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Antimicrobial Agents and Chemotherapy, April 2004, p. 1400-1401, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1400-1401.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activities of Newer Quinolones against Escherichia coli and Klebsiella pneumoniae Containing the Plasmid-Mediated Quinolone Resistance Determinant qnr

Minggui Wang,1,2 Daniel F. Sahm,3 George A. Jacoby,4 Yingyuan Zhang,2 and David C. Hooper1*

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114,1 Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai 200040, China,2 Focus Technologies, Herndon, Virginia 20171,3 Infectious Disease Department, Lahey Clinic, Burlington, Massachusetts 018054

Received 10 October 2003/ Returned for modification 19 December 2003/ Accepted 30 December 2003


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ABSTRACT
 
Seventeen qnr-containing transconjugants were constructed with azide-resistant Escherichia coli J53 as the recipient, and the MICs of 12 quinolones were tested by agar dilution methods. Sitafloxacin, BAYy3118, and premafloxacin had higher activity in vitro than ciprofloxacin against transconjugants and donors containing qnr. The donors had higher quinolone MICs than the transconjugants.


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TEXT
 
Plasmid-mediated quinolone resistance was discovered in a clinical isolate of Klebsiella pneumoniae from Birmingham, Ala. (6). The gene responsible, qnr, has since been detected in more than 20 clinical strains of K. pneumoniae and Escherichia coli isolated in the United States and China. qnr confers low-level ciprofloxacin resistance (4, 6, 9, 11; M. Wang, D. F. Sahm, G. A. Jacoby, and D. C. Hooper, unpublished observations). Newer quinolones have enhanced potency against many resistant strains. Some newer quinolones have the same or only slightly higher MICs for DNA gyrase or topoisomerase IV mutants or mutants with efflux pump overexpression (1, 2, 8). They have not yet been studied for the protective effects of qnr. We constructed transconjugants containing different qnr plasmids and determined the activity of newer quinolones against both transconjugants and donor strains.

Construction of qnr-containing transconjugants. Seventeen transconjugants were obtained by conjugation with azide-resistant E. coli J53AzR as the recipient from 14 unique qnr-containing clinical strains, six E. coli and eight K. pneumoniae, which were screened in former studies (11; Wang et al., unpublished observations). Nine transconjugants were from six E. coli donors (transconjugants of different phenotypes were selected from each of three donors), seven from K. pneumoniae donors, and one from UAB1 (the original K. pneumoniae strain found to contain plasmid pMG252 carrying qnr).

Activity of newer quinolones against transconjugants. The MICs of 12 fluoroquinolones were tested by agar dilution (7). The fluoroquinolones tested included AM-1121 (Bristol-Myers Squibb, Princeton, N.J.), BAYy3118 and ciprofloxacin (Bayer Corporation, West Haven, Conn.), garenoxacin and gatifloxacin (Bristol-Myers Squibb), gemifloxacin (GlaxoSmithKline, West Sussex, United Kingdom), levofloxacin (Ortho/McNeil Pharmaceuticals, Raritan, N.J.), moxifloxacin (Bayer Corporation), norfloxacin (Sigma Chemical Co., St. Louis, Mo.), premafloxacin, which was previously under development for veterinary use (Pharmacia & Upjohn, Kalamazoo, Mich.), sitafloxacin (Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan), and sparfloxacin (Dainippon Pharmaceutical Co., Ltd., Osaka, Japan).

Sitafloxacin, BAYy3118, and premafloxacin had four- to eightfold higher in vitro activity (MIC for 90% of strains, 0.125 to 0.25 µg/ml) than did ciprofloxacin (MIC for 90% of strains, 1 µg/ml) against transconjugants containing qnr. Compared to plasmid-free J53, the MIC of sitafloxacin increased 15-fold, that of BAYy3118 increased 32-fold, and that of ciprofloxacin increased 125-fold. These three newer quinolones were also more active than ciprofloxacin against the donor strains which contained qnr and other resistance mechanisms. The activities of gatifloxacin, levofloxacin, AM-1121, gemifloxacin, and moxifloxacin were similar to that of ciprofloxacin. All quinolone MICs of the donors were all higher than those of the transconjugants, indicating the occurrence of additional resistance mechanisms in the donor strains that acted in concert with qnr (Table 1).


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  		TABLE 1. In vitro activity of newer quinolones against transconjugants containing qnr and donor strainsa

The MICs of each quinolone against eight transconjugants constructed from donor strains of K. pneumoniae isolated in the United States were the same or differed by no more than twofold. The quinolone MICs for nine transconjugants constructed from donor strains of E. coli isolated in Shanghai, China, exhibited substantial differences in susceptibility (ciprofloxacin MICs ranged from 0.125 to 2 µg/ml). The MICs of the three newer quinolones sitafloxacin, BAYy3118, and premafloxacin were substantially lower than that of ciprofloxacin. All E. coli donors were highly resistant to ciprofloxacin (MIC, 64 to >=256 µg/ml), while MICs of ciprofloxacin for K. pneumoniae donors were lower, 2 to 16 µg/ml (Table 2).


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  		TABLE 2. Comparison of the MICs of transconjugants of E. coli with transconjugants of K. pneumoniae and of MICs of the donors

Several newer quinolones appear to have greater and more closely balanced activity against DNA gyrase and topoisomerase IV (1, 3). Purified Qnr has been shown to block ciprofloxacin inhibition of both DNA gyrase (10) and topoisomerase IV (J. Tran, G. Jacoby, and D. Hooper, unpublished observations) and to have additive effects with gyrA mutations in intact cells (5). In this study we showed that some newer quinolones have enhanced in vitro activity against transconjugants carrying qnr on a plasmid, indicating that their increased potency extends to the new qnr-mediated resistance mechanism. Sitafloxacin, BAYy3118, and premafloxacin were the most potent of the quinolones studied against the qnr-containing transconjugants, exceeding even the potency of ciprofloxacin, heretofore one of the most active quinolones against gram-negative bacteria.

The MICs of each quinolone against eight transconjugants constructed from clinical strains of K. pneumoniae were similar or identical despite differences in the plasmids carrying qnr (Wang et al., unpublished data). In contrast, there were differences in the level of resistance in transconjugants constructed from E. coli donor strains isolated in Shanghai (11). These differences suggest differences in the levels of expression of qnr. Levels of qnr expression and the molecular basis for the observed differences are under investigation.

qnr can supplement resistance via altered quinolone target enzymes, efflux pump activation, or deficiencies in outer membrane porin channels (5). The higher resistance to all quinolones tested in donor compared to transconjugant strains reflects such additional chromosomal resistance mutations.


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ACKNOWLEDGMENTS
 
This work was supported by grants AI43312 (to G.A.J. and D.C.H.) from the National Institutes of Health, U.S. Public Health Service, and grants from Daiichi Pharmaceutical Co., Ltd., and Kyorin Pharmaceuticals (to D.C.H.).


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


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Antimicrobial Agents and Chemotherapy, April 2004, p. 1400-1401, Vol. 48, No. 4
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.4.1400-1401.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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