Population pharmacokinetics of ciprofloxacin in neonates and young infants less than three months of age.

Ciprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography-mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

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.

Cerebrospinal fluid penetration of high doses of intravenous ciprofloxacin in meningitis.

Nosocomial meningitis due to gram-negative organisms is a difficult clinical problem to manage because of both antibiotic resistance and poor penetration of many antimicrobials across the blood-brain barrier. Ciprofloxacin has potential in treating this condition when used in high doses. We investigated the plasma and cerebrospinal fluid (CSF) levels of ciprofloxacin in a patient with Pseudomonas aeruginosa meningitis who was treated with 400 mg of intravenous ciprofloxacin every 8 hours. Ciprofloxacin levels in plasma peaked at 10.29 mg/L without resulting in accumulation (8-hour trough levels, <1 mg/L), whereas the CSF level increased to 0.9 mg/L. This CSF level was confirmed to be similar 1 week later. After 1 week of therapy, during which there were no side effects attributable to ciprofloxacin, the organism was eradicated, and there was some clinical improvement. We recommend that 400 mg of intravenous ciprofloxacin every 8 hours be considered for treatment of difficult-to-treat gram-negative bacillary meningitis.

Inhibitory effect of new quinolones on GABA(A) receptor-mediated response and its potentiation with felbinac in Xenopus oocytes injected with mouse-brain mRNA: correlation with convulsive potency in vivo.

Convulsions induced by the interaction of new quinolone antimicrobial agents (NQs) and nonsteroidal anti-inflammatory drugs (NSAIDs) were previously reported, and blockade of GABA(A) receptor by NQs and its potentiation with NSAIDs were considered as one of its possible mechanisms. However, useful methodology for prediction of convulsive potencies of NQs with or without NSAIDs in vivo based on in vitro screening was not established. Therefore, we applied the Xenopus oocytes translation system of exogenous messenger RNA (mRNA) to examine the mechanism of convulsion induced by interaction of NQs and NSAIDs, and the relationship between convulsive potencies in vivo and inhibitory effect on GABA-induced current response in vitro was investigated. This system also has alternative possibility for the in vivo toxicological studies sacrificing innumerous animals. Glutamic acid, kainic acid, quisqualic acid, NMDA, and serotonin-induced currents were not modified by ENX of NQs and/or FLB of NSAIDs, while glycine- and ACh-induced currents were slightly inhibited. GABA (10 microM)-induced current was inhibited by norfloxacin (NFLX), ciprofloxacin, ENX, and ofloxacin (OFLX) with IC50 of 17, 33, 58, and 280 microM, respectively. IC50 of NQs decreased to 1/3 (OFLX)-1/165 (NFLX) in the presence of 10 microM FLB, while FLB did not modulate the GABA response in the absence of NQs. CSF concentration of ENX at the time of convulsion in clinical situation approximated the IC50 of ENX for the GABA response. The increase of incidence for NQs-induced convulsion by concomitant NSAIDs in vivo could also be explained by the potentiation of inhibitory effects of NQs with FLB in the normal range of CSF concentration of these drugs. We also examined convulsive potency (threshold dose for convulsion) in CNS by intracerebral infusion of NQs to mice with or without FLB pretreatment, and significant correlations between the convulsive potencies and IC50 of NQs for the GABA response were observed. These findings suggested that the blockade of GABA-ersic neurotransmission in CNS is a dominant mechanism of convulsion induced by NQs and that the convulsant-adverse reaction of NQs in vivo may be predicted from the inhibitory effect on the GABA(A) receptor in vitro using the Xenopus oocytes translation system of exogenous mRNA.

Determination of the in vivo post-antibiotic effects of ciprofloxacin and rifampicin.

A modified rabbit meningitis model is described for determining the PAE in vivo, which utilised a self-standing device for repeatedly sampling pure CSF. The model allowed the PAEs of ciprofloxacin and rifampicin on Escherichia coli ATCC 25922 to be determined following PAE induction in vitro, or in vivo in CSF after intrathecal injection or during the last 1.5 h of a 7 h iv continuous infusion. The estimated volumes of distribution of ciprofloxacin and rifampicin in CSF were 0.68 +/- 0.24 mL and 0.74 +/- 0.04 mL, respectively, and the terminal elimination half lives were 1.8 +/- 0.5 h and 2.2 +/- 0.3 h, respectively. PAEs of approximately 2 h were obtained in vivo and in vitro after exposing E. coli to 3 x MIC of ciprofloxacin in vitro and to 1 x MIC of drug in vivo. When the organism was exposed to rapidly declining concentrations in vivo, only a minimal PAE was observed for both antibiotics. Moreover, a PAE of 3.1 +/- 1.3 h of rifampicin was obtained in vivo, being smaller than the 4.8 h PAE observed in vitro, which might be explained by the binding of 45 +/- 6.5% rifampicin to proteins in the CSF.

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)

The treatment of neonatal meningitis due to gram-negative bacilli with ciprofloxacin: evidence of satisfactory penetration into the cerebrospinal fluid.

We describe two cases of neonatal meningitis due to Gram-negative bacilli treated successfully with ciprofloxacin. Examination of serial samples of cerebrospinal fluid indicated the effect of meningeal inflammation on penetration of this drug into the CSF.

In vitro postantibiotic effects following multiple exposures of cefotaxime, ciprofloxacin, and gentamicin against Escherichia coli in pooled human cerebrospinal fluid and Mueller-Hinton broth.

Multiple exposures with cefotaxime in either Mueller-Hinton broth or cerebrospinal fluid had no effect on killing or the duration of postantibiotic effect (PAE) in Escherichia coli strains tested. However, upon multiple exposures in Mueller-Hinton broth, ciprofloxacin and gentamicin PAEs significantly decreased with a concomitant reduction in bacterial killing. A reduction in bacterial killing following multiple ciprofloxacin and gentamicin exposures was also seen with cerebrospinal fluid; however, the PAE was maintained.

Cerebrospinal fluid transport and disposition of the quinolones ciprofloxacin and pefloxacin in rats.

The disposition of ciprofloxacin and pefloxacin in the rat cerebrospinal fluid (CSF) was investigated after i.v. and i.c.v. administration. After injection into the lateral ventricle, the terminal half-life of pefloxacin was shorter than that of ciprofloxacin. After i.v. infusions, the relative CSF exposure, expressed as CSF: area under the plasma concentration time curve ratio, were found to be 10.4 +/- 2.8% for ciprofloxacin and 42.4 +/- 3.0% for pefloxacin. The unit impulse response methodology was applied in order to assess the CSF transport profile. The plasma-CSF transport clearance of pefloxacin and the total amount of drug transported into the CSF were significantly higher compared with ciprofloxacin. Although pefloxacin exhibited a linear CSF transport profile, the plasma-CSF transport clearance of ciprofloxacin was found to be nonlinear at the dose level studied. Pefloxacin was converted in the brain to the active metabolite norfloxacin (N-desmethyl pefloxacin). The difference in CSF exposure of both quinolones and the presence of active metabolites of N-methylated quinolones in the CSF may be of clinical relevance in the treatment of CNS infections, but differences in antimicrobial activity have to be taken into account as well.

Enhanced entry of ciprofloxacin into the rat central nervous system induced by fenbufen.

The effects of fenbufen on the transport of ciprofloxacin (CPFX) into the brain and cerebrospinal fluid (CSF) were investigated in rats. Periodically after a bolus i.v. dose of CPFX (10 mg/kg), alone or with fenbufen (20 mg/kg), to rats, aliquots of CSF and blood were collected and then the whole brain was readily excised from the animal after sacrifice by microwave irradiation. Serum levels of CPFX in the terminal phase were significantly elevated by the coadministration with fenbufen. However, the extent of CPFX binding to serum protein was not affected by fenbufen. Immediately after the coadministration with fenbufen, brain and CSF levels of CPFX were raised by about 15 to 70% and 70 to 100%, respectively. Both brain/serum unbound and CSF/serum unbound level ratios were increased by fenbufen at relatively early periods after drug injection. Analysis based on physiological models indicated that fenbufen significantly increased the apparent diffusion clearances of CPFX across blood-brain and blood-CSF barriers. These findings suggest that coadministered fenbufen may facilitate the entry of CPFX into the central nervous system not only by elevation of serum level but also by enhancement of permeability across the blood-brain or blood-CSF barrier.

Penetration of ciprofloxacin into human cerebrospinal fluid in patients with inflamed and non-inflamed meninges.

The penetration of ciprofloxacin into the cerebrospinal fluid (CSF) in 25 patients with non-inflamed meninges and in 9 patients with inflamed meninges was studied. In the patients with non-inflamed meninges plasma and CSF were obtained 1-10 h after the second dose of ciprofloxacin and in the patients with inflamed meninges 1, 2, 3, 5, 7 and 9 h after the second dose. In the first group (non-inflamed meninges) data from 6 patients were obtained 4, 5 and 6 h post-dose. Mean ciprofloxacin concentrations in the CSF ranged from 0.073 mg/l to 0.106 mg/l during this observation time, while in the second group (inflamed meninges) they ranged from 0.089 to 0.260 mg/l. These results demonstrate that ciprofloxacin diffuses into the CSF at concentrations which exceed the MICs of Neisseria meningitidis and most gram-negative aerobic bacilli.

Entry of ciprofloxacin into cerebrospinal fluid during bacterial, viral and tuberculous meningitis.

We studied the entry of ciprofloxacin into the cerebrospinal fluid (CSF) in 37 patients with various types of meningitis (bacterial meningitis 10 patients, viral 12 patients, tuberculous 7 patients). Eight patients were in the control group with normal CSF finding. Mean ciprofloxacin concentrations in the CSF 50-60 minutes after 200 mg of ciprofloxacin was given in infusion were 0.20 +/- 0.12 mg/L in patients with bacterial meningitis, which was significantly higher than in other tested groups (p = 0.0325). Ciprofloxacin achieved concentrations in the CSF 6.5-39% of serum (mean value 15% +/- 9%) in the bacterial meningitis group, while in the groups with viral and tuberculous meningitis the levels were significantly lower (approximately 9% of serum) but still higher than in the control group (approximately 5% of serum). Our data suggest that ciprofloxacin should be very cautiously used in selected patients with bacterial meningitis caused by multiple resistant strains of gram negative bacteria.

High-performance liquid chromatographic determination of ciprofloxacin in rat brain and cerebrospinal fluid.

A novel high-performance liquid chromatographic method for the fluorometric determination of a newer quinolone, ciprofloxacin (CPFX), in rat brain and cerebrospinal fluid (CSF) was developed. CPFX in brain homogenate was extracted and injected onto a reversed-phase column without fluorescence derivatization. CSF was directly analyzed without the extraction procedure. Calibration curves were linear over the concentration ranges of 10 to 500 ng/g for brain and 5 to 500 ng/ml for CSF. The recoveries of CPFX added to brain were more than 97% with a coefficient of variation of less than 4%. The present method was sensitive and reliable enough to be utilized for detailed pharmacokinetic studies of CPFX in rat brain and CSF.

Possibility for induction of convulsion by fleroxacin and its disposition in the central nervous system in animals.

Fleroxacin and its metabolites were examined for their possibility of the induction of convulsion in mice, inhibitory activity on GABA receptor binding, and disposition in the central nervous system of mice, rats and dogs. No convulsion was evoked in mice at high oral combination doses of fleroxacin and fenbufen. Brain-to-serum concentration ratios of fleroxacin after oral dose were 0.13 in mice, 0.19 in rats and 0.28 in dogs. Rats showed no accumulation of fleroxacin in brain and similar elimination from brain to that from serum after the oral dose. Dogs exhibited the similar distribution of fleroxacin into various brain regions. The inhibitory effect of fleroxacin on GABA receptor binding was relatively weak and slightly potentiated in the presence of 4-biphenylacetic acid. Demethyl fleroxacin showed more potent inhibitory activity on GABA receptor binding and potentiation with 4-biphenylacetic acid. The combination of intravenous demethyl fleroxacin and oral fenbufen showed no convulsion in mice. Fleroxacin N-oxide showed only slight inhibitory activity on GABA receptor binding, being not influenced with 4-biphenylacetic acid.

Ciprofloxacin penetration into human breast milk: a case report.

The concentration of ciprofloxacin achieved in human breast milk following oral administration of a single 500-mg dose was investigated. A 24-year-old white woman, 17 days postpartum, was being treated for resolving acute renal failure. Oral ciprofloxacin was prescribed for a suspected urinary tract infection. Due to suspected pediatric toxicity and a lack of published information describing ciprofloxacin excretion in breast milk, the antibiotic was discontinued after one 500-mg dose. All breast milk was collected at four-hour intervals and was tested for the presence of ciprofloxacin by bioassay. Ciprofloxacin breast milk concentrations were 9.1, 9.1, 9.1, and 6.0 mumol/L at 4, 8, 12, and 16 hours postdose, respectively. These ciprofloxacin concentrations were similar to other published body fluid concentrations following a single oral 500-mg dose.

Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges.

Nine patients with external ventriculostomy and suffering from hydrocephalus, due to non-inflammatory central nervous system diseases, were given ciprofloxacin (200 mg twice daily iv). Ciprofloxacin concentrations in serum and CSF were measured by HPLC. Single-dose pharmacokinetics were determined in three patients, and 60 and 600 min post-dose levels after repeated administration in six patients. CSF concentrations were maximal 60-120 min after the end of the infusion. The CSF elimination half-life was 260-430 min compared with 145-170 in serum. Post-dose levels at 60 min ranged from 0.042 to 0.223 mg/l (median = 0.110). Repeated administration did not lead to substantial increases in serum and CSF concentrations. With respect to MIC90 values reported for bacteria involved in CNS infections, the CSF concentrations of ciprofloxacin obtained under our experimental conditions would be considered subtherapeutic. Thus ciprofloxacin therapy of CNS infections may be inadequate when only minor impairment of the blood-CSF barrier exists.

Penetration of ciprofloxacin into the spinal fluid in patients with viral and bacterial meningitis.

Cerebrospinal fluid (CSF) concentrations of ciprofloxacin (Ciprobay) were measured by high performance liquid chromatography (HPLC) in 20 patients with varying degrees of meningeal inflammation. Underlying clinical syndromes were viral meningitis (n = 10), convalescent phase of acute bacterial meningitis (n = 9), and acute phase of bacterial meningitis (n = 1). CSF concentrations following an intravenous dose of 200 mg ranged between 0.028 and 0.11 mg/l (5.8-26.8% of corresponding serum levels) in patients with viral meningitis, and between 0.049 and 0.389 mg/l (5.9-77.0% of corresponding serum levels) in patients with bacterial meningitis. Taken together with the findings of other authors, the results indicate a potential usefulness of ciprofloxacin as an alternative agent for treatment of meningitis due to susceptible gram-negative microorganisms.

Penetration of ciprofloxacin into cerebrospinal fluid of patients with bacterial meningitis.

We evaluated the diffusion of ciprofloxacin into the cerebrospinal fluid (CSF) in 23 patients with bacterial meningitis or ventriculitis undergoing treatment with other antibiotics. Three successive ciprofloxacin doses of 200 mg were administered intravenously at 12-h intervals, first between days 2 and 4 and again between days 10 and 20 after the admission. Concentrations of ciprofloxacin in plasma and CSF obtained at 60, 120, 240, and 480 min after the third infusion were determined by high-performance liquid chromatography. In addition, serial samples were obtained from ventricular fluid in four patients. The concentrations of ciprofloxacin in CSF ranged from 0.35 to 0.56 micrograms/ml. These concentrations were equal to or higher than the MICs for most of the enterobacteria.