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Sir, Fluoroquinolones are broad-spectrum antibacterial agents commonly used in clinical practice. When quinolones became widely used, bacterial resistance to them emerged rapidly and, over the past three decades, resistance has continued to increase. In Gram-negative bacteria, quinolone resistance is due primarily to mutations in chromosomal genes encoding quinolone targets DNA gyrase and topoisomerase IV. More recently, plasmid-mediated mechanisms have been reported, such as those mediated by qnr genes encoding pentapeptide repeat proteins, aac(6′)-Ib-cr, encoding an acetyltransferase, and qepA or oqxAB, encoding active efflux pumps. The CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria to define clinical breakpoints for fluoroquinolones in Enterobacteriaceae are indicated in Table 1. The EUCAST/European Medicines Agency has set somewhat lower breakpoints and those values have been accepted by the BSAC Resistance Surveillance Project. Although the epidemiological cut-off of ciprofloxacin for Escherichia coli has been established at 0.032 mg/L (www.eucast.org), the definition of wild-type strains is difficult due to the possible expression of unknown low-level quinolone resistance mechanisms. Plasmid-mediated quinolone resistance (PMQR) genes confer low levels of quinolone resistance, and their precise effect on selection for quinolone resistance in association with other mechanisms is not well known. Recently we have reported the influence of qnrA, qnrB and qnrS genes on the development of quinolone resistance in E. coli wild-type strains, and isogenic E. coli harbouring a Ser83Leu substitution in GyrA and/or a Ser80Arg substitution in ParC. Strains containing the combined substitutions—Ser83Leu in GyrA and Ser80Arg in ParC—in E. coli ATCC 25922 remained susceptible to fluoroquinolones, according to CLSI breakpoints. In contrast, the presence and expression of qnr genes increased the MIC of ciprofloxacin up to 2 mg/L, the intermediate susceptibility value according to CLSI guidelines (Table 1). However, in all cases the clinical category of every isogenic combination was susceptible or intermediately susceptible. When we analysed these results using the EUCAST breakpoints we observed significant differences in terms of clinical category. E. coli containing qnr genes as the only mechanism of resistance were always susceptible to fluoroquinolones as was observed using CLSI breakpoints. Strains containing the substitution Ser83Leu in GyrA in E. coli ATCC 25922 remained susceptible to fluoroquinolones according to EUCAST breakpoints, while the derived strains expressing the qnrS1 gene were categorized as resistant to ciprofloxacin, moxifloxacin and norfloxacin, and those expressing qnrA1 or qnrB1 were categorized as resistant to norfloxacin, in contrast to what was observed using CLSI breakpoints (Table 1). Strains containing the combined substitutions—Ser83Leu in GyrA and Ser80Arg in ParC—in E. coli ATCC 25922 remained susceptible to fluoroquinolones, except norfloxacin, according to EUCAST breakpoints. In contrast, the presence and expression of qnr genes increased the MIC of fluoroquinolones to 1–8 mg/L, making most of these strains resistant to fluoroquinolones according to EUCAST breakpoints. It has been observed that Qnr proteins facilitate selection of higher-level quinolone-resistant mutants, despite which the therapeutic relevance of the acquisition of qnr genes to the bactericidal activity of fluoroquinolones remains unclear. In this context previous in vivo studies have shown that the presence of qnr genes in association with additional quinolone resistance mechanisms seems to be relevant for the in vivo activity of these antimicrobial agents. According to our results, 10 major errors (susceptible to resistant) and seven minor errors (intermediate to resistant) could be observed when we compare CLSI criteria against EUCAST criteria and these differences could be related to higher quinolone-resistant mutant frequency in strains harbouring PMQR genes. In a recent study, the combined effect of topoisomerase mutations on fluoroquinolone resistance in isogenic E. coli C600 strains showed that at least three mutations—two of which had to be in gyrA—were necessary to exceed CLSI resistance

the journal of antimicrobial chemotherapy/journal of antimicrobial chemotherapy

Discrepancies in fluoroquinolone clinical categories between the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI for Escherichia coli harbouring qnr genes and mutations in gyrA and parC