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Introduction: De-escalation is the key to balance judicious antibiotic usage for life-threatening infections and reducing the emergence of antibiotic resistance caused by antibiotic overuse. Robust evidence is lacking regarding the safety of antibiotic de-escalation in culture negative sepsis.Materials and Methods: Children admitted to the PICU during the first 6 months of 2019 with suspected infection were included. Based on the clinical condition, cultures and septic markers, antibiotics were de-escalated or continued at 48–72 h. Outcome data like worsening of primary infection, acquisition of hospital acquired infection, level of ICU support and mortality were captured.Results: Among the 360 admissions, 247 (68.6%) children received antibiotics. After excluding 92 children, 155 children with 162 episodes of sepsis were included in the study. Thirty four episodes were not eligible for de-escalation. Among the eligible group of 128 episodes, antibiotics were de-escalated in 95 (74.2%) and continued in 33 (25.8%). The primary infection worsened in 5 (5.2%) children in the de-escalation group and in 1 (3%) in non de-escalation group [Hazard ratio: 2.12 (95%CI: 0.39–11.46)]. There were no significant differences in rates of hospital acquired infection, mortality or length of ICU stay amongst the groups. Blood cultures and assessment of clinical recovery played a major role in de-escalation of antibiotics and the clinician's hesitation to de-escalate in critically ill culture negative children was the main reason for not de-escalating among eligible children.Conclusion: Antibiotic de-escalation appears to be a safe strategy to apply in criticallly ill children, even in those with negative cultures.