Anti–Methicillin-Resistant Staphylococcus aureus (MRSA) Cephalosporins Plus Daptomycin as Initial Therapy for MRSA Bacteremia: Does a “Hit Hard and Fast” Strategy Improve Outcomes?

Background The study aim was to evaluate the effectiveness of anti-methicillin-resistant Staphylococcus aureus (MRSA) cephalosporins in combination with daptomycin (anti-MRSA Ceph + DAP) compared to other antimicrobial regimens (OARs) as initial treatment of MRSA bloodstream infection (BSI).Methods This retrospective observational study enrolled patients with MRSA-BSI from 1 January 2020 to 31 December 2024 at 4 large Italian hospitals. The primary endpoint was 90-day all-cause mortality. Cox regression was used for primary endpoint analysis; results were confirmed with inverse probability of treatment weighting (IPTW). Treatment efficacy was also assessed using the desirability of outcome ranking (DOOR) approach, assigning 1 additional point beyond recovery for 1 of the following negative outcomes: (i) persistent MRSA infection, (ii) persistent bacteremia (>= 5 days), (iii) drug resistance, (iv) any adverse event, and (v) 90-day relapse. A score of 7 was assigned for death at any time point.Results Overall, 465 patients were enrolled: Median age was 76 (IQR, 61-83) years, 59% male, with a Charlson Comorbidity Index score of 7 (IQR, 4-8). Of them, 50 (11%) and 116 (25%) patients had endocarditis and metastatic infection, respectively. Importantly, 90-day mortality occurred in 181 (39%) patients, while 260 (56%) experienced at least 1 negative outcome included in DOOR analysis. Overall, patients in the anti-MRSA Ceph + DAP arm had a 59.9% (95% CI, 52.4%-67.4%) probability of having a better outcome than those in the OAR arm. Particularly, anti-MRSA Ceph + DAP was associated with reduced mortality (aHR, 0.54 [95% CI, .34-.85]), confirmed after adjustment with IPTW analysis.Conclusions Anti-MRSA Ceph + DAP could represent a valid initial therapy for MRSA-BSI, especially in patients with high risk of worse outcomes.This multicenter study showed that initial therapy with daptomycin plus anti-MRSA cephalosporins was associated with a 90-day mortality reduction and treatment failure in MRSA bloodstream infections, supporting early combination therapy as a promising strategy for high-risk, critically ill patients.