.v. administration, imipenem was cleared from the CNS in a manner comparable to that of mannitol with only a small probenecid-sensitive process. Imipenem thus has minimal affinity for the organic anion transport system in the choroid plexus, resulting in the slow elimination of this drug from the CNS. These results suggest that the difference between imipenem and benzylpenicillin in the ratio of CSF to unbound serum drug concentration is determined principally by the efflux process in the choroid plexus rather than the influx process through the blood-brain barrier.