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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Other: The study is observational.


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| imipenem TDM<br>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.<br>* The study is observational.<br>|
| meropenem TDM<br>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.<br>* The study is observational.<br>|
| piperacillin TDM<br>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.<br>* The study is observational.<br>|
| flucloxacillin TDM<br>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.<br>* The study is observational.<br>|
| amoxicillin TDM<br>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.<br>* The study is observational.<br>|
| ceftazidime TDM<br>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.<br>* The study is observational.<br>|
| cefepime TDM<br>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.<br>* The study is observational.<br>|

What is the study measuring?
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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) |