Evaluation of Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium

Study Overview
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Brief Summary
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Colistin is a polymixin antibiotic used in the treatment of multidrug-resistant gram-negative infections. Given the limited use of colistin and previous challenges with laboratory assays to determine plasma concentrations, there is a lack of knowledge of the pharmacokinetic profile of colistin. The purpose of the investigators observational prospective pharmacokinetic cohort study is to examine the steady-state pharmacokinetic and pharmacodynamic properties of intravenous colistimethate sodium in cystic fibrosis and critically ill patients.

Detailed Description
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Colistin, also known as polymixin E, is a peptide antibiotic that demonstrates concentration-dependent bactericidal killing against gram-negative pathogens including Pseudomonas and Acinetobacter. Originally discovered in the 1950s, its use has been limited due to the concern for its systemic toxicities including nephrotoxicity and neurotoxicity. However, a revival of colistin use has been seen in recent years due to the increased emergence of multidrug-resistant (MDR) gram-negative pathogens and a lack of alternative antimicrobial therapies. Colistin is administered intravenously as colistimethate sodium (CMS), an inactive prodrug that lacks antibacterial activity, and is hydrolyzed into its active form in plasma as colistin A and colistin B. Prior pharmacokinetic studies have demonstrated a wide range of pharmacokinetic/pharmacodynamics (PK/PD) findings for colistin. Variability in results have been attributed to an unreliable differentiation between colistin and CMS plasma concentrations with the use of microbiological assays, in addition to procedures that resulted in substantial in vitro hydrolysis of CMS to colistin during sample preparation. Refined laboratory methods such as high-performance liquid chromatography (HPLC) have circumvented such issues and provided opportunities for further pharmacokinetic profiling. Given the scarcity of its use and challenges with quantitative assays, the pharmacokinetic and pharmacodynamic profile of colistin has been poorly characterized particularly amongst cystic fibrosis and critically ill patients. Determination of such parameters in these patient populations is vital to optimize the maximum concentration to minimum inhibitory concentration (Cmax:MIC) ratio for maximal efficacy, minimize adverse effects and to reduce the development of bacterial resistance. Previous studies examining the steady-state pharmacokinetics of colistin in cystic fibrosis and critically ill patients have concluded that based on the in vitro pharmacodynamics against Pseudomonas aeruginosa, current dose recommendations may be inadequate to achieve desirable Cmax:MIC ratios and dose escalations may be warranted. The investigators study aims to determine steady-state colistin A and colistin B concentrations in cystic fibrosis and critically ill patients, evaluate pharmacodynamic parameters and relationship to microbiologic success, and monitor for the incidence of nephrotoxicity. The findings of this pilot study will be used to develop dosing recommendations for future pharmacokinetic studies of colistimethate sodium in cystic fibrosis and critically ill patients.

Official Title
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Evaluation of Steady-state Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium in Cystic Fibrosis and Critically Ill Patients

Conditions
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Colistin

Intervention / Treatment
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* Drug: colistimethate sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years old receiving intravenous colistimethate sodium for the treatment of infection Have cystic fibrosis and/or are critically ill (admitted to a critical care unit) Exclusion Criteria: Pregnancy Breastfeeding Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Colistin<br>Patients ≥ 18 years old receiving intravenous colistimethate sodium for the treatment of infection Have cystic fibrosis and/or are critically ill (admitted to a critical care unit) | Drug: colistimethate sodium<br> <br> * Other names: CMS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration time curve (AUC0-24) | Steady-state plasma concentrations will be obtained after at least 2 days of therapy. Blood draws (5 ml) will be taken just before the start of the colistimethate sodium infusion and at 30, 60, 120, 240, and 360 minutes after the IV infusion. | 0, 30, 60, 120, 240, and 360 minutes after the IV infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients experiencing nephrotoxicity | Nephrotoxicity defined as either 1) a rise in serum creatinine (SCr) > or = 0.5 mg/dl; 2) 50% increase in SCr or 3) 25% decrease in estimated creatinine clearance | Baseline, during colistin therapy course (expected to be approximately 14 days), and until hospital discharge (participants will be followed for the duration of hospital stay, expected to be 2-4 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacokinetics, cystic fibrosis, critical illness