High unbound flucloxacillin fraction in critically ill patients.

OBJECTIVES: To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies. PATIENTS AND METHODS: Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR. RESULTS: The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of >2.5 mg/L (100% fT>5×MIC, MIC = 0.5 mg/L). CONCLUSIONS: Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.

Monitoring Protein-Unbound Valproic Acid Serum Concentrations in Clinical Practice.

BACKGROUND: Valproic acid (VPA) is an effective antiepileptic drug and mood stabilizer. A key characteristic of VPA is its high and saturable protein binding at higher concentrations. Although the unbound concentration of VPA is responsible for its pharmacological activity, total drug concentrations are monitored in routine clinical practice. Therapeutic drug monitoring (TDM) of unbound VPA is recommended for specific clinical situations. The goal of this study was to evaluate TDM requests for unbound VPA in clinical practice. METHODS: All TDM requests at our laboratory for unbound VPA in 2014 and 2015 were evaluated retrospectively. In patients with potentially toxic unbound VPA concentrations (ie, >12 mg/L), we evaluated whether toxicity was noted and whether the dose adjustment advice was followed. Total and unbound VPA concentrations were measured by means of a validated immunoassay. RESULTS: A total of 273 unbound VPA serum concentrations in 132 different patients were analyzed. The main reasons for unbound VPA TDM were decreased renal function (34%) and a low serum albumin (27%). The median (range) unbound VPA concentration was 9.8 (2.5-47.6) mg/L. In 49 patients (37%), the initial unbound VPA concentration was above the threshold of 12 mg/L, potentially resulting in toxicity. Only 6 of these 49 patients had elevated total VPA concentrations. Clinical toxicity was noted in 38 of the 49 patients (77.6%) with elevated unbound VPA concentrations. Toxicities included drowsiness (n = 26), decreased consciousness (n = 4), rigidity (n = 2), and confusion (n = 2). In 36 of the 38 patients with elevated unbound VPA concentrations and clinical toxicity, a dose reduction was applied. In 27 of 36 patients who had their dose reduced, dose reduction was associated with improvement or resolution of VPA toxicity. CONCLUSIONS: TDM of unbound VPA is an important tool to manage VPA therapy in selected, vulnerable patients.

An Integral Pharmacokinetic Analysis of Piperacillin and Tazobactam in Plasma and Urine in Critically Ill Patients.

BACKGROUND AND OBJECTIVES: Although dose optimization studies have been performed for piperacillin and tazobactam separately, a combined integral analysis is not yet reported. As piperacillin and tazobactam pharmacokinetics are likely to show correlation, a combined pharmacokinetic model should be preferred to account for this correlation when predicting the exposure. Therefore, the aim of this study was to describe the pharmacokinetics and evaluate different dosing regimens of piperacillin and tazobactam in critically ill patients using an integral population pharmacokinetic model in plasma and urine. METHODS: In this observational study, a total of 39 adult intensive care unit patients receiving piperacillin-tazobactam as part of routine clinical care were included. Piperacillin and tazobactam concentrations in plasma and urine were measured and analyzed using non-linear mixed-effects modeling. Monte Carlo simulations were performed to predict the concentrations for different dosing strategies and different categories of renal function. RESULTS: A combined two-compartment linear pharmacokinetic model for both piperacillin and tazobactam was developed, with an output compartment for the renally excreted fraction. The addition of 24-h urine creatinine clearance significantly improved the model fit. A dose of 12/1.5 g/24 h as a continuous infusion is sufficient to reach a tazobactam concentration above the target (2.89 mg/L) and a piperacillin concentration above the target of 100% f T>1×MIC (minimum inhibitory concentration [MIC] ≤ 16 mg/L). To reach a target of 100% f T>5×MIC with an MIC of 16 mg/L, piperacillin doses of up to 20 g/24 h are inadequate. Potential toxic piperacillin levels were reached in 19.6% and 47.8% of the population with a dose of 12 g/24 h and 20 g/24 h, respectively. CONCLUSIONS: A regular dose of 12/1.5 g/24 h is sufficient in > 90% of the critically ill population to treat infections caused by Escherichia coli and Klebsiella pneumoniae with MICs ≤ 8 mg/L. In case of infections caused by Pseudomonas aeruginosa with an MIC of 16 mg/L, there is a fine line between therapeutic and toxic exposure. Dosing guided by renal function and therapeutic drug monitoring could enhance target attainment in such cases. GOV IDENTIFIER: NCT03738683.

A meta-analysis of protein binding of flucloxacillin in healthy volunteers and hospitalized patients.

OBJECTIVES: The aim of this study was to develop a mechanistic protein-binding model to predict the unbound flucloxacillin concentrations in different patient populations. METHODS: A mechanistic protein-binding model was fitted to the data using non-linear mixed-effects modelling. Data were obtained from four datasets, containing 710 paired total and unbound flucloxacillin concentrations from healthy volunteers, non-critically ill and critically ill patients. A fifth dataset with data from hospitalized patients was used for evaluation of our model. The predictive performance of the mechanistic model was evaluated and compared with the calculation of the unbound concentration with a fixed unbound fraction of 5%. Finally, we performed a fit-for-use evaluation, verifying whether the model-predicted unbound flucloxacillin concentrations would lead to clinically incorrect dose adjustments. RESULTS: The mechanistic protein-binding model predicted the unbound flucloxacillin concentrations more accurately than assuming an unbound fraction of 5%. The mean prediction error varied between -26.2% to 27.8% for the mechanistic model and between -30.8% to 83% for calculation with a fixed factor of 5%. The normalized root mean squared error varied between 36.8% and 69% respectively between 57.1% and 134%. Predicting the unbound concentration with the use of the mechanistic model resulted in 6.1% incorrect dose adjustments versus 19.4% if calculated with a fixed unbound fraction of 5%. CONCLUSIONS: Estimating the unbound concentration with a mechanistic protein-binding model outperforms the calculation with the use of a fixed protein binding factor of 5%, but neither demonstrates acceptable performance. When performing dose individualization of flucloxacillin, this should be done based on measured unbound concentrations rather than on estimated unbound concentrations from the measured total concentrations. In the absence of an assay for unbound concentrations, the mechanistic binding model should be preferred over assuming a fixed unbound fraction of 5%.

Personalised antimicrobial dosing: standing on the shoulders of giants.

Suboptimal use of antimicrobial drugs contributes to increasing antimicrobial resistance and may lead to therapeutic failure at the individual patient level. Considering the significant pharmacokinetic (PK) variation in special patient populations and the variability in pathogen susceptibility, personalised dosing of antimicrobial drugs is pivotal. Dosing based on PK and pharmacodynamic properties of antibiotics guided by therapeutic drug monitoring (TDM) maximises efficacy and minimises toxicity for individual patients. Model-informed precision dosing (MIPD) provides a means of predicting drug response and dose requirements in individual patients based on individual patient and pathogen characteristics. Clear concentration targets should be defined to make use of MIPD and TDM in clinical practice. Target selection, validation and publication in the drug label should be part of drug licensing.

Higher Dosage of Ciprofloxacin Necessary in Critically Ill Patients: A New Dosing Algorithm Based on Renal Function and Pathogen Susceptibility.

The objective of the present study was to develop a dosing algorithm for ciprofloxacin based on both renal function and pathogen susceptibility in critically ill patients. In this observational prospective multicenter pharmacokinetic study, a total of 39 adult intensive care unit patients receiving ciprofloxacin were included. On two occasions a total of 531 samples of ciprofloxacin were collected. Renal function is a significant covariate on ciprofloxacin clearance. A dose of 400 mg every 12 hours was sufficient to reach the preestablished target of area under the curve (AUC) in relation to the minimum inhibitory concentration (MIC) (AUC/MIC) > 125 in patients with an estimated glomerular filtration rate (eGFR) < 130 mL/min and an infection caused by a pathogen with an MIC ≤ 0.125 mg/L. For patients with infections caused by pathogens with an MIC ≥ 0.5 mg/L and eGFR> 100 mL/min, doses up to 600 mg four times daily or more were estimated to be required. This study provides a new dosing algorithm for ciprofloxacin in critically ill patients. In order to achieve adequate target attainment, the dosing of ciprofloxacin should be based on renal function and the MIC of the causative pathogen. Higher doses than the standard licensed dose are necessary to obtain target attainment for less susceptible pathogens and patients with high renal clearance. In the setting of impaired renal function, a daily dose of 400 mg (which is currently recommended) will not result in adequate target attainment for less susceptible pathogens.