Clinical trial NCT03790631: The OPTIMAL TDM Study: Determining Optimal Beta-lactam Plasma Concentrations Through Therapeutic Drug Monitoring
Official title: The OPTIMAL TDM Study: Determining Optimal Beta-lactam Plasma Concentrations Through Therapeutic Drug Monitoring
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Beta-lactam Antibiotics
Therapeutic Drug Monitoring
Toxicity
Efficacy
Imipenem
Meropenem
Piperacillin
Flucloxacillin
Amoxicillin
Ceftazidime
Cefepime
Lead sponsor: University of Geneva, Switzerland
Sponsor class: OTHER
Collaborators: name: University Hospital, Geneva
First posted: 2018-12-31
Enrollment: 771
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of clinical toxicity through day 30 after start of study antibiotic
timeFrame: day 30 after start of antibiotic
Secondary outcomes:
measure: Clinical response: incidence of clinical cure
timeFrame: day 30
measure: clinical response in patients with neutropenic fever: incidence of clinical cure in this subpopulation
timeFrame: day 30
measure: 30-day mortality attributable to the treated infection
timeFrame: day 30
measure: 30-day all-cause mortality
timeFrame: day 30
measure: incidence of reversible toxicity
timeFrame: day 30
measure: Incidence of Clostridium difficile infection
timeFrame: day 30
measure: Incidence of clinical toxicity of piperacillin-tazobactam when co-administered with vancomycin
timeFrame: day 30
measure: Incidence of emergence of resistance
timeFrame: day 30
measure: Incidence of undetectable beta-lactam plasma concentrations
timeFrame: day 30
measure: Incidence of off-label prescribing
timeFrame: day 30
measure: The correlation of free versus total flucloxacillin concentrations
timeFrame: day 30
measure: Median intermediate and trough plasma concentrations of tazobactam
timeFrame: through day 30
measure: Beta-lactam trough concentration/minimal inhibitory concentration (MIC) index
timeFrame: day 1 (±1)
Other outcomes:
Locations:
city: Geneva
country: Switzerland
facility: Geneva University Hospitals
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.