Optimizing Dosing of Colistin for Infections Resistant to All Other Antibiotics, Approved NIH Protocol Dated 12.06.07(DMID Protocol #07-0036)

Bacteremia Clinical Trial

Official title:

Pharmacokinetics and Pharmacodynamics of Intravenous Colistin- Pilot Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00235690
• Other study ID #: IRB# 0509011
• Secondary ID: NIH
• Status: Completed
• Phase: N/A
• First received: October 6, 2005
• Last updated: December 16, 2015
• Start date: June 2008
• Est. completion date: August 2015

Study information

• Verified date: December 2015
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

More than 80 patients at the University of Pittsburgh Medical Center have been infected with Pseudomonas aeruginosa, lacking susceptibility to all commercially available antibiotics except "colistin". This antibiotic was developed in the 1960s and preliminary pharmacokinetic studies were performed at that time. Dosing recommendations, on the basis of these pharmacokinetic studies, are listed in the drug's product information. However, there are no dosing recommendations for patients requiring renal replacement therapy (either intermittent hemodialysis or continuous venovenous hemofiltration). Furthermore, the science of antibiotic dosing ("pharmacodynamics") has changed significantly since the 1960s and it is quite possible that the dosing recommendations listed in the product information are not optimal. Furthermore, even though physicians refer to "colistin" administration, the only intravenous form of the drug is colistin methanesulfonate (CMS). CMS is converted in the body to colistin. Both CMS and colistin have different pharmacokinetic and antimicrobial activities. For this reason, we, the investigators at the University of Pittsburgh, are performing a pilot study of the pharmacokinetics of intravenous CMS/colistin in patients requiring this antibiotic for clinical purposes. Plasma concentrations will be determined around a CMS/colistin dose once the drug has reached steady state. Concentrations in pulmonary epithelial lining fluid will also be determined in patients with pneumonia. Microbiologic and clinical endpoints will be determined and will be correlated with these concentrations. The measurement of CMS and colistin levels will be determined by a laboratory in Australia which developed these assays. A submission is being made to the National Institutes of Health (NIH) for funding of a multicenter study which will address this research question with a greater sample size. The study proposed here is a pilot study in order to prove the feasibility of the research approach and to provide preliminary data for the NIH proposal.

Description:

At baseline (upon signing informed consent), the following information will be collected:

Demographic data - age, sex, height, weight, state of birth, underlying illnesses, underlying infection, immunosuppression, antibiotic use, laboratory results, current medication use, any other prior medical problems/history and clinical outcomes.

The research coordinator will contact the patient on days 14, 28 and 90 days after the infection to determine clinical outcome. If the patient is still an inpatient the research coordinator will visit the patient in their hospital room to evaluate the patient's health status. This visit will take about 10 minutes. If the patient has been discharged from the hospital, the patient will be contacted by telephone by the research coordinator to determine the health status, if no recent electronic medical record exists. This telephone contact will take about 10 minutes.

Blood work and microbiologic samples to be collected:

Collection of six samples of 3 mL blood on the third or fourth day of colistin therapy will occur. These samples will be collected:

• immediately pre-dose,

• at the end of the colistin infusion,

• 30 minutes after the end of the colistin infusion,

• 60 minutes after the end of the colistin infusion,

• 4 hours after the end of the colistin infusion,

• 12 hours after the end of the colistin infusion (or immediately prior to the next dose if the drug is being given every 12 hours).

Indwelling venous and arterial access lines, if already in place, will be utilized for the pharmacological study's blood draws.

Rationale: The samples will be utilized for quantification of plasma levels of colistin.

Collection of microbiologic samples within 48-96 hours of the initiation of colistin therapy. These samples are two sets of blood cultures if the patient had bacteremia, a mini-BAL for quantitative bacterial culture if the patient had pneumonia and a cerebrospinal fluid collection if the patient had Gram negative meningitis and has a cerebrospinal fluid drain in situ. Additionally, these samples will be used to determine the concentrations of colistin and CMS at the site of infection. A 3mL blood sample will be taken at the same time as these specimen collections to determine concomitant serum concentrations of colistin and CMS.

Rationale: These samples will be used to determine if there has been rapid bacteriologic clearance of infection and to determine the concentrations of drug at the site of infection.

The blood samples will be processed and stored in a -80° C freezer in a secured laboratory under the supervision of the principal investigator. These samples will then be sent to the laboratory of Drs Jian Li and Roger Nation in Melbourne, Australia, to determine the amount of colistin and CMS that reached the participant's blood following dose administration. All samples will be sent de-identified.

All samples will be analyzed to obtain the amount of colistin and CMS found in the blood. The biologic samples will be under the control of the principal investigator of this research project. To protect confidentiality, all personal identifiers (i.e., name, social security number, and birth date) will be removed (de-identified) and replaced with a specific code number. The information linking these code numbers to the corresponding subjects' identities will be kept in a separate, secure location. The investigators on this study will keep the samples indefinitely. All samples sent outside of the UPMC facility will be de-identified. If a subject withdraws and provides the request in writing, samples collected and not already processed will be destroyed. All samples at UPMC will be kept in the investigator's laboratory located in Scaife Hall, Room 812, 3550 Terrace Street. All patients will be seen at the UPMC facility while they are inpatients.

Other items to be collected for study purposes:

Microbiology - the organism that caused the infection will be sub-cultured in the clinical microbiology laboratory (after the diagnosis has been obtained since the microbiology lab would otherwise destroy the culture) and provided to the investigators. All subsequent Gram negative bacterial isolates will be sub-cultured and stored for similar purposes.

An unopened vial of colistin from the same batch as used for the patient will be collected for analysis, so the actual dose of colistin can be calculated.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: August 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Males or females greater than 18 years of age.

• All patients will remain in the hospital for pharmacokinetic sampling.

• All subjects must be on the medication colistin as part of their standard of care.

• All individuals approached for participation shall be able to read and comprehend English.

Exclusion Criteria: None

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Bacteremia
• Pseudomonas Infections

Intervention

Procedure:
• Blood draws
PK samples obtained around a clinical dosing of colistin

Other:
• Blood draw
PK blood samples will be obtained around a clinical dosing of colistin

Locations

Country	Name	City	State
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
University of Pittsburgh

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To provide pharmacokinetic data on intravenous (IV) CMS/colistin		5 years	No
Secondary	Determine if CMS/colistin dosing is suboptimal in ill patients		5 years	No