Efficacy of Lefamulin Against Staphylococcus aureus-Induced Bacteremia in a Neutropenic and Immunocompetent Murine Model

BACKGROUND: S. aureus (SA) is a major human pathogen that causes invasive, clinical infections including bacteremia. Lefamulin (LEF) is the first semi-synthetic, pleuromutilin antibiotic for IV and oral use in humans. LEF is currently in Phase 3 trials for the treatment of community-acquired bacterial pneumonia (CABP). LEF specifically inhibits bacterial protein synthesis by binding to the peptidyl transferase center (PTC) via four H-bonds and other interactions at the A- and P-site resulting in an “induced fit.” LEF has been shown to be highly active against bacterial pathogens causing bacteremia, including SA. This study investigated the efficacy of LEF and comparators against SA in a neutropenic and immunocompetent murine bacteremia model. METHODS: Experimentally induced MSSA bacteremia (inoculum ~2 × 10(7) CFU/mouse) was established in immunocompromised and immunocompetent mice. Infected mice received a single subcutaneous dose of either LEF or comparator (Table 1) 1 hours post-inoculation, mimicking human therapeutic exposures. A control group of infected mice were sacrificed directly before treatment to establish a baseline CFU count and comparison with the bacterial load of treated animals 24 hours post drug administration. RESULTS: Irrespective of the immune status, LEF showed superior efficacy to linezolid (LZD) and tigecycline (TGC) against MSSA, reducing the bacterial burden more than 4 log(10) CFU/mL within 24 hours (Table 1). A comparable reduction of bacterial burden was observed between LEF and daptomycin (DAP) or vancomycin (VAN) treatment. CONCLUSION: LEF showed comparable therapeutic outcome to DAP or VAN in this acute experimental infection model, while showing superior killing as compared with LZD or TGC. The efficacy of LEF was maintained under neutropenic conditions with >4log(10) ΔCFU/mL at clinically relevant exposures. This study supports continued evaluation of LEF for as a potential treatment of staphylococcal bacteremia. DISCLOSURES: E. Fischer, Nabriva Therapeutics AG: Employee and Shareholder, Salary; B. C. Kappes, Nabriva Therapeutics AG: Employee and Shareholder, Salary; W. W. Wicha, Nabriva Therapeutics AG: Employee and Shareholder, Salary