Abstract
Fosfomycin and nitrofurantoin are antibiotics of choice to orally treat non-complicated urinary tract infections (UTIs) of community origin because they remain active against bacteria resistant to other antibiotics. However, epidemiologic surveillance studies have detected a reduced susceptibility to these drugs. The objective of this study was to determine possible mechanisms of resistance to these antibiotics in clinical isolates of fosfomycin- and/or nitrofurantoin-resistant UTI-producing Escherichia coli. We amplified and sequenced murA, glpT, uhpT, uhpA, ptsI, cyaA, nfsA, nfsB, and ribE genes, and screened plasmid-borne fosfomycin-resistance genes fosA3, fosA4, fosA5, fosA6, and fosC2 and nitrofurantoin-resistance genes oqxA and oqxB by polymerase chain reaction. Among 29 isolates studied, 22 were resistant to fosfomycin due to deletion of uhpT and/or uhpA genes, and 2 also possessed the fosA3 gene. Some modifications detected in sequences of NfsA (His11Tyr, Ser33Arg, Gln67Leu, Cys80Arg, Gly126Arg, Gly154Glu, Arg203Cys), NfsB (Gln44His, Phe84Ser, Arg107Cys, Gly192Ser, Arg207His), and RibE (Pro55His), and the production of truncated NfsA (Gln67 and Gln147) and NfsB (Glu54), were associated with nitrofurantoin resistance in 15/29 isolates; however, the presence of oqxAB plasmid genes was not detected in any isolate. Resistance to fosfomycin was associated with the absence of transporter UhpT expression and/or the presence of antibiotic-modifying enzymes encoded by fosA3 plasmid-mediated gene. Resistance to nitrofurantoin was associated with modifications of NfsA, NfsB, and RibE proteins. The emergence and spread of these resistance mechanisms, including transferable resistance, could compromise the future usefulness of fosfomycin and nitrofurantoin against UTIs. Furthermore, knowledge of the genetic mechanisms underlying resistance may lead to rapid DNA-based testing for resistance.
Highlights
The high incidence of urinary tract infections (UTIs) and their usually mild character means that most patients receive empirical antibiotic treatment
The study included clinical isolates of fosfomycin- and/or nitrofurantoin-resistant E. coli with significant bacterial count selected from among urine cultures conducted for UTI analysis in the Microbiology Laboratory of Virgen de las Nieves University Hospital (Granada, Spain)
According to the PROVEAN analysis, only Gly84Asp and Pro212Leu substitutions could be significantly related to an alteration of glycerol-3-phosphate transporter (GlpT) functionality; the two isolates with this substitution proved able to grow in the presence of glycerol 3-phosphate (G3P)
Summary
The high incidence of urinary tract infections (UTIs) and their usually mild character means that most patients receive empirical antibiotic treatment. The characteristics of fosfomycin and nitrofurantoin make them especially useful for UTI treatment, including their rapid oral absorption, high urine concentration, and bactericide activity against a wide range of Gram-negative and Gram-positive bacteria. UTIs of community origin [2] They have been reported to preserve their activity against multi-resistant microorganisms, especially uropathogenic enterobacteria such as Escherichia coli and extended-spectrum beta-lactamase-producing isolates [3], these are usually less susceptible to fosfomycin and nitrofurantoin than are non-producers [4,5]
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