Benjamin A. Rogers

Mitsuhashi

Yohei Doi

Rogers, Benjamin A.

Doi, Yohei

University of Queensland eSpace

INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY APRIL 2 0 1 3 , VOL. 3 4 , NO. 4 
C O M M E N T A R Y 
Who Is Leading This Dance? Understanding the Spread of 
Escherichia coli Sequence Type 131 
Benjamin A. Rogers, MBBS, FRACP;1 Yohei Doi , M D , PhD 2 
(See the article by Banerjee et al, on pages 361-369.) 
Escherichia coli is part of our normal intestinal flora and a 
ubiquitous human pathogen. It causes a wide range of disease, 
including intestinal infection (from diarrhea to hemolytic 
uremic syndrome) and extraintestinal infection (from un-
complicated urinary tract infection to bacteremia and men-
ingitis). Although wild-type E. coli is intrinsically susceptible 
to most antimicrobials, extraintestinal E. coli strains have 
shown the ability to develop resistance to every class of agents 
introduced for human use. This trend goes back to the de-
velopment of sulfonamide and ampicillin resistance in the 
mid-twentieth century and seems unlikely to abate in the 
foreseeable future.1,2 
The previous decade has heralded some changes in the 
dynamics of resistance in E. coli. Resistance to sulfameth-
oxazole-trimethoprim and fluoroquinolones has skyrocketed 
worldwide, which is a significant trend, because it compro-
mises 2 valuable oral treatment options for infections caused 
by E. coli. Equally alarming has been a rapid increase in the 
incidence of E. co/x-producing extended-spectrum /3-lacta-
mase enzymes (ESBL-EC), and the expansion of ESBL-EC 
from nosocomial to community acquisition that has occurred 
in many regions. 
A breakthrough in understanding these epidemiologic 
shifts in resistance came in the mid-2000s, when researchers 
used multilocus sequence typing (MLST) to identify the dom-
inance of a particular bacterial clone, sequence type (ST) 131, 
among ESBL-EC strains.3'4 Subsequently, ST131 E. coli has 
been shown to have worldwide distribution. It spans not only 
clinical strains of ESBL-EC, in which ST131 frequently ac-
counts for greater than 25% of those isolates recovered, but 
also a significant proportion of fluoroquinolone-resistant 
strains and even asymptomatic carriage of ciprofloxacin-
resistant ST131 E. coli among healthy individuals.5 Overall, 
ST131 is now regarded as the single most important clone 
driving multidrug resistance in the community setting. 
With this in mind, the work by Banerjee et al6 reported in 
this issue of Infection Control and Hospital Epidemiology urges 
us to redefine the epidemiology of E. coli ST131. Here, the 
authors conducted a population-based, molecular epidemi-
ologic analysis of 299 consecutive clinical isolates of extra-
intestinal E. coli identified in Olmstead County, Minnesota. 
Because of this study design, the isolates represented a rel-
atively unbiased sample of community-associated, healthcare-
associated, and hospital-acquired infections without regard 
to antimicrobial susceptibility. It should be pointed out that 
39% of the isolates were from individuals with healthcare-
associated or hospital-acquired infections; thus, the sample 
represented a relatively "medicalized" population. 
In this context, ST131 accounted for 27% of the isolates. 
The most intriguing finding was that ST131 accounted for a 
much greater proportion of healthcare-associated than com-
munity-associated isolates (49% vs 15%). A whopping 76% 
of the isolates from long-term care facility (LTCF) residents 
were ST 131. As expected, ST131 accounted for a much bigger 
share of antimicrobial-resistant isolates, including over 80% 
of isolates that were nonsusceptible to fluoroquinolones and 
approximately half of isolates resistant to trimethoprim-sul-
famethoxazole; however, only 11% of the ST131 isolates were 
nonsusceptible to ceftriaxone, which is most commonly due 
to production of ESBL. The independent predictors for ST131 
included residence in a LTCF, urinary tract infection in the 
previous month, complex infection due to E. coli, and pre-
vious antimicrobial exposure (extended-spectrum cephalo-
sporin, macrolides, and fluoroquinolones). These predictors 
could all be considered potential markers of healthcare-
associated infection, although only residence in a LTCF is 
included in the most commonly adopted definition.7 
In summary, the data presented by Banerjee et al6 yield 
compelling odds ratios for these medical risk factors that are 
in favor of ST131, not against it. Although these findings 
seemingly contradict the largest body of work on this clone, 
which strongly delineates its community-associated nature,5 
Affiliations: 1. University of Queensland, UQ Centre for Clinical Research, Herston, Queensland, Australia; 2. Division of Infectious Diseases, University 
of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. 
Received December 21, 2012; accepted December 24, 2012; electronically published February 13, 2013. 
© 2013 by The Society for Healthcare Epidemiology of America. All rights reserved. 0899-823X/2013/3404-0006$15.00. DOI: 10.1086/669874 
UNDERSTANDING THE SPREAD OF E. COLI STI3I 37 I 
T A B L E 1. 
Method 
Key Information on Molecular Epidemiology Methods Used in Characterizing Sequence Type (ST) 131 Escherichia coli 
Typing targets Resolution for ST131 Key characteristics 
Multilocus sequence typing 
Pulsed-field gel electrophoresis 
fimH typing17 
Genomic sequence of 7 con-
served housekeeping genes 
present in all E. coli. Gene 
functions are unrelated to 
bacterial virulence and 
pathogenesis. 
DNA restriction sites (arbi-
trary sequences of 4-8 
base-pairs of DNA) scat-
tered throughout the E. 
coli genome. 
First identified ST131 as a 
global epidemic clone.3'4 
By definition, all strains 
type as ST131 under the 
Achtman scheme (http:// 
mlst.ucc.ie/mlst/dbs/ 
Ecoli). 
Types ST131 into a variety 
of pulsotypes (subclones). 
Distinguishes human and 
animal clones and demon-
strates geographical varia-
tion in circulating ST131 
clones.16 
Genomic sequence of a 469- ST131 show a variety of 
base-pair fragment of the 
gene encoding a subunit 
of the type 1 fimbriae, 
which is used by E. coli to 
adhere to urothelium (the 
gene is occasionally absent 
in nonuropathogenic 
strains). 
fimH types. Some of these 
correlate closely with 
other characteristics, in-
cluding fluoroquinolone 
resistance.18 
Provides very broad molecu-
lar epidemiological char-
acterization. Given STs 
may contain a large range 
of bacteria of quite diverse 
genetic makeup. 
Highly discriminatory typing 
method often used for 
spatially and temporally 
related outbreaks (eg, 
within a given healthcare 
network). May fail to 
identify spread of less 
closely related strains 
when used alone (eg, 
ST131 separates into a 
large number of 
pulsotypes). 
Given the functional nature 
of this gene, potentially 
identifies genetic traits 
that play a role in bacte-
rial pathogenesis. 
a number of historical8,9 and contemporary1011 studies have 
also demonstrated high rates of healthcare-associated and 
hospital-acquired ST131. However, none demonstrate these 
findings with the weight of the study by Banerjee et al.6 
This contrast in epidemiology warrants further consider-
ation. Simple explanations may be geographical and meth-
odological. First, the epidemiology of this clone undoubtedly 
varies by location.5 Second, the methodology of published 
studies varies. Many investigators set out to find ST131 in 
the context of community-associated ESBL-EC infection and 
carefully surveyed this particular group.12 Others have not 
stratified community-onset infections by healthcare associa-
tion at all. In retrospect, these studies may have been ex-
amining only the tip of the iceberg (ie, community-associated, 
ESBL-producing E. coli ST131) while largely ignoring the 
much more substantial remainder under the water (ie, health-
care-associated, fluoroquinolone-resistant E. coli ST131). An-
other possibility is also in play. We may be seeing a change 
in the epidemiology of ST131, with this unwanted resident 
increasingly moving from the community into acute care set-
tings, which is a path already travelled by predecessors such 
as community-associated methicillin-resistant Staphylococcus 
aureus.13 
Regardless of the "when" and "where," the question of 
"why" ST131 has become a resident of our healthcare system 
is important. Some portals of entry are clear. Banerjee et al6 
and a number of other researchers have identified LTCFs as 
a reservoir of ST131. Two-way traffic of patients and resistant 
organisms between LTCFs and acute care facilities is almost 
invariable, with the term "revolving door" used by some to 
characterize this.11 Heavy use of fluoroquinolones should 
likely shoulder some blame, although the true nature of their 
effect is not defined. Other than correlating individuals' pre-
vious fluoroquinolone exposure to infection with fluoro-
quinolone-resistant ST131 clones, we have no information 
on the broader ecological impact of fluoroquinolone use on 
the spread of ST131. We do know from other settings that 
overall population fluoroquinolone use closely correlates with 
rates of resistance amongst all E. coli14 and that, once estab-
lished, gastrointestinal carriage of fluoroquinolone resistance 
is prolonged compared with the carriage of resistance to other 
agents, such as ESBLs.15 It is also increasingly clear among 
ST131 that animals and human clones are genetically dis-
tinct.16 This suggests that problematic fluoroquinolone use 
driving this particular epidemic could be in the human pop-
ulation rather than the result of often-cited veterinary use 
and food contamination. 
The most elusive component of "why" relates to the mo-
lecular characteristics of the clone. Although not extensively 
discussed in this study, Baterjee et al6 offer some intriguing 
372 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY APRIL 2 0 1 3 , VOL. 3 4 , NO. 4 
data. Although ST131 was originally identified as an epidemic 
clone using MLST, the molecular-epidemiological equivalent 
of a 40,000-foot view, drilling down on ST131s with the other 
methods gives interesting insights (Table 1). Pulsed-field gel 
electrophoresis (PFGE), which is traditionally used within a 
defined spatial and temporal context, demonstrates that ap-
proximately half of the ST131 fluoroquinolone-resistant iso-
lates in the Banterjee et al6 study belonged to 2 specific PFGE 
pulsotypes. However, the more specific method to define the 
core subclone of fluoroquinolone-resistant ST131 appeared 
to be fimH typing, which is a recently defined single-locus 
sequence typing method that uses a section of the fimH gene.17 
Unlike the benign housekeeping genes of MLST, fimH is a 
virulence gene that codes for a subunit of type I fimbriae 
crucial for bacterial adhesion to urotheleium. Here, 99% of 
the fluoroquinolone-resistant ST131 isolates shared a specific 
allele, fimH3Q, whereas this allele was absent from any of the 
fluoroquinolone-susceptible ST131 isolates. This allele is 
likely more than just an epidemiological marker. In-depth 
examination offimH30-carrying strains by other investigators 
has suggested a positively selected patho-adaptive trait. These 
strains appear to have augmented urovirulence via an en-
hanced ability to bind to urothelium.18 In essence, this flu-
oroquinolone-resistant ST131 fimH30 subclone is now fine-
tuned for its host and environment and appears to be 
out-competing other ST131 subclones and non-ST131 
strains. 
The study was performed in a rather rural county in North 
America, and the generalizability of the authors' findings re-
mains to be seen. However, they will prompt us to redefine 
the way we think about this emerging and expanding epi-
demic, which has the potential to deprive us of most oral 
treatment options for infections due to this exceedingly com-
mon bacteria in the near future. 
ACKNOWLEDGMENTS 
We thank David Paterson for his review of the manuscript of this article. 
Financial support. B.A.R. is supported by an Australian Postgraduate 
Award Scholarship from the University of Queensland. Y.D. is supported in 
part by a career development award from the National Institutes of Health 
(K22AI080584). 
Potential conflicts of interest. Y.D. has received research grants from Merck 
and served on an advisory board for Pfizer. All other authors report no 
conflicts of interest relevant to this article. All authors submitted the ICMJE 
Form for Disclosure of Potential Conflicts of Interest, and the conflicts that 
the editors consider relevant to this article are disclosed here. 
Address correspondence to Yohei Doi, Division of Infectious Diseases, 
Department of Medicine, University of Pittsburgh School of Medicine, S829 
Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261 (yod4@pitt.edu). 
R E F E R E N C E S 
1. Datta N, Kontomichalou P. Penicillinase synthesis controlled by 
infectious R factors in Enterobacteriaceae. Nature 1965; 
208(5007):239-241. 
2. Mitsuhashi S, Harada K, Hashimoto H, Egawa R. Drug-resis-
tance of enteric bacteria. 5. Drug-resistance of Escherichia coli 
isolated from human being. Jpn J Exp Med 1961;31:53-60. 
3. Coque TM, Novais A, Carattoli A, et al. Dissemination of don-
ally related Escherichia coli strains expressing extended-spectrum 
/3-lactamase CTX-M-15. Emerg Infect Dis 2008;14(2):195-200. 
4. Nicolas-Chanoine MH, Blanco J, Leflon-Guibout V, et al. In-
tercontinental emergence of Escherichia coli clone 025:H4-
ST131 producing CTX-M-15. / Antimicrob Chemother 2008; 
61(2):273-281. 
5. Rogers BA, Sidjabat HE, Paterson DL. Escherichia coli 025b-
ST131: a pandemic, multiresistant, community-associated 
strain. J Antimicrob Chemother 2011;66(1):1—14. 
6. Banerjee R, lohnston B, Lohse C, et al. Escherichia coli sequence 
type 131 is a dominant, antimicrobial-resistant clonal group 
associated with healthcare and elderly hosts. Infect Control Hosp 
Epidemiol 2013;34:361-369(in this issue). 
7. Friedman ND, Kaye KS, Stout JE, et al. Health care-associated 
bloodstream infections in adults: a reason to change the accepted 
definition of community-acquired infections. Ann Intern Med 
2002;137(10):791-797. 
8. Lau SH, Reddy S, Cheesbrough J, et al. Major uropathogenic 
Escherichia coli strain isolated in the northwest of England iden-
tified by multilocus sequence typing. / Clin Microbiol2008;46(3): 
1076-1080. 
9. Blanco M, Alonso MP, Nicolas-Chanoine MH, et al. Molecular 
epidemiology of Escherichia coli producing extended-spectrum 
^-lactamases in Lugo (Spain): dissemination of clone 025b:H4-
ST131 producing CTX-M-15. / Antimicrob Chemother 2009; 
63(6):1135-1141. 
10. Brisse S, Diancourt L, Laouenan C, et al. Phylogenetic distri-
bution of CTX-M- and non-extended-spectrum-/3-lactamase-
producing Escherichia coli isolates: group B2 isolates, except 
clone ST131, rarely produce CTX-M enzymes. / Clin Microbiol 
2012;50(9):2974-2981. 
11. Burke L, Humphreys H, Fitzgerald-Hughes D. The revolving 
door between hospital and community: extended-spectrum /3-
lactamase-producing Escherichia coli in Dublin. / Hosp Infect 
2012;81(3):I92-198. 
12. Doi Y, Park YS, Rivera JI, et al. Community-associated extended-
spectrum-/3-Lactamase (ESBL)-producing Escherichia coli infec-
tion in the United States. Clin Infect Dis 2012. 
13. Seybold U, Kourbatova EV, lohnson JG, et al. Emergence of 
community-associated methicillin-resistant Staphylococcus au-
reus USA300 genotype as a major cause of health care-associated 
blood stream infections. Clin Infect Dis 2006;42(5):647-656. 
14. Cheng AC, Turnidge J, Collignon P, Looke D, Barton M, Gottlieb 
T. Control of fluoroquinolone resistance through successful reg-
ulation, Australia. Emerg Infect Dis 2012;18(9):1453-1460. 
15. Rogers BA, Kennedy KJ, Sidjabat HE, Jones M, Collignon P, 
Paterson DL. Prolonged carriage of resistant E. coli by returned 
travellers: clonality, risk factors and bacterial characteristics. Eur 
J Clin Microbiol Infect Dis 2012;31(9):2413-2420. 
16. Johnson JR, Nicolas-Chanoine MH, DebRoy C, et al. Compar-
ison of Escherichia coli ST 131 pulsotypes, by epidemiologic traits, 
1967-2009. Emerg Infect Dis 2012;18(4):598-607. 
17. Weissman SJ, Johnson JR, Tchesnokova V, et al. High-resolution 
two-locus clonal typing of extraintestinal pathogenic Escherichia 
coli. Appl Environ Microbiol 2012;78(5):1353-1360. 
18. Paul S, Linardopoulou EV, Billig M, et al. Role of homologous 
recombination in adaptive diversification of extra-intestinal 
Escherichia coli. J Bacteriol 2012;195:231-242. 


Who is leading this dance? Understanding the spread of Escherichia coli sequence type 131

Crossref

Infection Control and Hospital Epidemiology

Who Is Leading This Dance? Understanding the Spread of <i>Escherichia coli</i> Sequence Type 131

http://espace.library.uq.edu.au/view/UQ:298759/UQ298759_OA.pdf

Who is leading this dance? Understanding the spread of Escherichia coli sequence type 131

Abstract

Similar works

Full text

Available Versions

University of Queensland eSpace

University of Queensland eSpace

Crossref