Medical Device (MD) Derived Pharmacokinetic (PK) Parameters for Vancomycin (MD-PK) (MD-PK)

An Investigation Into How Medical Device Obtained Variables Influence the Pharmacokinetic Profile of Vancomycin: a Paediatric and Adult Critical Care Feasibility Assessment at a London Tertiary-care Hospital

Getting the right dose of antibiotic promptly is an important part of treating infections. Unfortunately, when an infection is severe (sepsis) the body changes how it processes antibiotics. Consequently, some people with severe infection retain antibiotics for too long (risking adverse effects), whilst others excrete antibiotics too quickly (risking under-treatment).

Mathematical models can help researchers understand drug handling variability (known as pharmacokinetics) between people. These models require very accurate information about drug administration and drug blood concentration timings. Researchers usually rely on someone recording these timings, but recording errors can make models inaccurate.

We would like to understand if using data from routinely used electronic drug infusion devices (recording the exact time of administration) can improve the accuracy of pharmacokinetic models. We intend to investigate this with an antibiotic (vancomycin) that clinicians already routinely monitor blood concentrations for. Adults and children treated at St George's Hospital intensive care units will be invited to participate in the study which will last for 28-days within a 14-month period. Participants will donate a small amount of extra blood and provide researchers access to their clinical data. Blood will be taken at special times during vancomycin treatment from lines placed as part of standard treatment, minimising any pain or distress. There will be no other changes to patient's treatment.

In the future, data from this study might help change the way we dose antibiotics. The National Institute for Health and Care Research and Pharmacy Research UK are supporting the study with funding.

Study Overview

• Status: Recruiting
• Conditions: Sepsis; Critical Illness; Septic Shock; Bacteremia; Infection, Bacterial; Antibiotic Side Effect; Antibiotic Resistant Infection; Adult Children
• Intervention / Treatment: Other: Drug Infusion Pump Monitoring

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Robert Oakley, MPharm; Phone Number: 3685 02086721255; Email: robert.oakley@nhs.net
• Study Contact Backup: Name: Dagan Lonsdale, MB BS, PhD; Phone Number: 02087250205; Email: dlonsdal@sgul.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, SW17 0QT
    • Recruiting
    • St Georges University Hospitals NHS Foundation Trust
    • Contact: Robert Oakley, MPharm; Phone Number: 3685 02086721255; Email: robert.oakley@nhs.net
    • Contact: Dagan Lonsdale, MB BS, PhD; Phone Number: 02087250205; Email: dlonsdal@sgul.ac.uk
    • Principal Investigator: Dagan Lonsdale, MB BS, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults and children admitted to an intensive care unit and administered intravenous vancomycin for prevention/treatment of an infection

Description

Inclusion Criteria:

• Admitted to either adult or paediatric intensive care unit (ICU) and receiving intravenous vancomycin (continuous or intermittent infusion only), to prevent or treat a clinical infection
• Informed consent form signed by participant/parent/legal guardian/legal representative (as determined by age group/capacity, consent may be retrospective) or signed informed personal/nominated consultee declaration
• Age from 1-day since birth

Exclusion Criteria:

• Previous enrolment into this study
• Treating clinician feels participant unlikely to survive beyond 48-hours from enrolment or treatment has been withdrawn for reasons of palliation
• Absence of in-dwelling vascular access from which samples may be drawn or removal of in-dwelling access prior to retrieval of a 3rd blood sample (for assay of vancomycin concentration)
• Non-continuous renal replacement (i.e. intermittent haemodialysis/ peritoneal dialysis)
• Hypersensitivity or allergies to vancomycin, its excipients, or the infusion fluid
• Treatment outside an ICU area

In paediatrics:

• Required blood sampling exceeds 3% of total blood volume in a four-week period or 1% at any single time (European Medicines Agency, 2009)
• Where there is disagreement between child consent/assent and parental/ legal guardian consent/assent

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Critically Ill Adults and Children; Adults and children from 1-day old admitted to a critical care unit.	Other: Drug Infusion Pump Monitoring; Intravenous vancomycin administration accuracy will be determined by comparing data obtained from drug infusion pumps with manually input administration times from the electronic Prescribing and Medicines Administration (ePMA) system.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Function Value	Pharmacokinetic model fit determined quantitively by Objective Function Value (2.log likelihood) using vancomycin administration time data recorded by patient's bedside drug infusion devices compared to manually recorded data	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participant Vancomycin Volume of Distribution	Calculation of participant's vancomycin volume of distribution (litres) using non-linear mixed effects modelling methods from obtained non-protein bound and total vancomycin concentrations and patient's drug infusion device obtained administration time data	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Participant Vancomycin Clearance	Calculation of participant vancomycin clearance (litres/hour) using non-linear mixed effects modelling methods using obtained non-protein bound and total vancomycin concentrations and participant's drug infusion device derived administration time data	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Participant 24-hour Area Under the Vancomycin Concentration Time Curve (AUC)	Calculation of participant's AUC (milligrams.hour/litre) using obtained non-protein bound and total vancomycin concentrations and participant's drug infusion device derived administration time data	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Participant 24-hour AUC:MIC Ratio	Calculation of the area under the 24-hour non-protein bound and total vancomycin concentration AUC/bacterial minimum inhibitory concentration (MIC) ratio using an empiric MIC of 1mg/L or MIC of obtained isolates (if available) using trapezial rule or vancomycin dose and calculated clearance	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association Between Participant's Mean 24-hour AUC:MIC and Microbiological Cure	Microbiological cure defined as eradicated baseline microorganisms and no new microorganisms are identified via bacterial cultures (if available), plus, the patient has received allocated treatment for at least 2-days with no modification or a failure	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Association Between Participant's Mean 24-hour AUC:MIC and Length of Intensive Care (ICU) Unit Stay	ICU stay quantified by days since admission, categories include: <2 days, < 7 days, <14 days, >14 days	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Association Between Participant's Mean 24-hour AUC:MIC and Infection Related Mortality	Cause of mortality will be derived from participant's medical notes	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Association Between Participant's Mean 24-hour AUC:MIC and Infection related ICU Re-admission	Cause of re-admission will be derived from participant's medical notes	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Association Between Participant's Mean 24-hour AUC:MIC and Vancomycin Associated Acute Kidney Injury (AKI)	AKI defined by Kidney Disease: Improving Global Outcomes (KDIGO) Criteria	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin
Association Between Participant's Mean 24-hour AUC:MIC and Adult National Early Warning Score (NEWS2) or Paediatric Early Warning Score (PEWS3)	Warning scores calculated on day of (and closest to) first dose of study recorded vancomycin treatment course, between 2-3 days since vancomycin course initiation and at end of vancomycin course or 28 days from first study recorded administration of vancomycin	Within collection of 15 vancomycin serum concentrations or 28 days from first study recorded administration of vancomycin

Collaborators and Investigators

• Sponsor: St George's, University of London
• Collaborators: University College, London

Publications and helpful links

General Publications

• Oakley R, Bakrania P, Yau T, Standing J, Lonsdale D. Variable adherence to and effectiveness of a vancomycin continuous infusion protocol within ICUs at a London tertiary-care hospital: a single-centre retrospective service evaluation 2022;4:dlac004.036. https://doi.org/10.1093/jacamr/dlac004.036
• Correction to: Improving adherence to and effectiveness of an adult critical care vancomycin continuous infusion protocol: a pilot quality improvement and administration data accuracy project. JAC Antimicrob Resist. 2023 Jun 8;5(3):dlad075. doi: 10.1093/jacamr/dlad075. eCollection 2023 Jun.

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2023
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: May 29, 2023
• First Submitted That Met QC Criteria: July 10, 2023
• First Posted (Actual): July 18, 2023

Study Record Updates

• Last Update Posted (Actual): January 11, 2024
• Last Update Submitted That Met QC Criteria: January 10, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Vancomycin; Pharmacokinetics; Accuracy; Critical Illness; Therapeutic Drug Monitoring; Data; Medical Device; Digital; Point of Care; Protein Binding; Drug Infusion Pump; Electronic Prescribing and Administration System
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections and Mycoses; Sepsis; Infections; Communicable Diseases; Bacteremia; Critical Illness; Bacterial Infections
• Other Study ID Numbers: 2022.0286

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Fully anonymised collected patient data may be shared if consent provided with select research collaborators

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No