Short summary

Optimal duration of empirical antibiotics for febrile neutropenia in children with cancer and profound neutropenia is a major research gap. We will investigate the efficacy and safety of discontinuation of antibiotics at 48 hours of apyrexia based on clinical symptoms in a randomized trial. The findings will allow evidence-based treatment and potential reduction of antibiotic therapy, hospital admissions, side effects, resistance development and health cost without compromising patient safety.

Rationale

In children with cancer, infections are a major cause of morbidity and mortality due to chemo-therapy-related immunosuppression, and patients with any signs of infection including fever must be treated promptly with broad spectrum antibiotics. However, the duration of antibiotic therapy in children with febrile neutropenia of unknown origin is not investigated. Traditionally, antibiotic therapy is continued until neutrophil recovery, but scientific evidence supporting this strategy is limited. Adult studies has shown that withdrawal of empirical antimicrobial therapy for neutropenic fever based on clinical assessment, despite severe neutropenia, can reduce antibiotic treatment significantly without compromising patient safety. This approach is warranted in children with cancer, but no randomized studies have been conducted in high risk children with prolonged neutropenia.

Description of the cohort

Eligible patients include children aged 0-17 years with cancer receiving antibiotic treatment for high risk neutropenic fever of unknown origin at one of the four centers treating children with cancer in Denmark during the study period. High-risk neutropenia is defined as neutropenia lasting for more than 7 days.

Patients will be randomized 1:1 to one of two treatments:

• Experimental group: Discontinuation of antibiotics, despite neutrophil count below 0.5x10⁹ cells/L, after 48 hours of apyrexia and clinical stability. A child is considered clinically stable when there is resolution of all symptoms and signs of infection, and normalization of vital signs.

• Control group: Discontinuation of antibiotics when - neutrophil count is above 0.5x10⁹ cells/L, and the child is afebrile and clinical stable OR - the child has received 10 days of antibiotics and have been afebrile and clinically stable for 7 days

The children will be followed 28 days after randomization.

Data and biological material

Children with fever will be evaluated and treated according to routine management of neutropenic fever. The children are followed 28 days after randomization and/or untill bone marrow recovery, and clinical data regarding the course of infection will be extracted from the patient journal and stored in a dedicated database.

In addition to the routine tests collected irrespective of the study, the following samples will be collected: • Fecal samples • Pharyngeal swabs • Plasma samples

Collaborating researchers and departments

Department of Pediatrics and Adolescent Medicine, University Hospital Odense

• Dorthe Grosen, overlæge

Department of Pediatrics and Adolescent Medicine, University Hospital Aarhus

• Birgitte Klug Albertsen, overlæge