Changes of colistin pharmacokinetics in critically ill patients due to the extracorporeal membrane oxygenation: protocol for the COL-ECMO2022 trial - a prospective, non-randomised, open-label phase IV pharmacokinetic clinical trial.

INTRODUCTION: Colistin is a lipopeptide antibiotic administered as an inactive prodrug-colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment. METHODS AND ANALYSIS: The COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant. ETHICS AND DISSEMINATION: The study has been approved by the Ethics Committee of St. Anne's University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals. TRIAL REGISTRATION NUMBERS: EudraCT Number 2022-000291-19; NCT05542446.

Use of fondaparinux in patients with heparin-induced thrombocytopenia on veno-venous extracorporeal membrane oxygenation: A three-patient case series report.

Heparin-induced thrombocytopenia is a life-threatening immune-mediated complication of unfractionated heparin therapy. Fondaparinux is a therapeutic alternative, but it has limited evidence for its use in patients on extracorporeal membrane oxygenation (ECMO). We present a series of three adult patients with COVID-19 on ECMO who were diagnosed with heparin-induced thrombocytopenia after 7-12 days of unfractionated heparin treatment and were switched to fondaparinux. Fondaparinux was initiated with an intravenous loading dose of 5 mg, followed by a dose of 2.5 mg subcutaneously every 8-12 h. Dosage was adjusted according to daily measured anti-Xa concentration with a target range of 0.4-0.7 mg/L. The total duration of treatment with fondaparinux and ECMO ranged from 13 to 26 days. One major bleeding episode unrelated to fondaparinux therapy was observed, and the transfusions requirement was also low in all patients. The ECMO circuit was changed once in each patient. This series provides a deep insight into the use of fondaparinux over an extended period of time in patients on ECMO. Based on the presented data, fondaparinux can be considered a reasonable and affordable anticoagulant in patients without a high risk of bleeding.

Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review.

The emerging resistance of Gram-negative bacteria is a growing problem worldwide. Together with the financial cost, limited efficacy, and local unavailability of newer antibiotics or their combinations, it has led to the reintroduction of colistin as a therapeutic alternative. Despite its protracted development and availability on the market, there is now a complex maze of questions surrounding colistin with a more or less straightforward relationship to its safety and efficacy. This review aims to offer a way to navigate this maze. We focus on summarizing the available literature regarding the use of colistin in critically ill patients, particularly on stability, pharmacokinetics, methods for determining plasma concentrations, and therapeutic drug monitoring benefits and limitations. Based on these data, we then highlight the main gaps in the available information and help define directions for future research on this drug. The first gap is the lack of data on the stability of intravenous and nebulization solutions at clinically relevant concentrations and under external conditions corresponding to clinical practice. Furthermore, pharmacokinetic-pharmacodynamic parameters should be validated using standardized dosing, including a loading dose. Based on the pharmacokinetic data obtained, a population model for critically ill patients should be developed. Finally, the interference of colistin with extracorporeal methods should be quantified.

[Pharmacological properties of colistin].

Colistin is a narrow-spectrum lipopeptide antimicrobial agent used to treat nosocomial infections caused by multidrug-resistant bacteria, especially in critically ill patients and those with cystic fibrosis. Colistin represents a concentration-time-dependent antibiotic with highly variable pharmacokinetics related to the heterogeneity of the target population and the necessity of bioactivation. Colistin is administered as the inactive prodrug colistimethate sodium. Nephrotoxicity and neurotoxicity are the most frequent adverse effects.

Standardization of clinical pharmacist's activities: Methodology.

STUDY OBJECTIVES: Establishing standardized and controlled system of work at a clinical pharmacy department and establishing effective recording of activities of a group of four clinical pharmacist when providing clinical pharmaceutical care (CPC) in a hospital. METHODS: The duration of evaluated period is 5.5 years. The first part was defining the purpose, methods and activities of clinical pharmaceutical care, the next part was designing the software for recording patient's data and CPC activities. To verify the functionality of our system the third part was conducted (from January 1, 2015 to June 30, 2015). RESULTS: CPC activities were defined precisely. During the 6 months period, 3946 patients were reviewed (17% of patients admitted), in this group, 41% patients was labeled as risk (these patients had one or more risk factor). 1722 repeated reviews were performed, 884 drug therapy recommendations were recorded. The calculated average time necessary for one CPC activity is 28 min. CONCLUSION: During the 5 year period, standardized system of work in clinical pharmacy department was established. This system is based on clearly defined activities and it enables external control. Our results supply data for negotiations with health insurance companies.

Evaluation of Clinical Pharmacists' Interventions in the Czech Republic.

STUDY OBJECTIVES: To determine the frequency of interventions, categorized by type of intervention and therapeutic class, made by a team of four clinical pharmacists over a 1-year period, and to assess the potential economic impact of these interventions. DESIGN: Prospective analysis. SETTING: Large medical center in Prague, Czech Republic. PATIENTS: A total of 9153 adults who were admitted to the general surgery, infectious diseases, oncology, orthopedics, and thoracic surgery and respiratory medicine services between January 1, 2014, and December 31, 2014. INTERVENTION: Four clinical pharmacists reviewed patients' medication profiles, participated in medical and surgical rounds, and made drug therapy-related recommendations to physicians. MEASUREMENTS AND MAIN RESULTS: Clinical pharmacists' interventions were categorized by therapeutic class and divided into eight types: introduction of a drug, discontinuation of a drug, dosage change, route of administration change, recommendation to continue therapy, recommendation to perform further evaluation (e.g., laboratory assessment), reintroduction of a missing medication, and therapeutic drug monitoring (request to measure a drug concentration and provide its interpretation). All interventions accepted by the attending physicians were recorded by using a software application. For the evaluation of the economic impact of the interventions, published statistical data were used from the Institute of Health Information and Statistics of the Czech Republic. During the 1-year period, the clinical pharmacists performed 1916 interventions. The most frequent intervention was drug discontinuation (27.9% of all interventions), and the drug category with the highest frequency of interventions was central nervous system drugs (25.1%). All interventions were accepted by the physicians. For the evaluation of potential economic impact, a select group of drugs was used, representing 14.4% of the interventions. The benefit:cost ratio was 3:1. CONCLUSION: All interventions made by clinical pharmacists were accepted by the physicians. Drug discontinuation was the most frequent intervention. The analysis of potential economic savings showed the positive impact of these interventions, with a benefit:cost ratio of 3:1.