Clinical effects of proton pump inhibitors: Focus on pharmacogenetics, kinetics and dynamics

This thesis describes the clinical effects of proton pump inhibitors, with focus on pharmacogenetics, kinetics and dynamics. The aims were to investigate the occurence of Rebound Acid Hypersecretion and to investigate the speed of onset, the duration of effect and the difference in acid-inhibition between esomeprazole, rabeprazole and pantoprazole. Furthermore the prevalence of CYP2C19 polymorphism was studied in a Caucasian population. The influence of CYP2C19 polymorphism on acid-inhibition and pharmacokinetics of proton pump inhibitors in Caucasians was also studied

Persistent candida arthritis successfully treated with micafungin instillation and surgery. A case report

We report a rare case of C. krusei knee arthritis treated with instillation of micafungin and arthroscopy. A 49-year-old man hospitalized for treatment of Acute

Micafungin versus anidulafungin in critically ill patients with invasive candidiasis: A retrospective study

_Background:_ In critically ill patients the incidence of invasive fungal infections caused by Candida spp. has increased remarkably. Echinocandins are recommended as initial treatment for invasive fungal infections. The safety and efficacy of micafungin compared to caspofungin is similar, but no comp

The effect of the TIM program (Transfer ICU Medication reconciliation) on medication transfer errors in two Dutch intensive care units

__Background:__ The transfer of patients to and from the Intensive Care Unit (ICU) is prone to medication errors. The aim of the present study is to determine whether the number of medication errors at ICU admission and discharge and the associated potential harm and costs are reduced by using the Transfer ICU and Medication reconciliation (TIM) program. __Methods:__ This prospective 8-month observational study with a pre- and post-design will assess the effects of the TIM program compared with usual care in two Dutch hospitals. Patients will be included if they are using at least one drug before hospital admission and will stay in the ICU for at least 24 h. They are excluded if they are transferred to another hospital, admitted and discharged in the same weekend or unable to communicate in Dutch or English. In the TIM program, a clinical pharmacist reconciles patient's medication history within 24 h after ICU admission, resulting in a "best possible" medication history and presents it to the ICU doctor. At ICU discharge the clinical pharmacist reconciles the prescribed ICU medication and the medication history with the ICU doctor, resulting in an ICU discharge medication list with medication prescription recommendations for the general ward doctor. Primary outcome measures are the proportions of patients with one or more medication transfer errors 24 h after ICU admission and 24 h after ICU discharge. Secondary outcome measures are the proportion of patients with potential adverse drug events, the severity of potential adverse drug events and the associated costs. For the primary outcome relative risks and 95% confidence intervals will be calculated. __Discussion:__ Strengths of this study are the tailor-made design of the TIM program and two participating hospitals. This study also has some limitations: A potential selection bias since this program is not performed during the weekends, collecting of potential rather than actual adverse drug events and finally a relatively short study period. Nevertheless, the findings of this study will provide valuable information on a crucial safety intervention in the ICU

Development of a multivariable prediction model for identification of patients at risk for medication transfer errors at ICU discharge

Introduction Discharge from the intensive care unit (ICU) is a high-risk process, leading to numerous potentially harmful medication transfer errors (PH-MTE). PH-MTE could be prevented by medication reconciliation by ICU pharmacists, but resources are scarce, which renders the need for predicting which patients are at risk for PH-MTE. The aim of this study was to develop a prognostic multivariable model in patients discharged from the ICU to predict who is at increased risk for PH-MTE after ICU discharge, using predictors of PH-MTE that are readily available at the time of ICU discharge. Material and methods Data for this study were derived from the Transfer ICU Medication reconciliation study, which included ICU patients and scored MTE at discharge of the ICU. The potential harm of every MTE was estimated with a validated score, where after MTE with potential for harm were indicated as PH-MTE. Predictors for PH-MTE at ICU discharge were identified using LASSO regression. The c statisticprovided a measure of the overall discriminative ability of the prediction model and the prediction model was internally validated by bootstrap resampling. Based on sensitivity and specificity, the cut-off point of the prediction model was determined. Results The cohort contained 258 patients and six variables were identified as predictors for PH-MTE: length of ICU admission, number of home medications and patient taking one of the following medication groups at home: vitamin/mineral supplements, cardiovascular medication, psycholeptic/analeptic medication and medication for obstructive airway disease. The c of the final prediction model was 0.73 (95%CI 0.67–0.79) and decreased to 0.62 according to bootstrap resampling. At a cut-off score of two the prediction model yielded a sensitivity of 70% and a specificity of 61%. Conclusions A multivariable prediction model was developed to identify patients at risk for PH-MTE after ICU discharge. The model contains predictors that are available on the day of ICU discharge. Once external validation and evaluation of this model in daily practice has been performed, its incorporation into clinical practice could potentially allow institutions to identify patients at risk for PH-MTE after ICU discharge, on the day of ICU discharge, thus allowing for efficient, patient-specific allocation of clinical pharmacy services

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

The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: The DOLPHIN trial protocol of a multi-centre randomised controlled trial

Background: Critically ill patients undergo extensive physiological alterations that will have impact on antibiotic pharmacokinetics. Up to 60% of intensive care unit (ICU) patients meet the pharmacodynamic targets of beta-lactam antibiotics, with only 30% in fluoroquinolones. Not reaching these targets might increase the chance of therapeutic failure, resulting in increased mortality and morbidity, and antibiotic resistance. The DOLPHIN trial was designed to demonstrate the added value of therapeutic drug monitoring (TDM) of beta-lactam and fluoroquinolones in critically ill patients in the ICU. Methods: A multi-centre, randomised controlled trial (RCT) was designed to assess the efficacy and cost-effectiveness of model-based TDM of beta-lactam and fluoroquinolones. Four hundred fifty patients will be included within 24 months after start of inclusion. Eligible patients will be randomly allocated to either study group: the intervention group (active TDM) or the control group (non-TDM). In the intervention group dose adjustment of the study antibiotics (cefotaxime, ceftazidime, ceftriaxone, cefuroxime, amoxicillin, amoxicillin with clavulanic acid, flucloxacillin, piperacillin with tazobactam, meropenem, and ciprofloxacin) on day 1, 3, and 5 is performed based upon TDM with a Bayesian model. The primary outcome will be ICU length of stay. Other outcomes amongst all survival, disease severity, safety, quality of life after ICU discharge, and cost effectiveness will be included. Discussion: No trial has investigated the effect of early TDM of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients. The findings from the DOLPHIN trial will possibly lead to new insights in clinical management of critically ill patients receiving antibiotics. In short, to TDM or not to TDM? Trial registration: EudraCT number: 2017-004677-14. Sponsor protocol name: DOLPHIN. Registered 6 March 2018. Protocol Version 6, Protocol date: 27 November 2019

Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients

_Objective:_ To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strateg

Safe use of proton pump inhibitors in patients with cirrhosis

Aims: Proton pump inhibitors (PPIs) belong to the most frequently used drugs, also in patients with cirrhosis. PPIs are extensively metabolized by the liver, but practice guidance on prescribing in cirrhosis is lacking. We aim to develop practical guidance on the safe use of PPIs in patients with cirrhosis. Methods: A systematic literature search identified studies on the safety (i.e. adverse events) and pharmacokinetics of PPIs in cirrhotic patients. This evidence and data from the product information was reviewed by an expert panel who classified drugs as safe; no additional risks known; additional risks known; unsafe; or unknown. Guidance was aimed at the oral use of PPIs and categorized by the severity of cirrhosis, using the Child–Turcotte–Pugh (CTP) classification. Results: A total of 69 studies were included. Esomeprazole, omeprazole and rabeprazole were classified as having ‘no additional risks known’. A reduction in maximum dose of omeprazole and rabeprazole is recommended for CTP A and B patients. For patients with CTP C cirrhosis, the only PPI advised is esomeprazole at a maximum dosage of 20 mg per day. Pantoprazole and lansoprazole were classified as unsafe because of 4- to 8-fold increased exposure. The use of PPIs in cirrhotic patients has been associated with the development of infections and hepatic encephalopathy and should be carefully considered. Conclusions: We suggest using esomeprazole, omeprazole or rabeprazole in patients with CTP A or B cirrhosis and only esomeprazole in patients with CTP C. Pharmacokinetic changes are also important to consider when prescribing PPIs to vulnerable, cirrhotic patients