Background and objective: Previous pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further... Show moreBackground and objective: Previous pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further investigation is needed for this population. Hence, we performed a pooled population PK analysis of ciprofloxacin after intravenous administration using individual patient data from three studies. Additionally, we studied the PK differences between these studies through a post-hoc analysis.Methods: Individual patient data from three studies (study 1, 2, and 3) were pooled. The pooled data set consisted of 1094 ciprofloxacin concentration-time data points from 140 ICU patients. Nonlinear mixed-effects modeling was used to develop a population PK model. Covariates were selected following a stepwise covariate modeling procedure. To analyze PK differences between the three original studies, random samples were drawn from the posterior distribution of individual PK parameters. These samples were used for a simulation study comparing PK exposure and the percentage of target attainment between patients of these studies.Results: A two-compartment model with first-order elimination best described the data. Inter-individual variability was added to the clearance, central volume, and peripheral volume. Inter-occasion variability was added to clearance only. Body weight was added to all parameters allometrically. Estimated glomerular filtration rate on ciprofloxacin clearance was identified as the only covariate relationship resulting in a drop in inter-individual variability of clearance from 58.7 to 47.2%. In the post-hoc analysis, clearance showed the highest deviation between the three studies with a coefficient of variation of 14.3% for posterior mean and 24.1% for posterior inter-individual variability. The simulation study showed that following the same dose regimen of 400 mg three times daily, the area under the concentration-time curve of study 3 was the highest with a mean area under the concentration-time curve at 24 h of 58 mg·h/L compared with that of 47.7 mg·h/L for study 1 and 47.6 mg·h/L for study 2. Similar differences were also observed in the percentage of target attainment, defined as the ratio of area under the concentration-time curve at 24 h and the minimum inhibitory concentration. At the epidemiological cut-off minimum inhibitory concentration of Pseudomonas aeruginosa of 0.5 mg/L, percentage of target attainment was only 21%, 18%, and 38% for study 1, 2, and 3, respectively.Conclusions: We developed a population PK model of ciprofloxacin in ICU patients using pooled data of individual patients from three studies. A simple ciprofloxacin dose recommendation for the entire ICU population remains challenging owing to the PK differences within ICU patients, hence dose individualization may be needed for the optimization of ciprofloxacin treatment. Show less
Background: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic... Show moreBackground: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%integral T > 1-4xMIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.Methods: This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (integral T > MICECOFF and integral T > 4xMIC(ECOFF)) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.Results: A total of 147 patients were included, of whom 63.3% achieved PDT of 100% integral T > MICECOFF and 36.7% achieved 100% integral T > 4xMIC(ECOFF). Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) >= 90 mL/min/1.73 m(2), and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100% integral T > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Show less
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... Show morePurpose 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 integral AUC(0-24)/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/m(2), and eGFR of 58.5 mL/min/1.73 m(2). The median integral AUC(0-24) and integral C-max were 29.9 mg center dot 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 integral AUC(0-24)/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 integral AUC(0-24)/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. Show less
