Antibiotic resistance threatens the delivery of safe and effective healthcare resulting in 2 million infections and 23,000 deaths annually in the United States. Further complicating this epidemic are unexplained antibiotic treatment failures caused by bacteria that appear susceptible to an antibiotic. The phenomenon of heteroresistance occurs when a minor resistant subpopulation exists within a majority susceptible strain. We describe here several instances of heteroresistance to the last-line peptide antibiotic colistin. First, we observed colistin heteroresistant isolates of Enterobacter cloacae that were able to mediate lethal infection during colistin treatment. Interestingly, we observed that the resistant subpopulation was augmented by drug treatment as well as host immune pressure, through macrophages and host antimicrobial compounds. We additionally show that these heteroresistant strains can be misclassified as susceptible by routine susceptibility testing. This could conceivably lead to incorrect treatment with colistin which may lead to unexplained treatment failure. We additionally chacterized strains of colistin heteroresistant Klebsiella pneumoniae, which were additionally resistant to the last line carbapenems. Thus, these isolates would rely on a last line drug such as colistin and could also lead to colistin treatment failure. To assess the extent of heteroresistance in clinical isolates, we conducted a study of heteroresistance in a wide-ranging pool of carbapenem resistant Enterobacteriaceae in the United States. We observed a rate of heteroresistance of over 10% in these isolates. Over 90% of these isolates were misclassified as colistin susceptible, thus underestimating total colistin non-susceptibility by over 2-fold. These findings highlight a largely unappreciated phenomenon that could have a significant impact upon antibiotic treatment outcome, exacerbating the menace of antibiotic resistance.
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|File download under embargo until 17 August 2020||2018-06-24||File download under embargo until 17 August 2020|