Association between time-to-antibiotics and clinical outcomes in neutropenic fever after hematopoietic stem cell transplant

Background Guidelines recommend empiric antibiotics within one hour for neutropenic fever, extrapolated primarily from sepsis literature. Whether modest variation in time-to-antibiotics (TTA) affects outcomes in antibiotic-naïve hematopoietic stem cell transplant (HSCT) recipients remains unclear. Methods We conducted a retrospective cohort study of neutropenic fever episodes occurring within 30 days of HSCT at a single academic center (2018–2022). We included antibiotic-naïve episodes (no intravenous antibiotics in the 24 h preceding fever) with timestamp-validated TTA. Primary outcome was clinical deterioration (new vasopressor requirement ≥ 6 h, mechanical ventilation, or 90-day mortality). Secondary analyses examined bacteremia and blood culture yield. Results Among 224 antibiotic-naïve episodes, 17 (7.6%) experienced clinical deterioration. Median TTA was 1.2 h (IQR 0.8–2.2), with 86 (38.4%) receiving antibiotics within one hour. In the primary categorical analysis, TTA was not associated with deterioration (≤ 1 h vs > 1 h, adjusted OR 1.18, 95% CI 0.37–3.78, P = .78); a per-hour continuous parameterization was similarly null (adjusted OR 1.03, 95% CI 0.85–1.24, P = .80). Recognized pathogen bacteremia occurred in 59 episodes (26.3%) and was not associated with 90-day mortality (adjusted OR 1.98, 95% CI 0.50–7.90, P = .33); a sensitivity analysis using any-positive cultures (69/224 [30.8%]) yielded similar findings (OR 1.15, 95% CI 0.31–4.28, P = .84). Of 11 deaths, 10 (91%) occurred without preceding acute deterioration. Pre-antibiotic and post-antibiotic cultures had similar recognized pathogen positivity (27.1% vs 23.5%; adjusted OR 1.03, 95% CI 0.28–3.85, P = .97). Conclusion In antibiotic-naïve adult HSCT recipients with neutropenic fever, TTA was not associated with deterioration and bacteremia was not associated with mortality. Per-hour TTA effects were bounded below the minimum detectable effect size, challenging the extrapolation of the 1-h antibiotic rule from septic shock cohorts to this population. Multicenter validation is needed.