To clarify the relationship between CNS toxicity and penetration of fluoroquinolones into human cerebrospinal fluid (CSF), five agents, namely, norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), ciprofloxacin (CPFX) and fleroxacin (AM-833) were given preoperatively to 193 patients with urological diseases. CSF and blood samples were collected during spinal anesthesia at surgery.
1) Firstly, a single dose of 200 mg of drug was given to patients 3 h before lumbar anesthesia. The mean CSF concentration (mean±SE) of AM-833 (0.412±0.082μg/ml) was the highest, followed by OFLX, ENX, CPFX, and NFLX. There were statistically significant differences among AM-833, OFLX>ENX**>CPFX, NFLX**p<0.01, DUNCAN'S multiple comparison procedures) The CSF/serum concentration ratio showed essentially the same tendency.
2) NFLX, ENX or OFLX was given in consecutive doses of 600 mg /day, t. i. d. for 3 days, or CPFX at 600 mg/day, t.i.d. for 5 days, or AM-833 at 200 mg /day once a day for 3 days. CSF samples were collected 3 h after the last dose. In the consecutive dose group, CSF concentrations and CSF/serum ratios were as follows: ENX**(0.661±0.085μg/ml, 0.289±0.028), OFLX**(0.935 ± 0.156μg/ml, 0.315±0.032), CPFX**(0.128±0.014μg/ml, 0.125±0.011) and AM-833*(0.898±0.136μg/ml, 0.304±0.122)*p<0.05, **p<0.01, STUDENT'S t-test). Thus, higher CSF levels and CSF/serum ratios were demonstrated in the consecutive dose group.
3) In the single-dose group of 300 mg of AM-833, the CSF concentration was 0.599± 0.134 μg/ml and the CSF/serum ratio 0.198±0.228. In the consecutive dose group, these values were 1.292±0.154μg/ml and 0.323±0.217. These data suggest dose-dependency for fluoroquinolones.
4) A pharmacokinetic analysis was performed in 28 patients given OFLX and in 25 given AM-833. Plasma and CSF concentration-time profiles of these agents were fitted to a one-compartment open model. The half-life in plasma was 3.9 h for OFLX and 9.0 h for AM-833. CSF levels peaked at 6 h for OFLX and 7 h for AM-833, and subsequently decreased gradually.
These findings suggest that fluoroquinolones penetrated into CSF in patients who had never suffered from cerebrospinal disease.
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