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

Bitar, Nizar; Claes, R; Auwera, P Van der

doi:10.1128/aac.33.10.1686

Cited by 21 publications

(12 citation statements)

References 22 publications

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“…A nonlinear plasma-CSF transit dependent on the concentration of drug in plasma has been observed with ciprofloxacin in rats, which may have been caused by a carrier-mediated transport from CSF to blood (8). In contrast, the CSF ofloxacin concentrations measured in the present study were approximately twofold greater than those found after administration of the first dose of 200 mg to subjects with uninflamed meninges (2,20); i.e., at doses of 200 and 400 mg, passage from serum to CSF was approximately linear in humans.…”

Section: Discussioncontrasting

confidence: 50%

“…dose of 200 mg (2,15,20,21). The concentrations in CSF were, however, not high enough to be relied upon for use in treating central nervous system (CNS) infections caused by the staphylococci predominantly involved in ventriculitis (2,15,20,21 Table 1). Patients with CNS infections or impaired renal function (creatinine level in serum, >1.2 mg/dl) were not included.…”

mentioning

confidence: 99%

“…In subjects with inflamed and uninflamed meninges, ready passage of ofloxacin into the cerebrospinal fluid (CSF) has been observed after administration of an oral or intravenous (i.v.) dose of 200 mg (2,15,20,21). The concentrations in CSF were, however, not high enough to be relied upon for use in treating central nervous system (CNS) infections caused by the staphylococci predominantly involved in ventriculitis (2,15,20,21 Table 1).…”

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confidence: 99%

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

Nau

Kinzig

Dreyhaupt

et al. 1994

Antimicrob Agents Chemother

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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 (...

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Section: Discussioncontrasting

confidence: 50%

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confidence: 99%

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confidence: 99%

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

Nau

Kinzig

Dreyhaupt

et al. 1994

Antimicrob Agents Chemother

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“…or p.o., to volunteers or patients with normal renal function (1,5). Previous studies have not shown any change in the bioavailability of ofloxacin in infectious disease patients versus normal volunteers (1,2,6,7,11,13,14). The bioavailability of ofloxacin has been previously investigated after administration of single doses (5,15), but to our knowledge this is the first study that has investigated it under steady-state conditions.…”

Section: Methodsmentioning

confidence: 88%

“…The subjects were judged healthy on the basis of the results of the prestudy values of vital signs (pulse, oral temperature, and sitting blood pressure), laboratory profiles (hematology profile, blood chemistry, and urinalysis), urine toxicology screen, and human immunodeficiency virus screen. None of the subjects had a previous history of allergy to 2 h of a dose. For the morning doses, subjects fasted from at least midnight of the previous day.…”

Section: Methodsmentioning

confidence: 99%

Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers

Flor¹,

Rogge²,

Chow³

1993

Antimicrob Agents Chemother

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The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens.Ofloxacin is a synthetic carboxyquinolone antimicrobial agent with potent broad-spectrum bactericidal activity against gram-positive and gram-negative aerobic and facultatively anaerobic bacteria (8 Washout was performed during days 6 to 8. On day 9, the crossover took place and subjects again received p.o. or i.v. ofloxacin (400 mg ql2h) during days 9 to 12. On day 13, they received the last p.o. or i.v. morning dose. All subjects entered the study center at least 12 h prior to administration of the first dose and remained at the center until the last procedure was completed. Subjects were not allowed to eat within 2 h of a dose. For the morning doses, subjects fasted from at least midnight of the previous day. On days 5 and 13, food was not consumed after the prior evening meal until 2 h after the morning dose. Venous blood samples (5 ml) were drawn from each volunteer immediately prior to each dose on days 1, 3, 4, 9, 11, and 12. On days 5 and 13, blood samples were drawn immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 16, and 24 h after dosing began.Analytical procedures. Plasma samples were analyzed for ofloxacin by a sensitive and specific high-pressure liquid chromatographic method previously described (3). After extraction at pH 7 with dichloromethane, the extract was injected onto a C18 ,uBondapak column (25 cm by 4.6 mm [inner diameter]; Waters Associates Inc., Milford, Mass.). The mobile phase consisted of 1.74 g of potassium dihydrogen phosphate and 20 mg of 1-hexanesulfonic sodium salt (Eastman Kodak Co., Rochester, N.Y.) dissolved in 650 ml of distilled water, combined with 350 ml of methanol, and adjusted to pH 3 with phosphoric acid. The imidazolic derivative of ofloxacin (Daiichi Seiyaku) was used as the internal standard. Detection was done with a UV detector at 313 nm. The limit of quantitation was 0.01 mg/liter, and the extraction efficiency was more than 75%. The assay was linear over the concentration range of 0.025 to 9 mg/liter. The intra-and interday coefficients of variation ranged from 3 to 6% over the standard curve concentration range of 0.025 to 9 mg/liter.

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Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man

Nau

Zysk

Thiel

et al. 1993

Eur J Clin Pharmacol

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Various parameters which may be useful in quantification of drug transit from blood into CSF and vice versa after a short duration infusion are compared here by recalculating previously published data from our group. Due to the slower entry into and elimination from the CSF compartment as compared to the central compartment, the ratio of drug concentrations in CSF and serum sampled at the same time increase with time after an infusion. Therefore, concentration quotients of simultaneously drawn blood and CSF are inadequate to characterise CSF penetration. The ratio of the areas under the concentration-time curves in a body fluid and serum (AUCbody fluid/AUCs) is an established measure to quantify overall penetration from the central into a peripheral compartment. AUCCSF/AUCs is closely correlated with the quotient of the maximum CSF and serum concentrations (CmaxCSF/CmaxS) (rs = 0.87, n = 42, P < 0.001) and with the rate constant of distribution in CSF (CLin/VCSF) (rs = 0.80, n = 42, P < 0.001). Since CmaxCSF/CmaxS depends on the mode of drug administration, it is suggested that AUCCSF/AUCs be used to quantify overall drug transit into CSF. CLin/VCSF is of use when CSF can only be sampled once, or when the velocity of the transit of a drug into CSF is to be described. The CSF exit rate constant (CLout/VCSF) characterises elimination from CSF independent of the elimination from serum and may be applied to estimate the formation rate of CSF; in the present study it averaged 20 ml/h.

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

Cited by 21 publications

References 22 publications

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

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

Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers

Pharmacokinetic quantification of the exchange of drugs between blood and cerebrospinal fluid in man

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