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E. COLI EHEC - EUROPE: O80:H2, HYBRID INVASIVE PATHOGEN, ANTIMICROBIAL RESISTANCE

E. COLI EHEC - EUROPE: O80:H2, HYBRID INVASIVE PATHOGEN, ANTIMICROBIAL RESISTANCE

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A ProMED-mail post <http://www.promedmail.org> ProMED-mail is a program of the International Society for Infectious Diseases <http://www.isid.org>

Date: Thu 8 Nov 2018
Source: Emerging Infectious Disease journal [edited] <https://wwwnc.cdc.gov/eid/article/24/12/18-0272_article>


ref: Cointe A, Birgy A, Mariani-Kurkdjian P, et al. Emerging multidrug-resistant hybrid pathotype Shiga toxin-producing _E. coli_ O80 and related strains of clonal complex 165, Europe. Emerg Infect Dis. 2018. 24(12)
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Enterohemorrhagic _E. coli_ (EHEC), a subset of Shiga toxin-producing _E. coli_ (STEC), are major foodborne pathogens responsible for outbreaks and sporadic cases of gastrointestinal diseases ranging from simple diarrhea to hemorrhagic colitis, characterized by bloody diarrhea. The most serious complication, particularly in young children, is hemolytic uremic syndrome (HUS), defined by a combination of renal failure, thrombocytopenia, and hemolytic anemia (1). Post-STEC HUS is a major worldwide public health concern because it is the primary cause of acute renal failure in children (1). These clinical features result mainly from the action of the phage-encoded Shiga toxin (Stx), of which there are 2 types: Stx1, which has 3 subtypes, Stx1a, 1c, and 1d; and Stx2, which has 7 subtypes, Stx2a-g. In typical EHEC, adhesion to the intestinal epithelium is mediated by the locus of enterocyte effacement (LEE), a chromosomal pathogenicity island (PAI), shared with enteropathogenic _E. coli_ (EPEC) strains, which encodes a type III secretion system (T3SS), an adhesin called intimin, and its receptor Tir. Intimin, encoded by the eae gene, is a major virulence factor (VF) involved in the intimate attachment of typical EHEC to intestinal epithelium, causing characteristic attaching and effacing lesions. EHEC enterohemolysin (ehxA) is a pore-forming cytolysin carried by a plasmid involved in EHEC virulence. This plasmid, initially described as part of the O157 serogroup (pO157) (2), can carry 2 additional VFs, a catalase peroxidase, encoded by katP, and a serine protease, encoded by espP, which can cleave human coagulation factor V and might be involved in the development of hemorrhagic colitis (3).

Serogroup O157 is the predominant STEC serogroup worldwide, but non-O157 serogroups are increasingly associated with post-STEC HUS, and the unusual serogroup O80 is emerging in France and Europe. In 2016, O80 represented the 2nd most frequent serogroup isolated in France, after serogroup O26 (4). This phenomenon is no longer restricted to France; strains of serotype O80:H2, all belonging to sequence type (ST) 301, have been identified in Spain (5), the Netherlands (6), and Switzerland (7).

This serogroup is unique for several reasons. First, it is always associated with multiple determinants of resistance (that is, resistance to aminopenicillin, aminoglycoside, nalidixic acid, cotrimoxazole, tetracycline, or phenicols), whereas a resistance phenotype is uncommon among EHECs, which are generally fully susceptible to antimicrobials, except for rare clones, such as the epidemic O104:H4 German clone carrying a blaCTX-M-15 gene (8). Furthermore, unusual extraintestinal infections have recently been described for this serogroup (9,10), such as bacteremia, whereas EHEC is generally known to be a strictly intestinal pathogen. A recent case in the Netherlands illustrates the potential extreme pathogenicity of this serogroup; a 16-month-old boy died from multiorgan failure and extensive cerebral thrombotic microangiopathy attributable to an O80 Stx2d-producing _E. coli_ strain (6). Finally, O80 EHEC appears to be a hybrid pathotype that combines intestinal VFs (Shiga toxin [stx], intimin [eae], enterohemolysin [ehxA]) and extraintestinal VFs (aerobactin [iucC], salmochelin [iroN], an iron uptake protein encoded by sitABCD, serum resistance protein [issp], a putative secretion system I [etsC], omptin [ompTp], hemolysin [hlyF], and 2 bacteriocins [cia and cva]), suggesting the presence of a pS88-like plasmid (11). pS88 is a ColV plasmid, a key determinant of extraintestinal pathogenic _E. coli_ virulence in poultry and humans. This plasmid is involved in neonatal meningitis (11) and could explain the occurrence of extraintestinal dissemination in these EHEC infections. The recent diffusion in Europe, high potential extraintestinal pathogenicity, and multidrug resistance (MDR) of this hybrid pathotype led us to further characterize these strains, which might represent a major public health concern.

[The Methods and Results sections can be found at the source URL above
- Mod.LL]

Discussion
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We deciphered the molecular characteristics of O80:H2-CC165 EHEC, an emerging hybrid pathotype diffusing throughout Europe. This pathotype is armed to spread by means of a conjugative plasmid combining extraintestinal virulence with resistance to nearly all major classes of antibiotics, improved by the presence of several plasmid and chromosomally encoded bacteriocins, such as colicines I, V, M, and H47. We used the same criteria of MDR as a recent study in England (27) (blaTEM-1, strA-strB, sul1/sul2/dfrA, and tetA) and showed that 93% (26/28) of O80 STEC have this genotypic resistance profile, whereas only 5% of the strains identified within the O157 and O26 serogroups in the study in England had such a profile. MDR observed with this hybrid pathotype might complicate patient care, and the use of antimicrobial drugs during EHEC infections is still a subject of debate (28). However, the occurrence of invasive infections, such as bacteremia during EHEC infections, with this clone warrants antimicrobial treatment for such infections. In a previous study, the observed Stx rate was lower with a combination of azithromycin and ceftriaxone assays relative to basal secretion, and we proposed this association for the treatment of such infections (10).

Such a troubling plasmid has never been identified in human EHEC isolates. The only example of a similar mosaic plasmid was reported for S. enterica serovar Kentucky, in which an AmpC beta-lactamase gene (blaCMY-2) was integrated into a pS88-like plasmid (29). The insertion of an MDR-encoding island in a pS88-like plasmid containing extraintestinal virulence genes is particularly worrisome. Massive and inappropriate use of veterinary antibiotics, such as tetracycline, in food-animal production promotes antimicrobial drug resistance among animals, known to be reservoirs for STEC. This practice can select and favor the spread of such MDR-plasmids in human EHECs. Tetracycline still represented 36.5% of the tonnage of veterinary antibiotic use in 2015 in France (30). In our panel, all the sequenced O80 STEC strains carry the tetA gene, conferring resistance to tetracycline. Thus, large veterinary use of this drug might favor the selection of these hybrid strains and increase their diffusion.

We indicated a potential reservoir of these hybrid pathotype strains when we identified 3 O80:H2 strains isolated from cattle that carry the same VFs and resistance genes as human strains. However, the presence of the CC165 strains in chickens suggest that this clonal complex is also adapted to poultry. An initial description of pS88-like plasmids in avian pathogenic _E. coli_ strains reinforces this hypothesis (31). Moreover, the environmental survival of this clone in these potential reservoirs might be enhanced because of the resistance to mercury shared by all but one strain (36047), all carriers of the pS88-like plasmid, irrespective of their origin. Such resistance to heavy metals has been rarely described in EHEC strains (22).

We also detected an O80:H19-CC165 strain devoid of virulence genes, which might represent the ancestral precursor of CC165, and from which these hybrid pathotype strains might have been derived. This strain could be used for tracing the genetic history of this clone in future studies.

Our genetic description of the emerging hybrid pathotype _E. coli_ O80:H2, associated with O80-related strains, reveals the outstanding capacity of O80-CC165 to acquire the combination of virulence genes involved in intestinal and extraintestinal pathogenicity and genes conferring broad antibiotic resistance, including extended-spectrum beta-lactamase-encoding genes and those most recently identified, such as mcr-1. O80-CC165 strains, which are able to integrate multiple VFs with various consequences, MDR genes that encompass nearly all classes, and bacteriocins, represent a serious threat because of their exceptional versatility and should therefore be closely monitored in all countries in Europe.

References (Limited to those cited in the introduction and discussion sections included in this post; the full list is available at the source URL above)
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1. Garg AX, Suri RS, Barrowman N, et al. Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA. 2003; 290: 1360-70.
2. Schmidt H, Karch H, Beutin L. The large-sized plasmids of enterohemorrhagic _Escherichia coli_ O157 strains encode hemolysins which are presumably members of the _E. coli_ alpha-hemolysin family. FEMS Microbiol Lett. 1994; 117: 189-96.
3. Brunder W, Schmidt H, Karch H. EspP, a novel extracellular serine protease of enterohaemorrhagic _Escherichia coli_ O157:H7 cleaves human coagulation factor V. Mol Microbiol. 1997; 24: 767-78.
4. Bruyand M. Surveillance du syndrome hemolytique et uremique post-diarrheique chez les enfants de moins de 15 ans en France en 2016 [cited 2016 Feb 16]. <http://invs.santepubliquefrance.fr/content/download/138859/500759/version/1/file/Bilan_SHU_2016.pdf>
5. Blanco M, Blanco JE, Mora A, et al. Serotypes, virulence genes, and intimin types of Shiga toxin (verotoxin)-producing _Escherichia coli_ isolates from cattle in Spain and identification of a new intimin variant gene (eae-xi). J Clin Microbiol. 2004; 42:645-51.
6. Wijnsma KL, Schijvens AM, Rossen JWA, et al. Unusual severe case of hemolytic uremic syndrome due to Shiga toxin 2d-producing _E. coli_ O80:H2. Pediatr Nephrol. 2017; 32: 1263-8.
7. Fierz L, Cernela N, Hauser E, et al. Characteristics of Shigatoxin-producing _Escherichia coli_ strains isolated during 2010-2014 from human infections in Switzerland. Front Microbiol. 2017; 8:1471.
8. Bielaszewska M, Mellmann A, Zhang W, et al. Characterisation of the _Escherichia coli_ strain associated with an outbreak of haemolytic uraemic syndrome in Germany, 2011: a microbiological study. Lancet Infect Dis. 2011;11:671-676.
9. Mariani-Kurkdjian P, Lemaitre C, Bidet P, et al. Haemolytic-uraemic syndrome with bacteraemia caused by a new hybrid _Escherichia coli_ pathotype. New Microbes New Infect. 2014; 2: 127-31.
10. Soysal N, Mariani-Kurkdjian P, Smail Y, et al. Enterohemorrhagic _Escherichia coli_ hybrid pathotype O80:H2 as a new therapeutic challenge. Emerg Infect Dis. 2016; 22: 1604-12.
11. Peigne C, Bidet P, Mahjoub-Messai F, et al. The plasmid of _Escherichia coli_ strain S88 (O45:K1:H7) that causes neonatal meningitis is closely related to avian pathogenic _E. coli_ plasmids and is associated with high-level bacteremia in a neonatal rat meningitis model. Infect Immun. 2009; 77: 2272-84.
22. Venturini C, Hassan KA, Roy Chowdhury P, et al. Sequences of two related multiple antibiotic resistance virulence plasmids sharing a unique IS26-related molecular signature isolated from different _Escherichia coli_ pathotypes from different hosts. PLoS One. 2013; 8:e78862.
23. Feng P, Lampel KA, Karch H, Whittam TS. Genotypic and phenotypic changes in the emergence of _Escherichia coli_ O157:H7. J Infect Dis. 1998; 177: 1750-3.
24. Jost C, Bidet P, Carrere T, et al. Susceptibility of enterohaemorrhagic Escherichia coli to azithromycin in France and analysis of resistance mechanisms. J Antimicrob Chemother. 2016; 71: 1183-7.
25. Liu Y-Y, Wang Y, Walsh TR, et al. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis. 2016; 16: 161-8.
26. Dona V, Bernasconi OJ, Pires J, et al. Heterogeneous genetic location of mcr-1 in colistin-resistant _Escherichia coli_ isolates from humans and retail chicken meat in Switzerland: emergence of mcr-1-carrying IncK2 plasmids. Antimicrob Agents Chemother. 2017; 61: e01245-17.
27. Day M, Doumith M, Jenkins C, et al. Antimicrobial resistance in Shiga toxin-producing _Escherichia coli_ serogroups O157 and O26 isolated from human cases of diarrhoeal disease in England, 2015. J Antimicrob Chemother. 2017; 72: 145-52.
28. Freedman SB, Xie J, Neufeld MS, et al for the Alberta Provincial Pediatric Enteric Infection Team (APPETITE). Shiga toxin-producing _Escherichia coli_ infection, antibiotics, and risk of developing hemolytic uremic syndrome: a meta-analysis. Clin Infect Dis. 2016; 62: 1251-8.
29. Fricke WF, McDermott PF, Mammel MK, et al. Antimicrobial resistance-conferring plasmids with similarity to virulence plasmids from avian pathogenic _Escherichia coli_ strains in _Salmonella enterica_ serovar Kentucky isolates from poultry. Appl Environ Microbiol. 2009; 75: 5963-71.
30. Agence Nationale de Securite Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES): Suivi des ventes de medicaments veterinaires contenant des antibiotiques en France en 2015 [cited 2016 Feb 16]; <https://www.anses.fr/fr/system/files/ANMV-Ra-Antibiotiques2015.pdf>
31. Johnson TJ, Siek KE, Johnson SJ, Nolan LK. DNA sequence of a ColV plasmid and prevalence of selected plasmid-encoded virulence genes among avian _Escherichia coli_ strains. J Bacteriol. 2006; 188: 745-58.

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Communicated by: ProMED-mail <promed@promedmail.org>

[The 2016 post below (Soysal N, Mariani-Kurkdjian P, Smail Y, et al. Enterohemorrhagic _Escherichia coli_ hybrid pathotype O80:H2 as a new therapeutic challenge. Emerg Infect Dis 2016; 9: 1604-12), brought forth more information regarding this hybrid EHEC which contains a rare variant of the intimin gene and genetic determinants related to a plasmid, found mostly in avian pathogenic _E. coli_ and _E. coli_ that causes human neonatal meningitis, which is associated with extraintestinal virulence. This group, led by Stephane Bonacorsi, originally reported this atypical organism in an adult associated with HUS with a relapse associated with bacteremia (Mariani-Kurkdjian P, Lemaire C, Bidet P, et al. Haemolytic-uraemic syndrome with bacteraemia caused by a new hybrid _Escherichia coli_ pathotype. New Microbes New Infect 2014; 2(4): 127-131).

The 2016 study reported that 96 percent of the cases were associated with HUS but the authors do point out that the surveillance system for EHEC is voluntary in France and PCR assays for Shiga toxin in stool is only done in cases involving diarrhea with HUS suspicion so the denominator of total O80:H2 cases is not known. Likewise, whether this organism is zoonotic is also not clear and the areas in France with this strain are not where most cases of _E. coli_ O157 are reported.

Regarding the use of antimicrobials, the issue is relevant in these cases since some of them are associated with bacteremia which requires antimicrobial therapy. Azithromycin and ceftriaxone were not associated with increasing Shiga toxin production whereas ciprofloxacin was, in this study. In the large _E. coli_ O104:H4 outbreak in northern Germany, therapy was also used especially in those cases where the colon was perforated. In those reports, the carbapenem antimicrobials also did not increase toxin production. Whether these effects are strain specific is not clear at this time so should not necessarily be generalized to all EHEC. Of note, the _E. coli_ O104:H4 strain was a genetic hybrid between EHEC and enteroaggregative _E. coli_ and was not thought to be a zoonosis.

Extraintestinal invasive strains of EHEC will indeed introduce another layer of concern about these infections. - Mod.LL

HealthMap/ProMED-mail map of Europe: <http://healthmap.org/promed/p/6010>]

[See Also:
E. coli EHEC - Sweden: RFIhttp://promedmail.org/post/20180816.5968531
E. coli EHEC - Norway: O157, RFI http://promedmail.org/post/20180719.5915567
E. coli EHEC - Ireland (02): increased numbers http://promedmail.org/post/20180704.5888313
E. coli EHEC - France (02): O26, unpasteurized cheese, more cases http://promedmail.org/post/20180604.5837791
E. coli EHEC - Ireland: (Ulster) childcare center http://promedmail.org/post/20180527.5820927
E. coli EHEC - France: O26, unpasteurized cheese, alert, recall http://promedmail.org/post/20180511.5792857
E. coli EHEC - Canada: cheese, 2013, 60 day rule http://promedmail.org/post/20180220.5639238
E. coli EHEC - Denmark: O26 http://promedmail.org/post/20181106.6129035
E. coli EHEC - UK (02): (England) O157, raw pet food, fatal, 2017 http://promedmail.org/post/20181019.6100174
E. coli EHEC - UK: (England) fatal http://promedmail.org/post/20181005.6071314
E. coli EHEC - Ireland (03): (GY) daycare http://promedmail.org/post/20180722.5915568

2016
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E. coli EHEC - France: O80:H2, hybrid invasive pathogen, 2005-2014 http://promedmail.org/post/20160909.4474015]

Published 28-09-2017 in Focus on , last update 26-11-2018

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