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NCT Number: NCT03790631

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

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.

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Key information

Conditions

Beta-lactam Antibiotics Amoxicillin Cefepime Ceftazidime Efficacy Flucloxacillin Imipenem Meropenem Piperacillin Therapeutic Drug Monitoring Toxicity

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Geneva University Hospitals

Geneva, Canton of Geneva, 1205, Switzerland

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Hospitalized patients with suspected or confirmed systemic bacterial infection:
  • Receiving either imipenem-cilastatin, meropenem, amoxicillin (±clavulanic acid), flucloxacillin, piperacillin-tazobactam, ceftazidime or cefepime
  • Aged ≥18 years
  • Requiring intensive or intermediate-intensive (step-down) care OR severely immunosuppressed (see definitions)

Exclusion criteria

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

Treatment and study plan

The study is observational.

Other

The study is observational.

Primary outcomes

  1. Incidence of clinical toxicity through day 30 after start of study antibiotic

    Time frame: day 30 after start of antibiotic

    Incidence of clinical toxicity through day 30 after start of study antibiotic (as stratified by BL trough concentration)

Secondary outcomes

  1. Clinical response: incidence of clinical cure

    Time frame: day 30

    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.

  2. clinical response in patients with neutropenic fever: incidence of clinical cure in this subpopulation

    Time frame: day 30

    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).)

  3. 30-day mortality attributable to the treated infection

    Time frame: day 30

    30-day mortality attributable to the treated infection

  4. 30-day all-cause mortality

    Time frame: day 30

    30-day all-cause mortality

  5. incidence of reversible toxicity

    Time frame: day 30

    Proportion of adverse events (AE) that are reversible after discontinuation of the relevant BL antibiotic

  6. Incidence of Clostridium difficile infection

    Time frame: day 30

    Incidence of Clostridium difficile infection

  7. Incidence of clinical toxicity of piperacillin-tazobactam when co-administered with vancomycin

    Time frame: day 30

    Incidence of clinical toxicity of piperacillin-tazobactam (and other beta-lactam antibiotics) when co-administered with vancomycin

  8. Incidence of emergence of resistance

    Time frame: day 30

    Prevalence of emerging resistance to study antibiotics in clinical isolates (from baseline)

  9. Incidence of undetectable beta-lactam plasma concentrations

    Time frame: day 30

    Proportion of patients with undetectable beta-lactam trough and/or intermediate concentrations

  10. Incidence of off-label prescribing

    Time frame: day 30

    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)

  11. The correlation of free versus total flucloxacillin concentrations

    Time frame: day 30

    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).

  12. Median intermediate and trough plasma concentrations of tazobactam

    Time frame: through day 30

    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

  13. Beta-lactam trough concentration/minimal inhibitory concentration (MIC) index

    Time frame: day 1 (±1)

    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).

Sponsors and collaborators

Lead sponsor

University of Geneva, Switzerland

Other

Collaborators

  • University Hospital, Geneva

Registry information

Acronym: OPTIMAL TDM

Important dates

Study start
2019
Primary completion
2023
Study completion
2023
First posted
Dec 31, 2018
Registry last updated
May 20, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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