Efficacy of Extended Infusion of β-lactam Antibiotics for the Treatment of Febrile Neutropenia in Hematologic Patients

Study Overview
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Brief Summary
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This study evaluates the administration of beta-lactam antibiotics in extended infusion in hematological patients with febrile neutropenia after 5 days of treatment. The beta-lactam antibiotics analyzed are the following: piperacillin-tazobactam, cefepime and meropenem. Half of patients will receive the antibiotic in intermittent infusion, while the other half will receive it in extended infusion.

Detailed Description
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Febrile neutropenia (FN) is a very frequent complication in patients with hematological malignancies. It is associated with an important morbidity and mortality. Nowadays the use of betalactam antibiotics (BLA) in extended or continuous infusion (EI, CI) instead of intermittent infusion (II), has demonstrated a therapeutic success and lower mortality rate in critically ill intensive care patients. Neutropenic patients are a particular population since FN is assoicated with pathophysiological variations that compromise pharmacokinetic parameters of BLA, and may therefore, diminish their clinical efficacy. Information regarding the usefulness of BLA in EI in neutropenic hematologic patients is scarce. The objective of this randomized clinical trial is to demonstrate the clinical superiority of the administration of BLA in EI compared to II in patients with FN.

Official Title
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Efficacy of Extended Infusion of β-lactam Antibiotics for the Treatment of Febrile Neutropenia in Haematologic Patients: a Randomised, Multicentre, Open-label, Superiority Clinical Trial (BEATLE)

Conditions
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Febrile Neutropenia

Intervention / Treatment
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* Drug: Piperacillin-Tazobactam 4 g-0.5 g
* Drug: Cefepime 2000 mg
* Drug: Meropenem 1000 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (age ≥18 years) of both sexes. Patients admitted in Hematological wards. With any of the following diagnoses: Acute leukemia receiving chemotherapy. Autologous or allogeneic hematopoietic stem cell transplant recipients. With an episode of febrile neutropenia: ≥ 38.0ºC and <500 neutrophils/mm3 or <1000 with a predicted decrease within 24-48 hours. Patient requiring treatment with a beta-lactam antibiotic: cefepime, piperacillin /tazobactam or meropenem, in monotherapy or in combination with another antibiotic. Written informed consent has been obtained from the patient or their legal representative grants. Exclusion Criteria: Allergy to study drugs. Patient receiving systemic antibiotic treatment (except for prophylaxis) at the time of onset of febrile neutropenia. Absence of fever. Patients with epilepsy. Severe renal impairment (defined as creatinine clearance <30 mL / min) Previously enrolled patients in whom the time between the inclusion and the current episode is less than 5 weeks. Previously enrolled patients without current resolution of the first episode.

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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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Extended infusion<br>Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval | Drug: Piperacillin-Tazobactam 4 g-0.5 g<br>* Patients with FN who empirical treatment with piperacillin-tazobactam 4g/6h<br>Drug: Cefepime 2000 mg<br>* Patients with FN who required empirical treatment with cefepime 2g/8h<br>Drug: Meropenem 1000 mg<br>* Patients with FN who required empirical treatment with meropenem 1g/8h<br>|
| Active Comparator: Intermittent infusion<br>Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes | Drug: Piperacillin-Tazobactam 4 g-0.5 g<br>* Patients with FN who empirical treatment with piperacillin-tazobactam 4g/6h<br>Drug: Cefepime 2000 mg<br>* Patients with FN who required empirical treatment with cefepime 2g/8h<br>Drug: Meropenem 1000 mg<br>* Patients with FN who required empirical treatment with meropenem 1g/8h<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy of extended infusion: Number of patients with defervescence | Number of patients with defervescence (<37.5 ºC, for 24 hours) without modifying the antibiotic treatment | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic target | Number of patients in whom the free antibiotic concentration remains above the MIC of the suspected or isolated microorganism, for 50%, 75% and 100% of the dosing interval. | 5 days | 
| Inflammatory biomarker | Number of patients who normalize or decrease in more than 50% of the peak value of the C-reactive protein. | 5 days | 
| Overall mortality at 30 days | Number of patients who died for any reason | 30 days | 
| Bacteraemia clearance | Time in days until bacteraemia clearance. | 30 days | 
| Adverse events | Incidence of adverse events in both groups | 30 days | 
| Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Volume of distribution | Population mean value of volume of distribution of antibiotics during critical illness. Mean population volume of distribution will be derived from pooled data of antibiotic concentrations. Covariates of influence on volume of distribution will be incorporated within a population pharmacokinetic model. | 5 days | 
| Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Clearance | Population mean value of clearance of antibiotics during critical illness. Mean population clearance will be derived from pooled data of antibiotic concentrations. Covariates of influence on drug clearance will be incorporated within a population pharmacokinetic model | 5 days | 
| Covariables analysis: biometric values: weight | Assessment of the impact of patient's weight [in kg] | 5 days | 
| Covariables analysis: biometric values: age | Assessment of the impact of patient's age [in years] | 5 days | 
| Covariables analysis: biochemical data: serum albumin | Assessment of the impact of total serum albumin [in g/L] | 5 days | 
| Covariables analysis: biochemical data: blood urea | Assessment of the impact of the urea [in mmol/L] | 5 days | 
| Covariables analysis: biochemical data: blood creatinine | Assessment of the impact of the creatinine [in umol/L] | 5 days | 
| Covariables analysis: clinical data: 24h diuresis | Assessment of the impact of 24h diuresis [in mL/day] | 5 days | 
| Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for plasma concentrations | Analysis of the antibiotic pharmacokinetic profiles by means of appropriate software to calculate the actual mean and median values of the fraction of the time between two successive drug administrations during which plasma concentrations of meropenem, piperacillin and cefepime remain above a critical value (S breakpoint of the corresponding antibiotic [meropenem, piperacillin and cefepime: European Committee for Antimicrobials Susceptibility Testing [EUCAST] value) in the study population, and to determine its value in a simulated population (Monte Carlo simulations; 1000 simulated patients). | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Febrile neutropenia, Beta-lactam antibiotics, Cefepime, Meropenem, Piperacillin-tazobactam, Extended infusion