30
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Delivery of Aerosolized Liposomal Amikacin as a Novel Approach for the Treatment of Nontuberculous Mycobacteria in an Experimental Model of Pulmonary Infection

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references22

          • Record: found
          • Abstract: found
          • Article: not found

          A novel gene, erm(41), confers inducible macrolide resistance to clinical isolates of Mycobacterium abscessus but is absent from Mycobacterium chelonae.

          Mycobacterium abscessus infections tend to respond poorly to macrolide-based chemotherapy, even though the organisms appear to be susceptible to clarithromycin. Circumstantial evidence suggested that at least some M. abscessus isolates might be inducibly resistant to macrolides. Thus, the purpose of this study was to investigate the macrolide phenotype of M. abscessus clinical isolates. Inducible resistance to clarithromycin (MIC > 32 microg/ml) was found for 7 of 10 clinical isolates of M. abscessus previously considered susceptible; the remaining 3 isolates were deemed to be susceptible (MIC
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Nontuberculous mycobacterial pulmonary infections.

            Pulmonary infections due to nontuberculous mycobacteria (NTM) are increasingly recognized worldwide. Although over 150 different species of NTM have been described, pulmonary infections are most commonly due to Mycobacterium avium complex (MAC), Mycobacterium kansasii, and Mycobacterium abscessus. The identification of these organisms in pulmonary specimens does not always equate with active infection; supportive radiographic and clinical findings are needed to establish the diagnosis. It is difficult to eradicate NTM infections. A prolonged course of therapy with a combination of drugs is required. Unfortunately, recurrent infection with new strains of mycobacteria or a relapse of infection caused by the original organism is not uncommon. Surgical resection is appropriate in selected cases of localized disease or in cases in which the infecting organism is resistant to medical therapy. Additionally, surgery may be required for infections complicated by hemoptysis or abscess formation. This review will summarize the practical aspects of the diagnosis and management of NTM thoracic infections, with emphasis on the indications for surgery and the results of surgical intervention. The management of NTM disease in patients with human immunodeficiency virus (HIV) infections is beyond the scope of this article and, unless otherwise noted, comments apply to hosts without HIV infection.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections.

              Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients are intractable antibiotic targets because of their biofilm mode of growth. We have investigated the biofilm penetration, mechanism of drug release and in vivo antimicrobial activity of a unique nanoscale liposomal formulation of amikacin designed specifically for nebulization and inhaled delivery. Penetration of fluorescently labelled liposomes into sputum or P. aeruginosa (PA3064) biofilms was monitored by a filter assay and by epifluorescence or confocal scanning laser microscopy. Amikacin release in vitro and rat lung levels after inhalation of nebulized material were measured by fluorescence polarization immunoassay. A 14 day agar bead model of chronic Pseudomonas lung infection in rats was used to assess the efficacy of liposomal amikacin versus free aminoglycosides in the reduction of bacterial count. Fluorescent liposomes penetrated readily into biofilms and infected mucus, whereas larger (1 microm) fluorescent beads did not. Amikacin release from liposomes was mediated by sputum or Pseudomonas biofilm supernatants. Rhamnolipids were implicated as the major releasing factors in these supernatants, active at one rhamnolipid per several hundred lipids within the liposomes. Inhaled liposomal amikacin was released in a slow, sustained manner in normal rat lungs and was orders of magnitude more efficacious than inhaled free amikacin in infected lungs. Penetration of biofilm and targeted, sustained release from liposomes can explain the superior in vivo efficacy of inhaled liposomal amikacin versus free drug observed in a 14 day infection model. Inhaled liposomal amikacin may represent an important therapy for chronic lung infections.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                29 September 2014
                : 9
                : 9
                : e108703
                Affiliations
                [1 ]Department of Biomedical Sciences, Oregon State University, Corvallis, Oregon, United States of America
                [2 ]Department of Microbiology, Oregon State University, Corvallis, Oregon, United States of America
                [3 ]Insmed Incorporated, Monmouth Junction, New Jersey, United States of America
                University of Lausanne, Switzerland
                Author notes

                Competing Interests: We have the following interests: co-authors MEN and RG are employed by Insmed Incorporated. This study was funded by Insmed. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLoS ONE policies on sharing data and materials.

                Conceived and designed the experiments: SR LEB. Performed the experiments: SR MN LEB. Analyzed the data: SR LEB. Contributed reagents/materials/analysis tools: MN RG. Wrote the paper: SR LEB. Helped with the delivery the aerosol preparations to the animal's lungs: MN. Provided the drug preparation: MN RG.

                Article
                PONE-D-14-13823
                10.1371/journal.pone.0108703
                4180930
                25264757
                4b4d481a-8a0b-4d75-8ea8-efc1c6693de7
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 27 March 2014
                : 12 August 2014
                Page count
                Pages: 7
                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.
                Categories
                Research Article
                Medicine and Health Sciences
                Infectious Diseases
                Pharmacology
                Pulmonology
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

                Uncategorized
                Uncategorized

                Comments

                Comment on this article