{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:30:14Z","timestamp":1783575014276,"version":"3.55.0"},"reference-count":34,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Insmed Incorporated"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The increased prevalence of pulmonary methicillin-resistant Staphylococcus aureus (MRSA) infection in patients living with cystic fibrosis (CF) is concerning due to a correlation with reduced life expectancy and lack of available treatment options. RV94 is a next generation lipoglycopeptide designed for pulmonary delivery that preclinically demonstrated high potency against MRSA in planktonic and protected colonies and improved pulmonary clearance relative to same class molecules. Here, RV94 was formulated into a dry powder for inhalation (DPI) to investigate the localized treatment of pulmonary MRSA presented in a potentially more convenient dosage form. RV94 DPI was generated using a spray-drying process with 12.5 wt% trileucine and demonstrated aerosol characteristics (2.0 \u03bcm MMAD and 73% FPF) predictive of efficient pulmonary deposition. In vivo PK from a single dose of RV94 DPI delivered by inhalation to rats yielded lung levels (127 \u03bcg\/g) much greater than the MRSA minimum inhibitory concentration (0.063 \u03bcg\/mL), low systemic levels (0.1 \u03bcg\/mL), and a lung t1\/2 equal to 3.5 days. In a rat acute pulmonary MRSA model, a single dose of RV94 DPI delivered by inhalation either up to seven days prior to or 24 h after infection resulted in a statistically significant reduction in lung MRSA titer.<\/jats:p>","DOI":"10.3390\/pharmaceutics15092250","type":"journal-article","created":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T09:42:53Z","timestamp":1693474973000},"page":"2250","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Preclinical Investigation of a Lipoglycopeptide Dry Powder Inhalation Therapy for the Treatment of Pulmonary MRSA Infection"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6167-9043","authenticated-orcid":false,"given":"Donna M.","family":"Konicek","sequence":"first","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5341-6411","authenticated-orcid":false,"given":"Adam J.","family":"Plaunt","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachin","family":"Gharse","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasha J.","family":"Rose","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arielle","family":"Dorfman","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amruta","family":"Sabnis","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Baker","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Gauani","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald","family":"Chun","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhili","family":"Li","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter R.","family":"Perkins","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5773-4721","authenticated-orcid":false,"given":"David","family":"Cipolla","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6496-2968","authenticated-orcid":false,"given":"Vladimir S.","family":"Malinin","sequence":"additional","affiliation":[{"name":"Insmed Incorporated, Bridgewater, NJ 08807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1128\/CMR.15.2.194-222.2002","article-title":"Lung Infections Associated with Cystic Fibrosis","volume":"15","author":"Lyczak","year":"2002","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1126\/science.aad5589","article-title":"Airway acidification initiates host defense abnormalities in cystic fibrosis mice","volume":"351","author":"Shah","year":"2016","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1001\/jama.2010.791","article-title":"Association Between Respiratory Tract Methicillin-Resistant Staphylococcus aureus and Survival in Cystic Fibrosis","volume":"303","author":"Dasenbrook","year":"2010","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jcf.2011.08.006","article-title":"Prevalence and impact on FEV1 decline of chronic methicillin-resistant Staphylococcus aureus (MRSA) colonization in patients with Cystic Fibrosis. A single-center, case control study of 165 patients","volume":"11","author":"Vanderhelst","year":"2012","journal-title":"J. Cyst. Fibros."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e01776-19","DOI":"10.1128\/AAC.01776-19","article-title":"Phase I, Dose-Escalating Study of the Safety and Pharmacokinetics of Inhaled Dry-Powder Vancomycin (AeroVanc) in Volunteers and Patients with Cystic Fibrosis: A New Approach to Therapy for Methicillin-Resistant Staphylococcus aureus","volume":"64","author":"Waterer","year":"2020","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJM199901073400104","article-title":"Intermittent Administration of Inhaled Tobramycin in Patients with Cystic Fibrosis. Cystic Fibrosis Inhaled Tobramycin Study Group","volume":"340","author":"Ramsey","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1089\/jamp.2010.0855","article-title":"Development of an Inhaled Dry-Powder Formulation of Tobramycin Using PulmoSphere\u2122 Technology","volume":"24","author":"Geller","year":"2011","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.4137\/CCRPM.S10592","article-title":"Tobramycin Inhalation Powder (TIP): An Efficient Treatment Strategy for the Management of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis","volume":"7","author":"Lam","year":"2013","journal-title":"Clin. Med. Insights Circ. Respir. Pulm. Med."},{"key":"ref_9","unstructured":"(2021, December 10). Cystic Fibrosis Foundation. Available online: https:\/\/www.cff.org\/Trials\/Finder\/details\/466\/Phase-3-study-of-inhaled-vancomycin-in-adults-and-children-6-years-and-older-with-cystic-fibrosis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.jcf.2018.07.005","article-title":"Eradication of persistent methicillin-resistant Staphylococcus aureus infection in cystic fibrosis","volume":"18","author":"Dezube","year":"2019","journal-title":"J. Cyst. Fibros."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S64","DOI":"10.1002\/ppul.24139","article-title":"Biology and management of methicillin resistant Staphylococcus aureus in cystic fibrosis","volume":"53","author":"Akil","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/nature16057","article-title":"Novel antibody-antibiotic conjugate eliminates intracellular S. aureus","volume":"527","author":"Lehar","year":"2015","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e0031621","DOI":"10.1128\/AAC.00316-21","article-title":"Development and Preclinical Evaluation of New Inhaled Lipoglycopeptides for the Treatment of Persistent Pulmonary Methicillin-Resistant Staphylococcus aureus Infections","volume":"65","author":"Plaunt","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"105898","DOI":"10.1016\/j.ijantimicag.2020.105898","article-title":"Activity of pulmonary vancomycin exposures versus planktonic and biofilm isolates of methicillin-resistant Staphylococcus aureus from cystic fibrosis sputum","volume":"55","author":"Britt","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_15","first-page":"49","article-title":"Telavancin: A novel semisynthetic lipoglycopeptide agent to counter the challenge of resistant Gram-positive pathogens","volume":"4","author":"Das","year":"2017","journal-title":"Ther. Adv. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1128\/AAC.49.10.4344-4346.2005","article-title":"Efficacy of telavancin (TD-6424), a rapidly bactericidal lipoglycopeptide with multiple mechanisms of action, in a murine model of pneumonia induced by methicillin-resistant Staphylococcus aureus","volume":"49","author":"Reyes","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2073","DOI":"10.1007\/s40265-015-0505-8","article-title":"Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review","volume":"75","year":"2015","journal-title":"Drugs"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"187","DOI":"10.5414\/CN109651","article-title":"Telavancin-associated acute kidney injury","volume":"91","author":"Cavanaugh","year":"2019","journal-title":"Clin. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"326","DOI":"10.7164\/antibiotics.57.326","article-title":"Hydrophobic Vancomycin Derivatives with Improved ADME Properties: Discovery of Telavancin (TD-6424)","volume":"57","author":"Leadbetter","year":"2004","journal-title":"J. Antibiot."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/jac\/dkr518","article-title":"Acute renal insufficiency during telavancin therapy in clinical practice","volume":"67","author":"Marcos","year":"2012","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.jcf.2008.09.007","article-title":"High treatment burden in adults with cystic fibrosis: Challenges to disease self-management","volume":"8","author":"Sawicki","year":"2009","journal-title":"J. Cyst. Fibros."},{"key":"ref_22","unstructured":"United States Pharmacopeia and National Formulary (USP 43-NF 38) (2012). <601> Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders-Performance Quality Tests, United States Pharmacopeia."},{"key":"ref_23","unstructured":"European Pharmacopoeia (2008). 2.9.18. Preparations for Inhalation: Aerodynamic Assessment of Fine Particles, Monograph 20918, European Pharmacopoeia."},{"key":"ref_24","unstructured":"(2018). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria (Standard No. CLSI Standard M11). Approved Standard."},{"key":"ref_25","unstructured":"(2017). Performance Standards for Antimicrobial Susceptibility Testing (Standard No. CLSI Supplement M100)."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1080\/08958370802207318","article-title":"Association of Inhalation Toxicologists (AIT) Working Party Recommendation for Standard Delivered Dose Calculation and Expression in Non-Clinical Aerosol Inhalation Toxicology Studies with Pharmaceuticals","volume":"20","author":"Alexander","year":"2008","journal-title":"Inhal. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1023\/A:1023228925137","article-title":"Estimation of Confidence Intervals for Area Under the Curve from Destructively Obtained Pharmacokinetic Data","volume":"26","author":"Gagnon","year":"1998","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1002\/jps.21078","article-title":"Trileucine Improves Aerosol Performance and Stability of Spray-Dried Powders for Inhalation","volume":"97","author":"Charan","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1080\/17425247.2020.1702643","article-title":"Physical stability of dry powder inhaler formulations","volume":"17","author":"Shetty","year":"2020","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5475","DOI":"10.2147\/IJN.S34091","article-title":"New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis","volume":"7","author":"Duret","year":"2012","journal-title":"Int. J. Nanomed."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.ijmm.2013.09.012","article-title":"Extended Staphylococcus aureus persistence in cystic fibrosis is associated with bacterial adaptation","volume":"303","author":"Hirschhausen","year":"2013","journal-title":"Int. J. Med. Microbiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1086\/590157","article-title":"Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia","volume":"198","author":"Montgomery","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1099\/00222615-48-11-1005","article-title":"Factors affecting the course and severity of transnasally induced Staphylococcus aureus pneumonia in mice","volume":"48","author":"Kimura","year":"1999","journal-title":"J. Med. Microbiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1128\/iai.21.1.114-123.1978","article-title":"Pulmonary Infection of Mice with Staphylococcus aureus","volume":"21","author":"DeMaria","year":"1978","journal-title":"Infect. Immun."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/9\/2250\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:43:33Z","timestamp":1760129013000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/9\/2250"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,31]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["pharmaceutics15092250"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15092250","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,31]]}}}