β‐Lactam Adjunctive Therapy Compared to Vancomycin or Daptomycin Monotherapy in Adult Patients With Methicillin‐Resistant Staphylococcus aureus Bacteremia: An Update Systematic Review, Meta‐Analysis, and Trial Sequential Analysis

Background: This study evaluated the efficacy and safety of vancomycin (VAN) or daptomycin (DAP) combined with β‐lactams (BLs) versus monotherapy (STAN) for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Methods: PubMed, Web of Science, Embase, and Cochrane Library were searched until September 30, 2024, for RCTs or cohort studies comparing combination therapy (COMBO) and STAN in adult MRSA bacteremia. Outcomes included all‐cause mortality, 30‐day mortality, clinical failure, and safety. Subgroup and trial sequential analyses were performed. Results: Among 22 studies (3214 patients), the COMBO group did not reduce all‐cause mortality (RR = 1.16, 95% CI: 0.91–1.48, p = 0.24) and 30‐day mortality (RR = 1.18, 95% CI: 0.86–1.62, p = 0.31). Subgroup analyses suggested increased all‐cause mortality in high‐quality studies (RR = 1.29, 95% CI: 1.00–1.67, p = 0.05). Additionally, when VAN/DAP was administered randomly, COMBO was associated with higher all‐cause mortality (RR = 1.37, 95% CI: 1.05–1.78, p = 0.02) and 30‐day mortality (RR = 1.41, 95% CI: 1.01–1.96, p = 0.02). However, the COMBO reduced clinical failure rate (RR = 0.78, 95% CI: 0.65–0.93, p = 0.006), persistent bacteremia (RR = 0.70, 95% CI: 0.54–0.92, p = 0.01), and relapsed bacteremia (RR = 0.62, 95% CI: 0.48–0.80, p = 0.0003). No differences were observed in the microbiological failure rate, duration of bacteremia, or length of hospital stay. Furthermore, the COMBO group showed no significant increase in the incidence of acute kidney injury (AKI). Conclusions: COMBO did not lower mortality in MRSA bacteremia and may increase risk in certain subgroups. However, it improved microbiological outcomes without raising AKI risk. However, these microbiological advantages must be weighed against two concerning findings: a nonsignificant trend toward increased Clostridium difficile infection (CDI) risk and elevated mortality signals in high‐quality subgroup analyses. Given conflicting mortality signals, cautious clinical application and further RCTs are needed.