Randomized pharmacokinetic and pharmacodynamic comparison of fluoroquinolones for tuberculous meningitis.

Tuberculous meningitis (TBM) is the most lethal form of tuberculosis, and new treatments that improve outcomes are required. We randomly assigned adults with TBM to treatment with standard antituberculosis treatment alone or in combination with ciprofloxacin (750 mg/12 h), levofloxacin (500 mg/12 h), or gatifloxacin (400 mg/24 h) for the first 60 days of therapy. Fluoroquinolone concentrations were measured with plasma and cerebrospinal fluid (CSF) specimens taken at predetermined, randomly assigned times throughout treatment. We aimed to describe the pharmacokinetics of each fluoroquinolone during TBM treatment and evaluate the relationship between drug exposure and clinical response over 270 days of therapy (Controlled Trials number ISRCTN07062956). Sixty-one patients with TBM were randomly assigned to treatment with no fluoroquinolone (n = 15), ciprofloxacin (n = 16), levofloxacin (n = 15), or gatifloxacin (n = 15). Cerebrospinal fluid penetration, measured by the ratio of the plasma area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the cerebrospinal fluid AUC(0-24), was greater for levofloxacin (median, 0.74; range, 0.58 to 1.03) than for gatifloxacin (median, 0.48; range, 0.47 to 0.50) or ciprofloxacin (median, 0.26; range, 0.11 to 0.77). Univariable and multivariable analyses of fluoroquinolone exposure against a range of different treatment responses revealed worse outcomes among patients with lower and higher plasma and CSF exposures than for patients with intermediate exposures (a U-shaped exposure-response). TBM patients most likely to benefit from fluoroquinolone therapy were identified, along with exposure-response relationships associated with improved outcomes. Fluoroquinolones add antituberculosis activity to the standard treatment regimen, but to improve outcomes of TBM, they must be started early, before the onset of coma.

Effects of acute renal failure and ganciclovir on the pharmacodynamics of levofloxacin-induced seizures in rats.

Seizures have been reported in patients receiving fluoroquinolones, including levofloxacin (LVFX). In the present study, we investigated the effects of experimental renal failure and the concomitant treatment with ganciclovir on the pharmacodynamics of LVFX-induced seizures to identify whether these factors can alter the pharmacokinetics or the pharmacodynamics of LVFX. Male Wistar rats received an intravenous infusion of LVFX at 250, 500, or 1000 mg/h/rat until the onset of seizures, and samples of serum, brain, and cerebrospinal fluid (CSF) were obtained. The concentration of LVFX in CSF at the onset of seizures was not affected by the infusion rate, whereas that in serum and brain increased with increasing infusion rate. This suggests that the concentration of LVFX in CSF is an appropriate index of the drug concentration at the site of action. The concentration of LVFX in CSF at the onset of seizures was significantly lower in rats with renal failure than in the control rats. Pretreatment with methylguanidine, an uremic toxin, at 600 mg/h/rat for 8 min reduced the concentration of LVFX in CSF at the onset of seizures and the total body clearance of LVFX after the intravenous injection. In rats pretreated with ganciclovir at 500 mg/h/rat for 1 h, the concentration of LVFX in CSF at the onset of seizures was significantly lower than the control rats. These results suggest that renal failure and ganciclovir can be the risk factors for LVFX-induced seizures, and that they increase the sensitivity of the central nervous system to LVFX-induced seizures.

The influence of indomethacin co-administration on ofloxacin levels in plasma and cerebrospinal fluid in rats.

The possible increase of ofloxacin levels in serum and cerebrospinal fluid (CSF) by concomitant indomethacin administration was investigated in 120 healthy adult rats. The animals were administered intramuscular doses of ofloxacin 30 mg/kg alone (Group A, n = 60) or with indomethacin 2 mg/kg (Group B, n = 60). Blood and CSF samples were obtained from both groups at 30, 45, 60 and 90 min post-administration. Concentrations of ofloxacin were estimated using a microbiological assay. Co-administration of indomethacin did not affect plasma levels of ofloxacin significantly; however, higher levels were found in all CSF samples after co-administration with indomethacin, particularly after 90 min with 0.59 microg/ml versus zero median values when only ofloxacin was administered (P = 0.05). No central nervous system adverse effects were observed clinically. No correlation between levels of ofloxacin in plasma and CSF could be established either in rats administered only ofloxacin or in rats administered both drugs. The presented pharmacokinetic findings revealed that co-administration of ofloxacin and indomethacin may result in protracted quinolone levels in the CSF. However, the absence of significant correlation between concentrations of ofloxacin in plasma and CSF upon co-administration of indomethacin, as well as of central nervous system adverse effects, make the probability of an epileptogenic interaction between them unlikely. These results merit further clinical evaluation.

Ceftriaxone acts synergistically with levofloxacin in experimental meningitis and reduces levofloxacin-induced resistance in penicillin-resistant pneumococci.

Ceftriaxone acted synergistically with levofloxacin in time-killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L). Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25. In the experimental rabbit meningitis model, ceftriaxone (1x 125 mg/kg) was slightly less bactericidal (-0.30 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) cfu/mL(.)h) to either monotherapy. In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4. After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC). In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively. The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains.

Levofloxacin disposition in cerebrospinal fluid in patients with external ventriculostomy.

In vitro levofloxacin exhibits both potent or intermediate activity against most of the pathogens frequently responsible for acute bacterial meningitis and synergistic activity with some beta-lactams. Since levofloxacin was shown to penetrate the cerebrospinal fluid (CSF) during meningeal inflammation both in animals and in humans, the disposition of levofloxacin in CSF was studied in 10 inpatients with external ventriculostomy because of communicating hydrocephalus related to subarachnoid occlusion due to cerebral accidents who were treated with 500 mg of levofloxacin intravenously twice a day because of extracerebral infections. Plasma and CSF concentration-time profiles and pharmacokinetics were assessed at steady state. Plasma and CSF levofloxacin concentrations were analyzed by high-pressure liquid chromatography. The peak concentration of levofloxacin at steady state (C(max ss))was 10.45 mg/liter in plasma and 4.06 mg/liter in CSF, respectively, with the ratio of the C(max ss) in CSF to the C(max ss) in plasma being 0.47. The areas under the concentration-time curves during the 12-h dosing interval (AUC(0-tau)s) were 47.69 mg. h/liter for plasma and 33.42 mg. h/liter for CSF, with the ratio of the AUC(0-tau) for CSF to the AUC(0-tau) for plasma being 0.71. The terminal-phase half-life of levofloxacin in CSF was longer than that in plasma (7.02 +/- 1.57 and 5.51 +/- 1.36 h, respectively; P = 0.034). The ratio of the levofloxacin concentration in CSF to the concentration in plasma progressively increased with time, from 0.30 immediately after dosing to 0.99 at the end of the dosing interval. In the ventricular CSF of patients with uninflamed meninges, levofloxacin was shown to provide optimal exposure, which approximately corresponded to the level of exposure of the unbound drug in plasma. The findings provide support for trials of levofloxacin with twice-daily dosing in combination with a reference beta-lactam for the treatment of bacterial meningitis in adults. This cotreatment could be useful both for overcoming Streptococcus pneumoniae resistance and for enabling optimal exposure of the CSF to at least one antibacterial agent for the overall treatment period.

Cefotaxime acts synergistically with levofloxacin in experimental meningitis due to penicillin-resistant pneumococci and prevents selection of levofloxacin-resistant mutants in vitro.

Cefotaxime, given in two doses (each 100 mg/kg of body weight), produced a good bactericidal activity (-0.47 Deltalog(10) CFU/ml. h) which was comparable to that of levofloxacin (-0.49 Deltalog(10) CFU/ml. h) against a penicillin-resistant pneumococcal strain WB4 in experimental meningitis. Cefotaxime combined with levofloxacin acted synergistically (-1.04 Deltalog(10) CFU/ml. h). Synergy between cefotaxime and levofloxacin was also demonstrated in vitro in time killing assays and with the checkerboard method for two penicillin-resistant strains (WB4 and KR4). Using in vitro cycling experiments, the addition of cefotaxime in sub-MIC concentrations (one-eighth of the MIC) drastically reduced levofloxacin-induced resistance in the same two strains (64-fold increase of the MIC of levofloxacin after 12 cycles versus 2-fold increase of the MIC of levofloxacin combined with cefotaxime). Mutations detected in the genes encoding topoisomerase IV (parC and parE) and gyrase (gyrA and gyrB) confirmed the levofloxacin-induced resistance in both strains. Addition of cefotaxime in low doses was able to suppress levofloxacin-induced resistance.

Cerebrospinal fluid penetration of levofloxacin in patients with spontaneous acute bacterial meningitis.

We have assessed levofloxacin penetration in cerebrospinal fluid (CSF) and the liquor-to-plasma ratio (C(L)/C(P)) at 2 hours after dosing in 5 patients with spontaneous acute bacterial meningitis. CSF levofloxacin concentration at 2 hours after dosing was 1.99+/-0.67 microg/mL, and the C(L)/C(P) at 2 hours after dosing was 0.34+/-0.09.

Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model.

This study was designed to investigate the penetration across the blood-brain barrier of three doses of levofloxacin using a microdialysis probe implanted into the cerebrospinal fluid (CSF) of a rabbit pneumococcal meningitis model. The microdialysis guide cannula was implanted into rabbit subarachnoid space using a stereotaxic frame. After 3 days, 10(4) cfu Streptococcus pneumoniae serotype 3 in 0.3 mL saline was injected via intracisternal puncture and animals were allowed to incubate the organisms for 16-18 h. Groups of animals (n = 5) then received 7, 10.5 or 14 mg/kg iv of the drug over 10 min. Plasma samples were obtained via an ear vein 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h after the antibiotic infusion. CSF microdialysis effluent samples were collected every 0.5 h for the entire experiment. Plasma and microdialysis effluent samples were analysed by HPLC. AUC(0-8) in plasma and CSF were computed using the trapezoid rule. The elimination half-life in plasma and CSF was calculated using non-linear regression analysis. The unbound peak plasma concentrations for the three doses studied were 3.9, 6.4 and 10.3 mg/L, respectively. There was a significant increase in the plasma AUC(0-8) [29.7 +/- 6.3, 49.1 +/- 19.1 and 67.6 +/- 8.9 mg x h/L (P < 0.005)]. The unbound peak CSF concentrations were 3.8, 5.7 and 8.6 mg/L and occurred at 0-0.5 h after the administration of the dose. The AUC(CSF(0-8)) was significantly higher as the dose was increased (7 mg/kg, 15.8 +/- 6.6; 10.5 mg/kg, 37.3 +/- 7.8; and 14 mg/kg, 46.4 +/- 20.9 mg x h/L; P < 0.03). The penetration of levofloxacin averaged 53% for the 7 mg/kg dosage group, 76% for the 10.5 mg/kg group and 68% for the 14 mg/kg group. Our results demonstrate that levofloxacin penetration into the CSF averages 66% for the doses that would be used in clinical practice.

[Determination of levofloxacin in plasma and cerebrospinal fluid with HPLC and its pharmacokinetics in patients undergoing neurosurgical operations].

A RP-HPLC method was developed to determine the concentrations of levofloxacin in plasma and cerebrospinal fluid and its pharmacokinetics were studied in patients undergoing neurosurgical operations. C18H37 column was eluted with the mobile phase consisting of 10 mmol.L-1 KH2PO4-10 mmol.L-1(C4H9)4Br-CH3CN(45:45:10, pH 3.0) and the utraviolet absorbance was monitored at 295 nm. Ciprofloxacin was used as internal standard. The mean recoveries were 74.76% in plasma and 82.43% in cerebrospinal fluid, with the lowest detectable limits of 10 micrograms.L-1 and 6 micrograms.L-1, respectively. The RSD for the intra-day and inter-day were all less than 5%. A single oral administration of 300 mg levofloxacin tablet was given to 10 patients undergoing neurosurgical operations. The pharmacokinetic parameters in blood and in cerebrospinal fluid could be described by one compartment open model. The pharmacokinetic parameters were: blood Ke 0.12 +/- 0.04 h-1, T1/2 6.05 +/- 1.68 h, Tmax 1.05 +/- 0.29 h, Cmax 3.67 +/- 0.42 mg.L-1, AUC 33.43 +/- 7.32 mg.h.L-1, CLs 9.46 +/- 2.53 L.h-1, Vd 77.49 +/- 7.39 L; cerebrospinal fluid Ke 0.11 +/- 0.04 h-1, T1/2 6.95 +/- 1.88 h, Tmax 3.56 +/- 1.24 h, Cmax 1.68 +/- 0.25 mg.L-1, AUC 23.70 +/- 5.62 mg.h.L-1, CLs 13.70 +/- 5.11 L.h-1, Vd 126.61 +/- 13.20 L.

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. 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 min. 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 11.6 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 concentrations 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-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 Enterobacteriaceae, which are often involved in CSF shunt infection. 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 systems infections is optimal only with highly susceptible pathogens (MIC, less than or equal to 0.12 mg/liter).

Prediction of brain delivery of ofloxacin, a new quinolone, in the human from animal data.

We attempted to predict the delivery of ofloxacin (OFLX), a new quinolone antibacterial agent (NQ), into cerebrospinal fluid (CSF) in the human based on the physiological properties and pharmacokinetic parameters of NQs in various animals. Physiological properties for evaluation of drug delivery into CSF such as volume and the bulk flow rate of CSF and weight of choroid plexus, were compared among the rat, rabbit, cat, dog, and human. Statistically significant correlations with power values of 0.82-0.89 in the linear regression were observed on log-log plots between brain weight and those properties of each species. Delivery of OFLX into CSF from blood was analyzed by "diffusion and flow model" with unidirectional efflux process from CSF to blood. The blood-CSF diffusion clearance and the efflux clearance of OFLX in the human were extrapolated from animal data based on the allometric correlations between brain weight and these parameters in the rat, rabbit, and dog. The apparent volume of distribution and the total body clearance of NQs in the human could also be predicted from animal data based on the classical Adolph-Dedrick approach. To simulate the CSF concentration-time profile of OFLX in the human by using these predicted parameters, it was necessary to consider both the lumbar CSF compartment and the ventricular CSF compartment. Both plasma and CSF concentration-time profiles of OFLX predicted from only animal experimental data were in good agreement with those observed clinically.

Comparative study of permeability into rat cerebrospinal fluid of the quinolones: dependency on their lipophilicities.

Pharmacokinetic behavior involved in the entry of four quinolone antibacterial agents, norfloxacin (NFLX), ciprofloxacin (CPFX), ofloxacin (OFLX) and nalidixic acid (NA), into cerebrospinal fluid (CSF) was comparatively investigated in rats. Periodically, after the bolus i.v. dose of each quinolone (10 mg/kg), aliquots of CSF were collected by cisternal puncture and blood samples were then withdrawn from the jugular vein. CSF and serum (total and unbound) levels of the drugs were determined by HPLC method. Transport parameters for three new quinolones (NFLX, CPFX, OFLX) into CSF were obtained by physiological model analysis. Serum levels of OFLX and NFLX declined bi-exponentially with time, whereas the serum levels of NA and CPFX declined in mono-exponential and tri-exponential fashion, respectively. Fractions of each quinolone unbound to serum protein (approximately 0.7 for NFLX, CPFX, and OFLX, 0.12 for NA) were almost the same at any point in time. The CSF levels of these quinolones rose quite rapidly after drug administration, and then declined, along with their serum levels. Both the CSF level and the ratio of CSF concentration to serum unbound concentration were the highest for NA, followed by OFLX, CPFX and NFLX. These values of the four quinolones were almost proportional to the apparent partition coefficient (Papp) between n-octanol and phosphate buffer (pH 7.0) values of each reported in a previous paper [Tsuji et al., Antimicrob. Agents Chemother., 32, 190 (1988)]. In the three new quinolones, OFLX had a larger value of apparent diffusional clearance between blood and CSF (PAc) than CPFX and NFLX.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of fenbufen on the entry of new quinolones, norfloxacin and ofloxacin, into the central nervous system in rats.

The entry of two new quinolone antibacterial agents, norfloxacin and ofloxacin, into the central nervous system (CNS) of rats, and the effect of fenbufen on this was investigated. At various times after the administration of a bolus intravenous dose of norfloxacin or ofloxacin (10 mg kg-1) with or without fenbufen (20 mg kg-1), serum and cerebrospinal fluid (CSF) samples and whole brain were collected from the rats and the concentration of norfloxacin or ofloxacin in each sample was determined. Serum concentrations of both quinolones declined biexponentially with time and were significantly elevated by coadministration with fenbufen at the terminal phase. The fractions of these quinolones bound to serum protein were not altered by coadministration with fenbufen. Coadministered fenbufen raised the brain concentrations of both quinolones but did not affect their brain to serum unbound concentration ratios. In contrast, CSF to serum unbound concentration ratios as well as CSF concentrations of norfloxacin and ofloxacin were elevated by coadministration with fenbufen. Apparent diffusional clearances between blood and CSF of norfloxacin and ofloxacin estimated by the physiological model analysis increased by 1.9 and 2.6 times, respectively, after coadministration with fenbufen. These findings suggest that coadministered fenbufen may facilitate the entry of norfloxacin and ofloxacin into the CNS.

Concentrations of ofloxacin in serum and cerebrospinal fluid of patients without meningitis receiving the drug intravenously and orally.

The cerebrospinal fluid (CSF) penetration of ofloxacin given orally or or intravenously was studied in cancer patients without meningitis. Each patient was assigned to a different sampling time to assess the relation between time and penetration. Ofloxacin was measured in serum and CSF by high-pressure liquid chromatography and bioassay. In addition, the bactericidal titers were measured in CSF and serum against a set of relevant bacteria. Concentrations measured by high-pressure liquid chromatography and bioassay were well correlated. Peak concentrations in CSF (0.4 to 1 microgram/ml) were observed 2 to 4 h after infusion or oral administration. Peak concentrations in serum were observed just after infusion (2 to 3.5 micrograms/ml) or 1 to 2 h after oral administration (1.7 to 4 micrograms/ml). Measured bactericidal titers were well correlated with the titers expected from the MBC and concentration. High CSF bactericidal titers were observed against Neisseria meningitidis, Haemophilus influenzae, and Escherichia coli, whereas low or no bactericidal titers were obtained against Staphylococcus aureus, Listeria monocytogenes, and Streptococcus pneumoniae.

Diffusion of ofloxacin into cerebrospinal fluid of patients with purulent meningitis or ventriculitis.

The penetration of ofloxacin was studied in 22 patients with purulent meningitis or ventriculitis treated with conventional antibiotics. Three successive doses of 200 mg were infused at 12-h intervals during the acute stage of the disease. Ten patients received three additional doses when the meninges were considered to be healed. Cerebrospinal fluid (CSF) was drawn 0.5, 3, 6, or 12 h after the last infusion. Serial plasma and CSF samples were also obtained from patients with ventricular drainage. Concentrations in CSF ranged from 0.96 +/- 0.15 to 1.80 +/- 0.29 microgram/ml, depending on sampling time. The percentage of penetration in ventricular fluid, expressed as the ratio of the CSF area under the curve from 0 to 12 h to the plasma area under the curve from 0 to 12 h, was 73 +/- 6. Ofloxacin readily diffuses into CSF of patients with meningitis or ventriculitis and may be useful for treatment of CSF infections caused by susceptible pathogens.

Entry of the new quinolone antibacterial agents of ofloxacin and NY-198 into the central nervous system in rats.

The present study describes quantitatively the pharmacokinetics of the antibacterial agents, ofloxacin and NY-198 (quinolonecarboxylic acid derivatives), in the central nervous system in rats by physiological modeling of the penetration, distribution and sequestration processes. The stimulation curves corresponded well with the observed concentrations in the cerebrospinal fluid (CSF) and various brain regions after intravenous bolus administration. The estimated cerebrovascular diffusion clearances were considerably small compared with reported serum flow rates and similar among the brain parenchymal tissues examined. The distribution volume of each drug in each brain region was almost the same as the brain extracellular space (15 to 25% of the wet weight). It was also found that the Kp values of these drugs were similar among the various brain regions. These lines of evidence suggest that the antibacterial agents, ofloxacin and NY-198, localized only in the brain extracellular space and exhibited little region-specificity in distribution into the brain. Moreover, it was suggested from unexpectedly low CSF: serum concentration ratios after intravenous administration that these quinolones, which once diffused into CSF, could be sequestrated from CSF to blood via some transport system.