Highlights“Right first time” and achieving source control is crucial to optimize antibiotic management in neutropenic patients.The fear of missed pathogens and the risk of emergent resistant organisms require detailed knowledge of local patterns of susceptibility and a multidisciplinary team.A consistent pattern of safety requires shortening duration of therapy.Rapid diagnostic tools contribute to improve overall empiric antibiotic use, which should be a priority in neutropenic patients.A 5D approach is a core strategy to ensure improving antibiotic useEmphasis to a personalized prescription of antibiotics is required.AbstractThe emergence of antibiotic resistance poses a global health threat. High-risk patients such as those with neutropenia are particularly vulnerable to opportunistic infections, sepsis, and multidrug-resistant infections, and clinical outcomes remain the primary concern. Antimicrobial stewardship (AMS) programs should mainly focus on optimizing antibiotic use, decreasing adverse effects, and improving patient outcomes. There is a limited number of published studies assessing the impact of AMS programs on patients with neutropenia, where early appropriate antibiotic choice can be the difference between life and death. This narrative review updates the current advances in strategies of AMS for bacterial infections among high-risk patients with neutropenia. Diagnosis, drug, dose, duration, and de-escalation (5D) are the core variables among AMS strategies. Altered volumes of distribution can make standard dose regimens inadequate, and developing skills towards a personalized approach represents a major advance in therapy. Intensivists should partner antibiotic stewardship programs to improve patient care. Assembling multidisciplinary teams with trained and dedicated professionals for AMS is a priority.