KINETICS OF OFLOXACIN AND ITS METABOLITES IN CEREBROSPINAL-FLUID AFTER A SINGLE INTRAVENOUS-INFUSION OF 400 MILLIGRAMS OF OFLOXACIN

Ofloxacin has been reported to diffuse readily into the cerebrospinal fluid (CSF) in subjects with both inflamed and uninflamed meninges. Ho wever, with moderately susceptible bacteria, ofloxacin concentrations in CSF may be subtherapeutic after administration of an intravenous (i .v.) dose of 200 mg. For this reason, the kinetics of a higher dose of ofloxacin in CSF was studied with humans. Six patients with occlusive hydrocephalus caused by cerebrovascular diseases who had undergone ex ternal ventriculostomy received 400 mg of ofloxacin i.v. over 30 min. Serum and CSF samples were drawn repeatedly. Serum from 12 healthy vol unteers was sampled repeatedly after they had received 400 mg of oflox acin i.v. over 60 min. Ofloxacin, ofloxacin-N-oxide, and N-desmethyl-o floxacin concentrations were determined by high-pressure liquid chroma tography with fluorescence detection. The maximum ofloxacin concentrat ions in the serum of the patients ranged from 7.36 to 11.6 mg/liter (m ean, 9.55 mg/liter), the apparent volume of distribution/body weight w as 0.96 to 1.19 liters/kg (mean, 1.11 liters/kg), and the total body c learance was 115 to 280 ml/min (mean, 192 ml/min). In healthy voluntee rs, the volume of distribution/body weight and the total body clearanc e were higher and amounted to 1.27 +/- 0.18 liters/kg and 217 +/- 43 m l/min (means +/- standard: deviations), respectively. These difference s were attributed to the older ages of the patients than the volunteer s. In the CSF of patients, maximum concentrations of 1.00 to 2.85 mg/l iter (mean, 2.04 mg/liter) were observed 0.5 to 4 h following the comp letion of the ofloxacin infusion. Ofloxacin elimination from CSF was s lightly slower than that from serum (half-lives, 4.33 to 10.02 versus 4.27 to 9.14 h). The overall penetration of ofloxacin into CSF, as exp ressed by the ratios of the areas under the concentration-time curves, amounted to 0.59 to 0.81 (mean, 0.65). The more hydrophilic metabolit es ofloxacin-N-oxide and N-desmethyl-ofloxacin passed Less readily tha n ofloxacin into the CSF. In conclusion, the concentrations in CSF att ained after a single i.v. infusion of 400 mg of ofloxacin in the absen ce of meningeal inflammation appear to be high enough to inhibit the g rowth of most staphylococci and members of the family Enterobacteriace ae, which are often involved in CSF shunt infections. Yet, in view of pharmacodynamic studies suggesting a peak concentration in CSF of at l east 10-fold the MIC, the use of ofloxacin for central nervous system infections is optimal only with highly susceptible pathogens (MIC, les s than or equal to 0.12 mg/liter).