Short Versus Extended Treatment with a Carbapenem in Haematology Patients with High Risk Fever of Unknown Origin During Neutropenia: An Open-Label Multicentre Randomised Clinical Trial

Abstract

Background: Early antibiotic discontinuation in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia has been advocated to reduce unnecessary antibiotic treatment, but the safety of this strategy is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. Methods: In this randomised, multicentre, non-inferiority trial we assigned 292 haematology patients with fever of unknown origin during high-risk neutropenia (≥7 days) to short treatment, with carbapenem discontinuation after 72 hours (± 12 hours), or extended treatment, with carbapenem continuation for ≥ 9 days until being afebrile for 5 days or neutrophil recovery. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock/respiratory failure or death from day 4 until neutrophil recovery. Findings: Treatment failure in the intention-to-treat analysis (281 patients) was 19·4% (28/144) in the short treatment versus 15·3% (21/137) in the extended treatment arm (adjusted risk difference 4·0%, 90% confidence interval [CI] -1·7% to 9·7%, excluding the 10% non-inferiority threshold). Mortality until 30 days after neutrophil recovery occurred in five patients (3·5%) in the short treatment group and in one (0·7%) in the extended treatment group (adjusted risk difference 2·6%, 95% CI % 1·2 to 5·4%), of which none were related to infections with carbapenem-sensitive microorganisms. Interpretation: Early discontinuation of carbapenem treatment in neutropenic patients with fever was non-inferior to extended treatment with regard to treatment failure, but all-cause mortality before 30 days after neutrophil recovery was significantly higher in patients with persistent fever at day 3. Early discontinuation of carbapenem treatment is therefore possible in afebrile patients, but caregivers should be vigilant of other non-carbapenem susceptible infections in patients with persistent fever.: Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov (number NCT02149329). Funding Information: Dutch Research Council (ZonMw) and Fonds NutsOhra. Declaration of Interests: The authors 408 declare no competing interests. Ethics Approval Statement: The protocol was approved by the research ethics review committee of VU university medical centre (current name: Amsterdam University medical centres, location VUmc) and ethical bodies of each participating centre. An independent data and safety monitoring board oversaw study procedures and data quality during conduct of the study and performed a planned interim safety analysis. All participants provided written informed consent.