A Study of Cephalothin and Desacetylcephalothin in Cerebrospinal Fluid in Therapy for Experimental Pneumococcal Meningitis

Abstract

One explanation for the failure of cephalothin to cure patients with bacterial meningitis is that desacetylcephalothin, as in vivo metabolite that has less antibacterial activity than the parent drug, penetrates more efficiently into cerebrospinal fluid (CSF); In experimental pneumococcal meningitis in rabbits, the peak levels of cephalothin and desacetylcephalothin in CSF after an intramuscular injection of 250 mg of cephalothin/kg were, respectively, 1.43 +/- 4.9 microgram/ml (2.8% of peak serum level) and 1.69 +/- 0.57 microgram/ml (2.2% of peak serum level). The observed half-life of desacetylcephalothin in CSF (3.32/hr) was longer (P less than 0.01) than that of cephalothin (0.72/hr). Choroid plexuses isolated from the lateral cerebral ventricles of rabbits with meningitis took up cephalothin in vitro more avidly than desacetylcephalothin (P less than 0.05), and metabolism of cephalothin to desacetylcephalothin by isolated choroid plexuses was demonstrated directly. Thus, intrathecal metabolism of cephalothin by the choroid plexus may contribute to the unsatisfactory performance of cephalothin in bacterial meningitis.

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

“…Isolated choroid plexus can metabolize cephalothin to desacetyl-cephalothin (182). To our knowledge, the metabolism of cefotaxime and many other antibiotics within the CNS has not been studied systematically.…”

Pharmacokinetics of β-Lactam Antibiotics

“…The apparent half-life of desacetylcephalothin in rabbit CSF was much greater than cephalothin, and isolated rabbit choroid plexuses demonstrated the ability to metabolize cephalothin to desacetylcephalothin (NOLAN and ULMER 1980). Low levels of antimicrobial activity were noted in heart muscle samples obtained from children with Fallot's disease 60 min after receiving a 100 mg/kg intravenous dose of sodium cephalothin (ADAM et al 1976 a).…”

“…Studies in rabbits with confirmed meningitis would suggest that more than half of the antimicrobial activity detected in CSF may be attributable to desacetylcephalothin (NOLAN and ULMER 1978). The apparent half-life of desacetylcephalothin in rabbit CSF was much greater than cephalothin, and isolated rabbit choroid plexuses demonstrated the ability to metabolize cephalothin to desacetylcephalothin (NOLAN and ULMER 1980).…”