Oral Stepdown Therapy for Gram‐Negative Bloodstream Infections: A Systematic Review and Meta‐Analysis
Lorenzo Onorato, Ilaria De Luca, Marika Ferrante, Giuseppe Ricciardiello, Caterina Monari, Nicola CoppolaABSTRACT
Background
Early oral step‐down has been proposed as a strategy to optimize antimicrobial use in Gram‐negative bloodstream infections (BSIs).
Methods
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.
Results
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).
Conclusions
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.
Trial Registration
PROSPERO registration number: CRD420251056335