The OPTIMAL TDM Study: Determining Optimal Beta-lactam Plasma Concentrations Through Therapeutic Drug Monitoring (OPTIMAL TDM)

Little is known of beta-lactam antibiotics' true therapeutic plasma concentration range. The aims of this study are to define evidence-based, safe and effective upper and lower limits of the plasma concentrations of imipenem, meropenem, amoxicillin, flucloxacillin, piperacillin, ceftazidime and cefepime in patients at increased risk of serious bacterial infections and currently understudied pharmacokinetics (the critically ill, the elderly, and the immunosuppressed).

This prospective observational study will include adult patients with suspected or confirmed systemic bacterial infection receiving one of the above-named antibiotics and hospitalized in intensive-care, step-down, or hematology-oncology units of the Geneva University Hospitals (HUG).

Eligible patients will be identified via the electronic health record (EHR). Patients receiving traditional intermittent dosing or prolonged infusions will undergo TDM for at least one intermediate (mid-interval) and one trough level at 24 hours (-12 or +48 hours) after the therapy's start. Patients receiving continuous infusions will undergo TDM for at least one steady-state level. Clinical course will be observed for 30 days from the start of the study antibiotic (1st day of study antibiotic =day 1).

The primary outcome is incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration). Secondary outcomes are listed below.

Study Overview

• Status: Recruiting
• Conditions: Efficacy; Toxicity; Beta-lactam Antibiotics; Therapeutic Drug Monitoring; Ceftazidime; Amoxicillin; Meropenem; Imipenem; Piperacillin; Flucloxacillin; Cefepime
• Intervention / Treatment: Other: The study is observational.

Detailed Description

Little is known of beta-lactam antibiotics' true therapeutic plasma concentration range. The aims of this study are to define evidence-based, safe and effective upper and lower limits of the plasma concentrations of imipenem, meropenem, amoxicillin, flucloxacillin, piperacillin, ceftazidime and cefepime in patients at increased risk of serious bacterial infections and currently understudied pharmacokinetics (the critically ill, the elderly, and the immunosuppressed).

This prospective observational study will include adult patients with suspected or confirmed systemic bacterial infection receiving one of the above-named antibiotics and hospitalized in intensive-care, step-down, or hematology-oncology units of the Geneva University Hospitals (HUG).

Eligible patients will be identified via the electronic health record (EHR). Patients receiving traditional intermittent dosing or prolonged infusions will undergo TDM for at least one intermediate (mid-interval) and one trough level at 24 hours (-12 or +48 hours) after the therapy's start. Patients receiving continuous infusions will undergo TDM for at least one steady-state level. Clinical course will be observed for 30 days from the start of the study antibiotic (1st day of study antibiotic =day 1).

The primary outcome is incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration). Secondary outcomes are listed below.

• Study Type: Observational
• Enrollment (Anticipated): 700

Contacts and Locations

• Study Contact: Name: Angela Huttner, MD; Phone Number: +41 79 553 3396; Email: angela.huttner@hcuge.ch
• Study Contact Backup: Name: Dionysios Neofytos, MD; Phone Number: +41 79 553 3211; Email: Dionysios.Neofytos@hcuge.ch

Study Locations

• Switzerland
  • Geneva, Switzerland, 1205
    • Recruiting
    • Geneva University Hospitals
    • Contact: Angela Huttner, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Included patients will be adults (≤18 years) hospitalized in the intensive-care, step-down, or hematology-oncology units of the Geneva University Hospitals and treated with one of the above-listed 7 beta-lactam antibiotics for a suspected or confirmed bacterial infections.

Description

Inclusion Criteria:

- Hospitalized patients with suspected or confirmed systemic bacterial infection:

1. Receiving either imipenem-cilastatin, meropenem, amoxicillin (±clavulanic acid), flucloxacillin, piperacillin-tazobactam, ceftazidime or cefepime
2. Aged ≥18 years
3. Requiring intensive or intermediate-intensive (step-down) care OR severely immunosuppressed (see definitions)

Exclusion Criteria:

1. Planned imminent transfer to an outside hospital
2. Poor prognosis with life expectancy <1 week and/or intended transition to palliative care

Study Plan

How is the study designed?

Number of groups / cohorts

7

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
imipenem TDM; Adult patients receiving imipenem for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.
meropenem TDM; Adult patients receiving meropenem for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.
piperacillin TDM; Adult patients receiving piperacillin (with or without tazobactam) for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.
flucloxacillin TDM; Adult patients receiving flucloxacillin for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.
amoxicillin TDM; Adult patients receiving amoxicillin for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.
ceftazidime TDM; Adult patients receiving ceftazidime for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.
cefepime TDM; Adult patients receiving cefepime for suspected or confirmed bacterial infection. TDM will be performed to assess intermediate and trough levels once the patient is at steady-state.	Other: The study is observational.; The study is observational.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of clinical toxicity through day 30 after start of study antibiotic	Incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration)	day 30 after start of antibiotic

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical response: incidence of clinical cure	Clinical response to therapy through day 30 will be measured study-wide. "Clinical response" is either clinical cure (resolution of symptoms) or clinical failure (lack of improvement in signs and symptoms of infection OR recurrence of signs/symptoms of infection after initial improvement OR death in the 30-day study period considered at least possibly due to the infection). Where the MIC is unavailable, EUCAST epidemiologic cutoffs (ECOFF) will be used; if no organism is isolated, non-species-related breakpoints for targeted organisms (e.g., Pseudomonas aeruginosa) will be used.	day 30
clinical response in patients with neutropenic fever: incidence of clinical cure in this subpopulation	Clinical response (as in outcome no. 2) in the subgroup of patients with neutropenic fever at the time of BL therapy. ("Clinical response" is either clinical cure (resolution of symptoms) or clinical failure (lack of improvement in signs and symptoms of infection OR recurrence of signs/symptoms of infection after initial improvement OR death in the 30-day study period considered at least possibly due to the infection).)	day 30
30-day mortality attributable to the treated infection	30-day mortality attributable to the treated infection	day 30
30-day all-cause mortality	30-day all-cause mortality	day 30
incidence of reversible toxicity	Proportion of adverse events (AE) that are reversible after discontinuation of the relevant BL antibiotic	day 30
Incidence of Clostridium difficile infection	Incidence of Clostridium difficile infection	day 30
Incidence of clinical toxicity of piperacillin-tazobactam when co-administered with vancomycin	Incidence of clinical toxicity of piperacillin-tazobactam (and other beta-lactam antibiotics) when co-administered with vancomycin	day 30
Incidence of emergence of resistance	Prevalence of emerging resistance to study antibiotics in clinical isolates (from baseline)	day 30
Incidence of undetectable beta-lactam plasma concentrations	Proportion of patients with undetectable beta-lactam trough and/or intermediate concentrations	day 30
Incidence of off-label prescribing	Proportion of patients for whom (a) beta-lactam dosing is "off-label" according to Swiss recommendations and (b) there are no dosing recommendations (e.g., hemofiltration)	day 30
The correlation of free versus total flucloxacillin concentrations	The correlation of free versus total flucloxacillin concentrations (in a subset of patients, free flucloxacillin plasma levels will also be measured and compared to those of total flucloxacillin).	day 30
Median intermediate and trough plasma concentrations of tazobactam	In a subset of patients receiving piperacillin/tazobactam, median intermediate and trough plasma concentrations of tazobactam (beta-lactamase inhibitor) in proportion to piperacillin in patients receiving piperacillin-tazobactam	through day 30
Beta-lactam trough concentration/minimal inhibitory concentration (MIC) index	The trough beta-lactam (BL) concentration/minimal inhibitory concentration (MIC) index on day 1 (±1) will be measured in all patients for later correlation analyses with clinical outcomes (clinical success versus failure).	day 1 (±1)

Collaborators and Investigators

• Sponsor: University of Geneva, Switzerland
• Collaborators: University Hospital, Geneva

Publications and helpful links

General Publications

• Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the beta-lactam antibiotics: what is the evidence and which patients should we be using it for? J Antimicrob Chemother. 2015 Dec;70(12):3178-83. doi: 10.1093/jac/dkv201. Epub 2015 Jul 17.
• Bricheux A, Lenggenhager L, Hughes S, Karmime A, Lescuyer P, Huttner A. Therapeutic drug monitoring of imipenem and the incidence of toxicity and failure in hospitalized patients: a retrospective cohort study. Clin Microbiol Infect. 2019 Mar;25(3):383.e1-383.e4. doi: 10.1016/j.cmi.2018.11.020. Epub 2018 Dec 4.
• Huwyler T, Lenggenhager L, Abbas M, Ing Lorenzini K, Hughes S, Huttner B, Karmime A, Uckay I, von Dach E, Lescuyer P, Harbarth S, Huttner A. Cefepime plasma concentrations and clinical toxicity: a retrospective cohort study. Clin Microbiol Infect. 2017 Jul;23(7):454-459. doi: 10.1016/j.cmi.2017.01.005. Epub 2017 Jan 19.
• Muller AE, Huttner B, Huttner A. Therapeutic Drug Monitoring of Beta-Lactams and Other Antibiotics in the Intensive Care Unit: Which Agents, Which Patients and Which Infections? Drugs. 2018 Mar;78(4):439-451. doi: 10.1007/s40265-018-0880-z.
• Marti C, Stirnemann J, Lescuyer P, Tonoli D, von Dach E; OPTIMAL TDM Study Group; Huttner A. Therapeutic drug monitoring and clinical outcomes in severely ill patients receiving amoxicillin: a single-centre prospective cohort study. Int J Antimicrob Agents. 2022 Jun;59(6):106601. doi: 10.1016/j.ijantimicag.2022.106601. Epub 2022 May 6.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2019
• Primary Completion (Anticipated): December 31, 2023
• Study Completion (Anticipated): June 30, 2024

Study Registration Dates

• First Submitted: December 27, 2018
• First Submitted That Met QC Criteria: December 28, 2018
• First Posted (Actual): December 31, 2018

Study Record Updates

• Last Update Posted (Actual): May 10, 2023
• Last Update Submitted That Met QC Criteria: May 9, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Other Study ID Numbers: 2018-01830

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Data may be housed in a publicly accessible, non-profit digital repository such as Dryad or EUDAT.

Drug and device information, study documents

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