Antibiotic combinations that exploit heteroresistance to multiple drugs effectively control infection

• Type of Material: Article
• Authors: Victor I. Band, Emory University; David A. Hufnagel, Emory University; Siddharth Jaggavarapu, Emory University; Edgar X. Sherman, Emory University; Jessie E. Wozniak, Emory University; Sarah Satola, Emory University; Monica Farley, Emory University; Jesse Jacob, Emory University; Eileen Burd, Emory University; David Weiss, Emory University
• Language: English
• Date: 2019-10-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © The Author(s), under exclusive licence to Springer Nature Limited 2019.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41564-019-0480-z
• Title of Journal or Parent Work: Nature Microbiology
• Volume: 4
• Issue: 10
• Start Page: 1627
• End Page: 1635
• Grant/Funding Information: The GA EIP is funded by the Centers for Disease Control and Prevention.; D. A H. is supported by a postdoctoral research fellowship from the Cystic Fibrosis Foundation. E.X.S. is supported by T32 training grant AIl06699 from the National Institutes of Health (NIH).; D.S.W. is supported by a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease award and NIH grant AI141883.
• Keywords: Monotherapy; Therapy; Susceptibility; Life Sciences & Biomedicine; Gram-negative bacteria; Science & Technology; Resistance; Persistence; Sepsis; Microbiology; Synergy
• Research Categories: Biology, Microbiology; Health Sciences, Medicine and Surgery; Health Sciences, Immunology

Abstract

Antibiotic-resistant bacteria are a significant threat to human health, with one estimate suggesting they will cause 10 million worldwide deaths per year by 2050, surpassing deaths due to cancer1. Because new antibiotic development can take a decade or longer, it is imperative to effectively use currently available drugs. Antibiotic combination therapy offers promise for treating highly resistant bacterial infections, but the factors governing the sporadic efficacy of such regimens have remained unclear. Dogma suggests that antibiotics ineffective as monotherapy can be effective in combination2. Here, using carbapenem-resistant Enterobacteriaceae (CRE) clinical isolates, we reveal the underlying basis for the majority of effective combinations to be heteroresistance. Heteroresistance is a poorly understood mechanism of resistance reported for different classes of antibiotics3–6 in which only a subset of cells are phenotypically resistant7. Within an isolate, the subpopulations resistant to different antibiotics were distinct, and over 88% of CRE isolates exhibited heteroresistance to multiple antibiotics (‘multiple heteroresistance’). Combinations targeting multiple heteroresistance were efficacious, whereas those targeting homogenous resistance were ineffective. Two pan-resistant Klebsiella isolates were eradicated by combinations targeting multiple heteroresistance, highlighting a rational strategy to identify effective combinations that employs existing antibiotics and could be clinically implemented immediately.