Meta-analysis links ceftriaxone to higher 30-day mortality in MSSA bloodstream infections

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Annals of medicine Published May 11, 2026 Medically reviewed May 11, 2026 Study authors: Maraolo Alberto Enrico, Nobile Mariano, Gentile Ivan PubMed ↗ DOI ↗ By Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease

Key Takeaway

Consider avoiding ceftriaxone as initial therapy for MSSA bloodstream infections due to increased 30-day mortality risk.

This systematic review and meta-analysis of observational studies evaluated the comparative effectiveness of ceftriaxone versus standard-of-care (antistaphylococcal penicillins or cefazolin) for patients with methicillin-susceptible Staphylococcus aureus (MSSA) bloodstream infections, including 2568 patients. The primary outcome was 30-day and 90-day all-cause mortality; secondary outcomes included clinical success, microbiological clearance, and adverse event rates.

The meta-analysis found that ceftriaxone was associated with significantly higher 30-day all-cause mortality (OR 3.33; 95% CI 2.17-5.10), indicating potential harm. However, 90-day all-cause mortality was not significantly different between groups (OR 1.71; 95% CI 0.75-3.90). Secondary outcomes, including clinical success (OR 0.49; 95% CI 0.19-1.26) and microbiological clearance (OR 1.66; 95% CI 0.73-3.82), also showed no significant differences. Adverse event rates were similar between groups.

Important limitations include the observational nature of the included studies, meaning the association does not imply causation. No randomized trials were included, and the analysis did not adjust for potential confounders. The authors note that routine use of ceftriaxone for MSSA bloodstream infections, especially as initial therapy, is not supported by current evidence. Clinicians should interpret these findings cautiously, as 90-day mortality and secondary outcomes were not significantly different, and the evidence is based on observational data.

Study Details

Study typeMeta analysis

Sample sizen = 2,568

EvidenceLevel 1

PublishedDec 2026

PMID42112603

View Original 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.