Efficacy of extended infusion of β-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE)

Abstract

Background: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal βlactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. Methods: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK

Understanding and Managing Sepsis in Patients With Cancer in the Era of Antimicrobial Resistance

“…Other secondary outcomes include PK/pharmacodynamic target achievement, bacteremia clearance, CRP decrease, overall 30-day case-fatality rate, and adverse events. Finally, a population PK model of the BLA studied will be developed ( 133 ).…”

The Dutch Working Party on Antibiotic Policy (SWAB) Recommendations for the Diagnosis and Management of Febrile Neutropenia in Patients with Cancer

“…Currently, a multicenter, open-label, randomized, superiority clinical trial is being conducted in hematological neutropenic patients treated with cefepime, piperacillin–tazobactam, or meropenem to assess the clinical efficacy of extended versus intermittent beta-lactam infusion [ 51 ].…”

Time to defervescence evaluation for extended‐ vs. standard‐infusion cefepime in patients with acute leukemia and febrile neutropenia

“…The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment within the first 5 days of therapy. 19 From an antimicrobial stewardship perspective, these findings are significant in showing that utilizing a 50% reduced dose EI regimen provided a significantly faster time to defervescence compared with the FDA-approved SI regimen. Between the EI and the SI groups, there was a statistical difference in treatment duration (median 6.0 days vs. 8.0 days respectively, p = 0.002); however, these align with recommendations for duration of treatment of FN based on NCCN and IDSA guidelines which reflect a duration of treatment targeting a suspected source or empiric duration of 3-5 days if patient is afebrile with no infection identified or at least 7 days depending on ANC count recovery.…”