Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients.

PURPOSE: To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. METHODS: Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC0-24/MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. RESULTS: A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m2, and eGFR of 58.5 mL/min/1.73 m2. The median ƒAUC0-24 and ƒCmax were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC0-24/MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC0-24/MIC ratios. CONCLUSIONS: The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.

Assessment of contribution of BCRP to intestinal absorption of various drugs using portal-systemic blood concentration difference model in mice.

Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco-2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the correlation between the in vitro AQ for BCRP and in vivo contribution of BCRP on drug absorption, we evaluated the oral absorption of various compounds by portal-systemic blood concentration (P-S) difference method in wild-type (WT), Bcrp(-/-), and Mdr1a/1b(-/-) mice. In addition, we also calculated a rate of BCRP contribution (Rbcrp ). Ciprofloxacin and nitrofurantoin showed the low Rbcrp value (0.05 and 0.15), and their apparent fractions of intestinal absorption in WT mice were 46.5% and 63.7%, respectively. These results suggest that BCRP hardly affects their intestinal absorption in mice. On the other hand, the apparent fraction of intestinal absorption of topotecan and sulfasalazine was significantly lower in WT mice than in Bcrp(-/-) mice. Moreover, their Rbcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo Rbcrp calculated in this study was almost comparable to in vitro AQ obtained from Caco-2 permeability study. This study provides useful concepts in assessing the contribution of BCRP on intestinal absorption in drug discovery and development process.

Sensitive inexpensive chromatographic determination of an antimicrobial combination in human plasma and its pharmacokinetic application.

This study represents simple inexpensive chromatographic determination of ciprofloxacin (CIP) and tinidazole (TIN) simultaneously in human plasma using HPLC-DAD followed by a pharmacokinetic application. C18 column was used as stationary phase with isocratic elution of a mobile phase composed of acetic acid solution (2%) and acetonitrile (85: 15, v/v) and ornidazole as internal standard (IS) with UV detection at 318 nm. The two drugs and the IS were separated at 6.55, 7.91 and 11.07 min for CIP, TIN and IS, respectively, with good selectivity and sensitivity for their analysis in presence of plasma matrix components and the drugs' metabolites. Sample preparation involved only protein precipitation without any complicated extraction procedures decreasing analysis time. For method validation, FDA regulations for analysis in biological fluids were followed. Pharmacokinetic (PK) study on six healthy volunteers was conducted after single oral dose administration of 500 and 600 mg of CIP and TIN, respectively. Dugs' plasma levels were followed for 12 or 72 h post dosing for CIP and TIN, respectively, and different PK data for the two drugs were calculated and they were comparable to the reported values demonstrating successful future application of the presented method in PK, bioequivalence and bioavailability studies.

Ciprofloxacin Pharmacokinetics in Clinical Canine Patients.

BACKGROUND: Ciprofloxacin generic tablets approved for human use frequently are administered to dogs for treatment of bacterial infections because they are inexpensive and readily available. However, previous work indicated low and variable oral absorption in healthy research dogs. OBJECTIVE: To examine orally administered ciprofloxacin in a group of clinical canine patients using population pharmacokinetics in order to identify minimum inhibitory concentrations (MIC) that potentially could be achieved with orally administered ciprofloxacin in dogs. ANIMALS: Thirty-four clinical canine patients; mean weight, 22.95 kg (range, 4.6-57 kg). METHODS: Ciprofloxacin generic tablets intended for human use were administered to dogs in a prospective study (mean dose, 23.5 mg/kg). Sparse blood sampling was used to obtain population pharmacokinetic results with nonlinear mixed-effects modeling. These data were used to estimate a breakpoint for susceptible bacteria. Monte Carlo simulations were used to determine the probability of target attainment (PTA) for an area under the curve (AUC)/MIC ratio of ≥100, the pharmacokinetic-pharmacodynamic target for fluoroquinolones. RESULTS: The values for volume of distribution, peak concentration, and half-life were 10.7 L/kg (11.7%), 1.9 µg/mL (11.66%), and 4.35 hours (7.62%), respectively (mean, % coefficient of variation [CV]). The size of the dog was an important covariate with larger dogs achieving lower plasma drug concentrations than smaller dogs, despite a similar mg/kg dose. Ninety percent PTA was obtained for a MIC ≤ 0.06 µg/mL. CONCLUSIONS AND CLINICAL IMPORTANCE: A breakpoint (susceptible) of ≤0.06 µg/mL should be considered when ciprofloxacin tablets are administered to dogs at a dose of 25 mg/kg once daily, which is much lower than the breakpoint of ≤1 µg/mL in humans.

Pharmacokinetic and pharmacodynamic evaluations of a 10 mg/kg enrofloxacin intramuscular administration in bearded dragons (Pogona vitticeps): a preliminary assessment.

Enrofloxacin (E) is commonly used in veterinary medicine. It is necessary to perform pharmacokinetic/dynamic studies to minimize the selection of resistant mutants of bacteria and extend the efficacy of antimicrobial agents. Eight healthy adult Pogona vitticeps were assigned into two groups of equal size and treated with a single intramuscular injection of E at 10 mg/kg. Blood samples were withdrawn at different scheduled times for each group, and rectal swabs were collected. E and ciprofloxacin (active metabolite) blood concentrations were quantified by an HPLC validated method, while the in vitro antimicrobial susceptibility was evaluated by the Kirby-Bauer disc diffusion susceptibility test. The pharmacokinetic profiles of E gave similar pharmacokinetic parameters irrespective of the collection time schedule. Bacteria isolation showed the presence of both E. coli, Salmonella enterica subspecies enterica and subspecies 3a, Proteus spp., and Pseudomonas spp. The majority of isolated colonies were sensitive to E, but the treatment did not reduce the number of bacteria in faeces. Results suggest that E is able to reach blood concentrations high enough to kill susceptible bacteria (MIC < 0.9 µg/mL), but at the same time does not significantly affect intestinal bacteria.

Comparison of equal doses of continuous venovenous haemofiltration and haemodiafiltration on ciprofloxacin population pharmacokinetics in critically ill patients.

OBJECTIVES: Whilst commonly performed in ICUs, renal replacement therapies (RRTs) differ in their solute clearances. There is a paucity of data on ciprofloxacin clearances in different RRT techniques. The aim of this study was to compare the population pharmacokinetics of ciprofloxacin during equal doses of continuous venovenous haemofiltration (CVVHF) and continuous venovenous haemodiafiltration (CVVHDF) in septic patients. METHODS: Patients receiving 400 mg of ciprofloxacin intravenously 8 or 12 hourly and undergoing either CVVHF or CVVHDF were eligible. Up to 10 blood samples were collected over one dosing interval and analysed by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo simulation was undertaken using Pmetrics. RESULTS: Eighteen sampling intervals were included (8 CVVHDF and 10 CVVHF) from 11 patients (6 patients having sampling during both RRT modes). A two-compartment linear model best described the data. Increasing patient weight was the only covariate associated with increasing drug clearance. The mean (SD) parameter estimates were: clearance, 10.7 (5.3) L/h; volume of distribution of the central compartment, 21.3 (11.3) L; rate constant for drug distribution from the central compartment to the peripheral compartment, 10.9 (4.3) L/h; and rate constant for drug distribution from the peripheral compartment to the central compartment, 2.3 (1.8) L/h. After accounting for patient weight, the mean ciprofloxacin clearance was not statistically different between CVVHF and CVVHDF [11.8 (9.9) and 10.3 (7.4) L/h, respectively, P = 0.43]. CONCLUSIONS: The present study indicates a high pharmacokinetic variability of ciprofloxacin during CVVHF and CVVHDF with no significant differences in clearance apparent. Based on patient weight, higher ciprofloxacin dosing regimens should be used in critically ill patients when difficult-to-treat pathogens are suspected.

Validation of a sensitive HPLC/fluorescence method for assessment of ciprofloxacin levels in plasma and prostate microdialysate samples from rats.

Chronic bacterial prostatitis treatment consists of broad-spectrum antibiotic therapy for long periods of time. Drug penetration into the prostate makes the treatment a challenged. Ciprofloxacin is one of the most prescribed drugs for this treatment. A liquid chromatography with fluorescence detection method was developed and validated for determining ciprofloxacin concentrations in two different matrices: plasma and prostate microdialysate. Ciprofloxacin was separated on a C18 column eluted with a mobile phase constituted of a mixture of 0.4% aqueous triethylamine:methanol:acetonitrile (75:15:10, v/v/v) and 0.4% aqueous triethylamine:acetonitrile (88:12, v/v) for microdialysate and plasma samples, respectively. Linearity was obtained over a concentration range of 5-1000 ng/mL (microdialysate) and 10-2000 ng/mL (plasma), with coefficients of determination ≥0.9956. Precision was determined from the analysis of six quality control samples and showed RSD values <11.1 and 7.4% for intra and inter-assay precision, respectively. The accuracy ranged from 85.6 to 114.3%. The method was applied to a preliminary pharmacokinetic study to investigate ciprofloxacin concentrations in prostate, sampled by microdialysis, and plasma after a 7 mg/kg intravenous dose to Wistar rats. The method showed high sensitivity using only protein precipitation as plasma sample clean-up and was successfully applied to investigate ciprofloxacin prostate penetration.

Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design.

BACKGROUND AND OBJECTIVE: The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. METHODS: Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. RESULTS: Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. CONCLUSION: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements.

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.

Evaluation of enrofloxacin use in koalas (Phascolarctos cinereus) via population pharmacokinetics and Monte Carlo simulation.

Clinically normal koalas (n = 6) received a single dose of intravenous enrofloxacin (10 mg/kg). Serial plasma samples were collected over 24 h, and enrofloxacin concentrations were determined via high-performance liquid chromatography. Population pharmacokinetic modeling was performed in S-ADAPT. The probability of target attainment (PTA) was predicted via Monte Carlo simulations (MCS) using relevant target values (30-300) based on the unbound area under the curve over 24 h divided by the minimum inhibitory concentration (MIC) (fAUC0-24 /MIC), and published subcutaneous data were incorporated (Griffith et al., 2010). A two-compartment disposition model with allometrically scaled clearances (exponent: 0.75) and volumes of distribution (exponent: 1.0) adequately described the disposition of enrofloxacin. For 5.4 kg koalas (average weight), point estimates for total clearance (SE%) were 2.58 L/h (15%), central volume of distribution 0.249 L (14%), and peripheral volume 2.77 L (20%). MCS using a target fAUC0-24 /MIC of 40 predicted highest treatable MICs of 0.0625 mg/L for intravenous dosing and 0.0313 mg/L for subcutaneous dosing of 10 mg/kg enrofloxacin every 24 h. Thus, the frequently used dosage of 10 mg/kg enrofloxacin every 24 h subcutaneously may be appropriate against gram-positive bacteria with MICs ≤ 0.03 mg/L (PTA > 90%), but appears inadequate against gram-negative bacteria and Chlamydiae in koalas.

New approach to assess bioequivalence parameters using generalized gamma mixed-effect model (model-based asymptotic bioequivalence test).

In the pharmacokinetic (PK) study under a 2x2 crossover design that involves both the test and reference drugs, we propose a mixed-effects model for the drug concentration-time profiles obtained from subjects who receive different drugs at different periods. In the proposed model, the drug concentrations repeatedly measured from the same subject at different time points are distributed according to a multivariate generalized gamma distribution, and the drug concentration-time profiles are described by a compartmental PK model with between-subject and within-subject variations. We then suggest a bioequivalence test based on the estimated bioavailability parameters in the proposed mixed-effects model. The results of a Monte Carlo study further show that the proposed model-based bioequivalence test is not only better on maintaining its level but also more powerful for detecting the bioequivalence of the two drugs than the conventional bioequivalence test based on a non-compartmental analysis or the one based on a mixed-effects model with a normal error variable. The application of the proposed model and test is finally illustrated by using data sets in two PK studies.

Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation.

BACKGROUND: Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown. METHODS: Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC(0-24)/MIC ratio of ≥125. RESULTS: Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8-102 months. Absorption was generally rapid but variable; C(max) ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h) = 42.7 (L/h/70 kg) × [weight (kg)/70](0.75) × [1 + 0.0368 (Na(+) - 136)] × [1 - 0.283 (high risk)] and V (L) = 372 × (L/70 kg) × [1 + 0.0291 (Na(+) - 136)]. Estimates of AUC(0-24) ranged from 8 to 61 mg·h/L. The breakpoint for Gram-negative organisms was <0.06 mg/L with doses of 20 mg/kg/day and <0.125 mg/L with doses of 30 or 45 mg/kg/day. The cumulative fraction of response with 30 mg/kg/day was ≥80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa. CONCLUSIONS: An oral ciprofloxacin dose of 10 mg/kg three times daily (30 mg/kg/day) may be a suitable alternative antibiotic for the management of sepsis in severely malnourished children. Absorption was unaffected by the simultaneous administration of feeds.

Assessment of bioequivalence of ciprofloxacin in healthy male subjects using HPLC.

Pharmacokinetics and bioequivalence studies of two brands of ciprofloxacin 500 mg (Ciprofloxacin & Ciproxin) were evaluated in 14 healthy male volunteers after oral administration. The drug was analyzed in plasma samples by using HPLC. The peak plasma concentrations of (2.28+/-0.04 mg/L) and (1.9+/-0.02 mg/L) was attained in about 1.71 hours and 2.00 hours for both Test and Reference ciprofloxacin, respectively. The mean +/- SE values for total area under the curve (AUC) were 11.91+/-0.26 and 13.11+/-0.27 h.mg/L for both test and reference tablets respectively. This study indicated that all the differences in bioequivalence parameters for both ciprofloxacin formulations are statistically non-significant, hence both formulations are bioequivalent.

Simulated comparison of the pharmacodynamics of ciprofloxacin and levofloxacin against Pseudomonas aeruginosa using pharmacokinetic data from healthy volunteers and 2002 minimum inhibitory concentration data.

BACKGROUND: Until the 2002 approval of levofloxacin 750 mg QD, ciprofloxacin was the fluoroquinolone of choice against Pseudomonas aeruginosa infections. OBJECTIVE: This study evaluated the AUC:MIC ratios for ciprofloxacin 400 mg BID and TID and levofloxacin 750 mg QD, all administered intravenously, against P. aeruginosa using a Monte Carlo simulation. METHODS: Pharmacokinetic data for ciprofloxacin and levofloxacin and 2002 MIC distributions against P. aeruginosa were obtained from studies in healthy volunteers published in the peer-reviewed literature. Pharmacokinetic studies of each agent were identified by separate MEDLINE searches combining the MeSH heading pharmacokinetics with the generic name of the antimicrobial. Only human studies published in English between 1990 and 2001 were included. Included studies also had to meet 3 minimum criteria: evaluation of clinically relevant dosing regimens, use of rigorous study methods, and provision of mean (SD) values for the pharmacokinetic parameters of interest. When multiple studies met these criteria, a single study was selected for each antimicrobial regimen. Pharmacodynamic analysis was performed using a Monte Carlo simulation of 10,000 patients by integrating the pharmacokinetic parameters, their variability, and 2002 MIC distributions for each antimicrobial regimen. The probability of target attainment was determined for each regimen for an AUC:MIC ratio from 0 to 300. A > or =90% probability of target attainment was considered satisfactory. RESULTS: For ciprofloxacin 400 mg TID and levofloxacin 750 mg QD, the AUC:MIC ratio at the corresponding 2002 Clinical Laboratory Standards Institute break points of 1 and 2 microg/mL were 33 and 34, respectively. The probabilities of target attainment for a free AUC:MIC ratio >90 (equivalent to a total AUC:MIC ratio > or =125) were 47% for ciprofloxacin 400 mg BID, 54% for ciprofloxacin 400 mg TID, and 48% for levofloxacin 750 mg QD. CONCLUSION: When pharmacokinetic data from healthy volunteers and 2002 MIC data were used, none of the simulated fluoroquinolone regimens achieved a high likelihood of target attainment against P. aeruginosa.

[18F]Ciprofloxacin, a new positron emission tomography tracer for noninvasive assessment of the tissue distribution and pharmacokinetics of ciprofloxacin in humans.

The biodistribution and pharmacokinetics of the fluorine-18-labeled fluoroquinolone antibiotic [(18)F]ciprofloxacin in tissue were studied noninvasively in humans by means of positron emission tomography (PET). Special attention was paid to characterizing the distribution of [(18)F]ciprofloxacin to select target tissues. Healthy volunteers (n = 12) were orally pretreated for 5 days with therapeutic doses of unlabeled ciprofloxacin. On day 6, subjects received a tracer dose (mean injected amount, 700 +/- 55 MBq, which contained about 0.6 mg of unlabeled ciprofloxacin) of [(18)F]ciprofloxacin as an intravenous bolus. Thereafter, PET imaging and venous blood sampling were initiated. Time-radioactivity curves were measured for liver, kidney, lung, heart, spleen, skeletal muscle, and brain tissues for up to 6 h after radiotracer administration. The first application of [(18)F]ciprofloxacin in humans has demonstrated the safety and utility of the newly developed radiotracer for pharmacokinetic PET imaging of the tissue ciprofloxacin distribution. Two different tissue compartments of radiotracer distribution could be identified. The first compartment including the kidney, heart, and spleen, from which the radiotracer was washed out relatively quickly (half-lives [t(1/2)s], 68, 57, and 106 min, respectively). The second compartment comprised liver, muscle, and lung tissue, which displayed prolonged radiotracer retention (t(1/2), >130 min). The highest concentrations of radioactivity were measured in the liver and kidney, the main organs of excretion (standardized uptake values [SUVs], 4.9 +/- 1.0 and 9.9 +/- 4.4, respectively). The brain radioactivity concentrations were very low (<1 kBq. g(-1)) and could therefore not be quantified. Transformation of SUVs into absolute concentrations (in micrograms per milliliter) allowed us to relate the concentrations at the target site to the susceptibilities of bacterial pathogens. In this way, the frequent use of ciprofloxacin for the treatment of a variety of infections could be corroborated.

Assessment of antibiotic levels in lung tissue with erosion-controlled dosage forms.

The concentration-time curve of ciprofloxacin has been assessed in the blood compartment and in the lung tissue following oral administration of the drug. Immediate release and erosion-controlled dosage forms have been examined. A numerical model based on finite differences and taking into account all relevant data has been built: the kinetics of drug release in the gastrointestinal tract, drug absorption in the blood compartment and elimination, and the transient diffusion of the drug through the lung tissue. A partition coefficient for the drug at the tissue-blood interface has been considered to express the drug concentration at the tissue surface. The effect of dose frequency and erosion rate on the antibiotic versus time curves in the plasma and the lung tissue has been studied in detail.

Comparative crossover assessment of serum bactericidal activity and pharmacokinetics of ciprofloxacin and ofloxacin.

The study compared the pharmacokinetics and pharmacodynamics of ciprofloxacin and ofloxacin in 12 healthy male volunteers with normal renal function. Each volunteer received oral ciprofloxacin 500 mg, intravenous (i.v.) ciprofloxacin 400 mg, oral ofloxacin 400 mg, or i.v. ofloxacin 400 mg in a randomized, double-blind, crossover design with a one-week 'washout' period between doses. Mean peak serum concentrations were 4.48 and 5.44 mg/L for i.v. ciprofloxacin and ofloxacin, respectively. For the oral regimens, mean peak serum concentrations were 2.45 mg/L for ciprofloxacin and 4.44 mg/L for ofloxacin. Minimum bactericidal concentrations (MBC) and serum bactericidal activity (SBA) for each drug were measured against five strains of each of the following species: Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Pseudomonas aeruginosa, Acinetobacter anitratus, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae, using the microdilution method of the National Committee for Clinical Laboratory Standards (NCCLS). Ciprofloxacin was more active in vitro than ofloxacin against the tested species of Enterobacteriaceae and P. aeruginosa, while ofloxacin was slightly more active against A. anitratus. MBCs for the two drugs were similar for H. influenzae and S. aureus. Oral and i.v. ciprofloxacin in the doses given resulted in nearly equivalent SBA. Similarly, oral and i.v. ofloxacin had nearly equivalent SBA. For the i.v. and oral regimens of both agents, peak SBA was > or = 2 throughout the 12-hour test period against the Enterobacteriaceae and H. influenzae. At peak concentrations, both drugs had modest SBA against P. aeruginosa, A. anitratus, and S. aureus but little or no activity 8 and 12 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Transintestinal elimination of ciprofloxacin in humans--concomitant assessment of its metabolites in serum, ileum and colon.

Ciprofloxacin (200 mg) was infused to seven patients at the beginning of elective colorectal surgery. Thirty minutes after the end of infusion (i.e. 60 min after the start of the operation) ciprofloxacin reached concentrations of 1.60 mg/l in serum and of 3.42-6.07 mg/kg fresh weight in the ileum and colon. During the next 30 min (90 min after the start of operation) the concentration of ciprofloxacin in serum decreased to 86% of its initial level, but this decrease was less rapid than that observed in the ileal (to 56.8%) or colonic (to 74.8%) mucosa. Three metabolites could be identified (desethylen-, sulpho-, oxociprofloxacin). Initially, at 60 min the amount of these metabolites was about 15% of the total drug concentration in serum, but only 2-3% of that in the gut tissues. At 90 min the relative amount of metabolites was increased in serum as well as in the gut tissues. It is concluded that transintestinal elimination of ciprofloxacin is a general feature of the whole gut. Obviously, the elimination process is not due to degradation of ciprofloxacin within the gut wall.

Clinical and economic evaluation of oral ciprofloxacin after an abbreviated course of intravenous antibiotics.

PURPOSE: Oral ciprofloxacin has the requisite pharmacokinetic and antibacterial properties to rival the potency of intravenous antibiotics. This study was designed to determine whether oral ciprofloxacin could abbreviate the course of intravenous antibiotics in the treatment of serious infections. PATIENTS AND METHODS: Hospitalized adult patients were eligible for enrollment if they had a serious infection that was expected to require 8 or more days of intravenous antibiotic treatment. After conventional intravenous antibiotics were administered for 3 days, informed consent was obtained and patients were randomly assigned to either continue parenteral antibiotics (n = 53) or switch to oral ciprofloxacin 750 mg taken twice daily (n = 52). Ninety-nine of the 105 patients were evaluable for the assessment of efficacy. Clinical and bacteriologic efficacy, adverse events, and costs of the two treatments were compared. RESULTS: The two treatment groups were comparable for demographic characteristics, types of infections, bacteria isolated, initial intravenous antibiotic regimens, and duration of antibiotic treatment. The most common infections were of the skin and skin structure; bacteremia and infections of the lower respiratory tract, urinary tract, and bone and joint were also represented. The most commonly isolated pathogens were Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. The most frequently prescribed intravenous antibiotics before randomization included aminoglycosides, cephalosporins, vancomycin, and nafcillin; 52 evaluable patients were treated with combination therapy while 47 received monotherapy. The clinical and bacteriologic outcomes and adverse reaction frequency with oral ciprofloxacin were comparable to those of the continued intravenous antibiotic regimens. Ciprofloxacin was associated with an average cost savings of $293 per patient. CONCLUSION: When used after 3 days of intravenous antibiotics, oral ciprofloxacin was as safe and effective as full courses of intravenous antibiotics and provided substantial cost savings.