Efficacy and safety of withholding antimicrobial therapy in children with cancer, fever and neutropenia, with a demonstrated viral respiratory infection: a randomized clinical trial

Objectives To validate the efficacy and safety of withholding antimicrobial therapy in a new cohort of children with cancer and febrile neutropenia (FN) having a demonstrated viral respiratory tract infection (RTI). Methods Prospective, multicenter, non-inferiority, randomized study, approved by the ethical committee, in children presenting with FN at seven hospitals in Chile, evaluated at admission for diagnosis of bacterial and viral pathogens. Children who were positive for a respiratory virus (RV), negative for a bacterial pathogen and had a favorable evolution after 48-72 hours of antimicrobial therapy were randomized to either maintain or withhold antimicrobial therapy. The primary endpoint was the percentage of episodes with uneventful resolution, whereas the secondary endpoints were days of fever/hospitalization, requirement of antimicrobial treatment readministration, sepsis, pediatric intensive care unit (PICU) admission and death. Results A total of 301 of 939 children with FN episodes recruited between March 2021 and December 2023 had a RV as a unique identified microorganism, of which 139 had a favorable evolution at 48-72 hours and were randomized, 70 to maintain and 69 to withdraw antimicrobial therapy. The median days of antimicrobial therapy was 5 (IQR 3-6) versus 3 (IQR 3-6) days (p<0.001), with similar frequency of uneventful resolution (66/70 (94%) and 66/69 (96%), RR 1.01, (95% CI 0.93-1.09), absolute risk difference 0.01, (95% CI -0.05-0.08) and similar number of days of fever and days of hospitalization. No cases of sepsis, PICU admission or death were reported. Conclusions We validated the strategy of withdrawal antimicrobial therapy in children with FN and viral RTI, based on clinical and microbiological/molecular diagnostic criteria. This will enable advances in antimicrobial stewardship strategies with a possible future impact on antimicrobial resistance.