JAC Advance Access originally published online on February 7, 2006
Journal of Antimicrobial Chemotherapy 2006 57(4):666-672; doi:10.1093/jac/dkl020
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The role of horizontal gene transfer in the spread of trimethoprim–sulfamethoxazole resistance among uropathogenic Escherichia coli in Europe and Canada
1 Department of Epidemiology, University of Michigan, School of Public Health, 109 S Observatory, Ann Arbor, MI 48109, USA; 2 Department of Clinical Microbiology, Central Hospital, SE-351 85 Växjö, Sweden
* Corresponding author. Tel: +1-734-647-2407; Fax: +1-734-936-6732; E-mail: cfmarrs{at}umich.edu
Received 18 October 2005; returned 6 December 2005; revised 9 January 2006; accepted 13 January 2006
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Abstract |
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Objectives: To describe the distribution of trimethoprim–sulfamethoxazole resistance genes and the role of horizontal gene transfer and clonal expansion in recent increases of antibiotic resistance rates among uropathogenic Escherichia coli in Europe and Canada.
Methods: We identified antibiotic resistance alleles sul1, sul2, sul3 and dfr along with type 1 and type 2 integrons among 350 uropathogenic E. coli isolates from a cross-sectional study of acute, uncomplicated, community-acquired urinary tract infections in 16 western European countries and Canada (ECO
SENS).
Results: Trimethoprim resistance gene distributions showed no regional dependency (P = 0.84). The most common trimethoprim resistance gene was dfrA1, which occurred in 37.9% of dfr containing isolates. Similarly, the sulfamethoxazole resistance gene distributions did not vary significantly by region (P = 0.20). sul2, the most common sulfamethoxazole resistance gene, was found in 77.9% of sulfamethoxazole-resistant isolates. The distribution of type 1 and type 2 integrons varied slightly by region (P = 0.04) with type 1 integrons being the more common (85.9%). We observed 34 combinations of the sul genes, dfr genes and integron types; the most common combinations were broadly disseminated across every region examined.
Conclusions: Horizontal gene transfer plays a larger role than clonal expansion in the increase of trimethoprim–sulfamethoxazole resistance levels in Europe and Canada.
Keywords: urinary tract infections , epidemiology , antimicrobial resistance , integrons , E. coli
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Introduction |
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Urinary tract infections (UTIs) are among the most common bacterial infections treated in a physician's office.1,2 Standard treatment for acute uncomplicated UTI is a combination of trimethoprim and sulfamethoxazole, although with increasing resistance rates other antibiotics are commonly prescribed.3 In Europe, trimethoprim–sulfamethoxazole resistance rates among uropathogens rose from 0–5% before 19903,4 to 9–26% in 1999 and 2000.5
Most trimethoprim–sulfamethoxazole resistance genes reside within integrons, horizontally transferable genetic elements which play an important role in their dissemination.6 Type 1 integrons contain an integrase gene (int) that allows integration of new genes into the bacterial genome as gene cassettes.7,8 One class of genes commonly inserted in this manner are the dihydrofolate reductase (dfr) genes which confer resistance to trimethoprim.6,9 The sulfamethoxazole resistance gene sul1 is also associated with type 1 integrons, but not as a gene cassette.8 Type 2 integrons cannot acquire new gene cassettes due to a non-functional int gene.7 Type 2 integrons consist of a static array of resistance genes, one of which is dfrA1.8 Other common horizontally transferable elements are transposons and plasmids, on which sulfamethoxazole resistance genes sul2 and sul3 are often found.10,11
Both horizontal gene transfer and clonal expansion contribute to the spread of antibiotic resistance; however, the extent that each mechanism contributes to the observed rise in trimethoprim–sulfamethoxazole resistance is unclear. Horizontal gene transfer may be sufficiently common to drive the dissemination of antibiotic resistance alone, with clonal expansion working only to amplify the genes within individual hosts. Frequent horizontal gene transfer would broadly distribute resistance genes, resulting in many resistance gene combinations. Under these conditions we expect to find regionally independent gene distributions. Conversely, horizontal gene transfer may be rare. In this case, clonal expansion of bacteria with resistance genes would account for most of the growth in antibiotic resistance levels. Under these conditions we anticipate finding region-dependent gene distributions corresponding to individual strains with unique gene combinations.
We analysed integron and trimethoprim–sulfamethoxazole resistance genes from uropathogenic E. coli collected across western Europe and Canada in an effort to understand the population dynamics that help to spread antibiotic resistance. Understanding how trimethoprim–sulfamethoxazole resistance genes are spread will help in designing more effective strategies to preserve existing antibiotic susceptibilities.12–14
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Materials and methods |
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Isolates
We obtained 350 isolates of varying susceptibilities to sulfamethoxazole and trimethoprim from the ECOSENS project, a cross-sectional study of acute, uncomplicated, community-acquired UTIs in 16 western European countries and Canada. Methods for this survey have been described previously.5,15
Antibiotic resistance testing
All isolates were screened using the disc diffusion method for resistance to the following antibiotics: ampicillin, amoxicillin/clavulanic acid, mecillinam, cefadroxil, trimethoprim, sulfamethoxazole, trimethoprim/sulfamethoxazole, nalidixic acid, ciprofloxacin, nitrofurantoin, fosfomycin and gentamicin. The MIC data were interpreted in accordance with the standards of the Swedish Reference Group for Antibiotics (www.srga.org).16 The antibiotics of interest to this study and their corresponding diffusion diameter breakpoints were trimethoprim (5 µg) 
13 mm (corresponding to an MIC breakpoint of R > 4 mg/L), sulfamethoxazole (100 µg) 12 mm (corresponding to an MIC breakpoint of R > 128 mg/L) and trimethoprim/sulfamethoxazole (1.25/23.75 µg) 13 mm (corresponding to the MIC breakpoint of R > 16 mg/L). Antibiotic discs and agar were from Oxoid Limited (Basingstoke, UK). Results of antibiotic resistance testing have been published previously.5,15,17
sul1 and sul2 identification
sul1 and sul2 were identified by PCR amplification with primers constructed by Invitrogen (Carlsbad, USA). Amplification of sul1 was performed using the forward primer sul1f (5'-CTTCGATGAGAGCCGGCGGC-3') and reverse primer sul1r (5'-GCAAGGCGGAAACCCGCGCC-3').18 sul2 was identified using the forward primer sul2-F (5'-GCGCTCAAGGCAGATGGCATT-3') and the reverse primer sul2-B (5'-GCGTTTGATACCGGCACCCGT-3').14 Additionally, the 16S RNA gene was amplified in each reaction to serve as an internal positive control using the forward primer 16S-F (5'-GCGGACGGGTGAGTAATGT-3') and reverse primer 16S-B (5'-TCATCCTCTCAGACCAGCTA-3').14 Water was used as a negative control.
A 50 µL PCR mixture was used consisting of 3 µL of boiled lysate, 0.3 µM forward and reverse sul primer, 0.15 µM 16S-F and 16S-B primer, 1x PCR buffer, 3 mM MgCl2, 0.2 µM dNTPs and 1.25 U of Taq polymerase. Thermal cycler reaction conditions were as follows: 94°C for 5 min; 30 cycles of denaturation at 94°C for 40 s, annealing at 55°C for 40 s and extension at 72°C for 1 min. A final extension of 72°C was run for 5 min for sul1 and for 7 min for sul2.
sul3 identification
Different reaction conditions were used to amplify sul3. PCR was performed using a 25 µL reaction of 2 µL of boiled lysate, 1x PCR buffer, 3 mM MgCl2, 0.4 mM dNTPs, 1.5 U of Taq polymerase, 0.4 µM sul3F primer (5'-GAGCAAGATTTTTGGAATCG-3') and 0.4 µM sul3R primer (5'-CATCTGCAGCTAACCTAGGGCTTTGGA-3').11,19 A sequence-confirmed sul3-containing isolate from the ECOSENS collection served as the positive control and water was used as the negative control. Mixtures were centrifuged for 30 s at 3000 rpm. Thermal cycler conditions were 98°C for 1 min followed by 35 cycles of 98°C for 30 s, 51°C for 30 s and 72°C for 1 min. A final extension was performed at 72°C for 5 min.
Integron PCR detection
All isolates found to be resistant to trimethoprim and/or sulfamethoxazole were screened for the presence of both type 1 and type 2 integrons. Type 1 integrons were amplified using the primers hep58 (5'-TCATGGCTTGTTATGACTGT-3') and hep59 (5'-GTAGGGCTTATTATGCACGC-3').20 Type 2 integrons were amplified using the primers hep51 (5'-GATGCCATCGCAAGTACGAG-3') and hep74 (5'-CGGGATCCCGGACGGCATGCACGATTTGTA-3').21 DNA from a type 1 integron containing the dfrA5 gene and a type 2 integron containing the dfrA12 gene were used as a positive control for integron detection. Both water and the strain K12 were used as negative controls. Amplification was done with a 50 µL mixture of the following reagents: 2 µL of template DNA, 0.4 µM primers, 1x PCR buffer, 0.2 mM dNTPs, 1 mM MgCl2 and 2 U of Taq polymerase. The PCR conditions were as follows: 94°C for 30 s; 30 cycles of 94°C for 30 s, 55°C for 30 s and 72°C for 12 min; with a final extension at 72°C for 10 min.
dfr gene identification
Only trimethoprim resistance genes located inside type 1 integrons were characterized. Integrons were amplified as discussed above and extracted using a Qiagen QIAquick Gel Extraction Kit. The University of Michigan DNA Sequencing Core (Ann Arbor, USA) performed all sequencing using the forward primers hep58. When sequencing with forward primers revealed no dfr alleles, samples were resubmitted with reverse primers to provide a complete sequence. Integron sequences were compared with published dfr allele sequences (Table 1); matches were defined as isolates with >90% sequence similarity. We compared sequences using Lasergene software from DNAStar (Madison, USA).
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Statistical methods
Isolates were grouped into geographic regions corresponding to previous ECOSENS reports: Region 1—Austria, Germany and the Netherlands; Region 2—Belgium, France, Luxembourg and Switzerland; Region 3—Ireland and the United Kingdom; Region 4—Denmark, Finland, Norway and Sweden; Region 5—Canada; Region 6—Greece; and Region 7—Portugal and Spain.15 Regional distributions were analysed for independence using the Monte Carlo estimate of Fisher's exact test for the Pearson chi-square test and were considered significant at a P value 0.05. All statistical analyses were performed using SAS version 9.1 software.
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Results |
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Among the 350 isolates, 9 (2.6%) were resistant to trimethoprim only, 54 (15.4%) to sulfamethoxazole only and 154 (44.0%) were resistant to both trimethoprim and sulfamethoxazole. Further genetic analysis was limited to those 217 that had some resistance to trimethoprim, sulfamethoxazole or both.
One hundred and sixty-three isolates were resistant to trimethoprim. Fifty (30.7%) of these isolates contained no integrons and four (2.5%) had type 1 integrons, but no dfr allele. We were unable to obtain a complete integron sequence of one trimethoprim-resistant isolate. All of the remaining 108 (66.3%) trimethoprim-resistant isolates had an integron-associated dfr allele. Of these, 78 (72.2%) contained only type 1 integrons, 18 (16.7%) held only type 2 integrons and 12 (11.1%) contained both type 1 and type 2 integrons. Gene cassettes were distributed among the 90 isolates containing type 1 integrons as follows: 36 (40.0%) dfrA1, 8 (8.9%) dfrA5, 4 (4.4%) dfrA7, 4 (4.4%) dfrA12 and 28 (31.1%) dfrA17. Ten (11.1%) isolates with a type 1 integron contained dfr alleles only in a type 2 integron. Two (3.7%) trimethoprim-susceptible isolates contained integron-associated dfr gene cassettes: one with dfrA1 and one with dfrA5. Table 2 shows that the overall dfr allele distribution was mirrored in the region-stratified data, although the small sample from Region 6 (Greece) did show elevated levels of dfrA5. We observed no relationship between dfr distribution and region (P = 0.84).
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Two hundred and eight (59.4%) isolates were sulfamethoxazole resistant. Of these, 200 (96.2%) contained one or more sul alleles. sul2 was the most common allele, occurring in 162 (81.0%) cases. The next most common gene was sul1, which occurred in 106 (53.0%) isolates, of which 10 (9.4%) contained no type 1 integron. Both sul1 and sul2 occurred together in 74 (37%) isolates. The least common allele, sul3, appeared in only seven (3.5%) isolates. In one strain all three sul alleles were found together. Three (33.3%) sulfamethoxazole-susceptible isolates contained sul genes, one with sul1 and two with sul2. There was no evidence of a relationship between region and sul distribution (P = 0.20). The overall distribution was similar across all the examined regions (Table 3) though in regions 4, 6 and 7 the number of isolates with both sul1 and sul2 outnumbered those with only sul2. Isolates with sul2 contained a higher number of additional drug resistances than isolates without sul2 (P = 0.009).
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Integrons were found in 128 (59.0%) of those isolates resistant to trimethoprim and/or sulfamethoxazole. Type 1 integrons were the more prevalent, occurring in 110 (85.9%) of these isolates, while type 2 integrons were found in only 30 (23.4%). Type 1 and type 2 integrons were found together 12 (9.4%) times. We observed some regional variation in the distribution of integrons (P = 0.04) (Table 4). The UK and Ireland (Region 3) displayed the most divergent integron distribution, with an elevated percentage (36%) of type 2 integrons and no isolates with both integron types. Spain and Portugal (Region 7) were the only countries to have more isolates with both integron types than isolates with only type 2 integrons.
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Table 5 gives an overview of the large variety of resistance gene combinations discovered and the countries where they were found. We defined resistance gene combinations by the presence or absence of the three sul genes and both integron types. Where type 1 integrons were present we further divided the groupings according to which of the 17 known dfr genes they contained. Thirty-four different gene combinations were observed. The most common resistance gene combination was sul2 with no integron (30.9%), followed by the presence of sul1 and sul2 with a type 1 integron containing dfrA1 (11.1%). Both of these combinations were found in every region examined.
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Conclusions |
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Trimethoprim–sulfamethoxazole is an effective and inexpensive antibiotic combination used to treat a host of diseases. Two bacterial population genetic phenomena, horizontal gene transfer and clonal expansion, are thought to account for the recent rise in trimethoprim–sulfamethoxazole resistance rates; however, the relative importance of these mechanisms is unclear. Among the 217 uropathogenic E. coli isolates resistant to trimethoprim and/or sulfamethoxazole studied, we found sul and dfr alleles in all regions examined. For clonal expansion to account for this finding, a few widely distributed individuals under nearly identical selective conditions are required. More likely, these similarities are the result of widespread horizontal gene transfer which forces gene distributions to uniformity by providing each region with a migration pool of the same gene prevalence. This conclusion agrees with a recent phenotypic analysis of the entire ECO
SENS collection which suggested that clonal expansion plays a minor role in the dissemination of antibiotic resistance in general.22 Our observed trends in sulfamethoxazole-resistant allele distributions (sul2 > sul1 > sul3) corroborate previous studies.10,14,19 If direct selection were the sole force responsible for sustaining antibiotic resistance, we would expect to find only one gene providing resistance for each drug. Retaining additional genes would be a waste of resources resulting in a fitness burden. dfr alleles illustrate this point: only two (2.1%) trimethoprim-resistant isolates had multiple dfr genes. Conversely, 74 (38%) sulfamethoxazole-resistant isolates carried a plurality of sul alleles. Multiple copies of sul genes are likely to be maintained because of their modes of transfer: integrons and plasmids, which sustain duplicate genes by providing other genetically linked antibiotic resistance genes. The presence of sul1 in type 1 integrons and sul2's statistical association with additional drug resistances support this notion.
There have been few studies of the genetic distributions underlying trimethoprim resistance in Europe. Our results agree with three of those studies14,23,24 which have found dfrA1 to be very common in Europe. Conversely, studies performed in Korea25,26 and Australia21 found dfrA17 and dfrA12 to be the most common alleles. Something has likely occurred to cause this inter-regional diversity. Clonal expansion by isolates containing different dfr alleles is one possibility. Another possibility is that limited contact between continents has allowed different alleles to become common by genetic drift. Interestingly, the ECOSENS results and those from Korea and Australia showed the same five dfr alleles. Furthermore, we observed most of these five alleles in every region with a sample size larger than 10. These facts, along with the ubiquitously high levels of dfrA17, suggest that genetic drift of horizontally transferred genes is probably responsible for the divergent distributions.
Unlike individual genes, we observed regional variation in integron distributions. This may indicate that clonal expansion played a role in the dissemination of these genetic structures. Another possibility is that natural selection caused by different levels of antibiotic use selected for different gene distributions. Prescribing habits could select for differing levels of type 1 and type 2 integrons based on the full spectrum of their integrated resistance gene cassettes. Antibiotic use would limit the diversity of integrons, but not necessarily that of individual resistance genes. Thus, it is not surprising to find the highest prevalence of isolates containing both type 1 and type 2 integrons in Spain and Portugal, where antibiotic use and resistance are highest.
We observed a large diversity of resistance gene combinations, most of which were widely dispersed across the study area, suggesting horizontal gene transfer is the primary mode of antibiotic resistance spread. There are exceptions to this trend, such as the five isolates from Spain containing both sul genes, a type 1 integron with no dfr gene cassettes and a type 2 integron.
This diversity notwithstanding, some genes did occur together more often than others. Although this may reflect clonal expansion, a number of other explanations are possible: (i) genes occurring together may indicate standard gene placement within their respective horizontal gene elements. For instance, the 31 isolates with sul1 and type 1 integrons result from placement of sul1 within most type 1 integrons. (ii) They may be caused by absence of information. The predominance of sul2 with no corresponding integrons or dfr alleles reflects the fact that sul2 was the only allele with no relationship to integrons examined. (iii) Apparent relationships may simply reflect how common individual alleles are. Because they are so widely disseminated, the 24 isolates with both sul1 and sul2, a type 1 integron and dfrA1 are probably just the result of common alleles co-occurring by chance.
Besides these explicable exceptions, there are very few relationships between multiple genes. Where common gene combinations do exist, they are usually widely dispersed. These facts, along with the regional independence of individual gene distributions, suggest that horizontal gene transfer is playing a much larger role than clonal expansion in the spread of trimethoprim–sulfamethoxazole resistance. However, the effects of one gene cannot be seen as occurring in isolation. Other genes have an effect on, and are affected by, resistance genes to which they are linked by horizontal transfer elements such as plasmids and integrons. Our results suggest that surveillance for antibiotic resistance should track horizontal gene transfer elements as well as specific strains.
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None to declare.
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Acknowledgements |
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We are grateful to Patricia Tallman and Joan DeBusscher for their advice and technical help. This work was funded by grant DK55496 from the US National Institutes of Health.
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References |
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