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Abstract
Introduction Colistin is a lipopeptide antibiotic administered as an inactive prodrug—colistin methanesulfonate (CMS). Colistin is a drug with a narrow therapeutic window; the limiting factors are mainly nephrotoxicity and neurotoxicity, dependent on plasma concentrations. The number of patients with infections caused by multidrug-resistant Gram-negative bacteria sensitive only to colistin and the number of patients requiring extracorporeal membrane oxygenation (ECMO) support for severe respiratory failure increased significantly in association with COVID-19-induced infections. ECMO can generally affect the pharmacokinetics of drugs by creating a new compartment.
Methods and analysis The COL-ECMO2022 study is a prospective, non-randomised, single-centre, phase IV pharmacokinetic clinical trial designed to assess the influence of ECMO on the pharmacokinetics of colistin and CMS. Up to 30 patients treated with colistin will be included in the study and assigned to one of two arms, depending on the presence/absence of ECMO. All study participants will receive standard CMS dose intravenously. The plasma concentrations of colistin and CMS taken at defined intervals will be assessed by high-performance liquid chromatography-mass spectrometry. Patients will participate in the clinical trial for a maximum of three monitored dosing intervals. A population pharmacokinetic model will be developed to assess the influence of ECMO on pharmacokinetics. A difference greater than 25% is considered clinically significant.
Ethics and dissemination The study has been approved by the Ethics Committee of St. Anne’s University Hospital Brno (Number 10ML/2022-AM). Related manuscripts will be submitted to peer-review journals.
Trial registration numbers EudraCT Number 2022-000291-19; NCT05542446.
- Adult intensive & critical care
- CLINICAL PHARMACOLOGY
- MICROBIOLOGY
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STRENGTHS AND LIMITATIONS OF THIS STUDY
COL-ECMO2022 is a prospective, non-randomised, open-label phase IV pharmacokinetic study.
Only critically ill patients with and without extracorporeal membrane oxygenation (ECMO) will be recruited to provide information on this population, for which data on colistin pharmacokinetics is limited.
A maximum of three monitored dosing intervals are set for each subject to monitor trends in plasma concentrations over a more extended period of time and to limit the burden on subjects.
The primary outcome is to assess the impact of ECMO on colistin pharmacokinetics.
A limited sampling strategy of four samples per interval is a limitation of this study.
Introduction
The number of patients requiring extracorporeal membrane oxygenation (ECMO) for severe respiratory failure increased significantly during the COVID-19 pandemic. Most of these patients require long-term intensive care with the need for repeated antibiotic treatment. These factors lead to a higher frequency of infections with multidrug-resistant Gram-negative bacteria sensitive only to colistin.
ECMO circuits generally represent an additional pharmacokinetic compartment that increases the volume of distribution of drugs and may also affect their clearance by adsorption of the drug on the circuit surface.1 This phenomenon is determined by the lipophilicity of the drug and its binding to plasma proteins, but the material of the ECMO circuit components or their surface modification also have an influence.
Based on their chemical characteristics, the adsorption of colistin, or its prodrug, to the surface of the ECMO circuit seems unlikely. There are very limited data on the actual effect of ECMO on colistin pharmacokinetics.2 3 Nevertheless, colistin adsorption on polysulfone dialysis membranes has been previously published.4
Colistin is a lipopeptide antibiotic administered as an inactive prodrug—colistin methanesulfonate (CMS). Bioactivation of the prodrug is non-enzymatic by hydrolysis. Colistin is an antimicrobial agent with a concentration-dependent and time-dependent effect, where the target pharmacokinetic-pharmacodynamic parameter is the area under the plasma concentration curve (AUC). The target 24-hour steady-state AUC (AUCSS, 24-h) is approximately 50 mg×hour/L, which corresponds to a steady-state mean plasma concentration of approximately (Cavg, ss) 2 mg/L.5 Colistin is a drug with a narrow therapeutic window. The limiting factors are mainly nephrotoxicity and neurotoxicity, both dependent on plasma concentrations. Sorlí et al reported that the minimum plasma concentration (cmin) of 2.42 mg/L at the end of therapy, respectively, 3.33 mg/L on day 7 of colistin therapy is predictive for the development of acute renal failure.6
The estimation of the colistin AUC is complicated by several factors. The first is the rate of bioactivation of the prodrug, which can vary interindividually, between products of various manufacturers, or even in batches of one manufacturer.7 The second is the variability in the time to maximum plasma concentration (Tmax) of colistin, which depends not only on the rate of conversion of CMS to colistin but also on the rate of elimination of CMS. Clearance of CMS is dependent on creatinine clearance. When creatinine clearance decreases, more CMS is converted to colistin. The excretion of colistin is not fully described; however, significant tubular resorption was reported. The pharmacokinetics of colistin in critically ill patients have been described in detail in several studies.4 8–14
Because of the considerable heterogeneity of the pharmacokinetic parameters of colistin and the lack of a reliable population kinetic model, it is appropriate to use multiple samplings during a single dosing interval to calculate the AUC. This, together with the determination of the plasma concentration of the prodrug at the corresponding times, will give a better idea of the plasma concentration profile of both substances and improve the estimation of the colistin AUC. By comparing the achieved plasma concentrations of colistin and CMS in patients with and without ECMO, we can then estimate the presence and quantify the extent of adsorption of both agents to the ECMO circuit material or other processes induced by the ECMO circuit.
Study objectives
The objective of this phase IV pharmacokinetic trial is to assess the influence of ECMO on the pharmacokinetics of colistin and CMS in critically ill adults and to propose dosing guidance.
Methods
Trial design
The COL-ECMO2022 is an investigator-initiated trial. The COL-ECMO2022 clinical trial is a prospective, non-randomised, open-label, single-centre, phase IV pharmacokinetic clinical trial that has been started in September 2022. The COL-ECMO2022 study plans to include 30 participants with or without ECMO support receiving CMS as part of the standard medical care. The indication, dosage and duration of colistin administration are, therefore, entirely within the discretion of the attending physician. These study participants will be consecutively assigned to two groups until the planned number of participants: ECMO and non-ECMO, in a 1:1 ratio depending on their actual need for ECMO support. Both groups are treated by intravenous CMS at standard, approved dosing. The influence of ECMO on CMS and colistin pharmacokinetics will be assessed by comparing the pharmacokinetic endpoints of the study. Study subjects will participate in the clinical trial for up to three monitored CMS dosing intervals
Study setting
The principal investigator and St. Anne’s University Hospital Brno, the coordinating and only recruiting centre for the study, are responsible for the education and training of research staff, tracking participants’ enrolment, mathematical analysis, monitoring, pharmacovigilance, data management and reporting of the study.
Department of Pharmacology, Faculty of Medicine and Dentistry, Palacky University in Olomouc, is responsible for a qualitative and quantitative analysis of colistin and CMS in blood samples by liquid chromatography and mass spectrometry (LC-MS) determination.
Creatinine clearance from urine collection reflecting the observed interval(s) after colistin administration will be determined by the Department of Clinical Biochemistry, St. Anne’s University Hospital Brno.
Study population
Inclusion criteria
All consecutive patients will be included in the clinical trial if they meet all of the following criteria:
Age ≥18 years.
Men and women (with a negative pregnancy test prior to study enrolment in women of childbearing potential).
Hospitalised at the Department of Anaesthesiology and Intensive Care, St. Anne’s University Hospital Brno.
Indication for parenteral colistin (administered as CMS) as a part of standard medical care, that is, in patients with severe bacterial infection.
Informed consent was given. In unconscious patients, the study investigator will decide whether to include the patient in the study considering all individual risks.
Additional inclusion criterion
For some patients (15 participants expected), in addition to all the criteria listed in the Inclusion criteria section, the following inclusion criterion is provided:
1. ECMO support is needed as part of standard therapy for severe respiratory failure.
Exclusion criteria
A patient must not be included in the clinical trial if he/she meets any of the following criteria:
Pregnancy.
Breast feeding.
Refusal to give informed consent (primarily or after regaining consciousness).
Who will take informed consent?
The study protocol, including the informed consent, was reviewed and approved by the Institutional Review Board of the site (Ethics Committee of St. Anne’s University Hospital Brno) and by the National Regulatory Authority (NRA) (The State Institute of Drug Control). A trained study investigator describes the study to patients. Patients will receive written information about the study as well (see online data supplemental 1). The investigator will discuss with patients the design and characteristics of the study, potential benefits, and risks based on the written information provided to the participant. The investigator obtains written informed consent from patients willing to participate in the trial. If a patient is unable to give informed consent due to his/her medical condition (eg, unconsciousness), his/her ability to participate in the study will be assessed by the investigator. In this case, the Ethics Committee of St. Anne’s University Hospital Brno will be informed of the patient’s inclusion. The investigator will ask study participants in whom good quality consciousness is restored to give subsequent informed consent without unreasonable delay.
Supplemental material
Sample size
We plan to include 15 study participants in each group (ECMO and non-ECMO).
The sample size is difficult to calculate due to the significant variation of pharmacokinetic parameters among published studies, the unknown effect of ECMO on pharmacokinetics, and unknown interindividual variability.
If, at the time of completion of the planned recruitment, a large number of patients has been monitored for only one interval or there is a high frequency of deviations from the sampling protocol, or sample loss/damage is detected, the plan is to increase the sample size or even extend the overall study duration. On the other hand, colistin is a reserve and relatively toxic antibiotic. Therefore, there is only a limited number of suitable patients.
Interventions
The commencement of colistin therapy is the responsibility of an attending physician. Colistin will be given as CMS intravenously via the central venous catheter at the approved dosage: a loading dose of 9 million international units (MIU) over 30 min followed by a maintenance dose of 4.5 MIU over 30 min every 12 hours. There is a protocol for dose reduction in patients with impaired renal function, including patients treated with intermittent haemodialysis. The dosing interval is reduced to 8 hours, and the loading dose is increased to 12 MIU in patients requiring continuous renal replacement therapy (CRRT). The dosage strictly follows the local guideline proposed on the international guidelines.5 15 The protocol for colistin dosage applicable at the study site is in online data supplemental 2: Colistin dosage local protocol.
Supplemental material
The diagram presenting the course of the study is depicted in figure 1.
Trial schema for COL-ECMO2022 study. CMS, colistin methanesulfonate; ECMO, extracorporeal membrane oxygenation.
Visit 1: screening: patient selection phase
Patients meeting the inclusion criteria will be screened if not meeting any of the exclusion criteria. A urine pregnancy test will be performed on women of childbearing potential. The patient will be offered participation in the clinical trial and interviewed by the investigator, who clearly explains the purpose, design, benefits and risks of the trial. If the patient agrees to participate in the clinical trial, he/she will give informed consent. After signing the informed consent form, the patients will be recruited for this study and distributed to ECMO or non-ECMO groups according to their actual need for ECMO support. For patients unable to give informed consent, an interim informed consent will be signed by the investigator.
Visit 2 (visits 3 and 4 if colistin therapy continues): pharmacokinetics (blood samples collection)
A total of four (three in case of CRRT) blood samples will be taken during each monitored dosing interval. Based on the blood sample volume of 5 mL, up to 20 mL of blood will be drawn from the patient per monitored dosing interval. The timing of blood samples is summarised in figure 2.
Blood sampling schedule for COL-ECMO2022 study. Arrows indicate blood sampling time points. CRRT, continuous renal replacement therapy; D, administration of CMS dose as a 30 min intravenous infusion.
Blood samples will be taken from the arterial catheter, routinely placed in critically ill patients in intensive care unit. This will minimise blood loss and requires no further interference with the physical integrity of enrolled patients. The sample timing is precisely defined according to the start of the CMS infusion. A 12-hour urine collection will be performed during the monitored dosing interval to determine the creatinine clearance.
Blood samples will be preanalytically processed (centrifugation, freezing and storing separated plasma at −80°C).
The last blood sample collection in the third monitored interval is the last intervention in the study for an individual patient and is the time of termination of the patient’s participation in the clinical trial. This last intervention corresponds with blood sampling at 7 hours and 50 min after starting CMS infusion in CRRT patients and at 11 hours and 50 min after starting CMS infusion in patients without CRRT. CMS therapy can continue.
Participant timeline
The enrolment, intervention and visits schedule is summarised in table 1. The duration of the study participation for each subject is a maximum of three monitored dosing intervals.
Participant timeline for COL-ECMO2022 study
Criteria for discontinuing or modifying allocated interventions
The trial participant has the right to terminate participation in this clinical trial at any time, for any reason or without stating it.
The investigator must:
Instruct the participant on the right to early termination of participation.
Inform him/her that the termination of participation would not affect the physician’s approach, the method of further treatment or its quality.
Ask him/her to discuss this decision with the investigator in advance.
State in the records the date of early termination of the patient’s participation and the reason, if known.
Other reasons for the early termination of the subject’s participation include:
The investigator’s decision that further patient involvement is not in the patient’s best interests.
Pregnancy of a patient participating in the clinical trial.
Termination of the study by a decision of the sponsor or the regulatory authority.
Discontinuation of colistin therapy at the discretion of the attending physician before completion of the third monitored dosing interval.
Outcomes
Since the efficacy of colistin is dependent on the AUC, colistin average steady-state concentration (Css, avg) is the main objective. A difference between ECMO and non-ECMO patients larger than 25% is considered clinically significant. The toxicity correlates with colistin minimum plasma concentration. The endpoints are the following pharmacokinetic parameters: Cmax, Tmax, Ctrough, AUC, Vd, clearance and intercompartment clearance of CMS and colistin.
Patient and public involvement
None.
Data collection and management
Plans for assessment and collection of outcomes
The study will collect demographic and baseline characteristics from medical records and electronic medical records, including age, gender, ECMO support and baseline characteristics such as body weight, body height. Concomitant inhalation CMS and laboratory results will be documented in the paper medical records and entered by the trial investigator in the paper case report form (CRF).
Data management
The study data will be collected from medical records and manually entered into the paper CRF. The study team members will have access to the patients’ medical records. The investigators will be responsible for screening patients, obtaining informed consent, collecting study data and entering it into the CRF. Once recruitment is complete and the last intervention in the study is performed, pseudonymised data from the paper CRFs will be digitised into an Excel worksheet and formatted for use in pharmacokinetic software. Data will be digitally submitted for statistical processing as well. The statistician will analyse the study data in cooperation with the principal investigator. The data will be stored for 15 years after the completion of the study and then destroyed. To promote data quality, the CRFs of each participant will be reviewed by another member of the study team as a monitor.
Confidentiality
All study-related information will be stored securely at the study site. All participant information will be stored in locked file cabinets in areas with limited access. Forms, lists, logbooks, appointment books and any other listings that link participant ID numbers to add identifying information will be stored in a separate locked file in an area with limited access.
Statistical methods
A population pharmacokinetic model will be developed based on measured plasma levels of CMS and colistin. A non-linear mixed-effects model will be used for the calculation of population pharmacokinetic parameters. To improve the model fit, the following variables will be evaluated as covariates: ECMO therapy, creatinine clearance, renal replacement therapy, actual or adjusted body weight, and age. A difference of at least 25% between the ECMO and non-ECMO groups will be considered clinically significant.
The Shapiro-Wilk test will be used to evaluate the normal distribution. Student’s t-test or Mann-Whitney U test will be used for comparisons as appropriate. Data will be presented as means±SD or median (IQR); p values <0.05 will be considered statistically significant. Statistica software V.14.0 (TIBCO Software, U.S.A.) will be used for statistical analysis.
Ethics and dissemination
This protocol and the template informed consent form were reviewed and approved by the Ethical Committee of the University Hospital St. Anne’s Brno (Number 10ML/2022-AM on 13 July 2022) with respect to the scientific content and compliance with applicable research and human subject regulations. Any new protocol modifications will be sent for review by the ethics committee and will be amended at the clinical trial registry. Informed consent will be obtained from all participants prior to enrolment in the study. In unconscious patients, the study investigator will decide whether to include the patient in the study after considering all individual risks. In this case, the Ethics Committee of St. Anne’s University Hospital Brno will be informed of the patient’s inclusion. The investigator will ask study participants in whom good quality consciousness is restored to give subsequent informed consent without unreasonable delay.
We intend to submit the results of the study to be published in a peer-reviewed international medical journal and disseminate them to academic and healthcare professionals via presentations at conferences.
EudraCT Number of the study is 2022-000291-19 registered on 21 June 2022. Study registered at the Clinical Trials register https://clinicaltrials.gov/ct2/show/NCT05542446 on 15 September 2022.
Discussion
The COL-ECMO2022 trial is, as far as we know, the first of its kind. Its results will provide new pharmacokinetic data and a population pharmacokinetic model for critically ill patients and refine colistin dosage in patients on ECMO. However, several non-standard approaches in the methodology deserve more detailed justification. The first is the definition of inclusion criteria. It is not usual for inclusion criteria to be the logical opposite of exclusion criteria and vice versa. In this protocol, pregnancy fulfils this condition and the reason for the wording is a requirement of the NRA and national legislation. According to current national legislation, pregnant women can only be enrolled in clinical trials of a therapeutic or preventive nature directly aimed at the pregnancy or the unborn fetus. This is also why pregnancy has been established as an exclusion criterion despite being a standard-of-care trial. The second relevant reason is that it is a pharmacokinetic study in a small sample of critically ill patients. Pregnancy leads to significant changes in drug pharmacokinetics, which would lead to undesirable bias in the parameters obtained.
Another unusual practice is the inclusion by the investigator of a patient unable to consent to participate in the trial. The inclusion of unconscious patients in the trial is a touchy ethical issue on which the responsible institutional review board and the NRA had difficulty finding consensus when reviewing this trial. The usual practice of obtaining consent from a legally authorised representative, a close person or a pair of an independent physician with an independent witness was unacceptable. A compromise acceptable to both institutions was the procedure described above, whereby the principal investigator decides independently on the inclusion of the patient and informs the institutional review board ex post. Given the nature of the study, a waiver of informed consent would have been possible in many cases. And this is perhaps the reason why the procedure described above was finally acceptable. Notably, the process would likely be different if the study had been submitted under the new regulation; however, the first submission was made before the entry into force of Reg. (EU) 536/2014.
The next questions concern patients on CRRT. The first is the differentiation of colistin adsorption to the ECMO circuit and the CRRT circuit in ECMO+CRRT patients. Adsorption to the haemofilter is a known phenomenon that we consider in the dosing frequency. Thus, non-ECMO+CRRT patients will be the most appropriate comparison group to quantify adsorption to ECMO in those patients. For the other patient groups (ECMO+CRRT vs ECMO+non CRRT vs non-ECMO+non CRRT), the predictive value will only be in comparing trough concentrations between groups and concentrations taken at 30 min after the start of the infusion in particular groups. However, CRRT will be a binary covariate for the pharmacokinetic analysis, similar to ECMO. Hence, we should be able to distinguish the effect of either extracorporeal method on colistin pharmacokinetics. The second issue related to patients on CRRT is how creatinine clearance is determined. If patients are oliguric, we do not plan to collect urine (see note in table 1), given the limited significance of this value. Creatinine clearance, necessary for the construction of the population pharmacokinetic model, will be set to an average value of 30 mL/min, recognising the slight variability depending on the individual CRRT setting. We do not expect a high proportion of patients on CRRT in this study. However, we did not primarily want to exclude them from the study, even at the risk of bias that their pharmacokinetic parameters may introduce.
Several methodological limitations of this study can affect the outcomes negatively: anticipated sample size, implemented limited sampling strategy, CMS administration per standard medical care which the investigator cannot modify. First, the sample size was estimated based on pilot data to make the study feasible. The pilot data were collected during the COVID-19 pandemic when the patient profile differed from the routine. Following this, we chose a more conservative and still feasible target number of subjects. Second, since this is a standard-of-care trial, we implemented a limited sampling strategy to minimise patient burden and interference between study procedures and routine care. We also took into account the data published by Kim et al.16 The trough and concentration at 2 hours after initiation of the 30 min infusion showed the highest correlation with AUC. Third, although colistin dosing is not a study procedure and is subject to routine medical care, it respects local and international guidelines. The actual dosage is recorded in the CRF. As a result, a reliable and transferable population pharmacokinetic model can be constructed.
Trial status
Trial sponsor: St. Anne’s University Hospital in Brno, Pekařská 664/53, 656 91 Brno, Czech Republic
Protocol version 1.2, dated 25 May 2022. The recruitment was started in September 2022. Thirty patients are planned to be recruited by the end of December 2023. Completion of the study with data analysis is anticipated in December 2023.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors PS: design of the study, protocol writing, first author, principal investigator, statistical analysis. JR: design of the study, protocol writing. LS: design of the study, protocol revision. VK: protocol revision, design of the laboratory analytic part. KU: design of the study, design of the laboratory analytical part.
Funding Activities related to the development of a method for the determination of colistin in plasma were covered by a grant Verification of colistin adsorption on the ECMO circuit (DSGC-2021–0179) 'within the project OP VVV' Improvement of the Doctoral Student Grant Competition Schemes and their Pilot Implementation, reg.no. CZ.02.2.69/0.0/0.0/19_073/0016713.Some activities connected with study preparation are created in collaboration with MED MUNI through the CZECRIN project (LM2023049), supported by the national budget through MEYS and from the European Regional Development Fund—project CZECRIN_4 PATIENTS (CZ.02.1.01/0.0/0.0/16_013/0001826).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.