Evaluation of Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium

June 20, 2019 updated by: University of Colorado, Denver

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Observational

Enrollment (Actual)

16

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Aurora, California, United States, 80045
        • University of Colorado Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 87 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Inpatients at the University of Colorado Hospital

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Only
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Colistin
  • 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
Other Names:
  • CMS
  • colistin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Area under the plasma concentration time curve (AUC0-24)
Time Frame: 0, 30, 60, 120, 240, and 360 minutes after the IV infusion
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
Time Frame: 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)
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)

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients experiencing neurotoxicity
Time Frame: 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)
Neurotoxicity (headache, dizziness, weakness, facial and peripheral paresthesia, vertigo, visual disturbances, confusion, ataxia, and neuromuscular blockade, or other central nervous system related symptoms) as determined by patient report
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)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Colorado, Denver

Investigators

  • Principal Investigator: Ty Kiser, PharmD, University of Colorado, Denver

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2013

Primary Completion (Actual)

June 1, 2019

Study Completion (Actual)

June 1, 2019

Study Registration Dates

First Submitted

September 15, 2014

First Submitted That Met QC Criteria

November 6, 2014

First Posted (Estimate)

November 11, 2014

Study Record Updates

Last Update Posted (Actual)

June 24, 2019

Last Update Submitted That Met QC Criteria

June 20, 2019

Last Verified

June 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 13-2597

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Colistin

Clinical Trials on colistimethate sodium

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Germany

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe