Skip to main page content

• HOME
• Current Issue
• Archive
• Alerts
• About ASM
• Contact us
• Tech Support
• Journals.ASM.org

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, H. B. Articles by Hooper, D. C. Search for Related Content PubMed PubMed Citation Articles by Kim, H. B. Articles by Hooper, D. C.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, February 2009, p. 639-645, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01051-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Prevalence of Plasmid-Mediated Quinolone Resistance Determinants over a 9-Year Period

Hong Bin Kim,^1,2,4 Chi Hye Park,⁴ Chung Jong Kim,² Eui-Chong Kim,³ George A. Jacoby,⁵ and David C. Hooper^4*

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea,¹ Department of Internal Medicine,² Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea,³ Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts,⁴ Lahey Clinic, Burlington, Massachusetts⁵

Received 4 August 2008/ Returned for modification 13 October 2008/ Accepted 30 November 2008

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Recently, several plasmid-mediated quinolone resistance (PMQR) genes conferring low levels of quinolone resistance have been discovered. To evaluate the temporal change in the prevalence of PMQR genes over a decade in a tertiary hospital in the Republic of Korea, we selected every fifth isolate of Escherichia coli and Klebsiella pneumoniae and every third isolate of Enterobacter cloacae between 1998 and 2001 and between 2005 and 2006 from a collection of blood isolates. Six PMQR genes [qnrA, qnrB, qnrC, qnrS, aac(6')-Ib-cr, and qepA] were screened by multiplex PCR and then confirmed by direct sequencing, and the aac(6')-Ib-positive PCR products were digested with BtsCI to identify the aac(6')-Ib-cr variant. Of 461 isolates, 37 (8%) had one of the six PMQR genes; 13 (5%) of 261 E. coli strains, 13 (10%) of 135 K. pneumoniae strains, and 11 (17%) of 65 E. cloacae strains. qnrB was the most common PMQR gene and was found as early as 1998, whereas qnrS, aac(6')-Ib-cr, and qepA emerged after 2000. None of the isolates carried qnrA or qnrC. Ciprofloxacin resistance increased over time (P < 0.001), and the overall prevalence of PMQR genes tended to increase (P = 0.20). PMQR-positive isolates had significantly higher ciprofloxacin resistance and multidrug resistance rates (P = 0.005 and P < 0.001, respectively). The increasing frequency of ciprofloxacin resistance in Enterobacteriaceae was associated with an increasing prevalence of PMQR genes, and this change involved an increase in the diversity of the PMQR genes and also an increase in the prevalence of the mutations in gyrA, parC, or both in PMQR-positive strains but not PMQR-negative strains.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Fluoroquinolones are among the most commonly prescribed antimicrobials because of their broad-spectrum antimicrobial activity, and fluoroquinolone-resistant gram-negative pathogens have emerged worldwide. Quinolone resistance is traditionally mediated by the mutation of chromosomal genes encoding DNA gyrase and/or topoisomerase IV or by the mutation of genes regulating the expression of efflux pumps (5, 6).

It was thought that quinolone resistance could be acquired only by chromosomal mutations, until plasmid-mediated resistance to quinolones was described in a clinical isolate of Klebsiella pneumoniae in 1998 (12). Since then, four major groups of qnr determinants, qnrA, qnrB, qnrC, and qnrS, have been identified (7, 29), and two additional plasmid-mediated quinolone resistance (PMQR) genes have been described—aac(6')-Ib-cr, which encodes a variant aminoglycoside acetyltransferase that modifies ciprofloxacin (21), and qepA, which encodes an efflux pump belonging to the major facilitator subfamily (19, 32). These PMQR determinants are increasingly being identified worldwide in clinical isolates of Enterobacteriaceae (4, 11, 17, 22, 23, 27) and in clinical and environmental Aeromonas species isolates (1, 26).

Since the report of the first horizontally transmissible element, qnrA, conferring resistance to quinolones, many epidemiological surveys have been reported. However, most focused on Enterobacteriaceae with specific resistance phenotypes, such as resistance due to extended-spectrum β-lactamases and/or reduced susceptibility to nalidixic acid or fluoroquinolones (2, 3, 10, 16, 17, 23, 28) even though PMQR genes do not themselves confer full resistance to fluoroquinolones (23). In this study, we determined the changes with time in the prevalence of all so-far-known PMQR genes in consecutive clinical Enterobacteriaceae isolates in a South Korean tertiary care hospital, where the frequency of ciprofloxacin resistance has continued to rise for a decade.

(This work was presented in part at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy [ICAAC] and the 46th Annual Meeting of the Infectious Diseases Society of America [IDSA], Washington DC, 2008.)

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Bacterial isolates. Test isolates were taken from the blood isolates collection of Seoul National University Hospital, a tertiary 1,600-bed hospital in the Republic of Korea. We selected three 2-year periods (1998 to 1999, 2000 to 2001, and 2005 to 2006) in the interval from 1998 to 2006, based on resistance rates to ciprofloxacin, which represents the period before, during, and after the increase in ciprofloxacin resistance rate, respectively (Fig. 1). Every fifth consecutive isolate of Escherichia coli and K. pneumoniae, as well as every third consecutive isolate of Enterobacter cloacae, was included in the study.

View larger version (19K): [in this window] [in a new window]

FIG. 1. Trends of ciprofloxacin resistance rates among total E. coli, K. pneumoniae, and E. cloacae isolates recovered from blood cultures (from 1998 through 2006), and the prevalence of the PMQR genes among 461 randomly selected isolates from 1998 to 2001 and from 2005 to 2006.

Antimicrobial susceptibility tests. An antimicrobial disk diffusion test was carried out, in accordance with the Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) guidelines (14). The following 12 antibiotics were tested: amikacin, ampicillin (or cefotetan), aztreonam, cefotaxime, ceftazidime, cefuroxime, cephalothin, ciprofloxacin, gentamicin, imipenem, tobramycin, and trimethoprim-sulfamethoxazole (or piperacillin-tazobactam). The breakpoints for resistance were those recommended by the CLSI (14). In addition, the MIC for ciprofloxacin was determined by Etest (AB Biodisk, Solna, Sweden). Resistance rates were calculated as the number of intermediate and resistant strains over the total number of strains. Multidrug resistance (MDR) was defined as resistance to at least three different classes of antimicrobials.

Multiplex PCR. Colonies were suspended in 50 µl of water in a microcentrifuge tube and boiled to prepare DNA templates for PCR. Pairs of primers to amplify internal fragments were designed from the sequences from the National Center for Biotechnology Information website (http://www.ncbi.nlm.nih.gov/) and from the sequence of qnrC provided by Minggui Wang (Table 1) (29). Screening of the six PMQR determinants was carried out by two sets of multiplex PCR amplification, one for qnrA, qnrB, qnrC, and qnrS and the other for aac(6')-Ib and qepA. In each multiplex PCR, all of the primers were added to the template DNA and PCR SuperMix high-fidelity polymerase (Invitrogen, Carlsbad, CA). Clinical isolates that had previously been confirmed to carry the qnr genes, aac(6')-Ib, and aac(6')-Ib-cr by DNA sequencing and an E. coli TOP10 derivative harboring qepA (19) were used as positive controls. Positive and negative controls were included in each PCR. Amplification products were identified by their sizes after electrophoresis on 1.8% agarose gels at 130 V for 30 min and staining with ethidium bromide. Positive results for qnr genes were confirmed by direct sequencing of PCR products. The qnrB allele number was designated based on the recent proposal for qnr gene nomenclature (7).

View this table: [in this window] [in a new window]

TABLE 1. Primers used in this study

All PCR products positive for aac(6')-Ib were further analyzed by digestion with BtsCI (New England Biolabs, Ipswich, MA) to identify aac(6')-Ib-cr, which lacks the BtsCI restriction site present in the wild-type gene (17). The wild-type aac(6')-Ib PCR product yielded 210-bp and 272-bp fragments after restriction.

Sequencing of gyrA and parC. PCR amplifications of the quinolone resistance-determining regions (QRDRs) of gyrA and parC were carried out using the primers as shown in Table 1. Purified PCR products were sequenced on both strands, and then QRDR DNA sequences were compared with the sequences of E. coli, K. pneumoniae, and E. cloacae (GenBank accession numbers were AF052254, AF052258, and AF052256 for gyrA and NC000913, AF303641, and D88981 for parC, respectively).

Statistical analysis. The dosages of fluoroquinolone antimicrobials used in the source hospital were derived from pharmacy records over the study period. These data were converted into a number of defined daily doses (DDDs) and expressed as antimicrobial-use densities (the number of DDDs per 1,000 patient days), following the recommendation of the World Health Organization (WHO) (http://www.whocc.no/atcddd/).

Differences in proportions were compared using the ² test or Fisher's exact test, as appropriate, and temporal trends were examined with the Mantel-Haenszel ² test. The relation between ciprofloxacin resistance and prevalence of PMQR genes was assessed by calculating Spearman's correlation coefficient and the corresponding P value. All tests of significance were two-tailed, with the value set at 0.05. All statistical analyses were done using SPSS software (SPSS, Chicago, IL).

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Overall, 461 isolates were included in this study. Among them, 65 were provisionally identified as positive by the size of their amplification products by multiplex PCR. Although these results were reproducible, only 37 (8%) were confirmed to have at least one of six PMQR genes (Table 2). PMQR genes were detected in 13 (5%) of 261 E. coli isolates, 13 (10%) of 135 K. pneumoniae isolates, and 11 (17%) of 65 E. cloacae isolates. Isolates harboring qnrB and qnrS numbered 22 and 4, respectively, but no isolates were positive for qnrA or qnrC. Fifty-one isolates (11%) were positive for aac(6')-Ib, of which 10 (2% of the total) carried the cr variant. qepA was present in only one isolates (0.2%). Overall, qnrB was the most prevalent PMQR gene (22/461 [4.8%]). qnr genes were detected most frequently in E. cloacae, followed by K. pneumoniae, and lastly E. coli, the reverse of the order for aac(6')-Ib-cr prevalence.

View this table: [in this window] [in a new window]

TABLE 2. Prevalence of six PMQR determinants

Most qnrB genes (16/22) were of the qnrB4 or qnrB10 variant, which were present as early as 1998. Two other alleles, qnrB2 and qnrB5, were detected in five isolates and one isolate after the year 2000, respectively. Among qnr producers, qnrB2, qnrB4, and qnrB5 were found in E. coli, qnrB2, qnrB4, and qnrB10 in K. pneumoniae, and qnrB4 and qnrB10 in E. cloacae.

qnrB genes were found as early as 1998, but qnrS, aac(6')-Ib-cr, and qepA genes emerged subsequently after the year 2000. PMQR genes tended to be detected more frequently overall after 2000 than in the previous period studied (P = 0.25) (Table 3), though there was significant change in these genes in E. coli isolates (P = 0.012). The overall prevalence of PMQR genes showed an increasing trend over time (P = 0.19), and there was also a significant increase in rates of ciprofloxacin resistance over time (P < 0.001) (Fig. 1). Increasing ciprofloxacin resistance rates in Enterobacteriaceae tended to be correlated with increased prevalence of PMQR genes (Spearman's correlation coefficient = 0.657; P = 0.16). In addition, fluoroquinolone use increased from 27.8 (DDD per 1,000 patient days) in 2001 to 74.6 in 2006 (P < 0.0001).

View this table: [in this window] [in a new window]

TABLE 3. Characteristics of PMQR-positive and PMQR-negative isolates

Among the total isolates, those that were PMQR positive had significantly higher ciprofloxacin resistance and MDR rates (P = 0.005 and P < 0.001, respectively) (Table 3). In E. coli, however, the possession of PMQR genes was not associated with an increase in ciprofloxacin resistance or MDR rates. There was a trend for increasing ciprofloxacin resistance by species and by PMQR gene, but in K. pneumoniae, ciprofloxacin resistance and MDR rates were significantly associated with the presence of PMQR genes; 14 of the 37 isolates harboring PMQR genes were ciprofloxacin resistant by CLSI criteria. That 23 of the 37 isolates harboring PMQR genes were ciprofloxacin susceptible by CLSI criteria highlights the ability of these genes to circulate widely and, because of their limited reduction in susceptibility, to go undetected by routine susceptibility testing in the clinical microbiology laboratory. The MICs of ciprofloxacin for 37 PMQR gene-positive strains ranged from 0.008 to >32 µg/ml (median, 0.38 µg/ml).

We determined the mutations in the QRDRs of gyrA and parC for 126 strains, including all of the PMQR-positive strains and a sample of 89 PMQR-negative strains (49 that are ciprofloxacin susceptible and 40 that are ciprofloxacin resistant) randomly chosen from the three 2-year periods (26 from 1998 to 1999, 31 from 2000 to 2001, and 32 from 2005 to 2006). Substitutions at codons 83 and/or 87 in the gyrA gene were detected in 46% (58/126) of the strains, but no substitution was found at codon 81, 82, 84, or 106. Among the 58 strains with gyrA mutations, 48 had additional mutations at codons 80 and/or 84 in the parC gene. There were no strains with a parC QRDR mutation alone. The prevalence of amino acid substitutions in the QRDR of gyrA and/or parC increased significantly over time among PMQR-positive strains (P = 0.012), whereas it was stable for PMQR-negative strains (Table 4). The MICs of ciprofloxacin for 58 strains with the mutations in the QRDR of gyrA with or without parC ranged from 0.016 to >32 µg/ml (median, 4 µg/ml).

View this table: [in this window] [in a new window]

TABLE 4. Trend in the prevalence of amino acid substitutions in the QRDR of gyrA and/or parC in 126 selected strains

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The present study yielded a prevalence of 8.0% for PMQR genes among 461 consecutive isolates of E. coli, K. pneumoniae, and E. cloacae collected from 1998 to 2001 and from 2005 to 2006 in a tertiary hospital in the Republic of Korea. Although 65 were repeatedly positive by multiplex PCR, 28 initially qnr-positive strains were found to be false positive by sequencing. The reason why nonspecific bands were generated by multiplex PCR, even if not by monoplex PCR under the same condition, is not yet understood. Therefore, this method could be used only for screening, and further monoplex PCR for each qnr gene or direct sequencing of the PCR product would be warranted for confirmation.

Although the prevalence of each PMQR gene varied by species, the overall prevalence was higher in E. cloacae and K. pneumoniae than in E. coli, as noted by other authors (10, 18, 22, 31). The most frequent PMQR gene was qnrB, as in other studies (2, 13, 22, 27, 30, 31). Whereas the qnr genes predominated in K. pneumoniae and E. cloacae, aac(6')-Ib-cr was the most prevalent gene in E. coli. These differences are in accord with previous observations (17), but the cause is not yet understood. qepA, which was recently found in Japan and Belgium (19, 32), has been rarely present in the Republic of Korea, as has also been true in Japan and Brazil (13, 33). Since qnrB-positive isolates were identified as early as 1998, some of the PMQR genes have been present for at least a decade in K. pneumoniae and E. cloacae. Furthermore both the types of PMQR genes and the varieties of qnrB alleles diversified over time.

PMQR-positive strains were significantly more frequently ciprofloxacin resistant than were PMQR-negative strains (2.7-fold), with the dominant difference found in K. pneumoniae (9.6-fold). In addition, PMQR-positive K. pneumoniae and E. cloacae isolates had significantly higher MDR rates (17- to 28-fold) than did PMQR-negative isolates. Notably, qnrB accounted for 75% (18/24) of the PMQR genes detected in K. pneumoniae and E. cloacae. This result suggests an association between qnrB and other antibiotic resistance genes, which has also been noted by other investigators (3, 9, 15, 28). However, this linkage was not seen in E. coli isolates harboring the PMQR genes included in the study. In addition, the qepA-harboring isolate did not demonstrate the aminoglycoside resistance phenotype of rmtB, a gene closely linked to qepA in previous reports (19, 33). Therefore, further genetic analysis of the qepA plasmid(s) seems to be warranted.

There was an increasing trend in the number of PMQR-positive strains in the periods before and after 2000. In addition, there was a significant increase in the rates of ciprofloxacin resistance over the same time. Therefore, the increasing prevalence of PMQR genes may have been an important driving force for selection of quinolone resistance, although a causal link cannot be proven by this relationship alone. The demonstration in vitro that the low-level resistance conferred by qnrA may not only allow bacteria to survive in the presence of a quinolone but also substantially enhance the number of resistant mutants that can be selected from the population (8, 20, 24) supports the hypothesis that the increasing prevalence of the PMQR genes has contributed to the rise in resistance to fluoroquinolone in Enterobacteriaceae. Furthermore increases in selection pressure from the use of fluoroquinolones over the study period may have contributed both to the prevalence of the PMQR genes and to higher levels of ciprofloxacin resistance that these genes can facilitate.

In order to investigate the roles of the QRDR mutations and the PMQR genes in contributing to higher levels of ciprofloxacin resistance over time, we determined mutations in the QRDR of gyrA and parC from PMQR-positive and -negative strains. Although the overall prevalence of the amino acid substitutions in these genes fluctuated around 50% in PMQR-negative strains, it increased significantly from 0% in 1998 to 1999 to 50% in 2005 to 2006 among PMQR-positive strains, especially in strains with a ciprofloxacin resistance phenotype (from 0% to 78%). The presence of Qnr proteins or Aac(6')-Ib-cr is known to facilitate selection of resistance mutations in the presence of quinolone concentrations that would otherwise be lethal (8, 24). Thus, our data provide additional epidemiological support for the role of PMQR in promoting both QRDR mutations in gyrA and parC and increased quinolone resistance in clinical settings as well.

This study has some limitations. Although we designed new, simple, and rapid multiplex PCR methods to detect all known PMQR genes, some of the new qnr variants, especially qnrB8, would be overlooked. Therefore, the prevalence of the PMQR genes reported here should be considered a minimum estimate. We did not amplify the QRDRs in gyrB and parE, because mutations in these regions have been substantially less frequently detected and confer lower levels of resistance relative to those conferred by gyrA or parC mutations (5). We did not include strains from the period of 2002 to 2004. Although the lack of data over this period and the relatively small number of PMQR-positive strains might decrease the statistical power to detect temporal correlations, there was nevertheless a significant increasing prevalence of PMQR genes over time and an association between increased prevalence of PMQR genes and increasing ciprofloxacin resistance. Finally we could not infer how much each PMQR gene or multiple genes contribute(s) to increase ciprofloxacin MIC in each species. For E. coli, qnrA transferred on a plasmid together with aac(6')-Ib-cr conferred a ciprofloxacin MIC of 1.0 µg/ml (21), the breakpoint for ciprofloxacin susceptibility. The direct relationship of quinolone MIC and PMQR genes, however, has not been studied under defined genetic conditions in other species of Enterobacteriaceae.

In conclusion, the increasing frequency of quinolone resistance in Enterobacteriaceae was associated with an increasing prevalence and diversity of PMQR genes in consecutive samples of isolates and also an increasing prevalence of the QRDR mutations in PMQR-positive strains. These factors together with increasing use of fluoroquinolones created the opportunity for the emergence of highly quinolone-resistant clinical isolates associated with MDR that compromised therapeutic options in species that were initially highly susceptible to fluoroquinolones and would have been expected to have a low likelihood for the emergence of quinolone resistance.

 
We thank Que Chi Truong-Bolduc, Yanpeng Ding, and Minghua Wang for technical advice and Hee-Chang Jang and Sae-Ick Joo for retrieving the isolates. We also express our gratitude to Minggui Wang and Patrice Courvalin for the gifts of control strains for qnrC and qepA, respectively.

This work was supported in part by grants R01AI057576 (to D.C.H.) and R01AI043312 (to G.A.J.) from the National Institutes of Health, U.S. Public Health Service.

 
* Corresponding author. Mailing address: Division of Infectious Diseases, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114-2696. Phone: (617) 726-3812. Fax: (617) 726-7416. E-mail: dhooper{at}partners.org

Published ahead of print on 8 December 2008.

Top ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

1
1. Cattoir, V., L. Poirel, C. Aubert, C. J. Soussy, and P. Nordmann. 2008. Unexpected occurrence of plasmid-mediated quinolone resistance determinants in environmental Aeromonas spp. Emerg. Infect. Dis. 14:231-237.[Medline]
2
2. Cattoir, V., L. Poirel, V. Rotimi, C. J. Soussy, and P. Nordmann. 2007. Multiplex PCR for detection of plasmid-mediated quinolone resistance qnr genes in ESBL-producing enterobacterial isolates. J. Antimicrob. Chemother. 60:394-397.[Abstract/Free Full Text]
3
3. Corkill, J. E., J. J. Anson, and C. A. Hart. 2005. High prevalence of the plasmid-mediated quinolone resistance determinant qnrA in multidrug-resistant Enterobacteriaceae from blood cultures in Liverpool, United Kingdom. J. Antimicrob. Chemother. 56:1115-1117.[Abstract/Free Full Text]
4
4. Gay, K., A. Robicsek, J. Strahilevitz, C. H. Park, G. Jacoby, T. J. Barrett, F. Medalla, T. M. Chiller, and D. C. Hooper. 2006. Plasmid-mediated quinolone resistance in non-Typhi serotypes of Salmonella enterica. Clin. Infect. Dis. 43:297-304.[CrossRef][Medline]
5
5. Hooper, D. C. 1999. Mechanisms of quinolone resistance. Drug Resist. Updat. 2:38-55.[CrossRef][Medline]
6
6. Hooper, D. C. 2000. Mechanisms of action and resistance of older and newer fluoroquinolones. Clin. Infect. Dis. 31:S24-S28.[CrossRef][Medline]
7
7. Jacoby, G., V. Cattoir, D. Hooper, L. Martínez-Martínez, P. Nordmann, A. Pascual, L. Poirel, and M. Wang. 2008. qnr gene nomenclature. Antimicrob. Agents Chemother. 52:2297-2299.[Free Full Text]
8
8. Jacoby, G. A. 2005. Mechanisms of resistance to quinolones. Clin. Infect. Dis. 41(Suppl. 2):S120-S126.[CrossRef]
9
9. Jacoby, G. A., K. E. Walsh, D. M. Mills, V. J. Walker, H. Oh, A. Robicsek, and D. C. Hooper. 2006. qnrB, another plasmid-mediated gene for quinolone resistance. Antimicrob. Agents Chemother. 50:1178-1182.[Abstract/Free Full Text]
10
10. Jiang, Y., Z. Zhou, Y. Qian, Z. Wei, Y. Yu, S. Hu, and L. Li. 2008. Plasmid-mediated quinolone resistance determinants qnr and aac(6')-Ib-cr in extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in China. J. Antimicrob. Chemother. 61:1003-1006.[Abstract/Free Full Text]
11
11. Mammeri, H., M. Van De Loo, L. Poirel, L. Martínez-Martínez, and P. Nordmann. 2005. Emergence of plasmid-mediated quinolone resistance in Escherichia coli in Europe. Antimicrob. Agents Chemother. 49:71-76.[Abstract/Free Full Text]
12
12. Martínez-Martínez, L., A. Pascual, and G. A. Jacoby. 1998. Quinolone resistance from a transferable plasmid. Lancet 351:797-799.[CrossRef][Medline]
13
13. Minarini, L. A. R., L. Poirel, V. Cattoir, A. L. Darini, and P. Nordmann. 2008. Plasmid-mediated quinolone resistance determinants among enterobacterial isolates from outpatients in Brazil. J. Antimicrob. Chemother. 62:474-478.[Abstract/Free Full Text]
14
14. National Committee for Clinical Laboratory Standards. 2003. Performance standards for antimicrobial disk susceptibility tests. Approved standard M2-A8. NCCLS, Wayne, PA.
15
15. Nordmann, P., and L. Poirel. 2005. Emergence of plasmid-mediated resistance to quinolones in Enterobacteriaceae. J. Antimicrob. Chemother. 56:463-469.[Abstract/Free Full Text]
16
16. Pai, H., M. R. Seo, and T. Y. Choi. 2007. Association of QnrB determinants and production of extended-spectrum β-lactamases or plasmid-mediated AmpC β-lactamases in clinical isolates of Klebsiella pneumoniae. Antimicrob. Agents Chemother. 51:366-368.[Abstract/Free Full Text]
17
17. Park, C. H., A. Robicsek, G. A. Jacoby, D. Sahm, and D. C. Hooper. 2006. Prevalence in the United States of aac(6')-Ib-cr encoding a ciprofloxacin-modifying enzyme. Antimicrob. Agents Chemother. 50:3953-3955.[Abstract/Free Full Text]
18
18. Park, Y. J., J. K. Yu, S. Lee, E. J. Oh, and G. J. Woo. 2007. Prevalence and diversity of qnr alleles in AmpC-producing Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, and Serratia marcescens: a multicentre study from Korea. J. Antimicrob. Chemother. 60:868-871.[Abstract/Free Full Text]
19
19. Périchon, B., P. Courvalin, and M. Galimand. 2007. Transferable resistance to aminoglycosides by methylation of G1405 in 16S rRNA and to hydrophilic fluoroquinolones by QepA-mediated efflux in Escherichia coli. Antimicrob. Agents Chemother. 51:2464-2469.[Abstract/Free Full Text]
20
20. Robicsek, A., D. F. Sahm, J. Strahilevitz, G. A. Jacoby, and D. C. Hooper. 2005. Broader distribution of plasmid-mediated quinolone resistance in the United States. Antimicrob. Agents Chemother. 49:3001-3003.[Abstract/Free Full Text]
21
21. Robicsek, A., J. Strahilevitz, G. A. Jacoby, M. Macielag, D. Abbanat, K. Bush, and D. C. Hooper. 2006. Fluoroquinolone modifying enzyme: a novel adaptation of a common aminoglycoside acetyltransferase. Nat. Med. 12:83-88.[CrossRef][Medline]
22
22. Robicsek, A., J. Strahilevitz, D. F. Sahm, G. A. Jacoby, and D. C. Hooper. 2006. qnr prevalence in ceftazidime-resistant Enterobacteriaceae isolates from the United States. Antimicrob. Agents Chemother. 50:2872-2874.[Abstract/Free Full Text]
23
23. Robicsek, A., G. A. Jacoby, and D. C. Hooper. 2006. The worldwide emergence of plasmid-mediated quinolone resistance. Lancet Infect. Dis. 6:629-640.[CrossRef][Medline]
24
24. Rodríguez-Martínez, J. M., C. Velasco, I. Garcia, M. E. Cano, L. Martínez-Martínez, and A. Pascual. 2007. Mutant prevention concentrations of fluoroquinolones for Enterobacteriaceae expressing the plasmid-carried quinolone resistance determinant qnrA1. Antimicrob. Agents Chemother. 51:2236-2239.[Abstract/Free Full Text]
25
25. Rodríguez-Martínez, J. M., C. Velasco, A. Pascual, I. Garcia, and L. Martínez-Martínez. 2006. Correlation of quinolone resistance levels and differences in basal and quinolone-induced expression from three qnrA-containing plasmids. Clin. Microbiol. Infect. 12:440-445.[CrossRef][Medline]
26
26. Sánchez-Céspedes, J., M. D. Blasco, S. Marti, V. Alba, E. Alcalde, C. Esteve, and J. Vila. 2008. Plasmid-mediated QnrS2 determinant from a clinical Aeromonas veronii isolate. Antimicrob. Agents Chemother. 52:2990-2991.[Free Full Text]
27
27. Strahilevitz, J., D. Engelstein, A. Adler, V. Temper, A. E. Moses, C. Block, and A. Robicsek. 2007. Changes in qnr prevalence and fluoroquinolone resistance in clinical isolates of Klebsiella pneumoniae and Enterobacter spp. collected from 1990 to 2005. Antimicrob. Agents Chemother. 51:3001-3003.[Abstract/Free Full Text]
28
28. Wang, M., J. H. Tran, G. A. Jacoby, Y. Zhang, F. Wang, and D. C. Hooper. 2003. Plasmid-mediated quinolone resistance in clinical isolates of Escherichia coli from Shanghai, China. Antimicrob. Agents Chemother. 47:2242-2248.[Abstract/Free Full Text]
29
29. Wang, M., X. Xu, and S. Wu. 2008. A new plasmid-mediated gene for quinolone resistance, qnrC. Abstr. 18th Eur. Congr. Clin. Microbiol. Infect. Dis., abstr. O207.
30
30. Wu, J. J., W. C. Ko, S. H. Tsai, and J. J. Yan. 2007. Prevalence of plasmid-mediated quinolone resistance determinants QnrA, QnrB, and QnrS among clinical isolates of Enterobacter cloacae in a Taiwanese hospital. Antimicrob. Agents Chemother. 51:1223-1227.[Abstract/Free Full Text]
31
31. Wu, J. J., W. C. Ko, H. M. Wu, and J. J. Yan. 2008. Prevalence of Qnr determinants among bloodstream isolates of Escherichia coli and Klebsiella pneumoniae in a Taiwanese hospital, 1999-2005. J. Antimicrob. Chemother. 61:1234-1239.[Abstract/Free Full Text]
32
32. Yamane, K., J. I. Wachino, S. Suzuki, K. Kimura, N. Shibata, H. Kato, K. Shibayama, T. Konda, and Y. Arakawa. 2007. New plasmid-mediated fluoroquinolone efflux pump, QepA, found in an Escherichia coli clinical isolate. Antimicrob. Agents Chemother. 51:3354-3360.[Abstract/Free Full Text]
33
33. Yamane, K., J.-I. Wachino, S. Suzuki, and Y. Arakawa. 2008. Plasmid-mediated qepA gene among Escherichia coli clinical isolates from Japan. Antimicrob. Agents Chemother. 52:1564-1566.[Abstract/Free Full Text]

---

Antimicrobial Agents and Chemotherapy, February 2009, p. 639-645, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.01051-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Strahilevitz, J., Jacoby, G. A., Hooper, D. C., Robicsek, A. (2009). Plasmid-Mediated Quinolone Resistance: a Multifaceted Threat. Clin. Microbiol. Rev. 22: 664-689 [Abstract] [Full Text]  
• Kim, H. B., Wang, M., Park, C. H., Kim, E.-C., Jacoby, G. A., Hooper, D. C. (2009). oqxAB Encoding a Multidrug Efflux Pump in Human Clinical Isolates of Enterobacteriaceae. Antimicrob. Agents Chemother. 53: 3582-3584 [Abstract] [Full Text]  
• Jacoby, G. A., Gacharna, N., Black, T. A., Miller, G. H., Hooper, D. C. (2009). Temporal Appearance of Plasmid-Mediated Quinolone Resistance Genes. Antimicrob. Agents Chemother. 53: 1665-1666 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, H. B. Articles by Hooper, D. C. Search for Related Content PubMed PubMed Citation Articles by Kim, H. B. Articles by Hooper, D. C.