2026 Southeastern Residency Conference

Title:
Daptomycin Combination Therapy with Ceftaroline versus Anti-Staphylococcal Beta-Lactams for the Treatment of Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia

Authors:
Christopher Staten, PharmD
Kelvin Gandhi, PharmD, BCIDP
Lindsey Moeller, PharmD, BCPS

Background:
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is poorly defined and not well established; recent literature characterizes it as a bloodstream infection with ongoing positive blood cultures for two or more days despite receipt of targeted therapy against MRSA. Persistent bacteremia may occur in up to 39% of S. aureus bacteremia cases, and has been associated with increased mortality, risk of metastasis, and incidence of microbiologic relapse. Traditional pharmacotherapy includes either vancomycin or daptomycin, however when persistent MRSA bacteremia is present, synergistic therapy is oftentimes explored to assist in microbiological eradication. Combination therapies of beta-lactams with daptomycin are currently being clinically evaluated due to their theorized enhancement of daptomycin binding based on data from in vitro studies. Beta-lactam synergy with daptomycin may increase depolarization of the bacterial cell wall to improve daptomycin efficacy and bactericidal activity. Despite strong in vitro data, the in vivo data is inconsistent when demonstrating impact on clinical outcomes. Ceftaroline is most commonly utilized in clinical practice as the synergistic adjunctive agent of choice with daptomycin due to its strong in vitro data, however it is more costly compared to other studied adjunctive agents such as anti-staphylococcal beta-lactams (ASBL).

Methods: 
This was a retrospective multicenter cohort study that included hospitalized adult patients with at least one blood culture positive for MRSA from September 1, 2022 to October 31, 2025 at AdventHealth East Florida Division hospitals. Patients were allocated into two groups, either daptomycin plus ceftaroline (DPT/CFT), or daptomycin plus an ASBL (DPT/ASBL), which included cefazolin and oxacillin. Patients were included if they received 72 hours of combination therapy in either group. Excluded patients were those under 18 years of age, pregnant, or received less than 72 hours of combination therapy. The primary outcome was composite clinical failure; composed of 60-day mortality, 60-day recurrence, and persistent bacteremia at day five of combination therapy. A non-inferiority threshold was set at 10.0% based on incidence rates demonstrated by pertinent literature. A multivariate logistic regression was performed on the primary outcome to assess possible confounding variables.

Results: 
A total of 53 patients were investigated in this study, 41 in DPT/CFT and 12 in DPT/ASBL. The primary outcome of composite clinical failure was met in 13 (31.7%) in the DPT/CFT group and 3 (25.0%) patients in the DPT/ASBL group (ARD 6.71). The difference of 6.71% did reach the threshold set for non-inferiority of 10% difference. A multivariate logistic regression analysis showed no statistically significant associations identified for the primary outcome by ICU admission, Charlson Comorbidity Index (CCI), time to source control, and duration of combination therapy.

Discussion:
This retrospective analysis comparing daptomycin plus ceftaroline (DPT/CFT) to daptomycin plus ASBL (DPT/ASBL) for persistent MRSA bacteremia, demonstrated that DPT/ASBL was non-inferior to DPT/CFT. Of note, patients in the DPT/CFT arm were generally more critically ill; though not reflected in the differences in APACHE II score, CCI, or Pitt Bacteremia Score, they had more complicated sources of infection, higher ICU admission rates, and increased clinical instability, potentially impacting outcomes.

Conclusion: 
Nonetheless, our findings ultimately suggest that DPT/ASBL combination may be an alternative regimen to DPT/CFT in a select clinical context. This combination could provide an alternative option for persistent MRSA bacteremia, but prospective studies are needed to better define the comparative clinical efficacy and safety in different patient populations.