Association of time to antibiotics and clinical outcomes in patients with fever and neutropenia during chemotherapy for cancer : a systematic review

PURPOSE: Prompt antibiotic therapy is standard of care for patients with fever and neutropenia (FN) during chemotherapy for cancer. We systematically reviewed the association between time to antibiotics (TTA) and clinical outcomes. METHODS: The search covered seven databases; confounding biases and study quality were assessed with the ROBINS-I tool. Safety (death, intensive care unit (ICU) admission, sepsis) and treatment adequacy (relapse of infection, persistence or recurrence of fever) were assessed as primary outcomes. RESULTS: Of 6296 articles identified, 13 observational studies were included. Findings regarding safety were inconsistent. Three studies controlling for triage bias showed a possible association between longer TTA and impaired safety. Meta-analysis for TTA ≤ 60 min versus > 60 min was feasible on four studies, with three studies each reporting on death (OR 0.78, 95%CI 0.16-3.69) and on ICU admission (OR 1.43, 95%CI 0.57-3.60). No study reported data on treatment adequacy. Triage bias, i.e. faster treatment of patients with worse clinical condition, was identified as a relevant confounding factor. CONCLUSION: There seems to be an association between longer TTA and impaired safety. More knowledge about TTA effects on safety are important to optimise treatment guidelines for FN. Controlling for triage and other biases is necessary to gain further evidence. TRIAL REGISTRATION: Registration: PROSPERO [http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42018092948]