Abstract
Pulmonary infections caused by nontuberculous mycobacteria (NTM) are an increasing problem in individuals with chronic lung conditions and current therapies are lacking. We investigated the activity of liposomal amikacin for inhalation (LAI) against NTM in vitro as well as in a murine model of respiratory infection. Macrophage monolayers were infected with three strains of Mycobacterium avium, two strains of Mycobacterium abscessus, and exposed to LAI or free amikacin for 4 days before enumerating bacterial survival. Respiratory infection was established in mice by intranasal inoculation with M. avium and allowing three weeks for the infection to progress. Three different regimens of inhaled LAI were compared to inhaled saline and parenterally administered free amikacin over a 28 day period. Bacteria recovered from the mice were analyzed for acquired resistance to amikacin. In vitro, liposomal amikacin for inhalation was more effective than free amikacin in eliminating both intracellular M. avium and M. abscessus. In vivo, inhaled LAI demonstrated similar effectiveness to a ∼25% higher total dose of parenterally administered amikacin at reducing M. avium in the lungs when compared to inhaled saline. Additionally, there was no acquired resistance to amikacin observed after the treatment regimen. The data suggest that LAI has the potential to be an effective therapy against NTM respiratory infections in humans.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Inhalation
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Aerosols
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Amikacin / administration & dosage*
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Amikacin / pharmacology
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Amikacin / therapeutic use*
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Animals
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Antitubercular Agents / administration & dosage
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Antitubercular Agents / pharmacology
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Antitubercular Agents / therapeutic use*
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Cell Line
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Colony Count, Microbial
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Disease Models, Animal
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Drug Delivery Systems*
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Drug Resistance, Bacterial / drug effects
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Female
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Humans
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Intracellular Space / microbiology
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Liposomes
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Lung / drug effects
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Lung / microbiology
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Lung / pathology
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Mice, Inbred C57BL
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Microbial Sensitivity Tests
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Mycobacterium Infections, Nontuberculous / drug therapy*
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Mycobacterium Infections, Nontuberculous / microbiology
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Mycobacterium Infections, Nontuberculous / pathology
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Nontuberculous Mycobacteria / drug effects*
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Nontuberculous Mycobacteria / isolation & purification
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Respiratory Tract Infections / drug therapy*
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Respiratory Tract Infections / microbiology
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Respiratory Tract Infections / pathology
Substances
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Aerosols
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Antitubercular Agents
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Liposomes
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Amikacin
Grants and funding
This study was funded by Insmed. Co-authors MEN and RG are employed by Insmed. The funder provided support in the form of salaries for authors MEN and RG, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.