Omadacycline exhibits anti-inflammatory properties and improves survival in a murine model of post-influenza MRSA pneumonia

Post-influenza <i>Staphylococcus aureus</i> pneumonia, particularly methicillin-resistant <i>S. aureus</i> (MRSA), remains a major cause of mortality, highlighting the urgent need for newer therapeutic options. Omadacycline is an aminomethylcycline antibiotic that has demonstrated efficacy against MRSA across many infection models, but its potential in post-influenza A virus (IAV)-MRSA pneumonia remains unexplored. Using a murine model of this infection, we evaluated the effects of omadacycline and a comparator antibiotic, linezolid, on survival, inflammation, bacterial load, toxin production, and lung histopathology. In survival studies, omadacycline matched the effectiveness of oral linezolid at clinically relevant doses. In addition, both antibiotics, particularly omadacycline, attenuated the production of multiple pro-inflammatory cytokines and reduced neutrophil infiltration in the lungs, independent of their effects on pulmonary microbial burden, suggesting an immunomodulatory mechanism of action. Panton-Valentine leukocidin (PVL) toxin production <i>in vitro</i> and <i>in vivo</i> was also assessed, and while the role of PVL in this murine model remains unclear, both agents reduced PVL production. These findings provide the first preclinical demonstration of <i>in vivo</i> efficacy for omadacycline against IAV-MRSA pneumonia and its ability to modulate the host immune response, thereby reducing the excessive inflammation that is linked to mortality in this disease state. Further investigation into the precise interplay between omadacycline and immunomodulation in this disease state is warranted.