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

Efficacy Clinical Trial

— OPTIMAL TDM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03790631
• Other study ID #: 2018-01830
• Status: Recruiting
• Start date: January 14, 2019
• Est. completion date: June 30, 2024

Study information

• Verified date: May 2023
• Source: University of Geneva, Switzerland
• Contact: Angela Huttner, MD
• Phone: +41 79 553 3396
• Email: angela.huttner[@]hcuge.ch
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 700
• Est. completion date: June 30, 2024
• Est. primary completion date: December 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

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

Intervention

Other:
• The study is observational.
The study is observational.

Locations

Country	Name	City	State
Switzerland	Geneva University Hospitals	Geneva

Sponsors (2)

Lead Sponsor	Collaborator
University of Geneva, Switzerland	University Hospital, Geneva

Country where clinical trial is conducted

Switzerland, 

References & Publications (4)

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- — View 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. — View 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 Ju — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	30-day mortality attributable to the treated infection	30-day mortality attributable to the treated infection	day 30
Secondary	30-day all-cause mortality	30-day all-cause mortality	day 30
Secondary	incidence of reversible toxicity	Proportion of adverse events (AE) that are reversible after discontinuation of the relevant BL antibiotic	day 30
Secondary	Incidence of Clostridium difficile infection	Incidence of Clostridium difficile infection	day 30
Secondary	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
Secondary	Incidence of emergence of resistance	Prevalence of emerging resistance to study antibiotics in clinical isolates (from baseline)	day 30
Secondary	Incidence of undetectable beta-lactam plasma concentrations	Proportion of patients with undetectable beta-lactam trough and/or intermediate concentrations	day 30
Secondary	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
Secondary	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
Secondary	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
Secondary	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)