Impact of a clinical pharmacist's intervention on pneumococcal vaccination in a population of at- risk hospitalized patients: The IP-VAC study.

OBJECTIVES: The aim of this study was to evaluate the impact of clinical pharmacist intervention on compliance with pneumococcal vaccination (PV) recommendations in hospitalized patients. METHODS: This was a prospective, single-center, before-and-after study conducted in 2019-2020. Patients had to be over 18 years of age, at risk of pneumococcal infection, and with no PV. No changes were made in the observational phase. During the interventional phase, the clinical pharmacist discussed a prescription for preventive PV and a mention in the discharge letter. A pharmaceutical consultation sensitized the patient to the interest of PV. The clinical pharmacist ensured that a complete vaccination protocol would be carried out by the retail pharmacist within 3 months of hospitalization. RESULTS: One hundred and sixty-seven (167) patients were included. In the observational phase, 2.3% of patients received a complete vaccination protocol after discharge from primary care. The rate increased to 63.8% after the clinical pharmacist's intervention (p < 0.001). Vaccines were prescribed by hospital physicians in 97.5% of cases, while 40% of discharge letters included the indication for PV. CONCLUSION: The clinical pharmacist's intervention led to delivery of a complete PV protocol after discharge for over half the patients. This study demonstrated the feasibility of a pharmaceutical intervention to promote PV in hospital activities.

Ecoresponsible actions in operating rooms: A health ecological and economic evaluation.

BACKGROUND: In the current context of climate change, actions must be taken to improve the hospital's ecological footprint, particularly in the operating room, which is a major consumer of medical devices. METHODS: This prospective pilot study assessed the ecological and economic impacts of sustainable actions targeting medical devices designed by a multidisciplinary working group and implemented in the 24 operating rooms of a University Hospital over one year. The ecological analysis was based on the life cycle assessment method and categorized in seven impacts. The economic impact was assessed by a micro-costing analysis and divided in four main expense items: human and material resources, logistics, and waste management. RESULTS: In total, 13 actions were implemented with the aim of reducing waste volume, improving waste sorting, and increasing eco-responsible purchases. In one year, these 13 actions allowed avoiding the emission of 203 tons eq CO2. The environmental and human toxicity benefits were 707.8 and 156.2 tons of 1.4 dichlorobenzene, respectively. Concerning non-renewable resources, these actions avoided the extraction of 9 tons of oil (petroleum) and 610 kg of copper per year. These actions led to a land occupation reduction of 1071.3 m2year and to water saving of 552 m3. From the economic side, the implementation of these actions brought a gain of €3747.9 for the first year and of €5188.2 for the following years. CONCLUSION: The integration of sustainable measures in operating rooms leads to important ecological benefits and also generating savings. This more eco-responsible approach should be considered in all healthcare establishments that generate a significant annual volume of waste.

Assessing the costs of disposable and reusable supplies wasted during surgeries.

BACKGROUND: The management of disposable and reusable supplies might have an impact on the cost efficiency of the Operating Room (OR). This study aimed to evaluate the cost and reasons for wasted supplies in the OR during surgical procedures. METHODS: We conducted an observational and prospective study in a French university hospital. We assessed the cost of wasted supplies in the OR (defined by opened unused devices), the reasons for the wastage, and the circulator retrievals. At the end, we assessed the perception of surgeons and nurses relative to the supply wastage. RESULTS: Fifty routine procedures and five non-scheduled procedures were observed in digestive (n = 20), urologic (n = 20) and gynecologic surgery (n = 15). The median cost [IQR] of open unused devices was €4.1 [0.5; 10.5] per procedure. Wasted supplies represented up to 20.1% of the total cost allocated to surgical supplies. Considering the 8000 surgical procedures performed in these three surgery departments, the potential annual cost savings were 100 000€. The most common reason of wastage was an anticipation of the surgeon's needs. The circulating nurse spent up to 26.3% of operative time outside of the OR, mainly attending to an additional demand from the surgeon (30%). Most of the survey respondents (68%) agreed that knowing supply prices would change their behavior. CONCLUSIONS: This study showed the OR is a major source of wasted hospital expenditure and an area wherein an intervention would have a significant impact. Reducing wasted supplies could improve the cost efficiency of the OR and also decrease its ecological impact.

Assessment of patient adherence to anti-infective treatment after returning home.

OBJECTIVE: The lack of patient adherence to medical treatment has become a major concern for healthcare professionals. The World Health Organization estimated patient adherence to treatment at 50% only. The inadequate use of antibiotics can cause bacterial resistance the progression of which reduces therapeutic alternatives. The objective of this pilot study was to assess the patient's adherence to anti-infective agents prescribed for acute infection, after returning home. METHOD: Thirty-seven patients hospitalized in the Infectious and Tropical Diseases unit were included. Their adherence to anti-infective drugs was assessed indirectly through data collected by calling the pharmacy and the patient in the week following discontinuation of anti-infective treatment. RESULTS: Sixteen patients were identified as non-adherent (43.2%). A single patient could have several behaviors: extension of treatment (50%), dose modification (6.3%), voluntary omission (12.5%), and involuntary (6.3%). One patient (6.3%) did not take his anti-infective treatment. There was no major cause of non-adherence; every patient had his own reasons. The comparison of several criteria between adherent and non-adherent patients did not reveal any predictive risk factors. CONCLUSION: Our study results revealed for the first time that 50% of patients were adherent to anti-infective agents, after returning home. They confirm the need to implement preventive actions such as a discharge pharmaceutical consultation.

Population pharmacokinetics of nalbuphine after surgery in children.

BACKGROUND: Nalbuphine is an opioid analgesic agent widely used for control of mild-to-severe pain. However, limited data are available on the pharmacokinetics of this drug in children. The aim of this study was to characterize the population pharmacokinetics of nalbuphine in patients with ages ranging from 1 to 11 yr and to identify patient characteristics partially explaining inter-individual variability in nalbuphine pharmacokinetic parameters. METHODS: Twenty-two children were included in this study. They received nalbuphine after surgery by continuous infusion (loading dose, 0.2 mg kg(-1) over 10 min followed by continuous infusion of 0.8 mg kg(-1) over 24 h). If pain relief was not adequate, 0.1 mg kg(-1) bolus doses were allowed in 10 min. Eleven blood samples were collected per patient. The data were analysed by non-linear mixed-effect modelling with the use of a two-compartment structural model. RESULTS: Twenty patients completed the study. In the final model, the parameter values were standardized for a body weight of 70 kg using an allometric model. Population parameter estimates were: clearance 130 litre h(-1) 70 kg(-1), inter-compartment clearance 75.6 litre h(-1) 70 kg(-1), central volume of distribution 210 litre 70 kg(-1), and peripheral volume of distribution 151 litre 70 kg(-1). In the children of this study, total clearance expressed in litre h(-1) kg(-1) decreased significantly with increasing age and the elimination half-life significantly increased. CONCLUSIONS: The allometric power model developed in this study best reflected the data and may be useful for dose adjustment.

Evolution of fluoroquinolone resistance among Escherichia coli urinary tract isolates from a French university hospital: application of the dynamic regression model.

Escherichia coli urinary tract isolates were collected in 1997-2003 from Nimes University Hospital in order to investigate long-term trends in antibiotic resistance and to explore the relationship between antibiotic use and the emergence of resistance. Time-series analysis (ARIMA models) and dynamic regression models were used to investigate relationships between antibiotic use and resistance to ofloxacin and ciprofloxacin. Significant increases were seen in the frequency of ofloxacin (8.9 to 16.7%) and ciprofloxacin resistance (6.2 to 10.1%) (p < 0.001). Using multivariate dynamic regression analysis, it was found that an increased use of one defined daily dose (DDD)/1000 patient-days for ofloxacin, ciprofloxacin and norfloxacin induced average increases of 0.81%, 0.65% and 0.53% in E. coli ofloxacin resistance (p < 0.01), with average delays of 4, 4 and 6 months, respectively. An increase of 1 DDD/1000 patient-days of ciprofloxacin, ofloxacin and norfloxacin use induced increases of 0.73%, 0.82% and 0.63% in E. coli ciprofloxacin resistance (p < 0.01), with average delays of 4, 4 and 5 months, respectively. The use of nalidixic acid was not associated significantly with an increase in resistance to fluoroquinolones by multivariate analysis.

High-performance liquid chromatographic determination of cefepime in human plasma and in urine and dialysis fluid using a column-switching technique.

A high-performance liquid chromatographic method with UV absorbance was developed for the analysis of cefepime in human plasma and urine, and in dialysis fluid. Detection was performed at 280 nm. The assay procedure for cefepime in plasma involves the addition of an internal standard (cefpirome) followed by treatment of the samples with trichloracetic acid, acetonitrile and dichloromethane. To quantify cefepime in diluted urine (1:20) and in the dialysis fluid, samples spiked with the internal standard (cefpirome) were analysed using a column-switching technique. The HPLC column, Nucleosil C18, was equilibrated with an eluent mixture composed of acetonitrile-ammonium acetate (pH 4). Linear detector responses were observed for the calibration curve standards in the range 0.5 to 100 microg/ml, which spans what is currently thought to be the clinically relevant range for cefepime concentrations in body fluids. The limit of quantification was 0.5 microg/ml in the three matrices. Extraction recoveries proved to be more than 84%. Precision, expressed as %RSD, was in the range 1.5 to 9%. Accuracy ranged from 93 to 105%. This method was used to follow the time course of the concentration of cefepime in plasma, urine and dialysate outlet samples after a 10-min infusion period of 2 g of this drug in patients with acute renal failure undergoing hemodiafiltration.

Folic acid alters methotrexate availability in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the effects of repeated doses of folic acid on the pharmacokinetics of methotrexate (MTX) in patients with rheumatoid arthritis. METHODS: We studied 20 patients (ages 30-78 years) who received MTX intramuscularly (10 mm/week). MTX was administered alone or after treatment with folic acid (5 mg tablet once daily) for 13 days. Plasma samples were collected 2 and 8 h after dose intake. MTX concentrations in plasma and ultrafiltrate samples were measured by fluorescence polarization immunoassay. A Bayesian approach was used to determine individual MTX pharmacokinetic variables to minimize the number of samples collected. RESULTS: Folic acid supplementation led to reduced plasma MTX levels 2 and 8 h after MTX administration and reduced area under the plasma MTX concentration versus time curve (AUC) (about 20%; p < 0.02). Total clearance of MTX and Vd were higher when patients were also receiving folic acid than when they were taking MTX alone (p < 0.02). The plasma protein binding of MTX remains unchanged. CONCLUSION: The lower plasma MTX concentrations in patients taking folic acid supplements could be interpreted as increased cellular uptake of MTX; the folic acid supplements would promote the sequestering of MTX intracellularly. The decrease of MTX concentrations leads to reduced AUC; it is also possible that there are reduced AUC combined with increased intracellular folate levels. These results reopen the question of whether folic acid should be used immediately in all patients when MTX is begun.

Clozapine and metabolite concentrations during treatment of patients with chronic schizophrenia.

Results presented in this article are focused on the variability in pharmacokinetics. The purpose of this study was (1) to investigate intra- and interindividual variabilities of pharmacokinetic parameters of clozapine and its two main metabolites in plasma after multiple oral administration in 8 chronic schizophrenic patients (Study 1) and (2) to gain more information regarding plasma concentrations of these drugs after multiple doses in a group of 25 treatment-responsive patients (Study 2). Patients were treated with clozapine in fixed daily doses (given every 8-12 hours) between 200 and 900 mg. Plasma drug concentrations were determined by high-performance liquid chromatography. The mean volume of distribution and the total plasma clearance of clozapine, uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The terminal elimination half-lives averaged 10.5 hours for clozapine, 19.2 hours for norclozapine, and 8.6 hours for the N-oxide metabolite. Significant relationships were observed between clozapine and norclozapine (or clozapine N-oxide) plasma concentrations. Large inter- and intrapatient variations in pharmacokinetics were observed. Clozapine was generally well tolerated by the patients, with sedation, hypersialorrhea, and tiredness as the most common side effects encountered.

Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia.

The pharmacokinetic parameters of clozapine and its two main metabolites, N-desmethylclozapine (norclozapine, active metabolite) and clozapine N-oxide, were evaluated, after oral administration, in 19 patients with chronic schizophrenia. Plasma and red blood cell (RBC) drug concentrations were determined by high-performance liquid chromatography. Large interpatient variations in pharmacokinetic parameters of clozapine and its two metabolites were observed. Plasma clozapine concentration peaked, on average, at 2.3 hours. The mean volume of distribution and the total plasma clearance, uncorrected for bioavailability, were 6 L/kg and 38 L/hr, respectively. The terminal elimination half-lives averaged 7.6 hours for clozapine, 13 hours for norclozapine, and 7 hours for the N-oxide metabolite. The mean RBC/plasma concentration ratios were 23, 61, and 81% for clozapine, N-desmethylclozapine, and clozapine N-oxide, respectively. From RBC concentration data, the mean elimination half-lives were 7.6 hours for clozapine, 16 hours for N-desmethylclozapine, and 8 hours for the N-oxide metabolite. The average value for blood clearance of clozapine was 54.7 L/hr. Significant correlations were observed between dose and maximum plasma concentrations and between dose and area under the curve concentrations; these results suggested linear steady-state pharmacokinetics over the range of concentrations studied.

Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients.

OBJECTIVES: To determine the effects of impaired renal function on the pharmacokinetics of methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: 77 RA patients were included in this study. MTX was administered intramuscularly (7.5 to 15 mg). Subjects were divided into four groups, according to their creatinine clearance (CLCR); group 1: CLCR lower than 45 ml/min; group 2: CLCR between 45 and 60 ml/min, group 3: CLCR between 61 and 80 ml/min and group 4: CLCR higher than 80 ml/min. Blood samples were collected from each subject before drug administration and at two and eight hours after administration. Individual pharmacokinetic parameters were estimated using a Bayesian approach. RESULTS: MTX concentrations (total and free) were 1.3 to 1.6-times higher in group 1 than in groups 2, 3, and 4. For total and free MTX, t1/2 eliminations were 22.7 hours in group 1, 13.5 hours in group 2, 12 hours in group 3, and 11 hours in group 4. Clearance of total MTX was 64, 92, 96, 115 ml/min in groups 1 to 4, respectively, it was 118, 163, 171, 206 ml/min in groups 1 to 4 for the free MTX, respectively. Volume of distribution averaged 2.16 l/kg in group 1, 1.92 l/kg in group 2, 1.61 l/kg in group 3, and 1.56 l/kg in group 4. Elimination half life was significantly increased and total clearance was significantly reduced with the degree of renal impairment. Linear regression revealed good correlations between clearance values of MTX and creatinine clearance. CONCLUSION: Individual testing is required rather than a general decrease of the MTX dose based only on CLCR.

A Kinetic Model for Simultaneous Fit of Clozapine and Norclozapine Concentrations in Chronic Schizophrenic Patients during Long-Term Treatment.

OBJECTIVE: The pharmacokinetic profiles of clozapine and its main metabolite, norclozapine, were investigated in 18 chronic schizophrenic inpatients during long-term treatment. PATIENTS: Patients received stable daily doses (between 300 and 900mg) for at least 1 month. Plasma drug concentrations were determined by high performance liquid chromatography. The pharmacokinetic parameters were calculated from both noncompartmental and compartmental approaches with zero-order input rate using a kinetic model for simultaneous fit of clozapine and norclozapine (active metabolite) concentrations. RESULTS: Large interpatient variations in pharmacokinetic parameters of the two drugs were observed. Plasma clozapine concentration peaked on average at 2 hours. The mean elimination rate constants from compartments 1 (k(10)) and 2 (k(20 ), elimination rate constant of norclozapine) were 0.087 and 0.156h(-1), respectively. The rate of formation of norclozapine, k(12), averaged 1.25h(-1). The mean fraction of the administered dose converted to norclozapine was estimated to be 66%. The apparent clearance of clozapine (CL/F) averaged 44.7 L/h and the volume of distribution (V(c)/F) was 7.00 L/kg. The pharmacokinetics of clozapine after multiple doses were linear over the range of clozapine plasma concentrations of 145 to 1411 microg/L. CONCLUSION: This is the first study assessing the pharmacokinetic profile of clozapine plus norclozapine in plasma during long-term treatment. This pharmacokinetic model can be used to determine the population pharmacokinetic parameters of clozapine and norclozapine in order to optimise individual dosage regimens using a Bayesian methodology.

Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis. A comparison with young patients.

OBJECTIVE: To determine the pharmacokinetics of methotrexate (MTX) in a group of patients 65 to 83 years of age and to compare the pharmacokinetic data to those in patients 21 to 45 years of age. METHODS: Thirty-eight elderly patients (8 men, 30 women) and 24 young patients (6 men, 18 women) underwent this pharmacokinetic study. They received intramuscular administration of MTX each week, at a dose varying from 7.5 to 15 mg depending on the patient. MTX concentrations in plasma and ultrafiltrate samples were assayed by a fluorescence polarization immunoassay. Pharmacokinetic variables were estimated using a Bayesian approach with population parameters as a priori information together with 2 plasma MTX concentrations (2 and 8 h after injection). RESULTS: The extent of unbound fraction and the volume of distribution were not statistically significantly different between the 2 age groups. The elimination half-life measures of the free and total MTX were greatest in the elderly group (p < 0.001). The total clearances of free and total MTX were inversely proportional to age (p < 0.001). CONCLUSION: MTX clearance decreases with decreasing creatinine clearance and smaller doses may be chosen in this group. Thus, a dosage regimen should be adjusted in elderly patients or in those with renal impairment.

Determination of nalbuphine in human plasma by high-performance liquid chromatography with electrochemical detection. Application to a pharmacokinetic study.

A high-performance liquid chromatographic procedure has been developed for the measurement of nalbuphine in plasma. Separation is performed on a reversed-phase analytical column (Ultrasphere ODS, 250 x 4.6 mm I.D., particle size, 5 microns). Mobile phase consisted of methanol-phosphate buffer (20:80, v/v) (pH 3.4). Electrochemical detection was performed using an ESA Coulochem II Model 5200 electrochemical detector equipped with a Model 5020 guard cell working at 550 mV and a Model 5021 analytical cell operating in the oxidation screening mode, with the potential of the first electrode set at 60 mV and the second electrode set at 450 mV. The method involves sample clean-up by liquid-liquid extraction using a chloroform-isopropanol mixture. After centrifugation, the organic phase was back-extracted with 17 mM phosphoric acid and then the aqueous phase was injected onto the column. The limits of quantitation and detection were 0.3 and 0.1 ng/ml, respectively. The extraction recovery was 91.1 +/- 3.7%. The intra- and inter-assay coefficients of variation were below 10%. Stability tests under various conditions have been performed. This method has been used to determine the pharmacokinetic parameters of nalbuphine in children.

Determination of clozapine and its major metabolites in human plasma and red blood cells by high-performance liquid chromatography with ultraviolet absorbance detection.

An isocratic high-performance liquid chromatographic (HPLC) method with UV absorbance detection is described for the quantification of clozapine (8-chloro-11-(4'-methyl)piperazino-5H-dibenzo[b,e]-1,4-diazepine) and its two major metabolites in plasma and red blood cells (RBCs). The method involves sample clean-up by liquid-liquid extraction with ethyl acetate. The organic phase was back-extracted with 0.1 M hydrochloric acid. Loxapine served as the internal standard. The analytes were separated by HPLC on a Kromasil Ultrabase C18 analytical column (5 microns particle size; 250 x 4.6 mm I.D.) using acetonitrile-phosphate buffer pH 7.0 (48:52, v/v) as eluent and were measured by UV absorbance detection at 254 nm. The limits of quantiation were 20 ng/ml for clozapine and N-desmethylclozapine and 30 ng/ml for clozapine N-oxide. Recovery from plasma or RBCs proved to be higher than 62%. Precision, expressed as % C.V., was in the range 0.6-15%. Accuracy ranged from 96 to 105%. The method's ability to quantify clozapine and two major metabolites simultaneously with precision, accuracy and sensitivity makes it useful in therapeutic drug monitoring.

[Mycobacterium avium complex infections: the point on the treatments]. / Infections à mycobactéries du complexe aviaire: le point sur les traitements.

Mycobacterium avium complex (MAC) infections are the most frequent opportunistic infections in AIDS. Since progress in antiretroviral drugs enables AIDS patients to survive longer, these infections involve an increasing number of sick people. Few controlled assays have evaluated the efficiency of several antibiotics. When used in monotherapy, clarithromycin (one gram twice a day) appeared as the most efficient drug while the effectiveness of azithromycin, clofazimine, rifampin and liposomal encapsulated gentamicin have not been truly proved. Due to its bacteriologic and clinical effects, the most interesting polytherapeutic scheme is the association of clarithromycin (1 g twice a day), ethambutol (15 mg per kg and per day) and rifabutin (600 mg per day).

[Development of a practical guide for utilization of injectable drugs in neonatology and in pediatrics]. / Elaboration d'un guide pratique d'utilisation des médicaments injectables en néonatalogie et en pédiatrie.

Although medications continue to be used extensively in the hospitalized paediatric patient, our knowledge regarding many of these agents remains limited. To date, apart from anecdotal case reports or studies involving a very limited number of patients, few data regarding the dosing and usage of medications in neonates and paediatric patients are available in the literature. This work has been conducted in order to provide sources of information on the intravenous administration of medication to these patients. All recommendations should be individualised in accordance with the clinical situation.

Bayesian estimation of p-aminohippurate clearance by a limited sampling strategy.

This study describes a methodology to calculated p-aminohippurate (PAH) clearance (CL) and volume of distribution (V) with both the population parameters and one or two samples taken during the disposition and the elimination phase after a single intravenous infusion. The computer program P-PHARM was used, and a log-normal distribution and a heteroscedastic residual error distribution were assumed. Ninety-six patients with and without renal insufficiency were available for analysis, and a two-compartment model was used for data modeling. Population parameters were evaluated for 70 patients (mean number of observed concentration per individual, 6) by a three-step approach. In step 1, the computer program was used to estimate the average pharmacokinetic parameters without taking into account the demographic and/or biological factors. In step 2, the relationship between the posterior individual estimates and the covariables was investigated with multiple linear stepwise algorithm. In step 3, the population parameters were re-estimated considering the relationship with the covariables. From the regression performed in step 2, the following covariables were included: serum creatinine, body surface area, and body weight. The population averages of CL and V were 30.7 +/- 2.36 L/h and 10.6 +/- 1.29 L, respectively. To evaluate the predictive performance of the population parameters, the remaining 26 patients were used. The population parameters combined with one or two individual PAH plasma concentrations led to a bayesian estimation of individual CL and V. This estimation was compared with the classical procedure of parameter estimation (individual fitting from multiple blood samples).(ABSTRACT TRUNCATED AT 250 WORDS)

A reproducible, simple and sensitive HPLC assay for determination of ofloxacin in plasma and lung tissue. Application in pharmacokinetic studies.

A high-performance liquid chromatographic method with fluorometric detection was developed for the analysis of ofloxacin in plasma and lung tissue. The detection was performed at 280 nm for excitation and 500 nm for emission. The procedure involves the addition of an internal standard followed by treatment of the samples with acetonitrile and dichloromethane. The proposed technique is reproducible, selective, reliable and sensitive. Linear detector response was observed for the calibration curve standards in the range of 0.1-5 micrograms ml-1 for plasma and 0.025-2.5 micrograms g-1 for lung tissue. The limit of quantitation is 5 ng ml-1 or 5 ng g-1. The accuracy of the method is good; that is, the relative error is < 10%. This method was applied to the pharmacokinetic study of ofloxacin in 24 chronic obstructive pulmonary disease patients.

Multiple-dose pharmacokinetics of ceftibuten after oral administration to healthy volunteers.

The pharmacokinetics of ceftibuten in plasma and urine were investigated after oral administration. Twelve healthy subjects were treated orally twice daily with 400 mg of the drug for 7 days; on day 8, the subjects received a last dose of 400 mg of ceftibuten. Ceftibuten and its metabolite, the trans isomer of ceftibuten, were assayed in plasma and urine by a specific HPLC method with UV detection. Ceftibuten was rapidly absorbed, as evidenced by the mean time to the maximum observed cis-ceftibuten concentration of 2.4 h. To describe the drug intake process, a Weibull model was used. For the metabolite, the mean time to maximum concentration in plasma was 3.25 h. Mean values for the terminal half-life in plasma were 2.17 h for cis-ceftibuten and 3.19 h for trans-ceftibuten. The overall elimination half-life, tmax, and total and renal clearances of cis-ceftibuten were invariant with respect to duration of dosing. The area under the plasma concentration versus time curve from 0 to infinity and the Cmax of this drug were significantly higher on day 8 than the values predicted from the elimination half-life computed on day 1 of treatment and the dosing interval. The pharmacokinetic parameters of trans-ceftibuten were invariant with respect to duration of dosing. Ceftibuten was well tolerated; there were no clinically significant adverse clinical events. The results from the present study indicate that the levels of cis-ceftibuten in plasma as well as in urine remain above the MICs for susceptible organisms over the dosing interval.