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

Phase 4

• Conditions: Febrile Neutropenia
• Interventions: Drug: Piperacillin-Tazobactam 4 g-0.5 g; Drug: Cefepime 2000 mg; Drug: Meropenem 1000 mg

• Registration Number: NCT04233996
• Lead Sponsor: Hospital Universitari de Bellvitge

Brief Summary

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

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.

Study Timeline

• Study Start: 2019-06-05
• Study First Submitted: 2019-09-04
• Study First Submitted QC: 2020-01-16
• Study First Posted: 2020-01-21
• Status Verified: 2021-02
• Last Update Submitted: 2021-02-11
• Last Update Posted: 2021-02-12
• Primary Completion: 2021-12-30
• Study Completion: 2022-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. Adult patients (age ≥18 years) of both sexes.

2. Patients admitted in Hematological wards.

3. With any of the following diagnoses:

   1. Acute leukemia receiving chemotherapy.
   2. Autologous or allogeneic hematopoietic stem cell transplant recipients.

4. With an episode of febrile neutropenia: ≥ 38.0ºC and <500 neutrophils/mm3 or <1000 with a predicted decrease within 24-48 hours.

5. Patient requiring treatment with a beta-lactam antibiotic: cefepime, piperacillin /tazobactam or meropenem, in monotherapy or in combination with another antibiotic.

6. Written informed consent has been obtained from the patient or their legal representative grants.

Exclusion Criteria

1. Allergy to study drugs.
2. Patient receiving systemic antibiotic treatment (except for prophylaxis) at the time of onset of febrile neutropenia.
3. Absence of fever.
4. Patients with epilepsy.
5. Severe renal impairment (defined as creatinine clearance <30 mL / min)
6. Previously enrolled patients in whom the time between the inclusion and the current episode is less than 5 weeks.
7. Previously enrolled patients without current resolution of the first episode.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Extended infusion	Piperacillin-Tazobactam 4 g-0.5 g	Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval
Extended infusion	Meropenem 1000 mg	Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval
Extended infusion	Cefepime 2000 mg	Piperacillin-tazobactam, cefepime or meropenem will be administered in half time of the dosing interval
Intermittent infusion	Piperacillin-Tazobactam 4 g-0.5 g	Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes
Intermittent infusion	Cefepime 2000 mg	Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes
Intermittent infusion	Meropenem 1000 mg	Piperacillin-tazobactam, cefepime or meropenem will be administered in 30 minutes

Primary Outcome Measures

Name	Time	Method
Clinical efficacy of extended infusion: Number of patients with defervescence	5 days	Number of patients with defervescence (\<37.5 ºC, for 24 hours) without modifying the antibiotic treatment

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetic target	5 days	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.
Inflammatory biomarker	5 days	Number of patients who normalize or decrease in more than 50% of the peak value of the C-reactive protein.
Overall mortality at 30 days	30 days	Number of patients who died for any reason
Bacteraemia clearance	30 days	Time in days until bacteraemia clearance.
Adverse events	30 days	Incidence of adverse events in both groups
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Volume of distribution	5 days	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.
Pharmacokinetic analysis and population pharmacokinetics of meropenem, piperacillin and cefepime in neutropenic patients: Clearance	5 days	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
Covariables analysis: biometric values: weight	5 days	Assessment of the impact of patient's weight \[in kg\]
Covariables analysis: biometric values: age	5 days	Assessment of the impact of patient's age \[in years\]
Covariables analysis: biochemical data: serum albumin	5 days	Assessment of the impact of total serum albumin \[in g/L\]
Covariables analysis: biochemical data: blood urea	5 days	Assessment of the impact of the urea \[in mmol/L\]
Covariables analysis: biochemical data: blood creatinine	5 days	Assessment of the impact of the creatinine \[in umol/L\]
Covariables analysis: clinical data: 24h diuresis	5 days	Assessment of the impact of 24h diuresis \[in mL/day\]
Pharmacokinetic analysis and population pharmacokinetics: time above a critical concentration value for plasma concentrations	5 days	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).

Trial Locations

Locations (1)

Hospital Duran i Reynals; 🇪🇸 Hospitalet de Llobregat, Barcelona, Spain