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Antimicrobial Agents and Chemotherapy, July 2005, p. 3091-3094, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.3091-3094.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Association of Plasmid-Mediated Quinolone Resistance with Extended-Spectrum ß-Lactamase VEB-1

Laurent Poirel, Marc Van De Loo, Hedi Mammeri, and Patrice Nordmann*

Service de Bactériologie-Virologie, Hôpital de Bicêtre, Assistance Publique/Hôpitaux de Paris, Faculté de Médecine Paris-Sud, Université Paris XI, 94275 Le Kremlin-Bicêtre, France

Received 10 December 2004/ Returned for modification 5 February 2005/ Accepted 12 March 2005


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ABSTRACT
 
Association of the plasmid-mediated quinolone resistance determinant QnrA and the blaVEB-1 gene was identified in a single Enterobacter cloacae isolate from K.-Bicêtre, France, and in 11 out of 23 blaVEB-1-positive enterobacterial isolates from Bangkok, Thailand. This result may explain in part the association between quinolone and extended-spectrum ß-lactam resistance.


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TEXT
 
Quinolone resistance results mostly from chromosomal mutations in genes coding for DNA gyrase and topoisomerase IV and from changes in outer membrane or efflux proteins or their regulatory mechanisms in Enterobacteriaceae (28). However, plasmid-mediated resistance to quinolone was first reported in 1998 for a Klebsiella pneumoniae isolate from the United States (11). The plasmid-encoded protein responsible for resistance, named Qnr (and recently termed QnrA [A. Robicsek, D. F. Sahm, G. Jacoby, and D. C. Hooper, Abstr. 44th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C2-1898a, 2004]), protects DNA gyrase and topoisomerase IV from the inhibitory activity of quinolones (29; J. H. Tran, G. A. Jacoby, and D. C. Hooper, Abstr. 43rd Intersci. Conf. Antimicrob. Agents Chemother, abstr. C1-604, 2003). It confers resistance to nalidixic acid and increases fluoroquinolone MICs up to 32-fold (9, 11, 30, 31). qnrA-positive isolates are increasingly identified in the United States (7, 30), and there are scattered reports of their presence in Asia (31) and Europe (8, 9). Several qnrA-positive isolates produced clavulanic acid-inhibited extended-spectrum ß-lactamases (ESBL) such as SHV-7 and CTX-M-9 (31).

In a previous study, we reported a single qnrA-positive Escherichia coli isolate that produced the ESBL VEB-1 among nalidixic acid-resistant E. coli isolates at the Bicêtre Hospital in 2003 (9). The main goal of the present study was to search for QnrA determinants among nalidixic acid-resistant isolates (n = 152) belonging to other enterobacterial species from the same hospital and to search for any association between QnrA and VEB-1 among other characterized isolates. A series of blaVEB-1-positive and blaVEB-1-negative nonreplicate isolates from Thailand and strains that contained other reference ß-lactamases were screened (Table 1). A qnrA-like gene was searched for by PCR using previously reported primers (9, 31). A qnrA-like gene was detected in a single Enterobacter cloacae isolate (GOC) among all nalidixic acid-resistant isolates from Bicêtre Hospital in 2003. The estimated prevalence of this gene was 4% among ESBL-positive enterobacterial isolates (n = 24). E. cloacae GOC was isolated in January 2003 from the urine of a 22-year-old man who had multiple urinary tract infections due to cystic diverticulosis and who was treated successively with ciprofloxacin and imipenem. A qnrA-like gene was also detected in 11 out of 23 blaVEB-1-positive enterobacterial isolates (48%) from Bangkok in 1999 (Table 1). It was identified in Enterobacter sakazakii and constituted the first description of the gene in that species (Table 2). Sequence analysis of the PCR-amplified products identified the same qnrA gene in all cases (29). No qnrA-like gene was identified either in blaVEB-1-positive enterobacterial isolates from any country except France and Thailand, in ESBL-positive, blaVEB-1-negative enterobacterial isolates from Thailand, in blaVEB-1-positive Pseudomonas aeruginosa isolates from Thailand, or in other strains that contained reference ß-lactamase genes (Table 1). These results showed that the blaVEB-1 gene was frequently but not systematically associated with a QnrA determinant, and only in Enterobacteriaceae.


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  		TABLE 1. Strains screened for qnrA-like gene


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  		TABLE 2. MICs of quinolones for clinical isolates carrying the qnrA gene, their transconjugants (Tc strains), and the E. coli J53 recipient straina

Conjugations were carried out by a filter mating technique with E. coli J53 AzR as the recipient, as previously described (9). Conjugation experiments yielded qnrA-positive transconjugants for E. cloacae GOC and for most of the qnrA-positive enterobacterial isolates from Thailand except for E. coli E2, E. coli E10, and E. sakazakii E15 (Table 2). Electrophoresis of the plasmid extracts from these latter isolates and from the transconjugants obtained with the other clinical isolates as donors was followed by Southern hybridization, as described elsewhere (9, 21). The probes consisted of a 661-bp fragment for qnrA and a 627-bp fragment for blaVEB-1 (9). Each strain contained a single plasmid that cohybridized with qnrA- and veb-1-specific probes (Fig. 1). The molecular sizes of the plasmids ranged from 130 to 200 kb (Fig. 1; Table 2).



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  		FIG. 1. Plasmid DNAs from clinical isolates and transconjugants (A) and Southern hybridizations with the blaVEB-1 (B) and the qnrA-like (C) probe. Lanes: 1, E. coli J53/pQR1 (used as a control); 2, E. coli J53/pMG252 (used as a control); 3, E. coli TcE1; 4, E. coli E2; 5, E. coli TcE3; 6, E. coli TcE4; 7, E. coli TcE5; 8, E. coli TcE7; 9, E. coli TcE8; 10, E. coli E10; 11, E. sakazakii E15; 12, E. coli TcE16; 13, E. coli TcE18; 14, E. cloacae GOC; M, E. coli 50192 (used as a molecular size marker [9] and negative control).

Disk diffusion susceptibility testing and MIC determinations, performed as described elsewhere (9), showed that transconjugants were resistant to nalidixic acid, chloramphenicol, tobramycin, sulfonamides, and most ß-lactams, including ampicillin, cefotaxime, and ceftazidime. Resistance to trimethoprim was cotransferred only in transconjugant TcE3 (Table 2). Whereas transconjugants were always resistant to nalidixic acid, clinical isolates 7, 10, and 18 were susceptible (Table 2). These results are reminiscent of a previous study indicating that the QnrA determinant may be expressed at variable levels, possibly depending on host functions (10). As shown previously, combined mechanisms of resistance might explain resistance to fluoroquinolones in the qnrA-positive clinical strains (9-11).

Using a series of specific primers (3, 5, 12, 13, 14, 18, 20), the blaVEB-1 and blaOXA-10 genes were identified in all qnrA-positive isolates. Both of these ß-lactamase genes were located in a class 1 integron that has been characterized in detail previously (5, 9, 26). Using a PCR-based strategy, the structures of the qnrA-type-containing integrons identified from the resistance plasmids of the 12 enterobacterial isolates reported in this study were determined. The qnrA-like gene was located in sul1-type class 1 integrons. It was bracketed by a duplication of the 3' conserved sequence region of the class 1 integron and was not associated with a 59-bp element as reported previously (9). These sul1-type integrons were almost identical, at least in their central regions, to the sul1-type integron of pQR1 from the E. coli Lo strain previously found at the Bicêtre Hospital (Fig. 2), (9). A 2-bp deletion was found at the right boundary of the CR1 element that contained orf513 compared to the structure identified in pMG252 (Fig. 2) (31). This result indicated that the mobilization mechanism of the qnrA gene mediated by CR1 may vary. Further PCR amplifications revealed that strains 1, 4, 5, and GOC contained another copy of the orf513 gene immediately downstream of the sul1-type integron, whereas this orf513 duplication was not found for strains 2, 3, 7, 8, 10, 15, 16, and 18 (Fig. 2).



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  		FIG. 2. Schematic comparison of the different sul1-type integrons that contain the qnrA gene. Shown are the structures of sul1-type integrons identified in pMG252 from K. pneumoniae (A) (29), in pQR1 from E. coli Lo (B) (9), in enterobacterial isolates from Thailand and E. cloacae isolate GOC from Bicêtre (C), and in other enterobacterial isolates from Thailand (D). The vertical rectangle indicates the right-hand boundary of the CR1 element as determined previously (9), and the vertical arrow stands for a 2-bp deletion. Question mark indicates DNA sequences that are unknown but different from those reported in panels A, B, and C. Dashed vertical lines indicate the absence of the DNA fragment between qnrA and qacE{Delta}1 in pMG252.

This study further underlines the spread of the QnrA determinant in Europe (being the second report from France [9]) and in Southeast Asia. Association of the qnrA and blaVEB-1 genes may account in part for the association between expanded-spectrum cephalosporins and fluoroquinolone resistance (16). Finally, identification of QnrA-positive and nalidixic acid-susceptible clinical isolates raised concern about a hidden spread of this resistance determinant.

Nucleotide sequence accession numbers. The nucleotide sequences reported here have been assigned accession numbers AY931017 and AY931018.


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ACKNOWLEDGMENTS
 
This work was funded by a grant from the Ministère de l'Education Nationale et de la Recherche (UPRES-EA3539), Université Paris XI, France, and by the European Community (6th PCRD, LSHM-CT-2003-503-335). L.P. is a researcher from INSERM, Paris, France.


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FOOTNOTES
 
* Corresponding author. Mailing address: Service de Bactériologie-Virologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin-Bicêtre cedex, France. Phone: 33-1-45-21-36-32. Fax: 33-1-45-21-63-40. E-mail: nordmann.patrice{at}bct.ap-hop-paris.fr. Back


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Antimicrobial Agents and Chemotherapy, July 2005, p. 3091-3094, Vol. 49, No. 7
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.7.3091-3094.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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