{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T12:04:32Z","timestamp":1769947472616,"version":"3.49.0"},"reference-count":31,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T00:00:00Z","timestamp":1719792000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2024,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The AIDA randomized clinical trial found no significant difference in clinical failure or survival between colistin monotherapy and colistin\u2013meropenem combination therapy in carbapenem\u2010resistant Gram\u2010negative infections. The aim of this reverse translational study was to integrate all individual preclinical and clinical pharmacokinetic\u2013pharmacodynamic (PKPD) data from the AIDA trial in a pharmacometric framework to explore whether individualized predictions of bacterial burden were associated with the trial outcomes. The compiled dataset included for each of the 207 patients was (i) information on the infecting <jats:italic>Acinetobacter baumannii<\/jats:italic> isolate (minimum inhibitory concentration, checkerboard assay data, and fitness in a murine model), (ii) colistin plasma concentrations and colistin and meropenem dosing history, and (iii) disease scores and demographics. The individual information was integrated into PKPD models, and the predicted change in bacterial count at 24\u2009h for each patient, as well as patient characteristics, was correlated with clinical outcomes using logistic regression. The in\u00a0vivo fitness was the most important factor for change in bacterial count. A model\u2010predicted growth at 24\u2009h of \u22652\u2010log<jats:sub>10<\/jats:sub> (164\/207) correlated positively with clinical failure (adjusted odds ratio, aOR\u2009=\u20092.01). The aOR for one unit increase of other significant predictors were 1.24 for SOFA score, 1.19 for Charlson comorbidity index, and 1.01 for age. This study exemplifies how preclinical and clinical anti\u2010infective PKPD data can be integrated through pharmacodynamic modeling and identify patient\u2010 and pathogen\u2010specific factors related to clinical outcomes \u2013 an approach that may improve understanding of study outcomes.<\/jats:p>","DOI":"10.1111\/cts.13870","type":"journal-article","created":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T06:26:43Z","timestamp":1719901603000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integration of individual preclinical and clinical anti\u2010infective PKPD data to predict clinical study outcomes"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1258-8054","authenticated-orcid":false,"given":"Vincent","family":"Aranzana\u2010Climent","sequence":"first","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"},{"name":"Universit\u00e9 de Poitiers, PHAR2, Inserm U1070  Poitiers France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-4173","authenticated-orcid":false,"given":"Wisse","family":"van Os","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"},{"name":"Department of Clinical Pharmacology Medical University of Vienna  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-2618","authenticated-orcid":false,"given":"Amir","family":"Nutman","sequence":"additional","affiliation":[{"name":"National Institute for Antibiotic Resistance and Infection Control Israel Ministry of Health  Tel Aviv Israel"},{"name":"Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0564-4409","authenticated-orcid":false,"given":"Jonathan","family":"Lellouche","sequence":"additional","affiliation":[{"name":"National Institute for Antibiotic Resistance and Infection Control Israel Ministry of Health  Tel Aviv Israel"},{"name":"The Adelson School of Medicine Ariel University  Ariel Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9646-5376","authenticated-orcid":false,"given":"Yael","family":"Dishon\u2010Benattar","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Rambam Health Care Campus  Haifa Israel"},{"name":"The Cheryl Spencer Department of Nursing University of Haifa  Haifa Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-1177","authenticated-orcid":false,"given":"Nadya","family":"Rakovitsky","sequence":"additional","affiliation":[{"name":"Division of Epidemiology and Preventive Medicine Tel Aviv Sourasky Medical Centre  Tel Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-4874","authenticated-orcid":false,"given":"George L.","family":"Daikos","sequence":"additional","affiliation":[{"name":"First Department of Medicine Laikon General Hospital  Athens Greece"},{"name":"National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4431-3511","authenticated-orcid":false,"given":"Anna","family":"Skiada","sequence":"additional","affiliation":[{"name":"First Department of Medicine Laikon General Hospital  Athens Greece"},{"name":"National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Pavleas","sequence":"additional","affiliation":[{"name":"First Department of Medicine Laikon General Hospital  Athens Greece"},{"name":"National and Kapodistrian University of Athens  Athens Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5381-3537","authenticated-orcid":false,"given":"Emanuele","family":"Durante\u2010Mangoni","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine University of Campania Luigi Vanvitelli  Naples Italy"},{"name":"AORN Ospedali dei Colli\u2010Monaldi Hospital  Naples Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2116-7128","authenticated-orcid":false,"given":"Ursula","family":"Theuretzbacher","sequence":"additional","affiliation":[{"name":"Center for Anti\u2010Infective Agents  Vienna Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2317-1112","authenticated-orcid":false,"given":"Mical","family":"Paul","sequence":"additional","affiliation":[{"name":"Infectious Diseases Institute, Rambam Health Care Campus  Haifa Israel"},{"name":"The Ruth and Bruce Rappaport Faculty of Medicine Techion \u2013 Israel Institute of Technology  Haifa Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yehuda","family":"Carmeli","sequence":"additional","affiliation":[{"name":"National Institute for Antibiotic Resistance and Infection Control Israel Ministry of Health  Tel Aviv Israel"},{"name":"Faculty of Medical and Health Sciences Tel Aviv University  Tel Aviv Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-679X","authenticated-orcid":false,"given":"Lena E.","family":"Friberg","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Uppsala University  Uppsala Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30099-9"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2020.03.016"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2020.03.035"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2021.05.005"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2022.106616"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2015-009956"},{"key":"e_1_2_10_8_1","unstructured":"The European Committee on Antimicrobial Susceptibility Testing.Breakpoint tables for interpretation of MICs and zone diameters. Version 14.0.2024https:\/\/www.eucast.org"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01733-10"},{"key":"e_1_2_10_10_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Core Team","year":"2018"},{"key":"e_1_2_10_11_1","unstructured":"BealSL SheinerLB BoeckmannAJ BauerRJ.NONMEM 7.4 users guides.https:\/\/nonmem.iconplc.com\/nonmem743\/guides"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/psp.2013.24"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0169-2607(98)00067-4"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270006291035"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01989-18"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkx427"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1012299115260"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.06426-11"},{"key":"e_1_2_10_19_1","first-page":"11","article-title":"The pharmacokinetics of meropenem","volume":"96","author":"Drusano GL","year":"1995","journal-title":"Scand J Infect Dis Suppl"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-017-9550-0"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.7.1560"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe1906559"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.4103\/0970-9185.194772"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/00031305.2019.1583913"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2023.1104482"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13072"},{"key":"e_1_2_10_27_1","unstructured":"Rogn\u00e5sV KarlssonMO LeboviciL et\u00a0al.Bounded integer approach to model time\u2010varying SOFA scores from patients with carbapenem resistant infections. 28th Population Approach Group Europe 11\u201314 June 2019; Stockholm Sweden; Abstr 9052.https:\/\/www.page\u2010meeting.org\/?abstract=9052"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05453-11"},{"key":"e_1_2_10_29_1","unstructured":"Aranzana\u2010ClimentV ProuvensierL ColletT et\u00a0al.Spotting method as a high throughput alternative to the conventional spread plating method. 34th European Congress of Clinical Microbiology and Infectious Diseases 27\u201330 April 2024; Barcelona Spain; P2490.https:\/\/univ\u2010poitiers.hal.science\/hal\u201004575530"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics10121485"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2020.106059"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2666-5247(22)00121-5"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13870","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T18:48:54Z","timestamp":1721933334000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13870"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7]]},"references-count":31,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7]]}},"alternative-id":["10.1111\/cts.13870"],"URL":"https:\/\/doi.org\/10.1111\/cts.13870","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7]]},"assertion":[{"value":"2024-03-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13870"}}