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.

This is a multicenter, open-label, randomized controlled trial. Upon confirmation of Gram-negative bacteraemia, eligible patients are randomized 1:1 to one of two treatment strategies:

• Experimental Arm (Personalized Duration): Antibiotic therapy is discontinued once the patient achieves and maintains clinical stability for 72 consecutive hours. Clinical stability is defined as apyrexia (Tc < 38°C) for at least 48 hours and a stable or improving qSOFA score.
• Control Arm (Standard of Care): Antibiotic therapy duration follows local clinical practice, with a suggested minimum duration of 10 days, consistent with current European and Asian hematological guidelines.

In parallel, a prospective observational microbiological sub-study will utilize Shotgun Metagenomic Next-Generation Sequencing (mNGS) to analyze the evolution of the intestinal and blood microbiota. The goal is to compare the rate of MDR organism colonization and the reconstitution of the healthy microbiome between the two antibiotic duration strategies.

All participants will undergo clinical monitoring until day 28. For those enrolled in the sub-study, biological samples (stool, rectal swabs, and blood) will be collected at baseline (V1), at the end of treatment (V4), and at the end of the study (V5). These samples will be analyzed to identify clinically significant bacteria and antibiotic-resistance genes.

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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