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Volume 13, Number 5—May 2007

Expanded-spectrum β-Lactamase and Plasmid-mediated Quinolone Resistance

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To the Editor: The emergence of plasmid-mediated, and thus transferable, quinolone resistance determinants has been recently discovered (1) and shown to involve the pentapeptide repeat protein Qnr, which interacts with DNA gyrase and topoisomerase IV to prevent quinolone inhibition (2,3). Qnr determinants confer resistance to nalidixic acid and reduced susceptibility to fluoroquinolones (3). They have been identified worldwide in a variety of enterobacterial species and were often associated to expanded-spectrum β-lactamases (ESBLs) (2). The association between the ESBL VEB-1 and the QnrA1 determinants was reported (4). Because plasmid co-localization of QnrA and VEB-1 encoding genes has been reported repeatedly from scattered clonally-unrelated enterobacterial isolates, our objective was to use replicon typing to trace a possible dissemination of a common plasmid worldwide.

The blaVEB-1 and/or qnrA-positive plasmids that have been included in the study were from 17 isolates previously described in detail (38) (Table). Escherichia coli transconjugants (Tc) were obtained for 14 of 17 clinical isolates, allowing an accurate replicon typing since original clinical isolates might harbor several plasmids. They were collected from 1999 to 2005, from patients hospitalized in different parts of the world (Table). The 13 blaVEB-1-positive isolates were from 5 countries (France, Turkey, Algeria, Thailand, and Canada), scattered on 4 continents. Among them, the Providencia stuartii and Proteus mirabilis isolates from Algeria were negative for qnrA1. In addition, 4 blaVEB-1-negative but qnrA1-positive isolates recovered from France and Australia were also included in the study.

PCR-based replicon typing (PBRT), which recognizes FIA, FIB, FIC, HI1, HI2, I1-Ig, L/M, N, P, W, T, A/C, K, B/O, X, Y, and FII replicons (9), was applied to type the resistance plasmids from all the strains. Amplicons were confirmed by DNA sequencing and used as probes in hybridization experiments on purified plasmids (data not shown).

PBRT results showed that the 13 blaVEB-1-positive plasmids (including 11 qnrA1-positive) belonged to the IncA/C incompatibility group. DNA sequencing identified the A/C2 replicon variant (European Molecular Biology Laboratory no. AM087198) in all these plasmids (Table). Plasmids of this type were recently identified in the United States and in Italy carrying the AmpC-type cephalosporinase CMY-4–encoding gene (10). In 2 strains (E. coli TcGOC and Citrobacter freundii LUT), the IncA/C2 plasmids were associated with additional replicons, which suggests the presence of multiple plasmids or fusions between plasmids of different backbones. By contrast, all the 4 blaVEB-1-negative isolates but qnrA1-positive were negative for the A/C replicon, except transconjugant TcK147; however, sequencing identified an A/C1-type replicon in that strain. These results indicated that the genes encoding QnrA1 and VEB-1, when identified concomitantly in a given isolate, were always located on plasmids belonging to the same IncA/C2-incompatibility group that may vary in size and digestion pattern (Table; unpub. data). In addition, we showed that plasmids carrying the blaVEB-1 gene but lacking qnrA1 were also of the IncA/C2 type (Table). Plasmids that were blaVEB-1-negative but qnrA1-positive were of distinct replicon types, thus suggesting independent acquisition of the qnrA1 gene on different plasmids. It is remarkable that since VEB-1 is apparently always encoded by IncA/C2 plasmids, when genes for QnrA1 and VEB-1 are found together, they also occur on IncA/C2 plasmids.

Thus, evidence here shows that the IncA/C2 plasmid is the main vehicle of the blaVEB-1 gene worldwide, on which the qnrA1 gene may be added. The possibility that both blaVEB-1 and qnrA1 genes may be identified on a single genetic structure in several isolates has been recently shown with their identification within the same sul1-type integron (6).

Since results of these experiments provided a good marker for tracing blaVEB-1-positive plasmids, and taking in account the property of A/C-type plasmids to have a broad range of hosts (note: this has not been demonstrated for the specific A/C2 subgroup), we tried to amplify the A/C2 replicon in a collection of 15 blaVEB-1-positive and clonally unrelated Pseudomonas aeruginosa isolates from France, Thailand, India, and Kuwait. The blaVEB-1 gene was supposed to be chromosome-encoded in those isolates. PCR failed to give any positive results, confirming the absence of an IncA/C-type plasmid and also ruling out the hypothesis of IncA/C2-type plasmid co-integration at the origin of blaVEB-1 acquisition in P. aeruginosa.

The spread of plasmids carrying a large array of resistance genes among Enterobacteriaceae is of concern since this provides a convenient genetic mechanism for a given strain to become panresistant to antimicrobial drugs. In particular, the recent identification of the Qnr determinants have shown that plasmids may provide resistance (or at least reduced susceptibility) to quinolones and fluoroquinolones, whereas they are already known to carry resistance to β-lactams, aminoglycosides, chloramphenicol, tetracycline, rifampin, sulfonamides, and disinfectants. pQR1 (4) or p1 (6) are examples of well-characterized plasmids that mediate multidrug resistance by carrying blaVEB-1 and qnrA1, together with aminoglycoside resistance genes aadB, aacA1, and aadA1, chloramphenicol resistance gene cmlA, rifampin resistance gene arr2, disinfectant resistance gene qacI, and sulfonamides resistance gene sul1.

Our study showed that the IncA/C2-type plasmids may be the source of such worldwide dissemination. It means that 1 plasmid scaffold has brought the same (or at least very similar) multidrug resistance to multiple enterobacterial species in different continents.



We thank S. Bernabeu for technical assistance.

This work was funded by grants from the European Community (6th PCRD, LSHM-CT-2005-018705).


Laurent Poirel*Comments to Author , Laura Villa†, Alessia Bertini†, Johann D. Pitout‡, Patrice Nordmann*, and Alessandra Carattoli†
Author affiliations: *Hôpital de Bicêtre, K.-Bicêtre, France; †University of Calgary, Calgary, Alberta, Canada; ‡Istituto Superiore di Sanita, Rome, Italy;



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DOI: 10.3201/eid1305.061293

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Laurent Poirel, Service de Bactériologie-Virologie, Hôpital de Bicêtre, 78 Rue du Général Leclerc, 94275 Le Kremlin-Bicêtre, CEDEX, France;

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