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Published on: June 25, 2015
In Vivo Immune-Modulatory Activity of Lefamulin in an Influenza Virus A (H1N1) Infection Model in Mice
Susanne Paukner1, Sandra Kimber2, Charlotte Cumper2
1Nabriva Therapeutics GmbH, Leberstrasse 20, 1110 Vienna, Austria.
Abstract:
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.
Insights
Lefamulin, an antibiotic for community-acquired pneumonia (CAP), demonstrated significant immune-modulatory and anti-inflammatory effects in an influenza A/H1N1 model. It reduced lung immune cell infiltration and pro-inflammatory cytokines, suggesting benefits beyond antibacterial action.
Area of Science:
- Pharmacology
- Immunology
- Infectious Diseases
Background:
- Lefamulin is a novel systemic pleuromutilin antimicrobial approved for community-acquired pneumonia (CAP).
- Early studies suggested lefamulin possesses anti-inflammatory properties.
- The current study investigated lefamulin's immune-modulatory activity in an influenza A/H1N1-induced acute respiratory distress syndrome (ARDS) mouse model.
Purpose of the Study:
- To evaluate the immune-modulatory and anti-inflammatory effects of lefamulin.
- To compare lefamulin's effects with azithromycin and oseltamivir in an influenza A/H1N1 ARDS model.
- To assess lefamulin's impact on viral load, lung pathology, and survival.
Main Methods:
- An influenza A/H1N1 acute respiratory distress syndrome (ARDS) model was established in BALB/c mice.
- Mice were treated with lefamulin, azithromycin, or oseltamivir.
- Immune cell infiltration in the lungs, bronchioalveolar lavage fluid cytokine/chemokine concentrations, viral load, lung pathology, and survival rates were assessed.
Main Results:
- Lefamulin significantly reduced total immune cell infiltration (neutrophils, monocytes, T-cells, NK cells, B-cells) in the lungs.
- Lefamulin decreased pro-inflammatory cytokines (TNF-α, IL-6, IL-12p70, IL-17A, IFN-γ) and chemokines in bronchioalveolar lavage fluid.
- Lefamulin reduced viral load, improved gross lung pathology, and enhanced survival, outperforming azithromycin in reducing lung pathology.
Conclusions:
- Lefamulin exhibits significant anti-inflammatory and immune-modulatory activities in an influenza A/H1N1 ARDS mouse model.
- These findings suggest lefamulin may offer therapeutic benefits beyond its antibacterial properties for CAP patients.
- Lefamulin's immune-modulatory effects could potentially help prevent acute lung injury (ALI) and ARDS.
