Carbapenem-Resistant Klebsiella pneumoniae Exhibiting Clinically Undetected Colistin Heteroresistance Leads to Treatment Failure in a Murine Model of Infection

• DOI: 10.1128/mbio.02448-17
• Publication Date: 2018-03-05T13:18:03Z
• Authors: Victor I. Band; Sarah W. Satola; Eileen M. Burd; Monica M. Farley; Jesse T. Jacob; David S. Weiss
• Keywords: Colistin; Polymyxin; Carbapenem

ABSTRACT Antibiotic resistance is a growing crisis and grave threat to human health. It projected that antibiotic-resistant infections will lead 10 million annual deaths worldwide by the year 2050. Among most significant threats are carbapenem-resistant Enterobacteriaceae (CRE), including Klebsiella pneumoniae (CRKP), which mortality rates as high 40 50%. Few treatment options available treat CRKP, polymyxin antibiotic colistin often “last-line” therapy. However, increasing. Here, we identify multidrug-resistant, carbapenemase-positive CRKP isolates were classified susceptible clinical diagnostics yet harbored minor subpopulation of phenotypically resistant cells. Within these isolates, became predominant after growth in presence but returned baseline levels subsequent culture antibiotic-free media. This indicates was phenotypic, rather than due genetic mutation, consistent with heteroresistance. Importantly, therapy unable rescue mice infected heteroresistant strains. These findings demonstrate heteroresistance may cause vivo failure during K. infection, threatening use last-line for CRKP. Furthermore, data sound alarm caution interpreting susceptibility test results, identified fact resist unexplained failures. IMPORTANCE first report colistin-heteroresistant United States. Two distinct each led an model infection. The worrisome, especially since not detected current diagnostic tests. As carbapenem resistant, clinicians might turn caused such strains, knowing they harbor cells, potentially leading failure. Our warn testing results be unreliable undetected highlight need more accurate sensitive diagnostics.