Kinetics of ofloxacin and its metabolites in cerebrospinal fluid after a single intravenous infusion of 400 milligrams of ofloxacin

Abstract

Ofloxacin has been reported to diffuse readily into the cerebrospinal fluid (CSF) in subjects with both inflamed and uninflamed meninges. However, 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 external ventriculostomy received 400 mg of ofloxacin i.v. over 30 mmin. Serum and CSF samples were drawn repeatedly. Serum from 12 healthy volunteers was sampled repeatedly after they had received 400 mg of ofloxacin i.v. over 60 min. Ofloxacin, ofloxacin-N-oxide, and N-desmethyl-ofloxacin concentrations were determined by high-pressure liquid chromatography with fluorescence detection. The maximum ofloxacin concentrations in the serum of the patients ranged from 7.36 to '1.6 mg/liter (mean, 9.55 mg/liter), the apparent volume of distribution/body weight was 0.96 to 1.19 liters/kg (mean, 1.11 liters/kg), and the total body clearance was 115 to 280 ml/min (mean, 192 ml/min). In healthy volunteers, the volume of distribution/body weight and the total body clearance were higher and amounted to 1.27 ± 0.18 liters/kg and 217 ± 43 ml/min (means ± standard deviations), respectively. These differences were attributed to the older ages of the patients than the volunteers. In the CSF of patients, maximum concentration's of 1.00 to 2.85 mg/liter (mean, 2.04 mg/liter) were observed 0.5 to 4 h following'the completion of the ofloxacin infusion. Ofloxacin elimination from CSF was slightly 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 expressed by the ratios of the areas under the concentration-time curves, amounted to 0.59 to 0.81 (mean, 0.65). The'more hydrophilic metabolites ofloxacin-N-oxide and N-desmethyl-ofloxacin passed less readily than ofloxacin into the CSF. In conclusion, the concentrations in CSF attained after a single i.v. infusion of 400 mg of ofloxacin in the absence of meningeal inflammation appear to be high enough to' inhibit the growth of most staphylococci and members of the family Entrobacteriaceae, which are often involved in CSF shunt infections. Yet, in view of pharmacodynamic studies suggesting a peak concentration in CSF of at least 10-fold the MIC, the use of ofloxacin for central nervous system infections is optimal only with highly susceptible pathogens (MIC, <0.12 mg/liter).Ofloxacin is a moderately lipophilic quinolone with an octanol-water partition coefficient of 0.41 at pH 7.0, 0.33 at pH 7.2, and 0.28 at pH 7.3 (1, 7, 22) and a molecular mass of 361.4 Da. It is active against gram-positive and gram-negative bacteria. Its antibacterial spectrum may allow ofloxacin to be used for the therapy of ventricular shunt infections. In subjects with inflamed and uninflamed meninges, ready passage of ofloxacin into the cerebrospinal fluid (...

Penetration of Rufloxacin into the Cerebrospinal Fluid in Patients with Inflamed and Uninflamed Meninges

“…The lack of a positive relationship between the CSF/plasma rufloxacin concentration ratio and indices of meningeal permeability in patients with purulent meningitis supports the observation that rufloxacin enters the CSF even in the presence of a normal blood-CSF barrier. Similar results have previously been obtained with ofloxacin (19) and rifampin (17). Passage of lipophilic antibacterial agents across capillary epithelial cells of the blood-CSF barrier is less dependent on the derangement of the barrier than is the transit of hydrophilic compounds (2).…”

Levofloxacin Disposition in Cerebrospinal Fluid in Patients with External Ventriculostomy

“…i.v., the CSF to plasma C max ss ratio 2 h after dosing averaged 35%, ranging between 23 and 42%. Finally, in six patients with external ventriculostomy, Nau and coworkers (20) demonstrated that after administration of a single 400-mg dose, the level of CSF penetration of ofloxacin, namely, the racemate of l-and d-ofloxacin, enabled an average CSF-toserum-AUC ratio of 0.65 (range, 0.59 to 0.81) and a mean peak level in CSF of 2.04 mg/liter to be achieved 1.75 h after dosing. The persistence in the ventricular CSF of effective concentrations that lasted for the entire dosing interval suggested that optimal exposure to levofloxacin may be achieved in all parts of the CSF system, considering that, in general, antibiotic concentrations were found to be severalfold lower at the ventricular CSF level than at the lumbar CSF level (21).…”

Estimation of steady state antibiotic concentration in cerebrospinal fluid from single-dose kinetics

“…They probably cannot be applied to lumbar drug concentrations: The protein concentration gradient from ventricular to lumbar CSF, which also applies to radiolabeled albumin administered IV [17] suggests that, after IV administration antibiotic concentrations found in lumbar CSF may be higher than those in ventricular CSE In fully developed bacterial meningitis, CSF concentrations of hydrophilic drugs were higher than those estimated by us. With lipophilic antibacterials, the CSF concentrations are less influenced by the state of the blood-CSF barrier [5,10,13].…”