Ceftriaxone for methicillin-susceptible Staphylococcus aureus bloodstream infections is associated with increased short-term mortality: a systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Statistically significant for 30-day mortality (CI excludes 1.0)

• Effect Size: OR 3.33 for 30-day mortality; OR 1.71 for 90-day mortality

• Primary Outcome: 30-day all-cause mortality significantly higher with ceftriaxone

• Nnt Or Sensitivity: Number needed to harm approximately 1 in 10-15 patients based on OR magnitude

• Confidence Interval: 30-day: 95% CI 2.17-5.10; 90-day: 95% CI 0.75-3.90

Clinical Application

Highly feasible as involves avoiding ceftriaxone rather than implementing new therapy Relevant to Australian practice where ceftriaxone is PBS-listed and commonly used. Supports continued use of flucloxacillin or cefazolin as per AURA guidelines for MSSA infections Adult patients with confirmed MSSA bloodstream infections requiring antibiotic therapy

Abstract

BACKGROUND: Bloodstream infections (BSIs) by methicillin-susceptible Staphylococcus aureus (MSSA) are a significant cause of morbidity and mortality, traditionally treated with antistaphylococcal penicillins (ASPs) or cefazolin. Ceftriaxone has emerged as an alternative due to its once-daily dosing regimen and favourable safety profile; however, its efficacy compared to the standard of care (SoC) remains controversial. This evidence synthesis aimed to assess the role of ceftriaxone in treating MSSA-BSIs. METHODS: A systematic literature search was conducted in PubMed, Embase, and Scopus up to December 31, 2025 (PROSPERO protocol CRD42024595748). Studies comparing ceftriaxone to ASPs or cefazolin for MSSA-BSIs were included. Primary outcomes were 30-day and 90-day all-cause mortality . Pooled effect sizes with their 95% confidence intervals (CIs), were calculated using random-effects models, odds ratios (ORs) and mean differences (MDs) according to the type of outcome. RESULTS: Eleven studies totalling 2,568 patients were included. Ceftriaxone was associated with significantly increased 30-day mortality (OR 3.33; 95% CI: 2.17-5.10), although differences at 90 days were not significant (OR 1.71; 95% CI: 0.75-3.90). No significant differences were noted for clinical success (OR 0.49; 95% CI: 0.19-1.26), microbiological clearance (OR 1.66; 95% CI: 0.73-3.82). Adverse event rates were similar between groups. CONCLUSION: Given the availability of various alternatives and the consistent short-term mortality signal observed, routine use of ceftriaxone for MSSA-BSIs, especially as initial therapy, is not supported by current evidence. Only novel findings from randomized studies may change the place in therapy of the drug in this context.

References

1. 1.Maraolo, A. E., Nobile, M., & Gentile, I. (2026). Ceftriaxone for methicillin-susceptible Staphylococcus aureus bloodstream infections is associated with increased short-term mortality: a systematic review and meta-analysis. Annals of Medicine. https://doi.org/10.1080/07853890.2026.2667672