Beta-lactam Pharmacokinetics in Secondary Care

August 4, 2021 updated by: Imperial College London

Defining Adult Beta-lactam Antimicrobial Pharmacokinetics Across the Secondary Care Setting

Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide antimicrobial agents, given fears over the narrow therapeutic window of these agents and the serious adverse events associated with toxicity. However, in critical care the role of TDM for optimisation of therapy has been demonstrated to help optimise dosing of patients who tend to have variable pharmacokinetic parameters (J. A. Roberts et al,). This is of growing importance given that low concentrations of antimicrobial agents, below a micro-organisms minimum inhibitory concentration (MIC) is believed to be a major driver of AMR. The investigators set out to explore whether similar observations in PK-PD target variability are currently being observed across the secondary care setting (outside of critical care) and whether these appear to be impacting on clinical outcomes.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

STUDY PARTICIPANTS

  • Participants receiving oral or intravenous therapy will be included in this study.
  • Drug level sampling will be undertaken once the participant is at steady state (after at least 5 doses have been administered to those on treatment).
  • All patients will be consented using the participation information leaflet and consent form provided in appendix 1.

DRUG LEVEL SAMPLING

  • Patients will be identified for inclusion, and researchers will discuss inclusion in the study with the patient and provide clinical information for them to consider. Individuals will be recruited from all areas of secondary care (including, general medicine, general surgery, augmented care, and out-patient parenteral antimicrobial therapy [OPAT]).
  • They will then be consented by researchers after being given at least 24 hours to consider this information and as long as the patient has expressed interest in participating to their treating physician.
  • This will include permission for basic, anonymised demographic and clinical data to be collected related to the patients infection, for which they are receiving antimicrobial therapy.
  • An extra 3mLs of blood will be collected during the patient's routine daily phlebotomy round following their consent. They will be enrolled for up to 72 hours or two days of routine blood tests (whichever is shorter). Up to 10 samples may be taken during the 2 days the patient is enrolled, depending on the number of routine blood tests the patient receives during that day. No more than 3mLs will be taken per each routine blood sample. For example, if the individuals will only have routine blood tests taken at 8am on day 1 and day 2. Then only two extra samples will be taken (3mLs on D1 and 3mLs on D2).
  • The time they received their dose of antimicrobials, the length of infusion time (if available), and time the sample was collected will all be recorded.
  • PK/PD indices for evaluation will be calculated post-hoc during pharmacokinetic-pharmacodynamic analysis. TDM sampling can occur at any time during the dosing schedule (in line with routine blood testing).
  • A standard operating procedure for this study can be found in appendix 3.

SAMPLE PREPARATION AND ANALYSIS

  • All blood samples will be allowed to clot and placed on ice. They will be centrifuged at 2,400rpm for 10 minutes. Sera from each sample will be separated into three vials and stored at -80C.
  • Beta-lactam concentrations will be measured using validated high-performance liquid chromatography methods.

  • Samples will be stored for up to three years post completion of data collection.

    • Consent will be gained for samples to be used for calibration of electrochemical sensors in ex-vivo studies. This will be performed within 90 days of the samples being collected.

PHARMCOKINETIC-PHARMACODYNAMIC MODELLING

  • Data will be anonymised and analysed using Pmetrics in R.
  • Different pharmacokinetic models will be explored using in built statistical analysis options and visual predictive checks.
  • Pharmacodynamic models will then be incorporated into the model using evidence identified in the literature for selection of parameters.
  • Monte Carlo simulation will then be used to for simulation of target attainments and analysis of pharmacodynamic outcomes

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
65

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Participants from a non-critical care setting will be recruited after receiving at least 5 doses of target antimicrobial. Participants receiving oral and intravenous therapy will be eligible.

Description

Inclusion Criteria:

  • Adult subjects over 18 years old
  • Capacity to consent to participation
  • Receiving target antimicrobial (amoxicillin, amoxcillin-clavulanate, cefuroxime, ceftriaxone, flucloxacillin, meropenem, piperacillin-tazobactam) for at least 5 doses prior to sampling
  • Appropriate venous access (or for venous access to be gained)

Exclusion Criteria:

  • Children under 18 years old
  • Lacking capacity or prisoner
  • Anaemia or bleeding disorder, deemed significant by the patients physician
  • Patient's physician deems that they are not suitable for inclusion in the study
  • Patients unlikely to be receiving agent for study period

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Beta-lactam antibiotic
Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections.
Drug: Beta-lactam antibiotic
Routine clinical dosing
Other Names:
  • Penicillin

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT>MIC)
Time Frame: Two to 10 samples taken during the first 120 hours of antimicrobial therapy
Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.
Two to 10 samples taken during the first 120 hours of antimicrobial therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Imperial College London

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 12, 2017

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
August 1, 2019

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
August 1, 2019

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 19, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 24, 2017

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 26, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 30, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 4, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 207217
  • 16/LO/2179 (OTHER: REC)
  • 33017 (OTHER: NIHR CRN CPMS)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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