Abstract Objectives In Asian countries, blaCTX-M-55 is the second most common ESBL-encoding gene. blaCTX-M-55 frequently co-localizes with fosA and rmtB genes on epidemic plasmids, which remain sporadic outside Asia. During 2010–13, we investigated CTX-M-55-producing Escherichia coli isolates and their co-resistance to fosfomycin, aminoglycosides, fluoroquinolones and colistin as part of a global survey of ESBLs in animals in France. Methods blaCTX-M-55, fosA, rmtB and plasmidic quinolone and colistin resistance genes were characterized by PCR, sequencing and hybridization experiments. Plasmids were classified according to their incompatibility groups and subtypes. Genotyping was performed by MLST and repetitive extragenic palindromic sequence-based PCR. Results Twenty-one E. coli isolates from bovines (n = 16), dogs (n = 2), horses (n = 2) and a monkey harboured blaCTX-M-55, were MDR and belonged to ST744 (n = 9) and 10 other clones. blaCTX-M-55 was mostly located on IncF (n = 19), but also on IncI1 (n = 2) plasmids. On IncF33:A1:B1 plasmids, blaCTX-M-55 co-localized with the rmtB and aac(6′)-Ib genes and in one isolate with the fosA3 allele. Ten IncF46:A-:B20 plasmids, which were found in different clones from unrelated animals, also carried the mcr-3 gene. blaCTX-M-55-carrying IncF18:A-:B1 plasmids were found in different animal species from distinct locations and periods, and one additionally carried the fosA4 gene. One isolate harboured the mcr-1 gene, which did not co-localize with blaCTX-M-55. Conclusions A large diversity of E. coli clones and plasmid types supported the spread of blaCTX-M-55, together with atypical resistance genes, in various animal species in France. fosA and rmtB genes are emerging among animals in Europe and this issue is of concern for public health. Introduction ESBLs seriously challenge the use of β-lactams in human medicine and CTX-Ms are the most predominant ESBL family worldwide. Their success is based on their selective advantage in the presence of broad-spectrum cephalosporins and on the localization of the corresponding genes mostly on highly diffusible plasmids.1 In addition, blaCTX-M genes are often associated with ISs, such as ISEcp1, which further contribute to their dissemination. Also, blaCTX-M genes are usually co-located with other antimicrobial resistance genes on the same genetic platforms, thereby allowing possible co-selection.2 Thus, several factors have contributed to the spread of blaCTX-M genes across sectors, including humans, food and companion animals, wildlife and the food chain.3 To date, >200 variants of CTX-M enzymes have been described with variable affinities to their substrates, such as the widely spread CTX-M-15 variant harbouring greater hydrolysing activity against ceftazidime than cefotaxime. Among them, CTX-M-55 also belongs to the CTX-M-1 group and is a derivate of CTX-M-15, from which it only differs by the Ala80Val substitution.4 Interestingly, CTX-M-55 is the second most common ESBL subtype in Enterobacteriaceae in the Asian continent, especially in Escherichia coli of human and animal origins,5,6 and this particular epidemiology remains largely unexplained. blaCTX-M-55 genes are mostly located on epidemic self-mobilizable plasmids, such as those of the IncF, IncI1 and IncHI2 subtypes. They frequently co-localize with other resistance genes such as fosA3 alleles conferring resistance to fosfomycin, plasmid-mediated quinolone resistance genes and genes encoding 16S rRNA methyltransferases, among which the rmtB gene conferring pan-resistance to aminoglycosides is the most prevalent.7–9 This is a worrisome issue as fosfomycin has been reintroduced in clinical use for the treatment of infections sustained by carbapenem-resistant Enterobacteriaceae in humans.10 This picture is worsened by the presence of mechanisms such as the RmtB methyltransferase, which fully abolishes the bactericidal action of aminoglycosides. Reports of CTX-M-55 producers resistant to fosfomycin and aminoglycosides have been quite sporadic outside Asia in both animals and humans.11 Very recently, CTX-M-55-producing E. coli isolates were shown to be vectors of mcr-3 dissemination, possibly with Asian origin. As part of a global survey of ESBLs in animals in the frame of official monitoring programmes on antimicrobial resistance in France, we report here the characterization of multiple CTX-M-55-producing E. coli isolates and plasmids harbouring co-resistance to fosfomycin, aminoglycosides, fluoroquinolones and colistin in diverse animal species, in a context where, in contrast to CTX-M-1 and CTX-M-9/CTX-M-14, CTX-M-55 has rarely been reported yet in animals in France.12 Materials and methods Bacterial isolates, identification and antimicrobial susceptibility testing Between 2010 and 2013 in the framework of surveillance programmes for the presence of E. coli resistance to broad-spectrum cephalosporins in animals in France, a collection of 862 E. coli isolates suspected to produce an ESBL were analysed in the laboratory of the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) in Lyon. These isolates originated from various animal species, including cattle, dogs, horses and monkeys, and were collected from healthy (n = 148) or diseased (n = 714) animals, sampled at slaughterhouses or through the RESAPATH network, the national monitoring system for antimicrobial resistance in animals in France (www.resapath.anses.fr), respectively. Specimens were plated on chromID ESBL plates (bioMérieux, Marcy-l’Étoile, France) and one suspected positive colony was picked up from each positive plate. Identification of the isolates was achieved by MALDI-TOF MS (Microflex, Bruker). Susceptibility to 32 antibiotics (amoxicillin, piperacillin, ticarcillin, amoxicillin/clavulanic acid, piperacillin/tazobactam, ticarcillin/clavulanic acid, cefalotin, cefuroxime, cefotaxime, ceftiofur, ceftazidime, cefoxitin, cefepime, cefquinome, aztreonam, ertapenem, tetracycline, kanamycin, tobramycin, gentamicin, amikacin, apramycin, netilmicin, streptomycin, florfenicol, chloramphenicol, colistin, sulphonamides, trimethoprim, nalidixic acid, ofloxacin and enrofloxacin) was evaluated by disc diffusion on Mueller–Hinton agar (Bio-Rad, Marnes-La-Coquette, France) according to the guidelines of the Antibiogram Committee of the French Society for Microbiology (CA-SFM; www.sfm-microbiologie.org) and using the E. coli ATCC 25922 strain as quality control. Susceptibility to colistin was determined according to the MIC by broth microdilution.13 The interpretation was based on the breakpoints provided by CA-SFM for E. coli. Production of an ESBL was confirmed by a double-disc synergy test.14 Genetic typing of the isolates The clonal relatedness of the isolates was investigated by repetitive extragenic palindromic sequence (rep)-based PCR using DiversiLab (bioMérieux). Phylogenetic grouping was determined according to the method of Doumith et al.15 MLST was performed according to the scheme proposed by Achtman (http://mlst.warwick.ac.uk/mlst/dbs/Ecoli). Analysis of gene content and genetic background The presence of blaCTX-M genes was screened for by PCR according to previously published protocols.16 For isolates positive for the blaCTX-M-1 group, another PCR and sequencing was performed using the primers ISEcp1L1 (5′-CAGCTTTTATGACTCG-3′) and P2D (5′-CAGCGCTTTTGCCGTCTAAG-3′) in order to detect the presence of the insertion sequence ISEcp1 upstream from the blaCTX-M gene and to determine the variant. A screening for plasmidic genes conferring resistance to fluoroquinolones [oqxA/B, qnrA/B/C/D/S, qepA, aac(6′)-Ib], aminoglycosides [aac(6′)-Ib, rmtA, rmtB, rmtC, rmtD, rmtE, rmtF, rmtG, rmtH, armA], colistin (mcr1, mcr2, mcr3) and fosfomycin (fosA/C2) was conducted as well.17–23 The plasmid content was investigated by S1 nuclease restriction followed by PFGE.24 The localization of blaCTX-M genes and fluoroquinolone, aminoglycoside, fosfomycin and colistin resistance genes on a unique plasmid was investigated by hybridization using dioxigenin (DIG)-labelled probes specific to the genes of interest according to the manufacturer’s (Roche Diagnostics, Germany) instructions and/or transfer to a recipient cell by broth mating using E. coli strain K-12 J53, which is resistant to rifampicin, as the recipient.25 Plasmids were characterized by PCR-based replicon typing (DIATHEVA, Fano PU, Italy) and subtyped by PCR/sequencing.26 Results and discussion Twenty-one E. coli isolates resistant to broad-spectrum cephalosporins harboured blaCTX-M-55 preceded by ISEcp1 located 127 bp upstream from the start codon, except for three isolates (27732, 32736, 32738) in which ISEcp1 was located 48 bp from the start codon of blaCTX-M-55. Spacers of 127 and 48 bp are commonly found between the ISEcp1 and blaCTX-M genes, including blaCTX-M-55, even though wider distances have occasionally been found.27,28 Isolates were collected over the 2010–13 period and originated from bovines (n = 16), dogs (n = 2), horses (n = 2) and a monkey (Table 1). This investigation was not designed as a prevalence study, but highlights the presence of CTX-M-55-producing E. coli in diverse animal species outside Asian countries, including food-producing and companion animals. Recently, the incidence of blaCTX-M-55 among E. coli responsible for community-onset infections has dramatically increased in China, a country where blaCTX-M-55 is also the second most frequent blaCTX-M variant in food animals.6 Intriguingly, the detection of blaCTX-M-55 outside Asia has been sporadic so far and can often be traced back there.29 Only a few cases with no reported link with the Asian continent have been identified, including Salmonella enterica from the USA in 2007,30,E. coli from diseased humans in Ecuador in 2016,31 autochthonous E. coli in dairy farms in England with unspecified prevalence32 and E. coli in poultry farms in Brazil.33 In addition, recent case reports on the colistin resistance mcr-3 gene in Europe, and to a lesser extent the mcr-1 gene, have also demonstrated an association with blaCTX-M-55.34–39 In parallel, we reported in 2011 a CTX-M-55-producing Proteus mirabilis in a diseased monkey originating from Vietnam.40 In 2014, Enterobacter cloacae and E. coli isolates carrying blaCTX-M-55 were found in raw vegetables imported from Asia to Switzerland. Also in Switzerland, in 2013, three E. coli isolates harbouring blaCTX-M-55 were also found in freshwater.41,42 In the collection reported here, only the monkey isolate was of Asian origin and this animal was introduced in France through the same French animal centre as previously described.40 Table 1. Features of E. coli isolates carrying blaCTX-M-55 in French animals from 2010–13 Isolate Site of infection/ healthy Date of isolation Origin Host PG ST Plasmids carrying blaCTX-M-55 Other antimicrobial resistance genes Antimicrobial resistance pattern formula size (kb) STR KAN GEN TOB NET AMK CHL TET SUL TMP NAL ENR FOF CST 26592 unknown 10/01/2011 94 dog A 88 IncI1/ST16 97 R R R R 32738 skin 08/10/2012 71 horse B1 453 IncI1/ST31 97 qnrA R R R R R R 25351 ear 31/05/2010 94 dog B1 162 IncF18:A-:B1 75 qnrA, aac(6′)-Ib R R 27732 DT 06/06/2011 67 monkey B1 4380 IncF18:A-:B1 145a fosA4 R R R R R R R 32736 skin 06/11/2012 92 horse D 1340 IncF18:A-:B1 145a R R R R R R R R R R R 30271 healthy 30/04/2012 35 bovine A 2930 IncF18:A-:B1 145a mcr-1 R R R R R R R R R R R R 32189 death 18/03/2012 03 bovine A 10 IncF33:A1:B1 48 rmtB, aac(6′)-Ib R R R R R R R R R R R R 34248 DT 28/03/2013 58 48 fosA3, rmtB, aac(6′)-Ib R R R R R R R R R R R R R 29135 death 01/02/2012 46 bovine A 1291 IncF46:A-:B20 97 oqxA, aac(6′)-Ib, mcr-3 R R R R R R R R R R R R 31215 healthy 11/06/2012 19 bovine A 540 IncF46:A-:B20 97a R R R R R R R 30955 healthy 04/06/2012 19 97a mcr-3 R R R R R R R R 34228 DT 03/05/2013 12 bovine B1 1431 IncF46:A-:B20 48a qnrS, oqxA, aac(6′)-Ib R R R R R R R R R R R 30269 healthy 30/04/2012 35 97a mcr-3 R R R R R R R R R R R R 36075 DT 07/03/2013 22 97a aac(6′)-Ib,mcr-3 R R R R R R R R R R R R 28947 healthy 19/03/2012 35 97a oqxA, mcr-3 R R R R R R R R R R R R 28169 healthy 20/02/2012 24 bovine A 744 IncF46:A-:B20 97a R R R R R R R R R R R 36070 death 05/03/2013 22 97a aac(6′)-Ib, mcr-3 R R R R R R R R R R R R 29856 healthy 16/04/2012 35 97 mcr-3 R R R R R R R R R R R R 32196 RT 01/06/2012 46 97a oqxA,mcr-3 R R R R R R R R R R R R 33904 DT 07/03/2012 35 97a aac(6′)-Ib, mcr-3 R R R R R R R R R R R R 33058 DT 01/12/2012 46 97a aac(6′)-Ib, mcr-3 R R R R R R R R R R R R Isolate Site of infection/ healthy Date of isolation Origin Host PG ST Plasmids carrying blaCTX-M-55 Other antimicrobial resistance genes Antimicrobial resistance pattern formula size (kb) STR KAN GEN TOB NET AMK CHL TET SUL TMP NAL ENR FOF CST 26592 unknown 10/01/2011 94 dog A 88 IncI1/ST16 97 R R R R 32738 skin 08/10/2012 71 horse B1 453 IncI1/ST31 97 qnrA R R R R R R 25351 ear 31/05/2010 94 dog B1 162 IncF18:A-:B1 75 qnrA, aac(6′)-Ib R R 27732 DT 06/06/2011 67 monkey B1 4380 IncF18:A-:B1 145a fosA4 R R R R R R R 32736 skin 06/11/2012 92 horse D 1340 IncF18:A-:B1 145a R R R R R R R R R R R 30271 healthy 30/04/2012 35 bovine A 2930 IncF18:A-:B1 145a mcr-1 R R R R R R R R R R R R 32189 death 18/03/2012 03 bovine A 10 IncF33:A1:B1 48 rmtB, aac(6′)-Ib R R R R R R R R R R R R 34248 DT 28/03/2013 58 48 fosA3, rmtB, aac(6′)-Ib R R R R R R R R R R R R R 29135 death 01/02/2012 46 bovine A 1291 IncF46:A-:B20 97 oqxA, aac(6′)-Ib, mcr-3 R R R R R R R R R R R R 31215 healthy 11/06/2012 19 bovine A 540 IncF46:A-:B20 97a R R R R R R R 30955 healthy 04/06/2012 19 97a mcr-3 R R R R R R R R 34228 DT 03/05/2013 12 bovine B1 1431 IncF46:A-:B20 48a qnrS, oqxA, aac(6′)-Ib R R R R R R R R R R R 30269 healthy 30/04/2012 35 97a mcr-3 R R R R R R R R R R R R 36075 DT 07/03/2013 22 97a aac(6′)-Ib,mcr-3 R R R R R R R R R R R R 28947 healthy 19/03/2012 35 97a oqxA, mcr-3 R R R R R R R R R R R R 28169 healthy 20/02/2012 24 bovine A 744 IncF46:A-:B20 97a R R R R R R R R R R R 36070 death 05/03/2013 22 97a aac(6′)-Ib, mcr-3 R R R R R R R R R R R R 29856 healthy 16/04/2012 35 97 mcr-3 R R R R R R R R R R R R 32196 RT 01/06/2012 46 97a oqxA,mcr-3 R R R R R R R R R R R R 33904 DT 07/03/2012 35 97a aac(6′)-Ib, mcr-3 R R R R R R R R R R R R 33058 DT 01/12/2012 46 97a aac(6′)-Ib, mcr-3 R R R R R R R R R R R R DT, digestive tract; RT, respiratory tract; Origin, department of France; PG, phylogroup; STR, streptomycin; KAN, kanamycin; GEN, gentamicin; TOB, tobramycin; NET, netilmicin; AMK, amikacin; CHL, chloramphenicol; TET, tetracycline; SUL, sulphonamide; TMP, trimethoprim; NAL, nalidixic acid; ENR, enrofloxacin; FOF, fosfomycin; CST, colistin; R, resistance. Boldface indicates genes co-localized on the blaCTX-M-55 plasmid; shading, clonal (dark grey) and plasmid (light grey) groupings of the isolates. a Plasmid conjugated to the recipient E. coli strain K-12 J53, which is resistant to rifampicin. All but three isolates were MDR and belonged to phylogroups A (n = 16), B1 (n = 4) and D (n = 1). rep-PCR analysis showed four clusters including clonally related isolates (similarity ≥95%; Figure S1, available as Supplementary data at JAC Online). According to the MLST database, the isolates were associated with several STs reported previously. Some STs, such as ST4380, ST88, ST453, ST1431, ST162, ST2930, ST1291 and ST1340, occurred as scattered isolates; ST10 and ST540 were represented by two isolates each; and ST744 was the most predominant, represented by nine isolates. In particular, the two ST540 and the nine ST744 isolates were from different animals, farms, districts and years of sampling (Table 1). Among these, one ST744 isolate was found in a dead animal, whereas four others (30269, 28947, 28169, 29856) came from healthy animals slaughtered on different days in the same abattoir, so contamination during slaughter cannot be excluded. The four remaining ST744 isolates (33058, 32196, 33904, 36075) were from unrelated diseased animals in three different farms and districts. E. coli ST744 harbouring blaCTX-M-1 group have been previously found in cattle in China, fish in Portugal, chickens in Bangladesh and Algeria, pigs in Australia and wild birds in Germany. In most of those studies, E. coli ST744 also seemed to have clonally expanded, which is notable as the clonal spread of ESBL-producing E. coli is globally very uncommon in animals.43–45 ST744 has also been reported to spread carbapenemase or mcr-1/mcr-3 genes, also in association with blaCTX-M-55.34,46,47 The surprising emergence of CTX-M-55-producing E. coli in various animal species in France did not rely on clonal spread only. Indeed, blaCTX-M-55 genes were found in various plasmid families and subtypes, including IncF46:A-:B20 (n = 13), IncF18:A-:B1 (n = 4), IncF33:A1:B1 (n = 2), IncI1/ST31 (n = 1) and IncI1/ST16 (n = 1) plasmids, of which 15 generated trans-conjugants. By conjugation, blaCTX-M-55 and mcr-3 were transferred on a unique plasmid to the recipient cell, from all the positive isolates. A similar result was obtained for several fluoroquinolone resistance genes (Table 1). IncI1/ST16 was recently proved to epidemically spread blaCTX-M-55 in China and South Korea,27,28,48 similar to IncF18:A-:B1 plasmids, which have been reported as important vectors of blaCTX-M-55 in China.49 IncF33:A1:B1 is closely related to the IncF33:A-:B- plasmid, which also spreads blaCTX-M-55 in animals such as cattle, pigs, chickens, ducks and pets as well as healthy and diseased human beings in China, Japan and South Korea.22,50–52 Thus, all plasmid subtypes that were found to spread blaCTX-M-55 in this study were either highly similar or even identical to those carrying blaCTX-M-55 in Asian countries. These plasmids were not necessarily associated with specific E. coli clones, as exemplified by blaCTX-M-55 IncF46:A-:B20 plasmids found in different E. coli backgrounds from unrelated bovines. Even more remarkably, blaCTX-M-55 IncF18:A-:B1 plasmids were recognized in different E. coli clones from a monkey, a horse, a bovine and a dog from distinct locations and periods. Altogether, we report here an unexpected epidemiology of the Asia-related blaCTX-M-55 gene in various animal species in France supported by both clonal and plasmid-mediated spread. Another finding was the presence of the plasmid-mediated 16S rRNA methyltransferase rmtB gene in two isolates (34248 and 32189) from unrelated bovines in two districts in 2012 and 2013, respectively. These isolates formed a unique cluster according to rep-PCR typing and belonged to the widespread ST10 E. coli clone in animals and humans (Figure S1). In both isolates, as shown by Southern blot, blaCTX-M-55 was located on a 48 kb IncF33:A1:B1 plasmid together with aac(6′)-Ib and rmtB, and in isolate 34248 with the fosfomycin resistance fosA3 gene encoding a glutathione S-transferase. Thus, highly related IncF plasmid subtypes (F33: A-: B-, F2: A-: B-, F16: A1: B1, F24: A-: B-) are once more shown to be vehicles of blaCTX-M-55, fosA3 and/or rmtB in E. coli isolates from multiple farm animals, dogs and humans. Their spread outside Asia is infrequent and therefore of great concern, as illustrated by the recent introduction of fosA3 in Europe through a Portuguese patient who had travelled to Asia.53 Another fosA variant, fosA4, was also detected and co-localized with blaCTX-M-55 on the widely spread IncF18:A-:B1 plasmid, as mentioned above. Finally, the mcr-1 or mcr-3 colistin resistance genes were detected in most isolates from cattle, thereby confirming previous observations of their association with blaCTX-M-55.23,34–39 Conclusions We report here a large diversity of E. coli clones and plasmid types supporting the distribution of blaCTX-M-55 in various animal species in France in a context where CTX-M-55 producers have rarely been reported yet in Europe. We also report for the first time, to our knowledge, fosA and rmtB genes in animals in France, amongst the very rare cases worldwide outside Asia. These data are highly reminiscent of the molecular picture observed in Asian countries even though a direct link could not be made in our study, with the exception of the importation of a monkey. To determine whether these data reflect a change in ESBL epidemiology in animals in Europe would need further investigation. Notably in China, fosfomycin is prohibited in the animal sector. Therefore, the wide spread of fosA3 in animals in China has most probably occurred through co-selection with the use of other antibiotics, such as broad-spectrum cephalosporins, aminoglycosides, florfenicol or colistin, and is favoured by its localization on highly epidemic self-transferable plasmids. A similar situation might now occur in Europe. In all, the emergence of blaCTX-M-55 in association with fosA3, rmtB and mcr genes is of particular concern since any wider spread of those genes would challenge the efficacy of major treatments in human medicine. Acknowledgements We gratefully thank all of the peripheral laboratories of the RESAPATH network. Funding This work was supported by internal funding of the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), a grant of the Animal Health and Welfare (ANIHWA) ERA-Net project ANR-14-ANWA-0006-04 (France) and a grant from the Joint Programming Initiative on Antimicrobial Resistance (JPI-EC-AMR) project Trans-Comp-ESC-R JPIAMR2016-077 (France). Transparency declarations None to declare. Supplementary data Figure S1 is available as Supplementary data at JAC Online. References 1 Carattoli A. Plasmids and the spread of resistance. Int J Med Microbiol 2013; 303: 298– 304. Google Scholar CrossRef Search ADS PubMed 2 Canton R, Gonzalez-Alba JM, Galan JC. CTX-M enzymes: origin and diffusion. Front Microbiol 2012; 3: 1– 19. Google Scholar CrossRef Search ADS PubMed 3 Seiffert SN, Hilty M, Perreten V et al. 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Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Apr 1, 2018
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