Preclinical and clinical evaluation of vancomycin plus delpazolid combination therapy for MRSA bacteremia: a multicenter, double-blinded, randomized, parallel design, phase IIa clinical trial

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ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a serious clinical challenge due to limited treatments and high mortality. We conducted both preclinical and clinical studies to assess the potential role of delpazolid in combination with vancomycin. Synergistic effects of delpazolid with vancomycin or daptomycin were evaluated in vitro using checkerboard and time-kill assays, and in vivo using a Galleria mellonella model. A multicenter, double-blind, randomized, Phase IIa trial was conducted at six Korean hospitals between 26 April 2022 and 18 March 2024. Patients with MRSA bacteremia were randomized 1:1 to receive vancomycin monotherapy or vancomycin plus delpazolid for 14 to 42 days. The primary outcome was overall cure at day 14 (microbiological clearance and symptom resolution). Secondary endpoints included safety, adverse events, and delpazolid pharmacokinetics. In vitro checkerboard assays showed no interaction between delpazolid and vancomycin or daptomycin, while time-kill assays revealed antagonism only when delpazolid was combined with vancomycin. In the Galleria mellonella model, combination therapy improved survival over monotherapy. In the clinical study, 40 patients were enrolled, 38 received ≥1 dose (safety set), and 34 (monotherapy: 19; combination: 15) were included in the full analysis set. On day 14, overall cure was 52.6% in the monotherapy and 60.0% in the combination group ( P = 0.6675). Adverse event rates were similar across groups, with no significant safety concerns. In pharmacokinetic analyses, delpazolid showed favorable plasma levels when co-administered. These preliminary findings warrant further investigation in adequately powered trials to define the role of delpazolid plus vancomycin in the treatment of MRSA bacteremia. CLINICAL TRIALS The study is registered with ClinicalTrial.gov as NCT05225558 . IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia presents a serious clinical challenge due to limited treatments and high mortality. This study evaluated the potential role of delpazolid, an oral oxazolidinone, in combination with vancomycin for MRSA bacteremia. Preclinical studies demonstrated delpazolid’s antimicrobial activity comparable to vancomycin and daptomycin, and in the Galleria mellonella infection model, combination therapy significantly improved survival rates over monotherapy. The early-terminated Phase IIa clinical study showed that the combination regimen had an acceptable safety profile, with no apparent increase in adverse events compared to vancomycin monotherapy. While overall cure rates and bacteremia clearance were numerically higher in the combination group, these differences were not statistically significant. These preliminary findings underscore the need for larger, adequately powered clinical trials to clarify the clinical role of delpazolid combination therapy in MRSA infections.

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