Oral Stepdown Therapy for Gram-Negative Bloodstream Infections: A Systematic Review and Meta-Analysis.

Early oral step-down has been proposed as a strategy to optimize antimicrobial use in Gram-negative bloodstream infections (BSIs). We performed a systematic review and meta-analysis of full-text studies published in English and indexed in MEDLINE and EMBASE up to April 2025. Randomized controlled trials (RCTs) and observational studies including patients with Gram-negative BSIs managed either with oral step-down within 5 days of IV therapy or with continued IV therapy were eligible. Risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale for observational studies. Of 4120 screened records, 13 studies (3 RCTs and 10 cohort studies) including 10,000 patients met the inclusion criteria; 5016 of enrolled patients (52%) switched to oral therapy, mainly to fluoroquinolones (2992, 59.6%). A lower all-cause mortality was observed in patients receiving oral step-down (RR: 0.39, 95% CI: 0.16-0.93; p = 0.034). When stratifying studies according to timing of the switch to oral therapy, no significant difference in mortality was observed in studies with a median switch time ≤ 3 days (p = 0.29). Conversely, studies with a median switch time > 3 days showed a lower mortality rate in the oral step-down group, approaching statistical significance (p = 0.051). No significant differences were found between treatment groups in terms of clinical failure (p = 0.28). Microbiological failure was significantly less frequent among patients receiving oral step-down therapy (RR = 0.69, 95% CI: 0.49-0.97; p = 0.032), while adverse event rates were comparable (p = 0.52). However, sensitivity analyses limited to propensity score-adjusted data demostrated no significant differences in mortality (p = 0.32) or microbiological failure (p = 0.076). Oral step-down therapy for Gram-negative BSIs appears to be a valuable alternative to prolonged IV treatment, potentially reducing IV exposure, complications and healthcare costs without compromising clinical or microbiological outcomes. PROSPERO registration number: CRD420251056335.