Mechanisms Accounting for Fluoroquinolone Resistance in Escherichia coli Clinical Isolates

Abstract

Fluoroquinolone MICs are increased through the acquisition of chromosomal mutations in the genes encoding gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE), increased levels of the multidrug efflux pump AcrAB, and the plasmid-borne genes aac(6)-Ib-cr and the qnr variants in Escherichia coli. In the accompanying report, we found that ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs for fluoroquinolone-resistant E. coli clinical isolates were very high and widely varied (L. Becnel Boyd, M. J. Maynard, S. K. Morgan-Linnell, L. B. Horton, R. Sucgang, R. J. Hamill, J. Rojo Jimenez, J. Versalovic, D. Steffen, and L. Zechiedrich, Antimicrob. Agents Chemother. 53:229-234, 2009). Here, we sequenced gyrA, gyrB, parC, and parE; screened for aac(6)-Ib-cr and qnrA; and quantified AcrA levels in E. coli isolates for which patient sex, age, location, and site of infection were known. We found that (i) all fluoroquinolone-resistant isolates had gyrA mutations; (ii) ϳ85% of gyrA mutants also had parC mutations; (iii) the ciprofloxacin and norfloxacin MICs for isolates harboring aac(6)-Ib-cr (ϳ23%) were significantly higher, but the gatifloxacin and levofloxacin MICs were not; (iv) no isolate had qnrA; and (v) ϳ33% of the fluoroquinolone-resistant isolates had increased AcrA levels. Increased AcrA correlated with nonsusceptibility to the fluoroquinolones but did not correlate with nonsusceptibility to any other antimicrobial agents reported from hospital antibiograms. Known mechanisms accounted for the fluoroquinolone MICs of 50 to 70% of the isolates; the remaining included isolates for which the MICs were up to 1,500-fold higher than expected. Thus, additional, unknown fluoroquinolone resistance mechanisms must be present in some clinical isolates.Fluoroquinolones have become some of the most frequently prescribed antimicrobial agents worldwide. Fluoroquinolone MICs can be increased by mutations in the genes encoding the targets gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE), by increased levels of the multidrug efflux pump AcrAB (12,27,29), and by the presence of plasmid-borne mechanisms QnrA, QnrB, QnrS, and Aac(6Ј)-Ib-cr (9, 23, 28). However, these mechanisms do not equally affect the MICs of all fluoroquinolones; in general, ciprofloxacin and norfloxacin MICs are affected by all of these mechanisms, and gatifloxacin and levofloxacin MICs are less affected or are not affected (14,23,26). In a companion study, we found tremendous variation among the MICs of ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin, such that the four fluoroquinolones were affected to the same extent only in a small subset of isolates (ϳ5%) (4). In addition to the tremendous diversity in MICs of the four tested fluoroquinolones, we recently uncovered clear correlations between fluoroquinolone resistance in Escherichia coli isolates and patient age, patient sex, hospital location, and culture site (3). It is possible that these patient factors correlate with some of the MIC relationships or with some resis...

Characteristics of ciprofloxacin-resistant Enterobacteriaceae isolates recovered from wastewater of an Algerian hospital

“…There was a diversity of mutation patterns among the tested E. coli isolates. The S83L, D87N + S80I mutation profile has been reported to be the most prevalent in clinical settings and in the environment [13,[20][21][22][23], while the other profiles were found at low prevalence [21,23,24]; our results are in agreement with these reports. Among ParC substitutions, S80I was the most common, S80R and E84G were less frequent as previously reported [23], while L99M was described for the first time in this study.…”

The Impact of Mutations in Topoisomerase Genes and the Plasmid-Mediated Quinolone Resistance (PMQR) Determinants on the Resistance to Fluoroquinolones in Klebsiella pneumoniae

“…The results of previous studies indicated that the rate of resistance to ciprofloxacin is higher than levofloxacin among Enterobacteriaceae (21,22). However, in our study, all isolates resistant to ciprofloxacin were also resistant to levofloxacin but the average MIC for ciprofloxacin was higher than levofloxacin that indicate levofloxacin is slightly more effective against K. pneumoniae isolates.…”

Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase

“…Two of these water molecules are coordinated by a conserved serine and acidic residue (located four positions downstream) in the A subunit of the enzyme. Substitutions in the residues that anchor the bridge are the most prevalent cause of quinolone resistance (10)(11)(12)(13)(22)(23)(24)(25)(26)(27). In most species, the serine is mutated far more often than the acidic residue.…”