In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice.

Lefamulin is a first-in-class systemic pleuromutilin antimicrobial and potent inhibitor of bacterial translation, and the most recent novel antimicrobial approved for the treatment of community-acquired pneumonia (CAP). It exhibits potent antibacterial activity against the most prevalent bacterial pathogens that cause typical and atypical pneumonia and other infectious diseases. Early studies indicate additional anti-inflammatory activity. In this study, we further investigated the immune-modulatory activity of lefamulin in the influenza A/H1N1 acute respiratory distress syndrome (ARDS) model in BALB/c mice. Comparators included azithromycin, an anti-inflammatory antimicrobial, and the antiviral oseltamivir. Lefamulin significantly decreased the total immune cell infiltration, specifically the neutrophils, inflammatory monocytes, CD4+ and CD8+ T-cells, NK cells, and B-cells into the lung by Day 6 at both doses tested compared to the untreated vehicle control group (placebo), whereas azithromycin and oseltamivir did not significantly affect the total immune cell counts at the tested dosing regimens. Bronchioalveolar lavage fluid concentrations of pro-inflammatory cytokines and chemokines including TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ, and GM-CSF were significantly reduced, and MCP-1 concentrations were lowered (not significantly) by lefamulin at the clinically relevant 'low' dose on Day 3 when the viral load peaked. Similar effects were also observed for oseltamivir and azithromycin. Lefamulin also decreased the viral load (TCID50) by half a log10 by Day 6 and showed positive effects on the gross lung pathology and survival. Oseltamivir and lefamulin were efficacious in the suppression of the development of influenza-induced bronchi-interstitial pneumonia, whereas azithromycin did not show reduced pathology at the tested treatment regimen. The observed anti-inflammatory and immune-modulatory activity of lefamulin at the tested treatment regimens highlights a promising secondary pharmacological property of lefamulin. While these results require confirmation in a clinical trial, they indicate that lefamulin may provide an immune-modulatory activity beyond its proven potent antibacterial activity. This additional activity may benefit CAP patients and potentially prevent acute lung injury (ALI) and ARDS.

Efficacy of ceftobiprole in a murine model of bacteremia and disseminated infection.

Introduction. Ceftobiprole is an advanced-generation broad-spectrum parenteral cephalosporin with activity against MSSA and MRSA.Gap Statement. Ceftobiprole is not currently approved for use to treat S. aureus bacteremia and phase three clinical trials are taking place. Drug approval requires further pre-clinical evidence to support this new indication.Aim. The aim of this study was to evaluate the efficacy of ceftobiprole at the human equivalent efficacious exposure (considering a 500 mg q8h dosing regimen infused over 2 h) against MSSA and MRSA strains in a neutropenic murine model of bacteremia and disseminated infection.Methodology. Two bioluminescent-tagged strains (one MSSA and one MRSA strain) were selected based on their in vitro susceptibility and in vivo growth profiles. Bacterial c.f.u. counts in the blood, lung, kidney, and liver were determined 48 h post-infection or after death. The bioluminescent-tag allowed the visualization of the real-time effects of ceftobiprole therapy compared to the natural progression of the infection in untreated controls.Results. Treatment with ceftobiprole resulted in a significant reduction of the bacterial load with the bioluminescence reduced by 2-log units and bacterial c.f.u. counts reduced by 3- to 6-log units, depending on the organ and bacterial strain. Survival was 100 % in the ceftobiprole-treated group compared to only 0-20 % survival in the untreated control animals for both strains tested.Conclusion. These results suggest that treatment with ceftobiprole using a 500 mg q8h dosing regimen studied in several successful phase three trials, has potential as an antibiotic therapy to treat bacteremia and associated disseminated infections caused by either methicillin-susceptible or methicillin-resistant strains of S. aureus.