3 years ago

Frequency and mechanisms of spontaneous fosfomycin non-susceptibility observed upon disk diffusion testing of Escherichia coli.

Christi L McElheny, Marissa P Pacey, Mustapha M Mustapha, Serena F Kantz, Aaron Lucas, Yohei Doi, Vaughn S Cooper, Sarah L Bowler, Ryota Ito, A William Pasculle, Roberta Mettus
Fosfomycin maintains activity against most Escherichia coli clinical isolates, but growth of E. coli colonies within the zone of inhibition around the fosfomycin disk is occasionally observed upon susceptibility testing. We aimed to estimate the frequency of such non-susceptible inner colony mutants and identify the underlying resistance mechanisms. Disk diffusion testing of fosfomycin was performed on 649 multidrug-resistant E. coli clinical isolates collected between 2011 and 2015. For those producing inner colonies inside the susceptible range, the parental strains and their representative inner colony mutants were subjected to MIC testing, whole genome sequencing, qRT-PCR, and carbohydrate utilization studies. Of the 649 E. coli clinical isolates, 5 (0.8%) consistently produced non-susceptible inner colonies. Whole genome sequencing revealed deletion of uhpT encoding hexose-6-phosphate antiporter in 4 of the E. coli inner colony mutants, while the remaining mutant contained a nonsense mutation in uhpA. Expression of uhpT was absent in the mutant strains with uhpT deletion and was not inducible in the strain with the uhpA mutation unlike in its parental strain. All 5 inner colony mutants had reduced growth on minimal medium supplemented with glucose-6-phosphate. In conclusion, fosfomycin-non-susceptible inner colony mutants can occur due to loss of function or induction of UhpT but are rare among multidrug-resistant E. coli clinical strains. Considering that these mutants carry high biological costs, we suggest that fosfomycin susceptibility of strains that generate inner colony mutants can be interpreted based on the zone of inhibition without accounting for the inner colonies.

Publisher URL: http://doi.org/10.1128/JCM.01368-17

DOI: 10.1128/JCM.01368-17

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