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Our objective is to build a workflow leveraging omics and bacterial count data to identify antibiotic mechanisms that can be used to design and optimize combination regimens. For pharmacodynamic (PD) analysis, previously published static time\u2010kill studies (J Antimicrob Chemother <jats:italic>70<\/jats:italic>, 2015, 2589) were used with polymyxin B (PMB) and chloramphenicol (CHL) mono and combination therapy against three KP clinical isolates over 24\u2009h. A mechanism\u2010based model (MBM) was developed using time\u2010kill data in S\u2010ADAPT describing PMB\u2010CHL PD activity against each isolate. Previously published results of PMB (1\u00a0mg\/L continuous infusion) and CHL (<jats:italic>C<\/jats:italic><jats:sub>max<\/jats:sub>: 8\u00a0mg\/L; bolus q6h) mono and combination regimens were evaluated using an in vitro one\u2010compartment dynamic infection model against a KP clinical isolate (10<jats:sup>8<\/jats:sup> CFU\/ml inoculum) over 24\u2009h to obtain bacterial samples for multi\u2010omics analyses. The differentially expressed genes and metabolites in these bacterial samples served as input to develop a partial least squares regression (PLSR) in R that links PD responses with the multi\u2010omics responses via a multi\u2010omics pathway analysis. PMB efficacy was increased when combined with CHL, and the MBM described the observed PD well for all strains. The PLSR consisted of 29 omics inputs and predicted MBM PD response (<jats:italic>R<\/jats:italic><jats:sup>2<\/jats:sup>\u00a0=\u00a00.946). Our analysis found that CHL downregulated metabolites and genes pertinent to lipid A, hence limiting the emergence of PMB resistance. Our workflow linked insights from analysis of multi\u2010omics data with MBM to identify biological mechanisms explaining observed PD activity in combination therapy.<\/jats:p>","DOI":"10.1002\/psp4.12923","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T11:14:31Z","timestamp":1674213271000},"page":"387-400","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Proof\u2010of\u2010concept for incorporating mechanistic insights from multi\u2010omics analyses of polymyxin B in combination with chloramphenicol against <i>Klebsiella pneumoniae<\/i>"],"prefix":"10.1002","volume":"12","author":[{"given":"Patrick O.","family":"Hanafin","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina 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