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Antimicrobial Agents and Chemotherapy, February 2003, p. 559-562, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.559-562.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Prevalence of Plasmid-Mediated Quinolone Resistance

George A. Jacoby,1* Nancy Chow,1 and Ken B. Waites2

Infectious Disease Department, Lahey Clinic, Burlington, Massachusetts,1 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama2

Received 6 August 2002/ Returned for modification 16 September 2002/ Accepted 4 November 2002


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ABSTRACT
 
Quinolone resistance encoded by the qnr gene and mediated by plasmid pMG252 was discovered in a clinical strain of Klebsiella pneumoniae that was isolated in 1994 at the University of Alabama at Birmingham Medical Center. The gene codes for a protein that protects DNA gyrase from quinolone inhibition and that belongs to the pentapeptide repeat family of proteins. The prevalence of the gene has been investigated by using PCR with qnr-specific primers with a sample of more than 350 gram-negative strains that originated in 18 countries and 24 states in the United States and that included many strains with plasmid-mediated AmpC or extended spectrum ß-lactamase enzymes. qnr was found in isolates from the University of Alabama at Birmingham only during 6 months in 1994, despite the persistence of the gene for FOX-5 ß-lactamase, which is linked to qnr on pMG252. Isolates from other locations were negative for qnr. The prevalence of mcbG in the same sample was also examined. mcbG encodes another member of the pentapeptide repeat family and is involved in immunity to microcin B17, which, like quinolones, targets DNA gyrase. A single clinical isolate contained mcbG on a transmissible R plasmid. This plasmid and one carrying the complete microcin B17 operon slightly decreased sparfloxacin susceptibility but had a much less protective effect than pMG252. Plasmid-mediated quinolone resistance was thus rare in the sample examined.


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INTRODUCTION
 
Plasmid pMG252, which mediates low-level quinolone resistance, was discovered in a Klebsiella pneumoniae strain that was isolated in July 1994 from the urine of a patient at the University of Alabama at Birmingham Medical Center (UAB) (9). The plasmid increased resistance to both nalidixic acid and fluoroquinolones, had a broad host range, and belonged to the plasmid incompatibility group IncC (9). The only previous claim of naturally occurring, transmissible quinolone resistance (11) involved a plasmid from a Shigella dysenteriae isolate from Bangladesh, but the claim was later withdrawn (1).

The quinolone resistance gene (qnr) has been cloned and sequenced (16). Purified Qnr blocks ciprofloxacin inhibition of DNA gyrase and belongs to the pentapeptide repeat family of proteins (2) that also includes McbG, which with McbE and McbF protects a microcin B17-producing strain from self- inhibition (3). Microcins are a class of small inhibitory proteins (less than 10 kDa) that are encoded by bacterial plasmids and differ in their mechanisms of action. Microcin B17, like quinolones, targets DNA gyrase, and McbEFG has been reported to produce low-level resistance to quinolones such as sparfloxacin (8).

Plasmid pMG252 also encodes the AmpC-type ß-lactamase FOX-5, which has been found at other sites in the United States (15). Quinolone resistance is unexpectedly high (18 to 56%) in extended-spectrum ß-lactamase-producing (ESBL) isolates (5, 7, 14). The prevalence of qnr and mcbG in clinical isolates is not known. We have used PCR to determine the frequencies of both genes in a sample of more than 350 strains, including many with plasmid-mediated AmpC or ESBL enzymes, and have also traced the fate of qnr in resistant isolates from the UAB, where it was discovered.


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MATERIALS AND METHODS
 
Strains. K. pneumoniae UAB1 containing pMG252 (9) served as a positive control for the presence of qnr. Escherichia coli RYC1000(pMM39), a pBR322 derivative carrying mcbABCDEFG (3), came from Rosario Baquero and provided a positive control for mcbG. S. dysenteriae containing plasmid pICD01 (1), initially reported as conferring quinolone resistance (11), was provided by David Sack. E. coli J53 Azir (azide resistant) (6) was a common host for many plasmids.

In the UAB clinical laboratory, consecutive oxyimino-ß-lactam-resistant, gram-negative strains were collected between June 1994 and June 1995 (33 isolates) and from September 2000 to April 2001 (26 isolates). Each strain came from a unique patient. Strains were identified and antimicrobial susceptibility was determined according to routine laboratory protocols by using WalkAway 96 Gram-Negative MIC Combo Panels (Dade Microscan, West Sacramento, Calif.). By this evaluation, 24 of the UAB strains were ofloxacin resistant, 2 were intermediate, and 33 were susceptible. Other test strains were chosen to represent different genera of gram-negative bacilli and diverse geographical origins. The test strains came from Argentina, Bangladesh, Belgium, Brazil, Bulgaria, Canada, England, France, Germany, Greece, India, Italy, Japan, Korea, Mexico, Spain, Switzerland, Tunisia, and 24 states in the United States. Most were collected in the 1990s. In addition to 191 Klebsiella pneumoniae strains and 91 E. coli strains, the sample contained isolates of the following organisms (with numbers of isolates shown in parentheses): Achromobacter xylosoxydans (1), Acinetobacter baumannii (1), Acinetobacter calcoaceticus (1), Citrobacter koseri (1), Enterobacter cloacae (5), Klebsiella oxytoca (10), Kluyvera ascorbata (2), Morganella morganii (2), Proteus mirabilis (5), Providencia rettgeri (1), Providencia stuartii (1), Pseudomonas aeruginosa (20), Salmonella spp. (5), and Serratia marcescens (1). Sixteen stock E. coli strains carrying IncC plasmids R16a, R40a, R40b, R55, R57b, R57b-1, R64, JR211, R692, R707, R715b, R742, R816, plac, pMG202, and pMG203 were included. To ensure a diversity of plasmid types and to test for an association of qnr with extended-spectrum or AmpC-type ß-lactamase genes, the sample incorporated 68 stock plasmid-containing strains producing the following ß-lactamases: ACC-1; ACT-1; CARB-4; CMY-2 and -4; CTX-M-14; DHA-1; FOX-1, -3, -4, and-5; HMS-1; LAT-1; LCR-1; LXA-1; MIR-1; MOX-1 and -2; OHIO-1; OXA-1, -2, -3, -4, -5, -6, -7, and -10; PSE-1 and -3; SAR-1; SHV-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -11, -12, and -18; TEM-1, -2, -3, -4, -5, -6, -7, -8, -9,- 10, -11, -12,-15, -16, -19, -20, -21, -22, -24,-25, -26, -52, -61, -71, and -88.

PCR detection of qnr and mcbG. qnr (length, 657 bp; GenBank accession number AY070235) was amplified by using primers QP1 (5'-GATAAAGTTTTTCAGCAAGAGG; starting at the 12th qnr nucleotide) and QP2 (5'-ATCCAGATCGGCAAAGGTTA) to produce a 593-bp product. PCR conditions were 94°C for 1 min, 57°C for 30 s, and 72°C for 1 min for 30 cycles. mcbG (length, 564 bp; GenBank accession number X07875) was amplified by using primers McbG1 (5'-GAAAAAAGAATCACAAAACGACACC; starting at the 12th mcbG nucleotide) and McbG2 (5'-CCACTCCCATTCGTTTAAGTATTTT) to produce a 538-bp product. PCR conditions were 94°C for 1 min, 61°C for 30 s, and 72°C for 1 min. Products were detected by electrophoresis on a 1% agarose gel by using Tris-borate-EDTA buffer (Sigma, St. Louis, Mo.), stained with 0.5 mg of ethidium bromide/ml and photographed under UV light. Strains positive and negative for qnr and mcbG were included in each batch of strains tested. The amplification product obtained from pMG277 was analyzed further by using primers McbG1 and McbG2 via cycle sequencing (Perkin-Elmer Cetus, Norwalk, Conn.).

ß-Lactamase characterization. Unknown ß-lactamases were initially characterized, usually in E. coli J53 Azir transconjugants, by isoelectric focusing on polyacrylamide gels incorporating a pH 3.0 to 9.0 gradient with the PhastSystem (Pharmacia Biotech, Uppsala, Sweden) as described by Huovinen (4). The FOX-5 ß-lactamase of pMG252 was identified by cloning and nucleotide sequencing. Strains making AmpC-type enzymes with similar isoelectric points and producing a characteristic PCR product with FOX-specific primers came from Dallas, Fort Worth, and San Antonio, Tex.; Coral Gables, Fla., and northern Florida; Greensboro, N.C.; and Rochester, N. Y. (G. Jacoby, J. Tran, and M. Alvarez, Abstr. 39th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1481, 1999).

Other procedures.
Plasmids were transferred to E. coli J53 Azir by transformation or conjugation by using 200 µg of sodium azide per ml for counterselection. Antimicrobial agents other than quinolones were used in mating experiments to avoid selection of quinolone resistance chromosomal mutation. Strains were tested quantitatively for quinolone susceptibility by agar dilution by using Mueller-Hinton medium, ~104 organisms per spot, and overnight incubation at 37°C (12). E. coli J53 Azir and ATCC 25922 were used for quality control. Ciprofloxacin was obtained from Bayer Corporation (West Haven, Conn.), nalidixic acid was from Sigma, and sparfloxacin was from Rhône-Poulenc Rorer. Susceptibility to other antimicrobial agents was determined by disk testing (13). Sparfloxacin-resistant mutants were selected on Mueller-Hinton agar plates containing graded concentrations of the antibiotic spread with 5 x 107 to 10 x 107 bacteria.

RESULTS The qnr gene was sought by PCR by using specific primers in over 350 strains that included 13 genera of gram-negative bacilli originating in 24 states in the United States and 18 other countries. Since strains carrying qnr may test as quinolone susceptible, the sample included both quinolone-susceptible and -resistant isolates. The strains were, however, known to make at least 68 different ß-lactamases, including many ESBL and plasmid-mediated AmpC types. The sample also incorporated strains with 16 plasmids that, like pMG252, belonged to the IncC group and 59 oxyimino-ß-lactam-resistant isolates of E. coli, Klebsiella oxytoca, Klebsiella pneumoniae, Kluyvera ascorbata, and P. aeruginosa collected between June 1994 and April 2001 at the UAB.

At the UAB, qnr could be detected in isolates collected between July and December 1994 (Table 1). Positive isolates included one E. coli isolate, four Klebsiella pneumoniae isolates, and one Klebsiella sp. that came from cultures of urine and sputum. Each was isolated from a different patient. Three of the six strains were resistant to ciprofloxacin, nalidixic acid, and sparfloxacin. All could transfer the same set of antibiotic resistances to E. coli strain J53 Azir on plasmids of similar sizes. Quinolone resistance was, however, somewhat unstable on transfer. With strain UAB1 as the donor, 12 of 100 ceftazidime-resistant J53 transconjugants lost resistance to nalidixic acid, including three that also lost resistance to streptomycin and trimethoprim. J53 derivatives carrying qnr-bearing plasmids from each positive strain were more quinolone resistant than J53 without R plasmid (R-), but only the MIC of nalidixic acid was in the resistant range (Table 1). Ciprofloxacin MICs rose from 0.008 to 0.25 or 0.5 µg/ml, and sparfloxacin MICs increased from <=0.004 to 0.5 µg/ml. The PCR-positive isolates and their transconjugants produced FOX-5 ß-lactamase, but FOX-5- producing clinical isolates at the UAB from January and April 1995 were qnr negative, and none of the 26 UAB specimens collected between September 2000 and April 2001 contained qnr even though FOX-5 was still present in Klebsiella pneumoniae and Klebsiella oxytoca isolates. Strains with plasmid-mediated FOX-5 from Florida, North Carolina, New York, and Texas also failed to amplify with qnr primers.


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  		TABLE 1. Strain properties

The nalidixic acid-resistant strain from Bangladesh that was initially reported (11) to carry plasmid-mediated quinolone resistance was negative for qnr and transferred a plasmid carrying trimethoprim resistance only. The qnr gene was not detected in almost 300 other strains, including many with plasmid-mediated ESBL and AmpC enzymes. The gene was not found in the genomes of 14 genera of gram-negative organisms or in strains with 16 IncC plasmids.

The complete set of strains was also tested for the presence of mcbG by PCR. A single strain gave a positive result that was confirmed by sequencing the amplification product. mcbG was present on a transmissible plasmid (pMG277) mediating resistance to gentamicin, streptomycin, and tetracycline. Curiously, the mcbG-positive strain, E. coli UAB45, also came from the UAB. In J53 Azir, plasmid pMG277 produced a slight increment in resistance to sparfloxacin but did not affect susceptibility to ciprofloxacin or nalidixic acid (Table 1).

To test for the ability of plasmid-containing strains to facilitate selection of higher-level quinolone resistance mutants, plasmids pMG277, positive for mcbG, pMM39, carrying the mcbABCDEFG cluster, pICD01, originally thought to determine quinolone resistance and reported to facilitate nalidixic acid resistance mutations (1), and pMG252, with qnr, were transferred to E. coli J53 as a common host and the strains were spread on plates containing increasing concentrations of sparfloxacin (Table 2). Plasmid pICD01 did not enhance the selection of sparfloxacin-resistant mutants. J53 with pMG277 or pMM39 gave rise to mutants resistant to sparfloxacin at a concentration that was 2-fold higher than that for J53 R-, but their effect was much less dramatic than that of J53 with pMG252, which allowed the selection of mutants at a 32-fold-higher concentration.


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  		TABLE 2. Colonies per Mueller-Hinton agar plate containing increasing concentrations of sparfloxacin spread with 5 x 107 to 108 CFU of the indicated strains

DISCUSSION By using a gene-specific technique, qnr has been found only in strains from the UAB and only in samples collected over a 6-month period in 1994. Isolates from elsewhere, even those encoding the FOX-5 ß-lactamase that is linked to qnr on plasmid pMG252, were nonreactive by PCR. Quinolone resistance mediated by qnr thus appears to be rare, although amplification by PCR requires close sequence homology so that plasmids utilizing the same DNA gyrase-protective mechanism but with genes differing in a few nucleotides from primers QP1 and QP2 could have been overlooked.

Other plasmid-determined genes besides qnr may influence quinolone susceptibility. Plasmid pMM39 carrying mcbABCDEFG decreased sparfloxacin susceptibility two-fold (Table 2). Lomovskaya et al. first described this effect, reporting that the mcbEFG genes were sufficient to reduce sparfloxacin susceptibility, and attributed protection to the pump genes mcbE and mcbF (8). However, mcbG by itself is protective (D. Hooper and J.-L. Yu, personal communication) and encodes a protein that, like Qnr, belongs to the pentapeptide repeat family. PCR with mcbG-specific primers detected in more than 350 tests one strain that carried this gene on transmissible plasmid pMG277, which, like pMM39, decreased sparfloxacin susceptibility (Table 2). Protection was slight, however, and the E. coli clinical isolate in which pMG277 was found tested quinolone susceptible, although a J53(pMG277) transconjugant showed a small increase in sparfloxacin resistance (Table 1). A recently described protein from Mycobacterium smegmatis belongs to the pentapeptide repeat family and causes a four- to eight-fold decrease in sparfloxacin susceptibility (10). Similar proteins are found in Mycobacterium tuberculosis and Mycobacterium avium. All of these proteins are presumably determined by chromosomal genes, but their acquisition by an integron would provide one route for the evolution of plasmid-mediated quinolone resistance. So far the search for a qnr progenitor in the genomes of gram-negative bacteria has been unrevealing, but mycobacteria and organisms such as cyanobacteria, which produce many proteins in the pentapeptide repeat family, have not yet been examined.

Although qnr confers only low-level quinolone resistance and currently seems to be uncommon, its clinical importance lies in its ability to supplement resistance due to DNA gyrase, topoisomerase IV, porin, or efflux mutations (L. Martínez-Martínez, A. Pascual, I. García, J. Tran, and G. A. Jacoby, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C-99, 1998) and to allow selection of such chromosomal mutations at concentrations of quinolone that would be lethal in its absence. Thus, while the sparfloxacin MIC for E. coli J53 was <=0.004 µg/ml (Table 1), mutants of J53 carrying pMG252 could grow at a sparfloxacin concentration of 4 µg/ml (Table 2); in addition, in a clinical isolate of Klebsiella pneumoniae with porin mutations and undoubtedly others, pMG252 can raise the sparfloxacin MIC from 4 to 64 µg/ml and those of other fluoroquinolones to even higher levels (9).


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ACKNOWLEDGMENTS
 
We thank Rosario Baquero and David Sack for providing strains.

This work was supported by Public Health Service grant AI43312 from the National Institute of Allergy and Infectious Diseases to G.A.J.


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FOOTNOTES
 
* Corresponding author. Mailing address: Lahey Clinic, 41 Mall Rd., Burlington, MA 01805. Phone: (781) 744-8608. Fax: (781) 744-1264. E-mail: george.a.jacoby{at}lahey.org. Back


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Antimicrobial Agents and Chemotherapy, February 2003, p. 559-562, Vol. 47, No. 2
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.2.559-562.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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