Early Termination of Empirical Antibiotics in High-risk Febrile Neutropenia in Children With Cancer: an Open-label, Randomised, Controlled Trial

BACKGROUND: In children with cancer, infections are a major cause of morbidity and mortality due to chemotherapy-related immunosuppression, comprising up to 70% of all treatment-related deaths. The relationship between neutropenia and life-threatening infection has been well established, and any signs of infection including fever has to be treated promptly with broad spectrum antibiotics. However, the duration of antibiotic therapy in pediatric cancer patients with febrile neutropenia without a known source is unknown. Traditionally, antibiotic therapy is continued until neutrophil recovery, due to fear of relapse of infection potentially as life-threatening sepsis, but scientific evidence supporting this strategy is limited. It has been debated that the strategy may be over-cautious, leading to unnecessarily prolonged antibiotic treatments with important side effects, including extended hospital admissions, adverse drug events, super-infection with fungi and multi-resistant bacteria, and thus affecting the children on both short and long term.

Studies in adults have shown that withdrawal of empirical antimicrobial therapy 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. A few studies have documented that early discontinuation of empirical antibiotics in low-risk children with short-lasting neutropenia is safe, but as stressed by recent international guidelines, the question of optimal duration of empirical antibiotics for high-risk children with prolonged bone marrow suppression continues to be a major research gap.

HYPOTHESIS: Empirical antibiotic therapy of febrile neutropenia can safely be discontinued after 48 hours of apyrexia and clinical stability, despite severe neutropenia, in high-risk children with expected prolonged neutropenia.

AIM: To establish evidence-based treatment strategies for children with febrile neutropenia by performing a randomized controlled trial investigating the efficacy and safety of early termination of empirical antibiotic therapy.

METHODS: Children treated at one of the 4 pediatric oncology departments in Denmark who are admitted with neutropenic fever will be evaluated according to current routines, including complete physical examination, assessment of severity signs and source, blood samples (biochemistry and hematology), blood cultures (collected from the central venous catheter), and additional samples from infected sites as clinically indicated. After obtaining cultures, empiric antibiotic therapy for neutropenic fever is started. The type of antibiotics will depend on current local guideline. Children who remain febrile despite empirical antibiotic therapy will be treated and investigated according to local and international guidelines.