Fosfomycin susceptibility in carbapenem-resistant Enterobacteriaceae from Germany

Abstract

Due to the increase in multidrug-resistant Enterobacteriaceae, the interest in older antimicrobial agents, like fosfomycin, has increased. In this study, we used agar dilution for testing susceptibilities to fosfomycin in a collection of 107 carbapenem-nonsusceptible Enterobacteriaceae isolates, of which 80 produced various types of carbapenemases, including KPC, VIM, NDM, and OXA-48. Overall, 78% of the strains had fosfomycin MICs of ≤ 32 mg/liter and were thus considered to be susceptible according to the current EUCAST breakpoint. The MIC50 and MIC90 were 8 mg/liter and 512 mg/liter, respectively. Escherichia coli strains had significantly lower fosfomycin MICs than the Klebsiella pneumoniae and Enterobacter cloacae strains. Furthermore, comparisons of the susceptibility testing methods, like Etest and disk diffusion, were performed against agar dilution as the reference method. Essential agreement between Etest and agar dilution was 78.9%, and categorical agreement between the two methods was 92.5%, with 20% very major errors and 2.6% major errors. Disk diffusion was studied with 50-μg and 200-μg fosfomycin disks, but no inhibition zone breakpoint that reduced very major and major errors to an acceptable level was found. Etest and disk diffusion showed poor agreement with fosfomycin agar dilution.

FIG 1

Bland-Altman analysis of agreement between Etest and agar dilution. The differences of the log₂-transformed MICs obtained by agar dilution and Etest are plotted against their mean MIC values. The solid line represents the mean of the differences, the dotted lines indicate the lower and upper limits of the 95% confidence interval. The dashed line represents the linear fit between the mean MIC values and the difference between the log₂-transformed MICs obtained with the two methods.

FIG 2

Scattergram of MICs versus zone diameters for the 200-μg fosfomycin disk. The horizontal dashed line represents the EUCAST breakpoint for fosfomycin. The vertical dash-dot line indicates the breakpoint proposed by Lu et al. (17), and the vertical dotted line indicates the breakpoint proposed by Pasteran et al. (18).

FIG 3

Scattergram of MIC versus zone diameters for 50-μg fosfomycin disk. The horizontal dashed line represents the EUCAST breakpoint for fosfomycin. The vertical dotted line indicates the breakpoint proposed by Pasteran et al. (18).