{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:39:31Z","timestamp":1786977571473,"version":"build-2736575974"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,4]]},"abstract":"<jats:p>\n                    Mounting antimicrobial resistance to carbapenemase\u2010producing\n                    <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    (CPKP) highlights the need to optimize currently available treatment options. The objective of this study was to explore alternative dosing strategies that limit the emergence of resistance to preserve the utility of last\u2010line antibiotics by: (i) evaluating the pharmacodynamic (PD) killing activity of simulated humanized exposures to monotherapy and two\u2010drug and three\u2010drug combinations against CPKP bacterial isolates with different resistance mechanisms; and (ii) optimizing polymyxin B (PMB) exposure simulated in the three\u2010drug combination regimens to maximize the killing activity. Two CPKP clinical isolates (BAA2146 (NDM\u20101) and BRKP76 (KPC\u20102)) were evaluated over 168\u00a0hours using a hollow\u2010fiber infection model simulating clinically relevant PMB, fosfomycin, and meropenem dosing regimens. PMB\u2010based three\u2010drug combinations were further optimized by varying the initial exposure (0\u201324\u00a0hours) or maintenance dose received over the duration of treatment. The area under the bacterial load\u2010versus\u2010time curve (AUCFU) was used to determine PD activity. Overall reductions in PMB exposure ranged from 2 to 84%. BAA2146 and BRKP76 had median (range) AUCFUs of 11.0 (10.6\u201311.6) log\n                    <jats:sub>10\u00a0<\/jats:sub>\n                    CFU\u00a0hour\/mL and 7.08 (7.04\u201311.9) log\n                    <jats:sub>10<\/jats:sub>\n                    CFU hour\/mL, respectively. The PMB \u201cfront loaded\u201d 2.5\u00a0mg\/kg\/day\u00a0+\u00a00.5\u00a0mg\/kg maintenance dose in combination with meropenem and fosfomycin was a promising regimen against BRKP76, with an overall reduction in PMB exposure of 56% while still eradicating the bacteria. Tailored triple\u2010combination therapy allows for the optimization of dose and treatment duration of last\u2010line agents like PMB to achieve adequate drug exposure and appropriate PD activity while minimizing the emergence of resistance.\n                  <\/jats:p>","DOI":"10.1002\/cpt.2197","type":"journal-article","created":{"date-parts":[[2021,2,6]],"date-time":"2021-02-06T11:37:25Z","timestamp":1612611445000},"page":"1074-1080","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Evaluation Strategies for Triple\u2010Drug Combinations against Carbapenemase\u2010Producing\n                    <i>Klebsiella Pneumoniae<\/i>\n                    in an\n                    <i>In Vitro<\/i>\n                    Hollow\u2010Fiber Infection Model"],"prefix":"10.1111","volume":"109","author":[{"given":"Estefany","family":"Garcia","sequence":"first","affiliation":[{"name":"UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John K.","family":"Diep","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajnikant","family":"Sharma","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick O.","family":"Hanafin","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cely S.","family":"Abboud","sequence":"additional","affiliation":[{"name":"Instituto Dante Pazzanese de Cardiologia S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith S.","family":"Kaye","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases Department of Internal Medicine University of Michigan Medical School Ann Arbor Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Li","sequence":"additional","affiliation":[{"name":"Biomedicine Discovery Institute Department of Microbiology Monash University Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Velkov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics The University of Melbourne Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gauri G.","family":"Rao","sequence":"additional","affiliation":[{"name":"UNC Eshelman School of Pharmacy University of North Carolina Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.05035-11"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofy347"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiw282"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciy492"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw636"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky082"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00989-17"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00537-17"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02097-16"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025239"},{"key":"e_1_2_9_11_1","first-page":"297","article-title":"Impact of the New Delhi metallo\u2010beta\u2010lactamase on beta\u2010lactam antibiotics","volume":"8","author":"Zmarlicka M.T.","year":"2015","journal-title":"Infect. 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