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We investigated the activity of various antibiotics in combination with polymyxin B using time-kill studies (TKS). TKS were conducted with four nonclonal XDR<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. cloacae<\/jats:named-content>isolates with 5 log<jats:sub>10<\/jats:sub>CFU\/ml bacteria against maximum, clinically achievable concentrations of polymyxin B alone and in two-drug combinations with 10 different antibiotics. A hollow-fiber infection model (HFIM) simulating clinically relevant polymyxin B and tigecycline dosing regimens was conducted for two isolates over 240 h. Emergence of resistance was quantified using antibiotic-containing (3\u00d7 MIC) media. Biofitness and stability of resistant phenotypes were determined. All XDR<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. cloacae<\/jats:named-content>isolates were resistant to all antibiotics except for polymyxin B (polymyxin B MIC, 1 to 4 mg\/liter). All isolates harbored metallo-\u03b2-lactamases (two with NDM-1, two with IMP-1). In single TKS, all antibiotics alone demonstrated regrowth at 24 h, except amikacin against two strains and polymyxin B and meropenem against one strain each. In combination TKS, only polymyxin B plus tigecycline was bactericidal against all four XDR<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. cloacae<\/jats:named-content>isolates at 24 h. In HFIM, tigecycline and polymyxin B alone did not exhibit any killing activity. Bactericidal kill was observed at 24 h for both isolates for polymyxin B plus tigecycline; killing was sustained for one isolate but regrowth was observed for the second. Phenotypically stable resistant mutants with reduced<jats:italic>in vitro<\/jats:italic>growth rates were observed. Polymyxin B plus tigecycline is a promising combination against XDR<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">E. cloacae<\/jats:named-content>. However, prolonged and indiscriminate use can result in resistance emergence.<\/jats:p>","DOI":"10.1128\/aac.00270-16","type":"journal-article","created":{"date-parts":[[2016,6,22]],"date-time":"2016-06-22T03:08:33Z","timestamp":1466564913000},"page":"5238-5246","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["<i>In Vitro<\/i>Activity of Polymyxin B in Combination with Various Antibiotics against Extensively Drug-Resistant Enterobacter cloacae with Decreased Susceptibility to Polymyxin B"],"prefix":"10.1128","volume":"60","author":[{"given":"Yiying","family":"Cai","sequence":"first","affiliation":[{"name":"Singapore General Hospital, Department of Pharmacy, Singapore"},{"name":"National University of Singapore, Department of Pharmacy, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tze-Peng","family":"Lim","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Pharmacy, Singapore"},{"name":"Duke-NUS Medical School, Office of Clinical Sciences, Singapore, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2508-3941","authenticated-orcid":false,"given":"Jocelyn","family":"Teo","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Pharmacy, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suranthran","family":"Sasikala","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Pharmacy, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Winnie","family":"Lee","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Pharmacy, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Hong","sequence":"additional","affiliation":[{"name":"National University of Singapore, Department of Pharmacy, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric Chun Yong","family":"Chan","sequence":"additional","affiliation":[{"name":"National University of Singapore, Department of Pharmacy, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thean Yen","family":"Tan","sequence":"additional","affiliation":[{"name":"Changi General Hospital, Department of Laboratory Medicine, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuan-Tong","family":"Tan","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Infectious Diseases, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tse Hsien","family":"Koh","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Pathology, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li Yang","family":"Hsu","sequence":"additional","affiliation":[{"name":"National University of Singapore, Yong Loo Lin School of Medicine, Department of Medicine, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea L.","family":"Kwa","sequence":"additional","affiliation":[{"name":"Singapore General Hospital, Department of Pharmacy, Singapore"},{"name":"National University of Singapore, Department of Pharmacy, Singapore"},{"name":"Duke-NUS Medical School, Emerging Infectious Diseases, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.03.003"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.2165\/11597960-000000000-00000"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cir202"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/595011"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"870","DOI":"10.47102\/annals-acadmedsg.V37N10p870","article-title":"Polymyxins: a review of the current status including recent developments","volume":"37","author":"Kwa AL","year":"2008","unstructured":"Kwa AL, Tam VH, Falagas ME. 2008. 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