ColistinNCT02288429
Evaluation of Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium
An observational study of Colistin, run by University of Colorado, Denver at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 89 years
- Conditions the study is for
- Colistin
- What is being tested?
- colistimethate sodium
- Type of treatment
- Injection or infusion
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2013to Jun 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Inpatients at the University of Colorado Hospital
Who may be able to join
- 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)
Who cannot join
- Pregnancy
- Breastfeeding
- Prisoners
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Colorado Hospital
Aurora, California, 80045
About this study
Official title: 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.
Read the 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.
- Conditions
- Colistin
- Being tested
- colistimethate sodium
- Keywords
- pharmacokinetics, cystic fibrosis, critical illness
- Medical subject headings
- Cystic Fibrosis, Critical Illness
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
colistimethate sodiumDrug
Also called colistin, CMS
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: Drug: colistimethate sodium |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 0, 30, 60, 120, 240, and 360 minutes after the IV infusion
Secondary outcomes (1)
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
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2014 (estimated)
- Study startSep 2013
- Primary completionJun 2019
- Study completionJun 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for ColistinStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Prospective
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Ty Kiser, PharmD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02288429
- Sponsor's protocol ID
- 13-2597
- Status last verified
- Jun 2019
- First submitted
- 15 Sep 2014
- Last updated
- 24 Jun 2019
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- Individual data sharing
- No
Publications
Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited. Clin Microbiol Rev. 2008 Jul;21(3):449-65. doi: 10.1128/CMR.00006-08.
PubMed 18625681Karnik ND, Sridharan K, Jadhav SP, Kadam PP, Naidu RK, Namjoshi RD, Gupta V, Gore MS, Surase PV, Mehta PR, Gogtay JA, Thatte UM, Gogtay NJ. Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection. Eur J Clin Pharmacol. 2013 Jul;69(7):1429-36. doi: 10.1007/s00228-013-1493-9. Epub 2013 Mar 19.
PubMed 23508665Plachouras D, Karvanen M, Friberg LE, Papadomichelakis E, Antoniadou A, Tsangaris I, Karaiskos I, Poulakou G, Kontopidou F, Armaganidis A, Cars O, Giamarellou H. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009 Aug;53(8):3430-6. doi: 10.1128/AAC.01361-08. Epub 2009 May 11.
PubMed 19433570Li J, Coulthard K, Milne R, Nation RL, Conway S, Peckham D, Etherington C, Turnidge J. Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J Antimicrob Chemother. 2003 Dec;52(6):987-92. doi: 10.1093/jac/dkg468. Epub 2003 Oct 29.
PubMed 14585859Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, van Koningsbruggen S, Grasemann H. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006 Feb;57(2):306-11. doi: 10.1093/jac/dki461. Epub 2006 Jan 5.
PubMed 16396919Markou N, Markantonis SL, Dimitrakis E, Panidis D, Boutzouka E, Karatzas S, Rafailidis P, Apostolakos H, Baltopoulos G. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study. Clin Ther. 2008 Jan;30(1):143-51. doi: 10.1016/j.clinthera.2008.01.015.
PubMed 18343250Imberti R, Cusato M, Villani P, Carnevale L, Iotti GA, Langer M, Regazzi M. Steady-state pharmacokinetics and BAL concentration of colistin in critically Ill patients after IV colistin methanesulfonate administration. Chest. 2010 Dec;138(6):1333-9. doi: 10.1378/chest.10-0463. Epub 2010 Jun 17.
PubMed 20558557
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of Steady-state Pharmacokinetic and Pharmacodynamic Properties of Intravenous Colistimethate Sodium in Cystic Fibrosis and Critically Ill Patients
- ClinicalTrials.gov ID
- NCT02288429
- Acronym / sponsor ID
- 13-2597
- Conditions
- Colistin
- Keywords
- pharmacokinetics, cystic fibrosis, critical illness
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 16 participants (actual)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Study start
- Sep 2013
- Primary completion
- Jun 2019 (actual)
- Study completion
- Jun 2019 (actual)
- First posted
- 11 Nov 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Observational model
- Case only
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Colistin | – | Drug: colistimethate sodium* 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) |
Who may qualify
- Ages
- 18 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Inpatients at the University of Colorado Hospital
Key inclusion criteria (2 listed)
- 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)
Key exclusion criteria (3 listed)
- Pregnancy
- Breastfeeding
- Prisoners
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| colistimethate sodiumAlso: colistin, CMS | Drug | Colistin |
Primary outcome
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.
1 secondary outcome
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)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2019.
- Background: PubMed 18625681Landman D, Georgescu C, Martin DA, Quale J. Polymyxins revisited. Clin Microbiol Rev. 2008 Jul;21(3):449-65. doi: 10.1128/CMR.00006-08.
- Background: PubMed 23508665Karnik ND, Sridharan K, Jadhav SP, Kadam PP, Naidu RK, Namjoshi RD, Gupta V, Gore MS, Surase PV, Mehta PR, Gogtay JA, Thatte UM, Gogtay NJ. Pharmacokinetics of colistin in critically ill patients with multidrug-resistant Gram-negative bacilli infection. Eur J Clin Pharmacol. 2013 Jul;69(7):1429-36. doi: 10.1007/s00228-013-1493-9. Epub 2013 Mar 19.
- Background: PubMed 19433570Plachouras D, Karvanen M, Friberg LE, Papadomichelakis E, Antoniadou A, Tsangaris I, Karaiskos I, Poulakou G, Kontopidou F, Armaganidis A, Cars O, Giamarellou H. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009 Aug;53(8):3430-6. doi: 10.1128/AAC.01361-08. Epub 2009 May 11.
- Background: PubMed 14585859Li J, Coulthard K, Milne R, Nation RL, Conway S, Peckham D, Etherington C, Turnidge J. Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J Antimicrob Chemother. 2003 Dec;52(6):987-92. doi: 10.1093/jac/dkg468. Epub 2003 Oct 29.
- Background: PubMed 16396919Ratjen F, Rietschel E, Kasel D, Schwiertz R, Starke K, Beier H, van Koningsbruggen S, Grasemann H. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother. 2006 Feb;57(2):306-11. doi: 10.1093/jac/dki461. Epub 2006 Jan 5.
- Background: PubMed 18343250Markou N, Markantonis SL, Dimitrakis E, Panidis D, Boutzouka E, Karatzas S, Rafailidis P, Apostolakos H, Baltopoulos G. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study. Clin Ther. 2008 Jan;30(1):143-51. doi: 10.1016/j.clinthera.2008.01.015.
- Background: PubMed 20558557Imberti R, Cusato M, Villani P, Carnevale L, Iotti GA, Langer M, Regazzi M. Steady-state pharmacokinetics and BAL concentration of colistin in critically Ill patients after IV colistin methanesulfonate administration. Chest. 2010 Dec;138(6):1333-9. doi: 10.1378/chest.10-0463. Epub 2010 Jun 17.
- Individual participant dataSharing planned: No
Related trials for Colistin
Not yet recruitingPhase 3
Cefepime-Zidebactam Versus Ceftazidime-Avibactam With or Without Colistin for Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia
Hospital Acquired Bacterial Pneumonia (HABP), Ventilator Associated Bacterial Pneumonia (VABP)
Not yet recruitingPhase 2/3
Nebulised Colistimethate Sodium to Prevent Pediatric Ventilator-associated Pneumonia
Ventilator Associated Pneumonia
Recruiting
Inhaled Colistin to Prevent Ventilator-Associated Pneumonia in Patients With Acute Brain Injury
Ventilator-Associated Pneumonia (VAP), Inha'le'd
Active, not recruitingPhase 4
Colistin and Meropenem Versus Amikacin and Meropenem for MDR Gram Negative Bacteria Regarding Efficacy and Safety.
MDR Bacteria
Not yet recruitingPhase 3
Colistin Nephrotoxicity and Role of Alpha Lipoic Acid
Nephrotoxicity
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ty Kiser, PharmD principal investigator
University of Colorado, Denver
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Colistin, run by University of Colorado, Denver at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Area under the plasma concentration time curve (AUC0-24) (time frame: 0, 30, 60, 120, 240, and 360 minutes after the IV infusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02288429, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jun 2019.