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In the present study, the therapeutic potential of these drugs against pneumonic plague in mice was further evaluated when they were administered at up to 48 h postinfection. While the efficacy of TFP was somewhat diminished as treatment was delayed to 24 h, the protection of mice with AXPN and DXP increased as treatment was progressively delayed to 24 h. At 48 h postinfection, these drugs provided the animals with significant protection (up to 100%) against challenge with the agent of pneumonic or bubonic plague when they were administered in combination with levofloxacin. Likewise, when they were used in combination with vancomycin, all three drugs provided mice with 80 to 100% protection from fatal oral\n            <jats:named-content content-type=\"genus-species\">Clostridium difficile<\/jats:named-content>\n            infection when they were administered at 24 h postinfection. Furthermore, AXPN provided 40 to 60% protection against respiratory infection with\n            <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n            when it was administered at the time of infection or at 24 h postinfection. Using the same\n            <jats:italic>in vitro<\/jats:italic>\n            cytotoxicity assay, we identified an additional 76\/780 nonantibiotic drugs effective against\n            <jats:named-content content-type=\"genus-species\">K. pneumoniae<\/jats:named-content>\n            . For\n            <jats:named-content content-type=\"genus-species\">Acinetobacter baumannii<\/jats:named-content>\n            , 121 nonantibiotic drugs were identified to inhibit bacterium-induced cytotoxicity in murine macrophages. Of these 121 drugs, 13 inhibited the macrophage cytotoxicity induced by two additional multiple-antibiotic-resistant strains. Six of these drugs decreased the intracellular survival of all three\n            <jats:named-content content-type=\"genus-species\">A. baumannii<\/jats:named-content>\n            strains in macrophages. These results provided further evidence of the broad applicability and utilization of drug repurposing screening to identify new therapeutics to combat multidrug-resistant pathogens of public health concern.\n          <\/jats:p>","DOI":"10.1128\/aac.01943-17","type":"journal-article","created":{"date-parts":[[2017,11,6]],"date-time":"2017-11-06T16:30:27Z","timestamp":1509985827000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":30,"title":["Combating Multidrug-Resistant Pathogens with Host-Directed Nonantibiotic Therapeutics"],"prefix":"10.1128","volume":"62","author":[{"given":"Jourdan A.","family":"Andersson","sequence":"first","affiliation":[{"name":"Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Sha","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Kirtley","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Reyes","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Fitts","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara M.","family":"Dann","sequence":"additional","affiliation":[{"name":"Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok K.","family":"Chopra","sequence":"additional","affiliation":[{"name":"Institute for Translational Sciences, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"WHO Collaborating Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA"},{"name":"Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","volume-title":"Antibiotic\/antimicrobial resistance","author":"CDC","year":"2013","unstructured":"CDC. 2013. 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