Abstract: We included eight RCTs comprising a total of 662 distinct febrile neutropenia episodes. The studies included adults and children, and had variable design and criteria for discontinuation of antibiotics in both study arms. All included studies but two were performed before the year 2000. All studies included people with cancer with fever of unknown origin and excluded people with microbiological documented infections. We found no significant difference between the short-antibiotic therapy arm and the long-antibiotic therapy arm for all-cause mortality (RR 1.38, 95% CI 0.73 to 2.62; RD 0.02, 95% CI -0.02 to 0.05; low-certainty evidence). We downgraded the certainty of the evidence to low due to imprecision and high risk of selection bias. The number of fever days was significantly lower for people in the short-antibiotic treatment arm compared to the long-antibiotic treatment arm (mean difference -0.64, 95% CI -0.96 to -0.32; I² = 30%). In all studies, total antibiotic days were fewer in the intervention arm by three to seven days compared to the long antibiotic therapy. We found no significant differences in the rates of clinical failure (RR 1.23, 95% CI 0.85 to 1.77; very low-certainty evidence). We downgraded the certainty of the evidence for clinical failure due to variable and inconsistent definitions of clinical failure across studies, possible selection bias, and wide confidence intervals. There was no significant difference in the incidence of bacteraemia occurring after randomisation (RR 1.56, 95% CI 0.91 to 2.66; very low-certainty evidence), while the incidence of any documented infections was significantly higher in the short-antibiotic therapy arm (RR 1.67, 95% CI 1.08 to 2.57). There was no significant difference in the incidence of invasive fungal infections (RR 0.86, 95% CI 0.32 to 2.31) and development of antibiotic resistance (RR 1.49, 95% CI 0.62 to 3.61). The data on hospital stay were too sparse to permit any meaningful conclusions. We could make no strong conclusions on the safety of antibiotic discontinuation before neutropenia resolution among people with cancer with febrile neutropenia based on the existing evidence and its low certainty. Results of microbiological outcomes favouring long antibiotic therapy may be misleading due to lower culture positivity rates under antibiotic therapy and not true differences in infection rates. Well-designed, adequately powered RCTs are required that address this issue in the era of rising antibiotic resistance.

Plain-language summary: We included eight studies involving people with neutropenia and fever and comparing short antibiotic therapy to long antibiotic therapy until normalisation of neutrophils. A total of 662 episodes of fever in people with neutropenia were randomly assigned to a treatment group (314 to short antibiotic treatment and 348 to long antibiotic treatment). All trials excluded people who had bacteria growing in any culture before the time of randomisation. All studies except two excluded people with infection in a specific organ. Three trials did not report funding sources; three were funded by academic sponsors; one had academic sponsorship, but the antibiotics and placebos were provided by pharmaceutical companies; and one was sponsored by government funding. There was no difference in mortality between the short- and long-antibiotic therapy arm. There was no difference in the number of people with severe infections presenting as bacteria in blood. There were more cases of infections with positive cultures in people treated with short antibiotic courses compared to long antibiotic courses, but there was no difference in the rate of unfavourable outcome such as recurrence of fever, need for rehospitalization, and change or restart of antibiotics. We found no differences in the rate of fungal infections and development of antibiotic resistance, with few studies reporting the latter outcome. The number of days with fever was lower for people treated with short antibiotic courses compared to those treated with long antibiotic courses. In all trials the number of antibiotic treatment days was fewer in the short-antibiotic therapy arm by three to seven days compared to the long-antibiotic therapy arm. Data on hospital length of stay were insufficient to permit any meaningful conclusions. The overall certainty of evidence was low or very low, permitting little confidence in the results presented. Most of the included studies were old and not adequately designed. There were also many differences between the studies in terms of design and inclusion criteria. We assessed the certainty of the evidence for the primary outcome of all-cause mortality as low and for the outcomes of clinical failure and bacteraemia occurring after randomisation as very low.