Optimizing Dosing of Colistin for Infections Resistant to All Other Antibiotics, Approved NIH Protocol Dated 12.06.07(DMID Protocol #07-0036)
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, Hematology |
| Therapuetic Areas: | Hematology, Immunology / Infectious Diseases |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | June 2008 |
| End Date: | August 2015 |
Pharmacokinetics and Pharmacodynamics of Intravenous Colistin- Pilot Study
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.
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.
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.
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.
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
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