The goal of this clinical trial is to learn if a personalized duration of antibiotic therapy, based on clinical stability, is as effective as a standard duration of at least 10 days in hospitalized patients with hematologic malignancies (such as leukemia or lymphoma) who develop febrile neutropenia and Gram-negative bacteraemia.
The main questions it aims to answer are:
* Can a personalized antibiotic duration increase the number of days free from anti-Gram-negative therapy within 28 days without compromising patient safety? * How does the duration of antibiotic therapy (short vs. prolonged) affect the rate and modality of gut microbiota reconstitution?
Researchers will compare:
* Group A (Personalized Duration): Antibiotics are stopped after the patient maintains clinical stability (no fever and stable vital signs) for 72 consecutive hours. * Group B (Standard of Care): Antibiotics are continued for a standard duration, typically at least 10 days, based on current clinical surveys and physician decision.
Participants will:
* Be randomized to receive either the personalized or the standard duration of antibiotic therapy once a Gram-negative infection is confirmed in the blood. * Be monitored for 28 days to assess for new fever episodes, recurrence of infection, and overall survival. * If participating in the microbiological sub-study, provide biological samples (blood, feces, and rectal swabs) at specific time points (at the onset of fever, at the end of treatment, and at day 28). * Undergo specialized laboratory testing (Whole Metagenomic Sequencing) on the collected samples to evaluate the evolution of their intestinal and blood microbiota and the presence of antibiotic-resistant genes.
Diagnosed with a hematologic malignancy that is candidate for treatment with chemotherapy or bone marrow transplantation or chimeric antigen receptor T cell therapy (CAR-T)
Diagnosis of febrile neutropenia defined according to the guidelines of the Infectious Disease Society of America, IDSA; ref: Freifeld, A.G., et al., Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis, 2011. 52(4): p. e56-93.) as: Fever: single record of oral temperature >=38.3°C or a temperature >=38.0°C sustained over a period of one hour; Neutropenia: absolute neutrophil count < 1000 cells/microL; Expected duration of neutropenia >= 7 days
Diagnosis of bacteraemia defined by positive blood cultures (at least 1 vial positive for a non-contaminating microorganism)
Isolation of Gram-Negative species
Contextual diagnosis of pneumonia
Contextual diagnosis of intra-abdominal infection, in particular: neutropenic enterocolitis/typhlitis or biliary tract infection
Persistently positive blood cultures at randomization
Any condition that endangers the safety of the patient based on the judgment of the treating physician
Parallel
Clinical Stability-Driven Antibiotic Discontinuation Strategy
Other interventionA therapeutic strategy where the duration of antibiotic treatment for Gram-negative bacteraemia is determined by the achievement of clinical stability (defined as apyrexia for 48h and stable/improved qSOFA score) maintained for 72 consecutive hours
Standard of Care Antibiotic Duration
Other interventionThis intervention follows the standard clinical practice for treating Gram-negative bacteraemia in hematological patients. The duration of therapy is not fixed by a stability-driven rule but is based on the treating physician's decision, with a suggested minimum of 10 days.
Days Free from Anti-Gram-Negative Antibiotic Therapy within 28 days
Number of days that the participant is alive and free from any anti-Gram-negative antibiotic therapy, calculated from the date of the index blood culture collection (onset of infection) up to Day 28. Antibiotics active exclusively on Gram-positive bacteria (e.g., glycopeptides, daptomycin) and fluoroquinolone prophylaxis are excluded from this calculation.
Incidence of New Fever Episodes
Number of participants experiencing a new episode of fever (Tc ≥ 38.3°C) occurring after a period of apyrexia of at least 72 hours
28-day All-cause Mortality
Number of participants who died from any cause within 28 days from the onset of the index infection (date of first positive blood culture)
Relapse of Bloodstream Infection (BSI) by the Same Pathogen
Number of participants with a new positive blood culture for the same Gram-negative pathogen identified in the index episode
Recurrent BSI by Gram-negative Bacteria
Number of participants experiencing a new episode of bloodstream infection caused by any Gram-negative bacteria different from the index pathogen
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Valeria Cento
Lead sponsor
Humanitas University
Sponsor institution
Ministry of Education, Universities and Research, Italy
Collaborator
