{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:11:50Z","timestamp":1760227910888,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,30]],"date-time":"2022-04-30T00:00:00Z","timestamp":1651276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nanova Inc.","award":["R01HL138988","K99\/R00HL121152"],"award-info":[{"award-number":["R01HL138988","K99\/R00HL121152"]}]},{"name":"Droplette Inc.","award":["R01HL138988","K99\/R00HL121152"],"award-info":[{"award-number":["R01HL138988","K99\/R00HL121152"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Wound infection by multidrug-resistant (MDR) bacteria is a major disease burden. Systemic administration of broad-spectrum antibiotics colistin methanesulfonate (CMS) and vancomycin are the last lines of defense against deep wound infections by MDR bacteria. However, systemic administration of CMS and vancomycin are linked to life-threatening vital organ damage. Currently there are no effective topical application strategies to deliver these high molecular weight antibiotics across the stratum corneum. To overcome this difficulty, we tested if high molecular weight antibiotics delivered by Droplette micromist technology device (DMTD), a transdermal delivery device that generates a micromist capable of packaging large molecules, could attenuate deep skin tissue infections. Using green fluorescent protein-tagged E. coli and live tissue imaging, we show that (1) the extent of attenuation of deep-skin E. coli infection was similar when treated with topical DMTD- or systemic IP (intraperitoneal)-delivered CMS; (2) DMTD-delivered micromist did not spread the infection deeper; (3) topical DMTD delivery and IP delivery resulted in similar levels of vancomycin in the skin after a 2 h washout period; and (4) IP-delivered vancomycin was about 1000-fold higher in kidney and plasma than DMTD-delivered vancomycin indicating systemic toxicity. Thus, topical DMTD delivery of these antibiotics is a safe treatment for the difficult-to-treat deep skin tissue infections by MDR bacteria.<\/jats:p>","DOI":"10.3390\/pharmaceutics14050976","type":"journal-article","created":{"date-parts":[[2022,5,2]],"date-time":"2022-05-02T07:08:58Z","timestamp":1651475338000},"page":"976","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Transdermal Delivery of High Molecular Weight Antibiotics to Deep Tissue Infections via Droplette Micromist Technology Device (DMTD)"],"prefix":"10.3390","volume":"14","author":[{"given":"Lakshmi","family":"Pulakat","sequence":"first","affiliation":[{"name":"Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA 02111, USA"},{"name":"School of Medicine, Tufts University, Boston, MA 02111, USA"},{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5145-0584","authenticated-orcid":false,"given":"Howard H.","family":"Chen","sequence":"additional","affiliation":[{"name":"Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA 02111, USA"},{"name":"School of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhavi P.","family":"Gavini","sequence":"additional","affiliation":[{"name":"Droplette Inc., Boston, MA 02108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren A.","family":"Ling","sequence":"additional","affiliation":[{"name":"Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA 02111, USA"},{"name":"School of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4472-6570","authenticated-orcid":false,"given":"Yinian","family":"Tang","sequence":"additional","affiliation":[{"name":"Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Mehm","sequence":"additional","affiliation":[{"name":"Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregory L.","family":"Martin","sequence":"additional","affiliation":[{"name":"Tufts Medical Center, Molecular Cardiology Research Institute, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinna N.","family":"Beale","sequence":"additional","affiliation":[{"name":"School of Medicine, Tufts University, Boston, MA 02111, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian P.","family":"Mooney","sequence":"additional","affiliation":[{"name":"Charles W. Gehrke Proteomics Center, Division of Biochemistry, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4545-2417","authenticated-orcid":false,"given":"Hongmin","family":"Sun","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Department of Medicine, University of Missouri, Columbia, MO 65211, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S397","DOI":"10.1093\/cid\/cir153","article-title":"Combating antimicrobial resistance: Policy recommendations to save lives","volume":"52","author":"Spellberg","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.idc.2016.02.004","article-title":"Multidrug-Resistant Bacteria in the Community: Trends and Lessons Learned","volume":"30","author":"Paterson","year":"2016","journal-title":"Infect. Dis. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S69","DOI":"10.1093\/cid\/civ528","article-title":"Skin and soft-tissue infections: A critical review and the role of telavancin in their treatment","volume":"61","author":"Cardona","year":"2015","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.3389\/fmicb.2017.02409","article-title":"Combination Strategies to Enhance the Efficacy of Antimicrobial Peptides against Bacterial Biofilms","volume":"8","author":"Grassi","year":"2017","journal-title":"Front. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.pcl.2013.06.011","article-title":"Skin and soft tissue infections","volume":"60","author":"Mistry","year":"2013","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1111\/j.1468-3083.2011.04416.x","article-title":"Bacterial skin and soft tissue infections: Review of the epidemiology, microbiology, aetiopathogenesis and treatment: A collaboration between dermatologists and infectivologists","volume":"26","author":"Tognetti","year":"2012","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e10","DOI":"10.1093\/cid\/ciu296","article-title":"Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America","volume":"59","author":"Stevens","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1586\/eri.12.78","article-title":"Colistin: An update on the antibiotic of the 21st century","volume":"10","author":"Biswas","year":"2012","journal-title":"Expert Rev. Anti-Infect. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1086\/429323","article-title":"Colistin: The revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections","volume":"40","author":"Falagas","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1097\/QCO.0b013e328332e672","article-title":"Colistin in the 21st century","volume":"22","author":"Nation","year":"2009","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"291","DOI":"10.4103\/0974-777X.68538","article-title":"Multidrug resistant acinetobacter","volume":"2","author":"Manchanda","year":"2010","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1034\/j.1600-0625.2000.009003165.x","article-title":"The 500 Dalton rule for the skin penetration of chemical compounds and drugs","volume":"9","author":"Bos","year":"2000","journal-title":"Exp. Dermatol."},{"key":"ref_13","first-page":"3968690","article-title":"Systemic Toxicity of Intraperitoneal Vancomycin","volume":"2016","author":"Kumar","year":"2016","journal-title":"Case Rep. Nephrol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1345\/aph.1G668","article-title":"Vancomycin-induced elevation of liver enzyme levels","volume":"40","author":"Cadle","year":"2006","journal-title":"Ann. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1177\/1060028017720946","article-title":"Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients with Class III Obesity","volume":"51","author":"Choi","year":"2017","journal-title":"Ann. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1007\/s00228-012-1259-9","article-title":"Vancomycin-induced nephrotoxicity: Mechanism, incidence, risk factors and special populations","volume":"68","author":"Elyasi","year":"2012","journal-title":"Lit. Rev. Eur. J. Clin. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1007\/s00228-015-1865-4","article-title":"A review on colistin nephrotoxicity","volume":"71","author":"Javan","year":"2015","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1086\/600877","article-title":"Vancomycin therapeutic guidelines: A summary of consensus recommendations from the infectious diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists","volume":"49","author":"Rybak","year":"2009","journal-title":"Clin. Infect. Dis."},{"key":"ref_19","first-page":"565","article-title":"Dosing guidance for intravenous colistin in critically-ill patients","volume":"64","author":"Nation","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1093\/cid\/civ964","article-title":"Updated US and European Dose Recommendations for Intravenous Colistin: How Do They Perform?","volume":"62","author":"Nation","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/978-1-0716-1811-0_14","article-title":"Droplette: A Platform Technology to Directly Deliver Nucleic Acid Therapeutics and Other Molecules into Cells and Deep into Tissue Without Transfection Reagents","volume":"2394","author":"Quek","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1111\/j.1067-1927.2004.12601.x","article-title":"Rat models of skin wound healing: A review","volume":"12","year":"2004","journal-title":"Wound Repair Regen."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1002\/ar.23458","article-title":"Dermal Fibroblasts from Different Layers of Pig Skin Exhibit Different Profibrotic and Morphological Characteristics","volume":"299","author":"Zuo","year":"2016","journal-title":"Anat. Rec."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"32074","DOI":"10.1038\/srep32074","article-title":"A micromechanical comparison of human and porcine skin before and after preservation by freezing for medical device development","volume":"6","author":"Ranamukhaarachchi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.molimm.2014.10.023","article-title":"The immunology of the porcine skin and its value as a model for human skin","volume":"66","author":"Summerfield","year":"2015","journal-title":"Mol. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.cca.2014.12.012","article-title":"Novel LC-MS\/MS method for plasma vancomycin: Comparison with immunoassays and clinical impact","volume":"441","author":"Oyaert","year":"2015","journal-title":"Clin. Chim. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1136\/ejhpharm-2016-001128","article-title":"Colistin methanesulfonate infusion solutions are stable over time and suitable for home administration","volume":"25","author":"Post","year":"2018","journal-title":"Eur. J. Hosp. Pharm."},{"key":"ref_28","first-page":"694","article-title":"The use of vancomycin with its therapeutic and adverse effects: A review","volume":"19","author":"Bruniera","year":"2015","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_29","unstructured":"(2022, March 14). Pfizer, Vancomycin Hydrochloride for Injection, USP p. Available online: https:\/\/labeling.pfizer.com\/ShowLabeling.aspx?id=4647."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1093\/toxsci\/kfn203","article-title":"Gene expression analysis reveals new possible mechanisms of vancomycin-induced nephrotoxicity and identifies gene markers candidates","volume":"107","author":"Dieterich","year":"2009","journal-title":"Toxicol. Sci. Off. J. Soc. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1248\/bpb.b16-00932","article-title":"Time-Dependent Alterations of Vancomycin-Induced Nephrotoxicity in Mice","volume":"40","author":"Takigawa","year":"2017","journal-title":"Biol. Pharm. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"208","DOI":"10.4103\/0022-3859.118040","article-title":"Colistin: Re-emergence of the \u2018forgotten\u2019 antimicrobial agent","volume":"59","author":"Dhariwal","year":"2013","journal-title":"J. Postgrad. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1517\/13543784.17.7.973","article-title":"Re-emergence of colistin in today\u2019s world of multidrug-resistant organisms: Personal perspectives","volume":"17","author":"Falagas","year":"2008","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S206","DOI":"10.1093\/cid\/ciz004","article-title":"Current Treatment Options for Acute Skin and Skin-structure Infections","volume":"68","author":"Golan","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1097\/ICO.0000000000000184","article-title":"Use of topical colistin in multiple drug-resistant Pseudomonas aeruginosa bacterial keratitis","volume":"33","author":"Jain","year":"2014","journal-title":"Cornea"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/5\/976\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:05:23Z","timestamp":1760137523000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/5\/976"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,30]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["pharmaceutics14050976"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14050976","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2022,4,30]]}}}