A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections

Courtney L. Luterbach, Hongqiang Qiu, Patrick O. Hanafin, Rajnikant Sharma, Joseph Piscitelli, Feng Chang Lin, Jenni Ilomaki, Eric Cober, Robert A. Salata, Robert C. Kalayjian, Richard R. Watkins, Yohei Doi, Keith S. Kaye, Roger L. Nation, Robert A. Bonomo, Cornelia B. Landersdorfer, David van Duin, Gauri G. Rao, on behalf of the Antibacterial Resistance Leadership Group

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Abstract

Antimicrobial resistance is a global threat. As “proof-of-concept, ” we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting.

Original languageEnglish
Article number00591-22
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number10
DOIs
Publication statusPublished - Oct 2022

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