CTX-M ESBL-producing Enterobacteriaceae: estimated prevalence … · 2019-12-16 · CTX-M...

CTX-M ESBL-producing Enterobacteriaceae: estimated prevalence inadults in England in 2014

Cliodna A. M. McNulty1*, Donna M. Lecky1, Li Xu-McCrae2, Deborah Nakiboneka-Ssenabulya1, Keun-Taik Chung3,Tom Nichols4, Helen Lucy Thomas4, Mike Thomas5, Adela Alvarez-Buylla2, Kim Turner1, Sahida Shabir2,

Susan Manzoor2, Stephen Smith6, Linda Crocker1 and Peter M. Hawkey3

1Public Health England, Primary Care Unit, Microbiology Department, Gloucester Royal Hospital, Great Western Road, Gloucester GL13NN, UK; 2Public Health England, Heart of England NHS Foundation Trust, Public Health Laboratory, Bordesley Green E, Birmingham B9

5SS, UK; 3Institute of Microbiology and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; 4Public HealthEngland, 61 Colindale Avenue, London NW9 5EQ, UK; 5University of Southampton, Aldermoor Health Centre, Aldermoor Close,

Southampton SO16 5ST, UK; 6University Hospitals of Coventry & Warwickshire NHS Trust, Midlands & NW Bowel Cancer Screening Hub,Hospital of St Cross, Barby Road, Rugby CV22 5PX, UK

*Corresponding author. Tel: !44-300-422-5066; E-mail: [email protected]

Received 2 June 2017; returned 3 September 2017; revised 14 December 2017; accepted 2 January 2018

Background: ESBL-producing Enterobacteriaceae (ESBLPE) are increasing in prevalence worldwide and are moredifficult to treat than non-ESBLPE. Their prevalence in the UK general population is unknown, as the only previousUK ESBLPE faecal colonization study involved patients with diarrhoea.

Objectives: To estimate the prevalence of CTX-M ESBLPE faecal colonization in the general adult population ofEngland in 2014, and investigate risk factors.

Methods: A stratified random sample of 58337 registered patients from 16 general practices within four areasof England were invited to participate by returning faeces specimens and self-completed questionnaires.Specimens were tested for ESBLPE and carbapenemase-producing Enterobacteriaceae (CPE).

Results: 2430 individuals participated (4% of those invited). The estimated prevalence of colonization withCTX-M ESBLPE in England was 7.3% (95% CI 5.6%–9.4%) (Shropshire 774 participants, 4.9% colonization;Southampton City 740 participants, 9.2%; Newham 612 participants, 12.7%; Heart of Birmingham 234 individ-uals, 16.0%) and was particularly high in: those born in Afghanistan (10 participants, 60.0% colonization, 95% CI29.7%–84.2%); those born on the Indian subcontinent (India, Pakistan, Bangladesh or Sri Lanka) (259 partici-pants, 25.0% colonization, 95% CI 18.5%–32.9%); travellers to South Asia (India, Pakistan, Bangladesh, Sri Lankaor Nepal) in the last year (140 participants, 38.5% colonization, 95% CI 27.8%–50.5%); and healthcare domestics(8 participants, unweighted 37.5% colonization, 95% CI 8.5%–75.5%). Risk factors identified included: beingborn in the Indian subcontinent (aOR 5.4, 95% CI 3.0–9.7); travel to South Asia (aOR 2.9, 95% CI 1.8–4.8) or toAfrica, China, South or Central America, South East or Pacific Asia or Afghanistan (aOR 2.6, 95% CI 1.7–4.1) in thelast year; and working as a healthcare domestic (aOR 6.2, 95% CI 1.3–31). None of the 48 participants who tookco-amoxiclav in the last year was colonized with CTX-M ESBLPE. blaCTX-M-15 accounted for 66% of CTX-M ESBLPEpositives. 0.1% (two participants) were colonized with CPE.

Conclusions: CTX-M ESBLPE are established in the general population in England and prevalence is particularly highin people from certain countries of birth or with recent travel. We recommend that these findings be taken into ac-count in guidance on the empirical management of patients presenting with a likely Enterobacteriaceae infection.

Introduction

Extensive overuse of antibiotics worldwide has led to increasingprevalence of antibiotic-resistant Gram-negative bacteria (mainly

Escherichia coli) that produce ESBLs; 85%–90% of these beingCTX-M genotypes.1–4 Carriage is particularly high in South Asia.4

Between 2010 and 2015 total E. coli bloodstream and urine

VC The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecom-mons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the originalwork is properly cited. For commercial re-use, please contact [email protected]

1368

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infections in England have continued to rise and, moreover, resist-ance in E. coli to important hospital antibiotics such as co-amoxiclav and piperacillin/tazobactam rose significantly makingtreatment more difficult.5,6 ESBL-producing Enterobacteriaceae(ESBLPE) are opportunistic pathogens with large bowel coloniza-tion typically preceding an ESBLPE infection,7,8 so we believe thatunderstanding the prevalence of faecal colonization overall andfor certain sections of the general population will help inform em-pirical antibiotic guidance. Recent European studies indicate thattravellers to countries outside Europe have an up to 10-fold higherprevalence of ESBLPE faecal colonization than the local popula-tion.3,9,10 The prevalence of CTX-M ESBLPE in diagnostic faecalspecimens in a UK laboratory in 2010 was double in MiddleEastern/South Asian patients (22.8%) compared with Europeans(8.1%).11 Studies in returning European travellers have found thattravel to South Asia was the most important risk factor,12 whileantibiotic use10,12,13 and travellers’ diarrhoea were other possiblerisk factors for ESBLPE acquisition. Travel acquisition is importantas between 1% and 8% of returning travellers are hospitalized,14,15

equating to 3.1–24.8 million Europeans each year.16 Importantly,there are no studies of the colonization of ESBLPE in the UK generalpopulation.

This study aimed to estimate the prevalence of colonizationwith CTX-M ESBLPE across different sections of the adult generalpopulation of England in 2014, including different ethnic groups,and to investigate the potential risk factors for their carriage.

MethodsThe study was undertaken in four NHS Primary Care Trusts (PCTs) inEngland. PCTs were state-funded and commissioned primary medical carefrom general practices in England until 2015; this has now been taken overby Clinical Commissioning Groups. All the UK population are registered with,or have access to, a general medical practice whom they consult for pri-mary care. The four PCTs were purposively selected to capture the UK ethnicdiversity: Newham (London, highest ethnic diversity), Heart of Birmingham(predominantly Asian), Shropshire (rural, mostly white British) andSouthampton City (mixed ethnicity). Three to five willing Primary CareResearch Network practices from each PCT were non-randomly selected tobroadly represent each area with respect to ethnicity and deprivation.

Individuals aged �18 years in selected practices were stratified by re-cord of ethnicity (white, Asian, black, other/mixed or unknown), sex andage. Within each stratum individuals were randomly selected in 2013 and2014 to receive an invitation letter. Respondents were sent study informa-tion, a faeces sample collection kit (not rectal swab), £5 incentive offer anda questionnaire (Figure S1, available as Supplementary data at JAC Online)(including questions on age, ethnic group, country of birth, employment,household characteristics, hospitalization, antibiotic use, travel abroad inpast year and diet). Those not returning kits received a telephone reminder.Respondents were asked to collect scoops of faeces from both ends andthe middle of their faeces sample and place them in a sterile container,keep the container cool and return by first-class post within 24 h to a centrallaboratory. As sampling progressed, faeces returns were monitored and in-vitations to reach Asian, black and younger age group sample sizesincreased as necessary, including direct approach by general practice re-ceptionists to individuals in some ethnic groups. For some practices all indi-viduals within a given stratum were invited.

Laboratory analysisFaecal samples were screened for ESBLPE, using direct culture on selectivemedium (Brilliance

TM

ESBL agar, Oxoid Ltd) for 24 h. To increase sensitivity,

all samples were enriched as well as directly plated; 20 mg of each faecalsample was incubated for 24 h in 10 mL of brain heart infusion (BHI) brothcontaining 1 mg/L cefpodoxime17 and subcultured onto BrillianceTM agar asbefore.17,18 Oxidase-negative presumptive colonies of ESBLPE were definedas: !, 1–10 cfu; !!, 10–100 cfu; and !!!, �100 cfu. One colony fromeach different colony morphology, from each plate of Brilliance agar, wasidentified using MALDI-TOF MS (Bruker UK Ltd) and tested for the blaCTX-M

gene using multiplex PCR.19 Full-length gene amplification and sequencingidentified blaCTX-M genotypes (Table 1). A 10lg ertapenem disc was placedon all selective plates to detect potential carbapenemase-producingEnterobacteriaceae (CPE).20 Colonies growing in the zone of inhibition weretested by PCR for CPE genes.21

Data analysisTo estimate the prevalence of ESBLPE colonization for adults living inEngland in 2014 we used post-stratification weights based on the 2011 na-tional census and number of eligible individuals at selected practices. To es-timate the prevalence for each GP practice and PCT we used samplingweights based on the numbers of eligible individuals in each group at eachpractice. A new variable ‘region of origin’ was derived mainly from ethnicgroup and country of birth. Multivariable logistic regression models wereused to control for country of birth and region of origin (if born in the UK)(Table 2). Based on this preliminary analysis, factors that were associatedwith an increased risk of colonization were considered in further analysis.We also considered the strength of evidence and the number of missingvalues, and the evidence from other studies; we did not follow an auto-mated model selection process. The final multivariable model for coloniza-tion with CTX-M ESBLPE included country of birth and region of origin(if born in the UK) as a factor variable with eight categories, the base cat-egory of which was ‘born in some country not including the UK, India,Pakistan or Bangladesh (IPB), Sri Lanka, Afghanistan or the Middle East’(Table 3). From the final model we estimated the adjusted ORs (aORs) foreach risk factor, the percentage of carriers attributable to each risk factor(for example, travel to India) and, for groups of risk factors (for example,travel abroad in past year), the population attributable fraction (PAF). ThePAF is dependent on both the aOR and the probability of being exposed tothe factor.

Among participants colonized with CTX-M ESBLPE we calculated thepercentage colonized with a particular blaCTX-M genotype, and the percent-age belonging to particular ethnic groups among those who were carriersof a particular blaCTX-M genotype.

EthicsApproval for the study was obtained from the NRES Committee South West- Frenchay, Bristol, UK (13/SW/0017). The data we collected from GP prac-tices were anonymous.

Results

Of 76154 adult individuals registered in 16 GP practices, 58337 wereinvited to participate; 3389 (5.8%) expressed interest and were senta faeces kit, and 2331 (4.0%) returned a sample. A further 99 individ-uals invited by general practice receptionists participated, making atotal of 2430 participants. The number of stool specimens receivedfrom participants in each section of the adult population in England,the number of specimens positive for ESBLPE, and the unweightedand weighted percentage positive for ESBLPE are shown in Table 2.The estimated prevalence of colonization with CTX-M ESBLPEin adults living in England in 2014 was 7.3% (95% CI 5.6%–9.4%).Of the four PCTs, Heart of Birmingham teaching PCT (234 partici-pants) had the highest estimated prevalence at 16.0% (95% CI

CTX-M ESBL-producing Enterobacteriaceae prevalence JAC

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10.2%–24.2%) [Newham 612 participants, 12.7% (95% CI 9.1%–17.4%); Southampton City 740 participants, 9.2% (95% CI 6.1%–13.7%); and Shropshire County 774 participants, 4.9% (95% CI3.4%–7.0%)]. There was no evidence that estimated prevalence dif-fered by age or sex. There were high estimated prevalences for par-ticipants born in India (136 participants, 28.7% prevalence, 95% CI18.8%–41.2%), Pakistan (81 participants, 18.6% prevalence, 95% CI10.5%–30.8%), Bangladesh (34 participants, 23.5% prevalence, 95%CI 11.8%–41.3%), Sri Lanka (8 participants, 25.0% prevalence, 95%CI 7.2%–59.0%), Afghanistan (10 participants, 60.0% prevalence,95% CI 29.7%–84.2%) and the Middle East (18 participants, 15.5%prevalence, 95% CI 4.7%–40.5%) (Figure 1). The overall estimatedprevalence for those born in the Indian subcontinent (India,Pakistan, Bangladesh or Sri Lanka) combined (259 participants) was25.0%, (95% CI 18.5%–32.9%); differences between these fourcountries were non-significant (P"0.65). The estimated prevalencefor those born in the UK with an IPB region of origin was 15.7% (52participants), while for those born in the UK with a UK region of origin(1459 participants) it was 5.6% (95% CI 4.4%–7.1%, P"0.03).However there was a low estimated prevalence for those born inAfrica and of the IPB ethnic group (17 participants, 0% prevalence,95% CI 0%–19.5%).

Overall estimated prevalence of ESBLPE was the same in thosereporting taking any antibiotic in the last year (777 participants,6.8% prevalence 95% CI 5.1%–8.9%) or not (1427 participants,6.8% prevalence 95% CI 5.4%–8.6%). None of 48 participants whoreported having taken any co-amoxiclav in the past 12 monthscarried ESBLPE (0% prevalence, 95% CI 0%–7.4%, P"0.03).Estimated prevalence of ESBLPE in the 15 participants who hadtaken ciprofloxacin was 9.5%, (95% CI 2.5%–30.1%, P"0.61).

Two other groups with high estimated prevalence were thosewho had travelled to South Asia (India, Pakistan, Bangladesh, SriLanka or Nepal) in the last year (140 participants, 38.5% preva-lence, 95% CI 27.8%–50.5%) and those working as a domestic in ahealthcare setting [8 participants, unweighted prevalence 37.5%,95% CI 8.5%–75.5% (3/8; 1 black African, CTX-M-15, no travelabroad; 1 white British, CTX-M-15, travelled to India with partnerfor 12 days; 1 Asian Indian, CTX-M-27, travelled to India alone for42 days)]. If someone else in the participant’s household had beento India, Bangladesh, the Middle East, the Indian subcontinent orSouth East or Pacific Asia, this significantly increased the partici-pant’s risk for carrying blaCTX-M ESBL. Participants whose

housemates had travelled abroad in the last year to the Indiansubcontinent (India, Pakistan, Bangladesh or Sri Lanka) (120 par-ticipants, estimated prevalence 22.7%, 95% CI 14.2%–34.1%,P , 0.001), India (83 participants, estimated prevalence 24.9%95% CI 14.5%–39.2%, P , 0.001) and the Middle East (43 partici-pants, estimated prevalence 16.9%, 95% CI 7.5%–33.6%,P"0.02) had a higher prevalence. In 1071 of 1234 participants,both the housemate and the main participant had travelled to thesame country in the past 12 months.

Relative frequency of CTX-M genotypes (Figure 2)

Two hundred and eight participants were found to carry the CTX-Mgene; 184 (88%) by direct culture (25%!, 26%!!, 37%!!!)and a further 24 (12%) on enrichment; no single participant hadmore than one species of bacteria carrying CTX-M. Most isolates(199) were E. coli, 5 Klebsiella pneumoniae, 4 Enterobacter and 1Citrobacter. All isolates could be allocated a CTX-M grouping.Seventy-seven percent of participants with CTX-M ESBLPE (161/208) were colonized with CTX-M group 1; 25% (53/208) werecolonized with CTX-M group 9; 4% (9/208) were colonized withboth group 1 and group 9; and 1.4% (3/208) were colonized withCTX-M group 8, 25 or 26. Four isolates from group 1 and one isolatefrom group 9 could not be sequenced. The most common geno-type was blaCTX-M-15 (66%, 134/204) (Figure 2). Two other commongenotypes were blaCTX-M-14 (11%, 23/207) and blaCTX-M-27 (13%,27/207).

CTX-M genotypes and risk factors

Carriers of blaCTX-M-15 had a similar probability of being of whiteethnicity compared with carriers of other genotypes (62/134, 46%of blaCTX-M-15 were white; 46/134, 34% Asian IPB; and 26/134, 19%other ethnicity) and 84/129 (65%) had travelled abroad in the lastyear. A carrier of blaCTX-M-27 had a higher chance of being of theAsian-IPB ethnic group (16/27, 59% Asian IPB; 6/27, 22% white;5/27, 19% other ethnicity; 16/27, 59% travelled abroad) comparedwith carriers of other genotypes. A blaCTX-M-14 carrier had a higherchance of being of white ethnicity (19/23, 83% white; 2/23, 9%Asian IPB; 2/23, 9% other ethnicity; 14/23, 61% travelled abroad)compared with carriers of other genotypes. Carriers of the differentgenotypes CTX-M-15, -27 and -14 had a similar chance of having

Table 1. List of PCR and sequencing primers

CTX-M group Name Primer sequence Location

8 and 25/26 50CTXM26 TTG ATT AAC TAC AAC CCC AT CTX-M-26 (313–332)

30CTXM26 GAT ATC ATT CGT CGT ACC AT CTX-M-26 (747–728)

50CTXMF26-1 CTC TGC GCA ATC TGA CGT TG CTX-M-26 (575–594)

50CTXMF26-2 AAG GCG GGC GAT GTT AAT GA CTX-M-26 (18–37)

30CTXMR26-1 GCC AAT CGT ACG GGC AAA TG CTX-M-26 (477–458)

1 ISEcp1 AAA AAT GAT TGA AAG GTG GT ISEcp1 (#149 to #128)

30CTXM-1R ATA CAT CGC GAC GGC TTT CT CTX-M-1 (838–819)

50G1S1 ATG GTT AAA AAA TCA CTG CG CTX-M-15 (1–20)

9 50G9full GAA TAC TGA TGT AAC ACG GAT CTX-M-9 (#40 to #22)

30G9full AGT TAC AGC CCT TCG GCG AT CTX-M-9 (859–878)

McNulty et al.


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ia1

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Paki

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Ba

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34

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Nep

al

40

00

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]

Afg

ha

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10

66

0.0

60

.0[2

9.7

,84

.2]

Afr

ica

13

46

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5.8

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.5]

Au

stra

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a7

11

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9.5

[1.2

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Ca

rib

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n7

67

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7.6

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.1]

Ch

ina

17

00

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East

ern

Euro

pe

71

22

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Mid

dle

East

18

31

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15

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0.5

]

No

rth

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eric

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4.6

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Sou

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sto

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cA

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31

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Wes

tern

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(exc

l.U

Ka

nd

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an

d)

67

34

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9.5

]

Ma

uri

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00

00

[0,3

0.8

]

Co

un

try

of

bir

tha

mo

ng

the

Ind

ian

,Pa

kist

an

ior

Ba

ng

lad

esh

i(IP

B)

eth

nic

gro

up

Asi

an

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;bo

rnin

UK

46

81

7.4

18

.5[7

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],

0.0

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Asi

an

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;bo

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ia1

28

31

24

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9.5

[19

.2,4

2.4

]

Asi

an

-IPB

;bo

rnin

Paki

sta

n7

82

02

5.6

17

.8[9

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Asi

an

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Ba

ng

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34

82

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23

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1.8

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an

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17

00

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Asi

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som

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cou

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3.3

33

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8.9

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no

tA

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36

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5.9

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Eth

nic

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Wh

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15

32

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.2]

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ite-

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69

95

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.1[2

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1.1

]

McNulty et al.


Mix

ed-W

hit

ea

nd

Bla

ckC

ari

bb

ean

60

00

[0,4

5.9

]

Mix

ed-W

hit

ea

nd

Bla

ckA

fric

an

60

00

[0,4

5.9

]

Mix

ed-W

hit

ea

nd

Asi

an

16

21

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12

.5[3

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8.6

]

Mix

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ther

22

14

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6.2

]

Asi

an

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dia

n1

83

38

20

.82

6.1

[17

.6,3

6.8

]

Asi

an

-Pa

kist

an

i1

14

26

22

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7.4

[10

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8.0

]

Asi

an

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08

20

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0.0

[9.9

,36

.3]

Asi

an

-Ch

ines

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30

00

[0,1

4.8

]

Asi

an

-Oth

er6

81

42

0.6

20

.6[1

1.7

,33

.6]

Bla

ck-A

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an

10

05

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5.0

[2.2

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.3]

Bla

ck-C

ari

bb

ean

96

10

10

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1.2

[6.2

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.4]

Bla

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ther

30

00

[0,7

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]

Ara

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11

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14

.3[2

.0,5

8.1

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Oth

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10

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.8]

Reg

ion

of

ori

gin

d

UK

15

05

87

5.8

5.5

[4.3

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],

0.0

01

Irel

an

d3

82

5.3

4.8

[1.2

,17

.3]

Ind

ia1

92

39

20

.32

4.4

[16

.4,3

4.7

]

Paki

sta

n1

19

28

23

.51

8.6

[11

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8.9

]

Ba

ng

lad

esh

41

92

2.0

22

.6[1

1.8

,38

.9]

SriL

an

ka8

22

5.0

25

.0[7

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9.0

]

Nep

al

50

00

[0,5

2.2

]

Afg

ha

nis

tan

10

66

0.0

60

.0[2

9.7

,84

.2]

Afr

ica

11

86

5.1

6.6

[2.5

,16

.4]

Au

stra

lasi

a7

11

4.3

9.5

[1.2

,47

.8]

Ca

rib

bea

n1

18

11

9.3

8.2

[3.9

,16

.5]

Ch

ina

17

00

0[0

,19

.5]

East

ern

Euro

pe

77

22

.62

.8[0

.5,1

3.6

]

Mid

dle

East

16

21

2.5

12

.3[2

.8,4

1.2

]

No

rth

Am

eric

a9

11

1.1

11

.7[1

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5.7

]

Sou

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71

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]

Sou

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31

39

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4.5

[4.7

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Wes

tern

Euro

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(exc

l.U

Ka

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Irel

an

d)

77

79

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[4.6

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.5]

Mix

ed1

20

00

[0,2

6.5

]

Ma

uri

tiu

s/Se

ych

elle

s8

00

0[0

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.9]

Co

mb

ina

tio

no

fre

gio

no

fo

rig

ind

an

dco

un

try

of

bir

thw

ith

11

gro

up

s

bo

rnin

UK

;UK

ori

gin

14

59

85

5.8

5.6

[4.4

,7.1

],

0.0

01

bo

rnin

UK

;Asi

a-I

PBo

rig

in5

28

15

.41

5.7

[6.3

,33

.9]

bo

rnin

UK

;Ca

rib

bea

no

rig

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24

12

.51

1.9

[3.3

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.8]

bo

rnin

UK

;Oth

er

ori

gin

45

51

1.1

8.1

[3.0

,20

.2]

bo

rnin

Ind

ia1

36

33

24

.32

8.5

[18

.7,4

1.0

]

bo

rnin

Paki

sta

n8

12

12

5.9

18

.6[1

0.5

,30

.7]

bo

rnin

Ba

ng

lad

esh

34

82

3.5

23

.5[1

1.8

,41

.3]

bo

rnin

SriL

an

ka8

22

5.0

25

.0[7

.2,5

9.0

]

Co

nti

nu

ed



Tab

le2

.C

on

tin

ued

Fact

or

No

.of

spec

ime

ns

No

.of

bla

CT

X-M

ESB

LPE-

po

siti

vesp

ecim

ens

bla

CT

X-M

ESB

LPE-

po

siti

ve(u

nw

eig

hte

d%

)

Prev

ale

nce

[95

%C

I](w

eig

hte

d%

)a

Test

for

ad

iffe

ren

cein

pre

vale

nce

be

twee

nth

eg

rou

ps

of

each

fact

or

(Pva

lue)

OR

ad

just

edfo

rb

(co

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K)

(aO

R)

[95

%C

I]

Test

for

the

effe

cto

fea

chfa

cto

ra

fter

ad

just

men

tfo

rco

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K(P

valu

e)

bo

rnin

Afg

ha

nis

tan

10

66

0.0

60

.0[2

9.7

,84

.2]

bo

rnin

the

Mid

dle

East

18

31

6.7

15

.5[4

.7,4

0.5

]

bo

rnin

som

eo

ther

cou

ntr

y4

64

24

5.2

5.3

[3.3

,8.5

]

Co

mb

ina

tio

no

fre

gio

no

fo

rig

ind

an

dco

un

try

of

bir

thw

ith

8g

rou

ps

bo

rnin

UK

;UK

ori

gin

14

59

85

5.8

5.6

[4.4

,7.1

],

0.0

01

bo

rnin

UK

;Asi

a-I

PBo

rig

in5

28

15

.41

5.7

[6.3

,33

.9]

bo

rnin

UK

;Ca

rib

bea

no

rig

in3

24

12

.51

1.9

[3.3

,34

.8]

bo

rnin

UK

;Oth

er

ori

gin

45

51

1.1

8.1

[3.0

,20

.2]

bo

rnin

Ind

ia,P

aki

sta

n,B

an

gla

des

ho

rSr

iLa

nka

25

96

42

4.7

25

.0[1

8.5

,32

.9]

bo

rnin

Afg

ha

nis

tan

10

66

0.0

60

.0[2

9.7

,84

.2]

bo

rnin

the

Mid

dle

East

18

31

6.7

15

.5[4

.7,4

0.5

]

bo

rnin

som

eo

the

rco

un

try

46

42

45

.25

.3[3

.3,8

.5]

Do

you

wo

rkin

ah

ealt

hca

rese

ttin

g?

no

20

74

17

88

.66

.6[5

.5,8

.0]

0.6

01

0.8

9

yes

29

72

37

.77

.7[4

.6,1

2.6

]1

.0[0

.6,1

.7]

Typ

eo

fh

ea

lth

care

wo

rker

nu

rse

86

67

.05

.7[2

.1,1

4.5

]0

.39

0.8

[0.3

,2.1

]0

.25

care

ass

ista

nt

59

23

.48

.9[2

.2,2

9.9

]0

.4[0

.1,1

.9]

do

cto

r3

04

13

.31

8.0

[6.6

,40

.5]

1.6

[0.6

,4.6

]

do

mes

tic

83

37

.52

0.2

[3.9

,61

.1]

6.0

[1.1

,33

.3]

oth

erw

ork

inh

ealt

hca

re(i

ncl

.un

sp.)

11

48

7.0

5.6

[2.3

,13

.1]

1.1

[0.5

,2.3

]

no

tw

ork

ing

inh

ealt

hca

re2

07

41

78

8.6

6.6

[5.5

,8.0

]1

Typ

eo

fh

ea

lth

care

wo

rker

ha

nd

s-o

nh

ealt

hca

rew

ork

er1

75

12

6.9

8.7

[4.4

,16

.5]

0.1

40

.8[0

.4,1

.6]

0.5

3

ha

nd

s-o

ffh

ealt

hca

rew

ork

er(i

ncl

.un

sp.)

12

21

19

.06

.3[2

.9,1

3.2

]1

.4[0

.7,2

.6]

no

tw

ork

ing

inh

ealt

hca

re2

07

41

78

8.6

6.6

[5.5

,8.0

]1

Do

esyo

ur

wo

rkin

volv

eco

nta

ctw

ith

an

ima

ls?

no

22

19

19

28

.76

.8[5

.6,8

.1]

0.9

31

0.7

5

yes

85

67

.16

.5[2

.8,1

4.4

]1

.2[0

.5,2

.7]

Typ

eo

fw

ork

invo

lvin

gco

nta

ctw

ith

an

ima

ls

farm

wo

rk(i

ncl

.mea

tp

rep

.)4

85

10

.49

.7[3

.9,2

2.6

]0

.76

1.8

[0.7

,4.5

]0

.33

vete

rin

ary

wo

rk1

30

00

[0,2

4.7

]0

oth

erw

ork

wit

ha

nim

als

(in

cl.u

nsp

.)2

41

4.2

2.8

[0.4

,17

.8]

0.7

[0.1

,5.4

]

no

tw

ork

ing

wit

ha

nim

als

22

19

19

28

.76

.8[5

.6,8

.1]

1

McNulty et al.


Ha

veyo

ub

een

ho

spit

aliz

edin

the

pa

st1

2m

on

ths?

no

21

26

17

48

.26

.6[5

.4,8

.0]

0.6

31

0.7

3

yes

24

02

41

0.0

7.6

[4.4

,12

.9]

1.1

[0.7

,1.7

]

Ha

veyo

uta

ken

an

ya

nti

bio

tics

inth

ep

ast

12

mo

nth

s?

no

14

27

11

17

.86

.8[5

.4,8

.6]

0.9

61

0.8

8

yes

77

77

39

.46

.8[5

.1,8

.9]

1.0

[0.7

,1.4

]

Ha

veyo

uta

ken

an

ya

mo

xici

llin

inth

ep

ast

12

mo

nth

s?

no

18

35

14

78

.06

.8[5

.5,8

.4]

0.9

01

0.5

9

yes

36

93

71

0.0

6.6

[4.5

,9.7

]0

.9[0

.6,1

.3]

Ha

veyo

uta

ken

an

ytr

imet

ho

pri

min

the

pa

st1

2m

on

ths?

no

21

58

18

18

.46

.8[5

.7,8

.2]

0.6

41

0.8

2

yes

46

36

.55

.3[1

.7,1

5.0

]0

.9[0

.3,2

.8]

Ha

veyo

uta

ken

an

yer

yth

rom

ycin

inth

ep

ast

12

mo

nth

s?

no

21

57

17

98

.36

.7[5

.6,8

.1]

0.4

31

0.5

7

yes

47

51

0.6

10

.3[3

.6,2

6.1

]1

.3[0

.5,3

.5]

Ha

veyo

uta

ken

an

ycl

ari

thro

myc

inin

the

pa

st1

2m

on

ths?

no

21

78

18

18

.36

.8[5

.7,8

.2]

0.8

31

0.6

7

yes

26

31

1.5

5.9

[1.6

,19

.3]

1.3

[0.4

,5.0

]

Ha

veyo

uta

ken

an

yco

-am

oxi

cla

vin

the

pa

st1

2m

on

ths?

no

21

56

18

48

.57

.0[5

.8,8

.4]

0.0

31

0.0

04

yes

48

00

0[0

,7.4

]0

Ha

veyo

uta

ken

an

yci

pro

flo

xaci

nin

the

pa

st1

2m

on

ths?

no

21

89

18

08

.26

.8[5

.6,8

.1]

0.6

11

0.0

3

yes

15

42

6.7

9.5

[2.5

,30

.1]

3.0

[1.1

,8.1

]

Ha

veyo

uta

ken

an

yce

fale

xin

inth

ep

ast

12

mo

nth

s?

no

21

77

18

08

.36

.8[5

.6,8

.1]

0.3

41

0.3

1

yes

27

41

4.8

11

.4[3

.8,2

9.3

]1

.8[0

.6,5

.8]

Ha

veyo

uta

ken

an

yo

ther

an

tib

ioti

csin

the

pa

st1

2m

on

ths?

no

20

82

17

78

.56

.8[5

.6,8

.2]

0.9

71

0.2

6

yes

12

27

5.7

6.7

[2.5

,16

.7]

0.6

[0.3

,1.4

]

Ha

veyo

uta

ken

co-a

mo

xicl

av,

cip

rofl

oxa

cin

or

cefa

lexi

nin

the

pa

st1

2m

on

ths?

no

21

19

17

78

.46

.9[5

.7,8

.3]

0.2

21

0.7

6

yes

85

78

.24

.1[1

.7,9

.4]

0.9

[0.4

,1.9

]

Do

you

curr

entl

yh

ave

au

rin

ary

cath

eter

?

no

22

75

19

28

.46

.8[5

.7,8

.2]

0.2

71

0.6

2

yes

15

21

3.3

15

.5[3

.3,4

9.3

]1

.4[0

.4,5

.5]

Do

you

reg

ula

rly

eat

bee

f?

no

84

19

21

0.9

7.5

[5.8

,9.7

]0

.39

10

.87

yes

15

17

10

56

.96

.5[5

.1,8

.2]

1.0

[0.7

,1.4

]

Do

you

reg

ula

rly

eat

po

rk/h

am

/ba

con

?

no

55

87

61

3.6

11

.4[8

.5,1

5.1

],

0.0

01

10

.36

yes

16

81

10

36

.15

.8[4

.6,7

.3]

0.8

[0.6

,1.2

]

Do

you

reg

ula

rly

eat

lam

b?

no

94

06

67

.06

.5[4

.8,8

.7]

0.6

81

0.3

1

yes

12

91

12

19

.47

.1[5

.6,8

.9]

1.2

[0.9

,1.7

]

Co

nti

nu

ed



Tab

le2

.C

on

tin

ued

Fact

or

No

.of

spec

ime

ns

No

.of

bla

CT

X-M

ESB

LPE-

po

siti

vesp

ecim

ens

bla

CT

X-M

ESB

LPE-

po

siti

ve(u

nw

eig

hte

d%

)

Prev

ale

nce

[95

%C

I](w

eig

hte

d%

)a

Test

for

ad

iffe

ren

cein

pre

vale

nce

be

twee

nth

eg

rou

ps

of

each

fact

or

(Pva

lue)

OR

ad

just

edfo

rb

(co

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K)

(aO

R)

[95

%C

I]

Test

for

the

effe

cto

fea

chfa

cto

ra

fter

ad

just

men

tfo

rco

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K(P

valu

e)

Do

you

reg

ula

rly

eat

chic

ken

?

no

23

22

29

.57

.5[4

.6,1

2.1

]0

.67

10

.68

yes

21

05

17

68

.46

.7[5

.5,8

.1]

1.1

[0.7

,1.9

]

Do

you

reg

ula

rly

eat

fish

/sea

foo

d?

no

29

53

31

1.2

9.4

[6.0

,14

.3]

0.1

01

0.5

9

yes

20

01

15

77

.86

.3[5

.1,7

.6]

0.9

[0.6

,1.4

]

Do

you

reg

ula

rly

eat

sala

dp

rod

uct

s?

no

12

11

61

3.2

9.1

[5.2

,15

.4]

0.3

01

0.1

1

yes

22

07

17

98

.16

.7[5

.5,8

.1]

0.6

[0.4

,1.1

]

No

tre

gu

larl

yea

tin

gm

eat

no

21

72

17

88

.26

.6[5

.4,8

.0]

0.2

41

0.8

9

yes

17

62

01

1.4

9.2

[5.5

,15

.1]

1.0

[0.6

,1.8

]

No

tre

gu

larl

yea

tin

gm

eat,

fish

or

sea

foo

d(v

eget

ari

an

)

no

22

51

18

68

.36

.6[5

.5,8

.0]

0.2

51

0.5

5

yes

10

51

21

1.4

10

.0[5

.0,1

8.8

]0

.8[0

.4,1

.6]

Inth

ep

ast

yea

r,h

ave

you

spen

tti

me

ina

ny

cou

ntr

yo

uts

ide

the

UK

?

no

11

42

75

6.6

4.6

[3.3

,6.3

],

0.0

01

1,

0.0

01

yes

12

34

12

71

0.3

8.8

[7.1

,10

.8]

2.0

[1.5

,2.8

]

Ha

veyo

ub

een

ho

spit

aliz

ed

ab

roa

din

the

last

yea

r?

no

23

64

19

98

.46

.6[5

.5,8

.0]

,0

.00

11

0.0

4

yes

12

32

5.0

37

.7[1

3.1

,70

.8]

3.6

[1.1

,12

.2]

Ha

veyo

uh

ad

dia

rrh

oea

ab

roa

din

the

last

yea

r?

no

22

39

18

68

.36

.5[5

.4,7

.8]

0.0

91

0.0

3

yes

13

71

61

1.7

11

.2[6

.1,1

9.7

]1

.8[1

.0,3

.2]

Ha

veyo

ub

een

ab

roa

dto

Ind

iain

the

last

yea

r?

no

22

79

17

47

.66

.2[5

.1,7

.5]

,0

.00

11

0.0

01

yes

97

28

28

.93

3.7

[22

.6,4

7.0

]3

.2[1

.7,6

.2]

Ha

veyo

ub

een

ab

roa

dto

Paki

sta

nin

the

last

yea

r?

no

23

52

19

18

.16

.6[5

.5,7

.8]

,0

.00

11

0.0

07

yes

24

11

45

.84

8.6

[24

.8,7

3.1

]3

.6[1

.4,9

.1]

Ha

veyo

ub

een

ab

roa

dto

Ba

ng

lad

esh

inth

ela

stye

ar?

no

23

65

20

08

.56

.7[5

.6,8

.1]

0.1

61

0.9

3

yes

11

21

8.2

17

.4[4

.2,5

0.1

]0

.9[0

.2,4

.9]

Ha

veyo

ub

een

ab

roa

dto

SriL

an

kain

the

last

yea

r?

no

23

67

19

98

.46

.7[5

.6,8

.0]

,0

.00

11

0.0

2

yes

93

33

.33

9.8

[12

.4,7

5.6

]6

.4[1

.3,3

1.4

]

McNulty et al.


Ha

veyo

ub

een

ab

roa

dto

Nep

ali

nth

ela

stye

ar?

no

23

73

20

18

.56

.6[5

.5,7

.9]

,0

.00

11

0.1

1

yes

31

33

.37

6.8

[17

.9,9

8.0

]8

.9[0

.6,1

33

]

Ha

veyo

ub

een

ab

roa

dto

Sou

thA

sia

(In

dia

,Pa

kist

an

,Ba

ng

lad

esh

,Sri

Lan

kao

rN

epa

l)in

the

last

yea

r?

no

22

36

15

87

.15

.8[4

.7,7

.1]

,0

.00

11

,0

.00

1

yes

14

04

43

1.4

38

.5[2

7.8

,50

.5]

3.3

[2.0

,5.6

]

Ha

veyo

ub

een

ab

roa

dto

Afg

ha

nis

tan

inth

ela

stye

ar?

no

23

74

20

18

.56

.7[5

.6,8

.1]

0.4

31

0.2

2

yes

21

50

.01

7.1

[1.3

,76

.1]

3.5

[0.5

,25

.2]

Ha

veyo

ub

een

ab

roa

dto

Afr

ica

inth

ela

stye

ar?

no

22

35

18

48

.26

.2[5

.1,7

.5]

,0

.00

11

0.0

06

yes

14

11

81

2.8

16

.4[9

.4,2

7.0

]2

.2[1

.2,3

.7]

Ha

veyo

ub

een

ab

roa

dto

Au

stra

lasi

ain

the

last

yea

r?

no

23

41

20

08

.56

.7[5

.6,8

.1]

0.7

51

0.9

4

yes

35

25

.78

.6[1

.9,3

1.5

]0

.9[0

.2,4

.0]

Ha

veyo

ub

een

ab

roa

dto

the

Ca

rib

bea

nin

the

last

yea

r?

no

23

19

19

78

.56

.7[5

.6,8

.0]

0.4

91

0.5

0

yes

57

58

.89

.8[3

.3,2

5.5

]1

.4[0

.5,3

.9]

Ha

veyo

ub

een

ab

roa

dto

Ch

ina

inth

ela

stye

ar?

no

23

52

19

88

.46

.6[5

.5,7

.9]

0.0

31

0.0

6

yes

24

41

6.7

22

.9[7

.1,5

3.5

]2

.9[0

.9,9

.1]

Ha

veyo

ub

een

ab

roa

dto

East

ern

Euro

pe

inth

ela

stye

ar?

no

21

27

18

78

.86

.9[5

.7,8

.3]

0.5

11

0.7

7

yes

24

91

56

.05

.7[3

.3,9

.7]

0.9

[0.5

,1.6

]

Ha

veyo

ub

een

ab

roa

dto

the

Mid

dle

East

inth

ela

stye

ar?

no

23

29

19

58

.46

.7[5

.6,8

.0]

0.2

91

0.2

2

yes

47

71

4.9

10

.6[4

.5,2

3.0

]1

.7[0

.7,3

.8]

Ha

veyo

ub

een

ab

roa

dto

No

rth

Am

eric

ain

the

last

yea

r?

no

22

18

18

68

.46

.4[5

.3,7

.7]

0.0

71

0.0

6

yes

15

81

61

0.1

11

.3[6

.2,1

9.8

]1

.7[1

.0,3

.0]

Ha

veyo

ub

een

ab

roa

dto

Sou

tho

rC

entr

alA

mer

ica

inth

ela

stye

ar?

no

23

47

19

78

.46

.6[5

.5,7

.9]

0.0

51

0.0

4

yes

29

51

7.2

19

.4[6

.3,4

6.4

]3

.1[1

.1,9

.2]

Ha

veyo

ub

een

ab

roa

dto

Sou

thEa

sto

rPa

cifi

cA

sia

inth

ela

stye

ar?

no

23

09

19

18

.36

.4[5

.3,7

.7]

0.0

03

10

.00

1

yes

67

11

16

.41

7.4

[9.0

,31

.1]

3.3

[1.6

,6.5

]

Ha

veyo

ub

een

ab

roa

dto

aco

un

try

inW

este

rnEu

rop

e(n

ot

incl

.UK

an

dIr

ela

nd

)in

the

last

yea

r?

no

16

07

14

49

.06

.4[5

.1,7

.9]

0.4

11

0.1

9

yes

76

95

87

.57

.4[5

.5,1

0.0

]1

.3[0

.9,1

.8]

Ha

veyo

ub

een

ab

roa

dto

Ma

ldiv

es,M

au

riti

us

or

Seyc

he

lles

inth

ela

stye

ar?

no

23

58

20

28

.66

.8[5

.7,8

.1]

0.3

91

0.1

4

yes

18

00

0[0

,18

.5]

0

Ha

veyo

ub

een

ab

roa

dto

:Au

stra

lia,t

he

Ca

rib

bea

n,E

ast

ern

Euro

pe,

the

Mid

dle

East

,No

rth

Am

eric

a,W

este

rnEu

rop

e(n

ot

incl

.UK

an

dIr

ela

nd

),M

ald

ives

,

Ma

uri

tiu

so

rSe

ych

elle

sin

the

last

yea

r?

no

13

35

11

98

.96

.0[4

.7,7

.7]

0.2

01

0.0

3

yes

10

41

83

8.0

7.6

[5.9

,9.8

]1

.4[1

.0,2

.0]

Co

nti

nu

ed



Tab

le2

.C

on

tin

ued

Fact

or

No

.of

spec

ime

ns

No

.of

bla

CT

X-M

ESB

LPE-

po

siti

vesp

ecim

ens

bla

CT

X-M

ESB

LPE-

po

siti

ve(u

nw

eig

hte

d%

)

Prev

ale

nce

[95

%C

I](w

eig

hte

d%

)a

Test

for

ad

iffe

ren

cein

pre

vale

nce

be

twee

nth

eg

rou

ps

of

each

fact

or

(Pva

lue)

OR

ad

just

edfo

rb

(co

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K)

(aO

R)

[95

%C

I]

Test

for

the

effe

cto

fea

chfa

cto

ra

fter

ad

just

men

tfo

rco

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K(P

valu

e)

Ha

veyo

ub

een

ab

roa

dto

:Afr

ica

,Ch

ina

,So

uth

or

Ce

ntr

alA

mer

ica

,So

uth

East

or

Paci

fic

Asi

ao

rA

fgh

an

ista

nin

the

last

yea

r?

no

21

25

16

67

.85

.6[4

.6,6

.8]

,0

.00

11

,0

.00

1

yes

25

13

61

4.3

16

.6[1

1.3

,23

.7]

2.8

[1.8

,4.3

]

Nu

mb

ero

fa

du

lts

livin

gin

resp

on

den

t’s

ho

use

ho

ld(i

ncl

.res

po

nd

ent)

14

13

29

7.0

6.1

[3.8

,9.5

]0

.02

(tes

tfo

r

tren

d:P

"0

.06

)

10

.65

(tes

tfo

r

tren

d:P

"0

.96

)2

11

77

87

7.4

5.9

[4.6

,7.5

]1

.0[0

.6,1

.6]

34

06

39

9.6

8.3

[5.3

,13

.0]

1.1

[0.6

,1.8

]

42

08

19

9.1

6.1

[3.5

,10

.6]

0.8

[0.4

,1.6

]

58

61

51

7.4

18

.8[9

.8,3

2.9

]1

.7[0

.8,3

.5]

6!

67

10

14

.97

.6[3

.0,1

7.9

]0

.9[0

.3,2

.1]

Nu

mb

ero

fch

ildre

na

ged

5–1

7ye

ars

livin

gin

resp

on

den

t’s

ho

use

ho

ld

01

88

81

52

8.1

6.9

[5.6

,8.4

]0

.18

(tes

tfo

r

tren

d:P

"0

.77

)

10

.24

(tes

tfo

r

tren

d:P

"0

.47

)1

24

51

56

.13

.6[1

.8,7

.0]

0.6

[0.3

,1.0

]

21

56

20

12

.89

.5[5

.1,1

7.1

]1

.1[0

.6,1

.9]

3!

68

12

17

.68

.1[3

.4,1

7.9

]0

.8[0

.4,1

.6]

Nu

mb

ero

fch

ildre

na

ged

0–4

yea

rsliv

ing

inre

spo

nd

ent’

sh

ou

seh

old

02

07

81

65

7.9

6.4

[5.2

,7.8

]0

.12

(tes

tfo

r

tren

d:P

"0

.28

)

10

.85

(tes

tfo

r

tren

d:P

"0

.24

)1

21

02

51

1.9

9.9

[6.1

,15

.6]

1.0

[0.6

,1.7

]

2!

69

91

3.0

4.6

[1.9

,10

.4]

1.2

[0.6

,2.3

]

Nu

mb

ero

fch

ildre

na

ged

0–1

7ye

ars

livin

gin

resp

on

den

t’s

ho

use

ho

ld

01

71

91

32

7.7

6.5

[5.2

,8.1

]0

.96

(tes

tfo

r

tren

d:P

"0

.44

)

10

.78

(tes

tfo

r

tren

d:P

"0

.96

)1

29

12

37

.97

.0[4

.2,1

1.6

]0

.8[0

.5,1

.3]

22

46

27

11

.07

.1[4

.1,1

2.0

]1

.0[0

.6,1

.6]

3!

10

11

71

6.8

7.9

[3.9

,15

.1]

0.9

[0.5

,1.6

]

Nu

mb

ero

fp

eop

leliv

ing

inre

spo

nd

ent’

sh

ou

seh

old

13

77

27

7.2

5.8

[3.6

,9.4

]0

.07

(tes

tfo

r

tren

d:P

"0

.06

)

10

.71

(tes

tfo

r

tren

d:P

"1

.00

)2

90

16

47

.16

.2[4

.8,8

.1]

1.0

[0.6

,1.7

]

33

93

30

7.6

7.2

[4.3

,11

.8]

0.9

[0.5

,1.6

]

43

17

21

6.6

4.6

[2.5

,8.2

]0

.7[0

.4,1

.4]

51

83

25

13

.79

.6[6

.0,1

5.1

]1

.2[0

.7,2

.3]

69

11

41

5.4

13

.2[6

.1,2

6.4

]1

.0[0

.4,2

.2]

74

61

02

1.7

19

.0[8

.0,3

8.7

]1

.5[0

.6,3

.8]

8!

49

81

6.3

6.6

[2.9

,14

.0]

0.7

[0.3

,1.7

]

Do

you

ha

vea

ny

cats

livin

gin

you

rh

ou

seo

rfl

at?

no

19

39

16

98

.76

.9[5

.7,8

.4]

0.7

01

0.7

4

yes

42

23

27

.66

.3[4

.1,9

.7]

1.1

[0.7

,1.6

]

Do

you

ha

vea

ny

do

gs

livin

gin

you

rh

ou

seo

rfl

at?

no

19

89

17

88

.97

.1[5

.9,8

.6]

0.2

01

0.8

8

yes

36

22

26

.15

.0[3

.0,8

.3]

1.0

[0.6

,1.7

]

McNulty et al.


Do

you

ha

vea

ny

rab

bit

sliv

ing

inyo

ur

ho

use

or

fla

t?

no

21

21

18

38

.66

.5[5

.4,7

.8]

0.9

41

0.7

9

yes

45

36

.76

.8[1

.9,2

1.6

]0

.8[0

.2,3

.0]

Do

you

ha

vea

ny

gu

ine

ap

igs

livin

gin

you

rh

ou

seo

rfl

at?

no

20

91

18

28

.76

.6[5

.5,7

.9]

0.2

31

0.2

1

yes

36

12

.80

.9[0

.1,6

.4]

0.3

[0.0

4,2

.0]

Do

you

ha

vea

ny

ha

mst

ers

livin

gin

you

rh

ou

seo

rfl

at?

no

20

92

18

38

.76

.7[5

.5,8

.1]

0.2

31

0.4

3

yes

30

13

.32

.2[0

.3,1

4.1

]0

.5[0

.08

.3.0

]

Do

you

live

ina

nu

rsin

gh

om

e,ca

reh

om

eo

rre

sid

enti

alh

om

e?

no

23

48

20

08

.56

.8[5

.7,8

.1]

1.0

01

0.1

4

yes

90

00

[0,3

3.6

]0

Isth

ere

an

yon

ein

you

rh

ou

seh

old

wh

ow

ork

sin

ah

ealt

hca

rese

ttin

g?

no

20

45

17

38

.56

.7[5

.5,8

.1]

0.9

71

0.8

1

yes

28

72

38

.06

.8[4

.0,1

1.3

]0

.9[0

.6,1

.5]

Isth

ere

an

yon

ein

you

rh

ou

seh

old

wh

ose

wo

rkin

volv

esco

nta

ctw

ith

an

ima

ls?

no

22

25

18

98

.56

.9[5

.7,8

.3]

0.3

91

0.7

6

yes

91

66

.64

.7[2

.0,1

0.9

]1

.1[0

.5,2

.7]

Isth

ere

an

yon

ein

you

rh

ou

seh

old

wh

oh

as

bee

nh

osp

ita

lized

inth

ep

ast

yea

r?

no

20

96

17

88

.56

.9[5

.7,8

.3]

0.6

11

0.4

0

yes

25

02

18

.45

.9[3

.2,1

0.5

]0

.8[0

.5,1

.4]

Isth

ere

an

yon

ein

you

rh

ou

seh

old

wh

oh

as

take

na

nti

bio

tics

inth

ep

ast

yea

r?

no

15

46

11

47

.46

.4[5

.1,8

.1]

0.9

11

0.5

7

yes

73

77

39

.96

.6[4

.9,8

.9]

1.1

[0.8

,1.5

]

Isth

ere

an

yon

ein

you

rh

ou

seh

old

wh

oh

as

spen

tti

me

ab

roa

din

the

last

yea

r?

no

13

18

96

7.3

5.6

[4.3

,7.3

]0

.03

1,

0.0

01

yes

10

17

10

31

0.1

8.3

[6.5

,10

.5]

1.8

[1.3

,2.4

]

Ho

use

ma

teb

een

toIn

dia

inth

ela

stye

ar

no

22

51

17

87

.96

.5[5

.4,7

.8]

,0

.00

11

0.0

1

yes

83

21

25

.32

4.9

[14

.5,3

9.2

]2

.4[1

.3,4

.6]

Ho

use

ma

teb

een

toPa

kist

an

inth

ela

stye

ar

no

23

14

19

58

.46

.8[5

.7,8

.1]

0.2

11

0.8

5

yes

20

42

0.0

15

.6[3

.9,4

5.5

]1

.1[0

.3,3

.6]

Ho

use

ma

teb

een

toB

an

gla

des

hin

the

last

yea

r

no

23

24

19

98

.66

.8[5

.7,8

.2]

1.0

01

0.0

2

yes

10

00

0[0

,30

.8]

0

Ho

use

ma

teb

een

toSr

iLa

nka

inth

ela

stye

ar

no

23

26

19

78

.56

.8[5

.6,8

.1]

0.0

61

0.1

3

yes

82

25

.02

6.6

[5.5

,69

.5]

3.7

[0.7

,19

.6]

Ho

use

ma

teb

een

toth

eIn

dia

nsu

bco

nti

nen

t(I

nd

ia,P

aki

sta

n,B

an

gla

des

ho

rSr

iLa

nka

)in

the

last

yea

r

no

22

14

17

27

.86

.4[5

.3,7

.7]

,0

.00

11

0.0

5

yes

12

02

72

2.5

22

.7[1

4.2

,34

.1]

1.7

[1.0

,3.0

]

Ho

use

ma

teb

een

toA

fgh

an

ista

nin

the

last

yea

r

no

23

32

19

98

.56

.8[5

.7,8

.2]

1.0

01

0.3

9

yes

20

00

[0,8

4.2

]0

Ho

use

ma

teb

een

toA

fric

ain

the

last

yea

r

no

22

39

19

08

.56

.6[5

.5,8

.0]

0.2

01

0.2

7

yes

95

99

.51

1.5

[5.0

,24

.3]

1.5

[0.7

,3.0

]

Co

nti

nu

ed



Tab

le2

.C

on

tin

ued

Fact

or

No

.of

spec

ime

ns

No

.of

bla

CT

X-M

ESB

LPE-

po

siti

vesp

ecim

ens

bla

CT

X-M

ESB

LPE-

po

siti

ve(u

nw

eig

hte

d%

)

Prev

ale

nce

[95

%C

I](w

eig

hte

d%

)a

Test

for

ad

iffe

ren

cein

pre

vale

nce

be

twee

nth

eg

rou

ps

of

each

fact

or

(Pva

lue)

OR

ad

just

edfo

rb

(co

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K)

(aO

R)

[95

%C

I]

Test

for

the

effe

cto

fea

chfa

cto

ra

fter

ad

just

men

tfo

rco

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

ifb

orn

inth

eU

K(P

valu

e)

Ho

use

ma

teb

een

toA

ust

rala

sia

inth

ela

stye

ar

no

23

04

19

78

.66

.7[5

.6,8

.0]

0.4

31

0.8

6

yes

30

26

.71

2.5

[2.5

,44

.0]

1.1

[0.3

,4.9

]

Ho

use

ma

teb

een

toth

eC

ari

bb

ean

inth

ela

stye

ar

no

22

88

19

68

.66

.8[5

.7,8

.1]

0.6

61

0.8

5

yes

46

36

.58

.9[2

.6,2

6.9

]1

.1[0

.3,3

.8]

Ho

use

ma

teb

een

toC

hin

ain

the

last

yea

r

no

23

13

19

68

.56

.7[5

.6,8

.0]

0.0

71

0.1

6

yes

21

31

4.3

20

.1[5

.6,5

1.4

]2

.6[0

.7,9

.9]

Ho

use

ma

teb

een

toEa

ster

nEu

rop

ein

the

last

yea

r

no

21

26

18

58

.76

.9[5

.7,8

.2]

0.8

61

0.7

9

yes

20

81

46

.76

.5[3

.4,1

2.1

]1

.1[0

.6,1

.9]

Ho

use

ma

teb

een

toth

eM

idd

leEa

stin

the

last

yea

r

no

22

91

18

98

.26

.7[5

.6,8

.0]

0.0

21

0.0

3

yes

43

10

23

.31

6.9

[7.5

,33

.6]

2.5

[1.1

,5.6

]

Ho

use

ma

teb

een

toN

ort

hA

mer

ica

inth

ela

stye

ar

no

21

92

18

58

.46

.8[5

.6,8

.1]

0.7

01

0.1

5

yes

14

21

49

.97

.6[4

.2,1

3.4

]1

.6[0

.9,2

.8]

Ho

use

ma

teb

een

toSo

uth

or

Cen

tra

lAm

eric

ain

the

last

yea

r

no

23

09

19

68

.56

.8[5

.7,8

.1]

0.7

71

0.1

6

yes

25

31

2.0

8.1

[2.5

,23

.4]

2.4

[0.7

,8.2

]

Ho

use

ma

teb

een

toSo

uth

East

or

Paci

fic

Asi

ain

the

last

yea

r

no

22

85

19

18

.46

.5[5

.4,7

.8]

0.0

11

0.0

06

yes

49

81

6.3

17

.9[8

.4,3

4.1

]3

.1[1

.4,7

.1]

Ho

use

ma

teb

een

toW

este

rnEu

rop

e(n

ot

incl

.UK

an

dIr

ela

nd

)in

the

last

yea

r

no

17

08

14

98

.76

.8[5

.5,8

.3]

0.9

11

0.1

1

yes

62

65

08

.06

.9[4

.9,9

.7]

1.4

[0.9

,1.9

]

Ho

use

ma

teb

een

toa

no

ther

reg

ion

of

the

wo

rld

inth

ela

stye

ar

no

23

17

19

88

.56

.8[5

.7,8

.1]

0.9

21

0.8

1

yes

17

15

.97

.5[1

.1,3

7.7

]0

.8[0

.1,5

.5]

Als

osh

ow

na

reth

eO

Rs

for

po

ten

tia

lris

kfa

cto

rsfo

rco

lon

iza

tio

na

fter

ad

just

men

tfo

rth

ep

erso

n’s

cou

ntr

yo

fb

irth

an

dth

ep

erso

n’s

reg

ion

of

ori

gin

ifb

orn

inth

eU

K.

aTo

esti

ma

teth

ep

reva

len

ceo

fES

BLP

Eco

lon

iza

tio

nfo

ra

du

lts

livin

gin

Eng

lan

din

20

14

we

use

dw

eig

hts

ba

sed

on

the

20

11

na

tio

na

lcen

sus

an

dth

en

um

ber

of

elig

ible

ind

ivid

ua

lsa

tth

ese

lect

edp

ract

ices

.Wei

gh

tsfo

ret

hn

icg

rou

p,a

ge

gro

up

an

dse

xw

ere

calc

ula

ted

for

all

ind

ivid

ua

lsb

ase

do

nth

ece

nsu

sd

ata

alo

ne.

Toes

tim

ate

the

pre

vale

nce

for

each

GP

pra

ctic

ea

nd

PCT

we

use

dw

eig

hts

ba

sed

on

the

nu

mb

ers

of

elig

ible

ind

ivid

ua

lsin

each

gro

up

at

each

pra

ctic

e.bC

ate

go

ries

of

this

fact

or

vari

ab

lere

ferr

edto

inth

ista

ble

incl

ud

e:B

orn

inth

eU

K:U

Ko

rig

in;B

orn

inth

eU

K:I

nd

ia,P

aki

sta

no

rB

an

gla

des

ho

rig

in;B

orn

inth

eU

K:C

ari

bb

ean

ori

gin

;Bo

rnin

the

UK

:oth

er

ori

gin

;Bo

rnin

Ind

ia;B

orn

inPa

kist

an

;Bo

rnin

Ba

ng

lad

esh

;Bo

rnin

SriL

an

ka;B

orn

inA

fgh

an

ista

n;B

orn

inth

eM

idd

leEa

st;a

nd

Bo

rnin

som

eo

ther

cou

ntr

y.c Et

hn

icg

rou

pw

as

self

-dec

lare

db

yea

chp

art

icip

an

tw

hen

com

ple

tin

gth

ere

sea

rch

qu

esti

on

na

ire.

dR

egio

no

fo

rig

in/o

rig

inis

der

ived

fro

mth

ese

lf-d

ecla

red

eth

nic

gro

up

an

dco

un

try

of

bir

th.

McNulty et al.


Tab

le3

.Fi

na

lmu

ltiv

ari

ate

mo

del

for

colo

niz

ati

on

wit

hC

TX-M

ESB

LPE

Ris

kfa

cto

rC

ate

go

ries

Nu

mb

ero

fp

eop

leex

po

sed

toth

eri

skfa

cto

rin

the

mo

del

(n"

23

19

)a

OR

[95

%C

I];

Pva

lue

Perc

enta

ge

PAF

[95

%C

I]Pe

rcen

tag

ePA

F[9

5%

CI]

Co

un

try

of

bir

tha

nd

reg

ion

of

ori

gin

aif

bo

rnin

the

UK

Bo

rnin

the

Ind

ian

sub

con

tin

ent

(In

dia

,Pa

kist

an

,Ba

ng

lad

esh

or

SriL

an

ka)

25

65

.4[3

.0,9

.7];

,0

.00

12

3.8

[15

.9,3

0.9

]2

7.7

[19

.5,3

5.1

]

Bo

rnin

Afg

ha

nis

tan

94

6.0

[9.6

,21

8];

,0

.00

12

.8[1

.3,4

.3]

Bo

rnin

the

Mid

dle

East

18

4.7

[1.3

,17

.0];

0.0

21

.1[#

0.4

,2.6

]

Bo

rnin

the

UK

an

do

fU

Ko

rig

in1

45

11

.3[0

.8,2

.1];

0.2

49

.9[#

7.1

,24

.1]

15

.3[#

3.5

,30

.6]

Bo

rnin

the

UK

an

do

fIP

Bo

rig

in5

23

.8[1

.5,9

.2];

0.0

04

2.8

[0.1

,5.4

]

Bo

rnin

the

UK

an

do

fC

ari

bb

ean

ori

gin

32

3.4

[1.0

,10

.9];

0.0

41

.4[#

0.6

,3.3

]

Bo

rnin

the

UK

an

do

fso

me

oth

ero

rig

ino

ro

fm

ixed

ori

gin

45

2.2

[0.7

,6.5

];0

.17

1.3

[#1

.0,3

.5]

Co

mp

are

dw

ith

(Ref

eren

ceca

teg

ory

):B

orn

inso

me

cou

ntr

yo

ther

tha

nU

K,I

PB,S

riLa

nka

,Afg

ha

nis

tan

or

the

Mid

dle

East

46

4Re

fere

nce

Refe

ren

ceRe

fere

nce

Tra

vela

bro

ad

inth

ep

ast

yea

rS

ou

thA

sia

13

32

.9[1

.8,4

.8];

,0

.00

11

2.1

[5.9

,7.8

]2

7.9

[16

.0,3

8.1

]

•In

dia

�Sr

iLa

nka

•Pa

kist

an

�N

epa

l

•B

an

gla

des

h

Co

mp

are

dw

ith

(Ref

eren

ceca

teg

ory

):

No

tra

velt

oSo

uth

Asi

a

21

86

Ref

eren

ceRe

fere

nce

Co

un

trie

so

uts

ide

Asi

aw

ith

hig

her

risk

24

62

.6[1

.7,4

.1];

,0

.00

19

.9[4

.3,1

5.1

]

•A

fric

a�

Sou

thEa

sto

rPa

cifi

cA

sia

•C

hin

a�

Afg

ha

nis

tan

•So

uth

or

Cen

tra

lAm

eric

a

Co

mp

are

dw

ith

(Ref

eren

ceca

teg

ory

):

No

tra

velt

oco

un

trie

so

uts

ide

Asi

aw

ith

hig

her

risk

20

73

Ref

eren

ceRe

fere

nce

Oth

er

cou

ntr

ies

10

21

1.3

[0.9

,1.8

];0

.15

7.9

[#3

.5,1

8.1

]

•A

ust

rala

sia

�M

au

riti

us

•Th

eC

ari

bb

ean

�Se

ych

elle

s

•Th

eM

idd

leEa

st�

Ma

ldiv

es

•N

ort

hA

mer

ica

�Eu

rop

e(e

xcl.

UK

&Ir

ela

nd

)

Co

mp

are

dw

ith

(Ref

eren

ceca

teg

ory

):

No

tra

velt

oO

ther

cou

ntr

ies

12

98

Ref

eren

ceRe

fere

nce

Do

mes

tic

wo

rkin

ah

ealt

hca

rese

ttin

gYe

s8

6.2

[1.3

,31

];0

.03

1.1

[#0

.2,2

.3]

Co

mp

are

dw

ith

(Ref

eren

ceca

teg

ory

):N

o2

31

1R

efer

ence

Refe

ren

ce

aR

egio

no

fo

rig

in/o

rig

inis

de

rive

dfr

om

the

self

-dec

lare

det

hn

icg

rou

pa

nd

cou

ntr

yo

fb

irth

.



travelled abroad in the last year. Of the 199 E. coli, 87% (173/199)were ST131. ST131 was not significantly more common in CTX-Mcarriers who had spent time anywhere abroad in the last year, or inthe Indian subcontinent (India, Pakistan, Bangladesh or Sri Lanka),compared with those who had not (spent time anywhere abroad87% ST131 versus not spent time abroad 79%, P"0.17; spenttime abroad in the Indian subcontinent 91% ST131 versus notspent time in the Indian subcontinent 82%, P"0.17).

Risk factors for colonization with CTX-M ESBLPE

After adjusting for country of birth and region of origin (if born inthe UK) we found no evidence for an independent association be-tween CTX-M ESBLPE colonization and GP practice, age group, sex,overall antibiotic use in the past year or hospitalization in the pastyear (Table 2). Factors that remained significant after adjusting forcountry of birth and region of origin (if born in the UK) and weretherefore considered for inclusion in the final model included: par-ticipant’s travel abroad, or diarrhoea or hospitalization abroad inthe last year; use of ciprofloxacin or co-amoxiclav; being a domes-tic healthcare worker; and housemates’ travel abroad (overall andby country) in the last year. When added to the final multivariablemodel, there was no strong evidence that colonization was inde-pendently associated with either taking antibiotics in the last year(aOR 0.99, 95% CI 0.7–1.4, P"0.95), hospitalization abroad in thelast year (aOR 2.7, 95% CI 0.8–9.1, P"0.11, 3/12 colonized), diar-rhoea while abroad in the last year (aOR 1.1, 95% CI 0.6–1.9,P" 0.84, 16/137 colonized) or travel abroad by a participant’shousemate in the past year (aOR 1.4, P"0.11, 103/1071 colon-ized). Use of ciprofloxacin remained a significant risk factor for

ESBLPE-CTX-M in the final model (4/15 ESBLPE positive, aOR 3.2,P"0.03), whereas co-amoxiclav was protective for presence ofESBLPE-CTX-M (0/48 ESBLPE positive, aOR 0, P"0.006).

Being born in the Indian subcontinent (India, Pakistan,Bangladesh or Sri Lanka) was the most important identified riskfactor for faecal colonization (aOR 5.4, 95% CI 3.0–9.7), and we es-timate it accounted for 23.8% (95% CI 15.9%–30.9%) of peoplecolonized in England in 2014 (Table 3). Being born in Afghanistan(aOR 46.0, 95% CI 9.6–218) or the Middle East (aOR 4.7, 95% CI1.3–17.0) were factors strongly associated with colonization, butbeing relatively rare we estimate them to have accounted for rela-tively few people colonized [2.8% (95% CI 1.3%–4.3%) and 1.1%(95% CI#0.4% to 2.6%), respectively]. We found no evidencewhen tested in the final model that birth in or travel to other coun-tries including Eastern Europe increased risk of colonization (travelto Eastern Europe aOR 0.8, P"0.42; born in Eastern Europe aOR0.5, P"0.38). There was no evidence that being born in the UKwith a UK region of origin was a risk factor for colonization(aOR 1.3, 95% CI 0.8–2.1, P"0.24); but as there were so many par-ticipants in this group, we estimate it accounted for 9.9%(95% CI#7.1% to 24.1%) of people colonized. Being born in the UKwith an IPB region of origin was strongly associated with coloniza-tion (aOR 3.8, 95% CI 1.5–9.2), and we estimate it accounted for2.8% (95% CI 0.1%–5.4%) of people colonized. Being born in theUK with a Caribbean region of origin was almost as strongly associ-ated with colonization as being born in the UK with an IPB region oforigin (aOR 3.4, 95% CI 1.0–10.9), and we estimate it accountedfor 1.4% (95% CI#0.6% to 3.3%) of people colonized.

Travel to South Asia (India, Pakistan, Bangladesh, Sri Lanka orNepal) in the last year was strongly associated with colonization

*IPB = India, Pakistan or Bangladesh

0 10 20 30 40 50 60 70 80 90% Prevalence of colonization with CTX-M ESBLPE

Born UK : UK origin

Born UK : Asia-IPB* origin

Born UK : Caribbean origin

Born UK : Other origin

Born India

Born Afghanistan

Born Middle East

Born some other country (incl.Caribbean)

Born IPB or Sri Lanka

Born Sri Lanka

Born Bangladesh

Born Pakistan

England Overall

Region of origin/origin is derived from the self-declared ethnic group and country of birth

Figure 1. Prevalence of colonization with CTX-M ESBLPE by country of birth and region of origin if born in the UK (with 95% CI). Adults from thegeneral population of England in 2014. Dotted line is the estimated 2014 prevalence in England.

McNulty et al.


(aOR 2.9, 95% CI 1.8–4.8), and we estimate it accounted for 12.1%(95% CI 5.9%–17.8%) of people colonized. Travel to Africa, China,South or Central America, South East or Pacific Asia or Afghanistanin the last year also increased the risk of colonization (aOR 2.6,95% CI 1.7–4.1), and we estimate it accounted for 9.9% (95% CI4.3%–15.1%) of people colonized. Travel to other countries in thelast year put participants at a small increased chance of coloniza-tion (aOR 1.3, 95% CI 0.9–1.8; P"0.15) and, being relatively com-mon, we estimate it accounted for 7.9% (95% CI #3.5% to 18.1%)of people colonized. Working as a domestic in the healthcare set-ting was strongly associated with colonization (aOR 6.2, 95% CI1.3–31.0), but, being relatively rare, we estimate it to have ac-counted for just 1.1% (95% CI#0.2% to 2.3%) of people colonized.Collectively all risk factors in the final multivariable model ex-plained 60.4% (95% CI 40.0%–73.8%) of cases.

Only 0.1% of participants (2/2430) were colonized with CPE; nei-ther was born in the UK, and both had a history of travel to India inthe past year.

Discussion

The 7.3% estimate for the prevalence of faecal colonization withCTX-M ESBLPE in adults living in England in 2014, and the high esti-mated prevalence in those born in South Asia (India, Pakistan,Bangladesh or Sri Lanka) and in those travelling to certain areasincluding South Asia, is of concern and has implications for empir-ical antimicrobial prescribing for suspected infections caused byEnterobacteriaceae and infection prevention and controlwithin healthcare in England and beyond. The significantly higher

estimated prevalence (15.7%) in the 52 participants born in the UKwith an IPB region of origin, compared with those born in theUK with a UK region of origin (1459 participants, estimated preva-lence 5.6%), is interesting; the higher estimated prevalence maybe due to acquisition during repeated travel to their country of ori-gin, or from visits by family and friends to or from their country oforigin, during the last year or more than 1 year ago, or acquisitionfrom relatives in the home.22

Previous studies in the UK

The only previous faecal colonization study of ESBLPE in the UK(in 2010) showed that Middle Eastern or South Asian (India,Pakistan, Bangladesh, Sri Lanka or Nepal) patients being investi-gated for gastrointestinal infections had a significantly higherprevalence than Europeans.11 Although UK studies estimatingESBLPE infection rates in hospitalized patients or patients withurine infections (UTIs) have suggested (similar to this presentstudy) that rates of ESBLPE infection vary widely between differentareas of the UK23,24 they have not investigated other risk factors.

Previous studies of a general population in NorthernEurope

A 2011 postal study in urban Amsterdam estimated that the over-all prevalence of ESBLPE faecal colonization was 8.6% and travelto Asia or Africa (aOR 2.1–2.2) in the last year increased the risk.Unlike the present or other studies, they found antibiotic use inthe last year and travel to North America (aOR 2.7) were also

Group 1161, 77%

Group 8*3, 1.4%

CTX-M-15

CTX-M-1

CTX-M-55

CTX-M-3

CTX-M-32

New?

Not Typed

134 (66%)

9 (4.4%)

2 (1%)

1 (0.5%)

4 (2%)

3 (1.5%)

8 (3.9%)

CTX-M-14:19/23, 83% White2/23, 9% Asian IPB

2/23, 9% Other ethnicity14/23, 61% Travel abroad

CTX-M-27

CTX-M-14

27 (13%)

23 (11%)

CTX-M-9

New?

Not Typed 1 (0.5%)

1 (0.5%)

1 (0.5%)

CTX-M-15:62/134, 46% White

46/134, 34% Asian IPB26/134, 19% Other ethnicity84/129, 65% Travel abroad

CTX-M-27:6/27, 22% White

16/27, 59% Asian IPB5/27, 19% Other ethnicity16/27, 59% Travel abroad

Group 953, 24%

As each isolate could have more than one genotype, the relative frequencies for the different genotypes sum to more than 100% of individuals as nine individual isolates carried both CTX-M group 1 and group 9 genes

*The three isolates in group 8 were not sequenced

Figure 2. Relative frequency of the blaCTX-M genotypes from 208 individuals, characterizations of these genotypes and risk factors for them.



risk factors.3 The Amsterdam study found, as in the present study,that country of origin was important, as having a mother born inAsia was a risk factor independent of foreign travel (aOR 2.4). Inthe present and Amsterdam studies, hospitalization abroad in thepast year led to significantly higher faecal colonization and risk inthe univariable analysis, but neither found hospitalization abroadsignificant on multivariable analysis.3 The Amsterdam study didnot investigate travellers’ diarrhoea as a risk factor.3

A 2014/15 general population study in the rural SouthernNetherlands estimated the prevalence of faecal colonization withESBL/AmpC Enterobacteriaceae to be 4.5%. This is similar to our esti-mate for adults living in Shropshire in 2014, which is also rural with al-most the entire population born in the UK and of UK origin. This study,like ours, found travel to Africa, Asia and Latin America (aOR 2.9), wasa risk factor for carriage.25 Participants living in close proximity tomink farms (but not other farms) and keeping cows for a hobby in thelast 5 years (aOR 3.56) had increased risk.25 Despite other studiesshowing that contact with broiler farms increased risk in theNetherlands,26 neither contact with animals, pets or eating meat(including chicken) increased the risk of ESBLPE colonization in ourstudy. The risk factor associated with animals may only be evidentwhen you closely examine particular livestock, which we did not do.

A systematic review of faecal colonization27 with Ambler class AESBLPE in healthy individuals between 1992 and 2014 found thatESBLPE colonization had increased over time and was presentworldwide in 2014. The pooled estimated prevalence was highestin the West Pacific (46%), followed by South East Asia and Africa(22%), the Eastern Mediterranean (15%) and Northern Europe(4%). Factors associated with a higher risk of colonization wereinternational travel (RR 4.06) and antibiotic use in the previous year(RR 1.58), but this was a univariate analysis.27 The significant effectof antibiotic use in that review may not have remained on multi-variable analysis or may be caused by relatively greater use ofbroader spectrum antibiotics (especially quinolones) in countriesoutside Northern Europe and in travellers. Interestingly, althoughoverall antibiotic use was not a significant risk factor in our study,participants reporting ciprofloxacin use in the past year did havesignificantly increased estimated prevalence and this risk re-mained in the final multivariable model (aOR 3.2, P" 0.03).However, all four cases who reported taking ciprofloxacin and wereCTX-M ESBLPE positive had other risk factors (all four participantswere of Asian ethnicity, three were hospitalized in the past yearand one travelled to Pakistan). In contrast, reported co-amoxiclavuse in the last year appeared to be protective, as none of these48 participants was positive for CTX-M ESBLPE (0%, P"0.03). This isan important and interesting finding that needs further investiga-tion. Although co-amoxiclav has limited clinical activity againstCTX-M ESBLPE it is possible that there are high enough concentra-tions in the gut to eliminate faecal carriage. In contrast, ciprofloxa-cin would be expected to encourage colonization as almost all UKCTX-M ESBLPE are resistant.28 Only one of the previously publishedstudies of ESBLPE colonization in the general population reportedestimated prevalence by region of origin, and found birth in Africa,or parents born in Africa or Asia, to be an important risk factor.3

Previous studies of travellers

Like this study, studies of travellers from other European countrieshave identified travel outside Europe, and especially to the Middle

East, Africa and South Asia, to be a risk for ESBLPE faecal coloniza-tion and acquisition;10,27,29–31 with travel to Southern India beingthe greatest risk.10 In several studies, travellers’ diarrhoea and theuse of antimicrobials were independent risk factors for acquiringESBLPE, which is not consistent with our own findings.10,27,29–31

However, another 2012 study of travellers from a Swiss travel clinicto South Asia found length of stay, visiting friends and relativesand eating ice-cream were risk factors for acquisition of ESBLPE E.coli; whereas travellers’ diarrhoea was not a risk factor.13 Visitingfriends or relatives is probably a marker of being born in South Asia,which was a risk factor for colonization in our present study. Instudies like this and ours, which included a larger proportion oftravellers visiting relatives, travellers’ diarrhoea may not be suchan important marker for faecal colonization, as these travellers’gut microbiome may have already adapted to the South Asian dietand environmental flora. Although travel abroad by a housematewas associated with significantly higher carriage, this did not re-main significant in the final model. Travel abroad by a housematewas closely correlated with spending time abroad by the partici-pant themselves (1071/1234); so it is therefore not possible to dis-tinguish between the effect of this variable and the effect of travelabroad by the person themselves.

Two longitudinal studies of travellers who were ESBLPE carrierson return from abroad report the prevalence of carriage 12 monthsafter returning to be 11.3% and 2.2%, respectively, confirming thattravel abroad more than 1 year ago could be an important factorto investigate in future studies.10,32 Our questions about travelabroad were limited to the last year; this omission could be import-ant for travellers who travel repeatedly to areas with higher preva-lence of CTX-M ESBLPE and poor hygiene or sanitation, for exampleparticipants born in the UK of IPB or Caribbean origin who may bemore likely to repeatedly visit family and friends. This would helpto explain the higher carriage and risk conferred by being UK-bornbut of IPB or Caribbean origin.

Unlike the 2016 systematic review we did not find that esti-mated prevalence of CTX-M ESBLPE was significantly higher inthose born in or travelling to Eastern Europe (15/249 participantsCTX-M ESBLPE positive, aOR 0.9, 95% CI 0.5–1.6, P"0.77).27 Thismay be because sanitation facilities in these countries are betterthan on the Indian subcontinent (India, Pakistan, Bangladesh or SriLanka) so that acquisition in these countries is less common.

In our study the estimated prevalence of CTX-M ESBLPE amongthose working as domestics in healthcare was 37.5% (3/8 partici-pants, 95% CI 8.5%–75.5%). The risk factor was found to be inde-pendently associated with an increased risk of colonization; andthese eight participants were not similarly exposed to any otherparticular risk factor. Domestics in healthcare settings may be putat increased risk through their work cleaning toilet facilities; cer-tainly studies suggest that environmental acquisition may be re-sponsible for the spread of ESBLPE.13 Transmission of ESBLPEoccurs between patients in healthcare settings and staff do not al-ways adhere to infection control guidelines.33

As in other studies3,11,24,34 the dominant CTX-M ESBLPE geno-type was blaCTX-M-15, making up 66% of carriers of CTX-M ESBLPE.Interestingly we saw very few carriers of blaCTX-M-1, typically associ-ated with European farm animals,35,36 suggesting little acquisitionfrom these sources. This is supported by our lack of evidence thateither having a meat diet or working with animal livestock were riskfactors for CTX-M ESBLPE colonization. A quarter of carriers in our

McNulty et al.


study carried a genotype belonging to CTX-M group 9, similar to theprevious UK study of diagnostic faeces samples in Birmingham.11

blaCTX-M-27 made up half of the group 9 CTX-Ms in our study, butwas not found in the Birmingham study; in contrast, we found onlyone blaCTX-M-9, whereas this constituted 74% of group 9 in theBirmingham study.11 blaCTX-M-27, which is part of group 9, is a vari-ant of blaCTX-M-14 that has been reported both from the Far Eastand from Europe, and in the UK has been reported at a low fre-quency from food animals, notably dairy cattle.37 In our study, car-riers of blaCTX-M-27 were mainly from the Asian-IPB ethnic group(59%), whereas carriers of blaCTX-M-14 were mainly from the whiteethnic group (83%); this variation by ethnicity warrants further in-vestigation. In a Spanish study38, CTX-M-14-producing E. coli weremainly isolated from community UTIs; this was also found in aWelsh study, where 83% of the CTX-M-14 genotype were commu-nity acquired39 and they were more common in rural areas.40 CTX-M-14 E. coli may be indigenous in the UK community, possiblyacquired from cattle.41 Consistent with other work, we found nogroup 2 isolates.1

The present study shows that the ST131 clone was the mostprevalent among the isolated E. coli demonstrating that the spreadof CTX-M-15 in the UK may be due to this clone. Our results indicatethat being born in or travel to the Indian subcontinent (India,Pakistan, Bangladesh or Sri Lanka) was the biggest overall risk fac-tor, but in the IPB countries the ST131 clone is uncommon.42,43 Thismay help us to further explore CTX-M ESBLPE originating in the UK.

As no data exist on the frequency of community colonization ofCPE in the UK, we used our study to gain some insight into theirprevalence. Our culture methods, whilst potentially missing someOXA-type carbapenemases, are recognized reference laboratorymethods.20 Like other European studies, we found a low incidence ofCPE (0.1%) in England in 2014;44,45 the two positive participants (oneAsian woman with E. coli OXA-48 with CTX-M group 9, and one UKman with E. coli NDM-1 with CTX-M-15) had both travelled to SouthAsia (India, Pakistan, Bangladesh, Sri Lanka or Nepal). This representsa potential route for the introduction and future spread of CPE.

Strengths

This is the first study to estimate the prevalence of colonizationwith CTX-M ESBLPE in the UK general population. We invited a strati-fied random sample of individuals from the general populationfrom GP patient lists rather than selecting patients who had givendiagnostic faecal samples or returning travellers who are unrepre-sentative of the general population. An added value of this study isthe specific focus on ethnicity and the oversampling to retrieve suf-ficient data in ethnic minority groups, which enabled us to achievesufficient power to identify some ethnicities and some countries ofbirth as risk factors. The questionnaires that were returned werewell completed and allowed us to investigate a broad range of po-tential independent risk factors for CTX-M ESBLPE colonization.Rather than use swabs, we used faecal samples that increase sensi-tivity of detection of ESBLPE by 10%17,46 and enrichment, whichincreased our sensitivity of isolating CTX-M ESBLPE by 12%.17

Limitations

We only sought CTX-M ESBLPE (and not ESBLPE carrying the otherb-lactamase genes blaTEM, blaOXA and blaSHV) as CTX-Ms still

constitute more than 90% of ESBLPE genotypes and cause moreESBLPE infections than any other type of ESBLPE worldwide.3,47,48

We have not examined the genetic context of blaCTX-M, whichwould have given an insight into its linkage to IS elements.However, this would be unlikely to impact on the control of ESBLPEtransmission. For those exposed to a relatively rare risk factor, thesample size was small and the CI was wide.

We did not ask about the characteristics of the housemate whotravelled or their relationship to the participant, and housematetravel did not remain a significant risk in the final multivariablemodel (P"0.11). However, it was not our intention to study trans-mission. In future studies it would be interesting to confirmwhether housemates usually travelled to the same countries withthe participant or at a different time. Many cases of CTX-M faecalcolonization may be unexplainable by any risk factor we could con-ceivably have collected data on; so, it is possible we have investi-gated all the important risk factors. However, it is also possible thatsome cases could be explained by a risk factor that we did nothave sufficient power to detect or we did not ask about. Questionsabout travel abroad and about antibiotic use were limited to thelast year, so this study was not able to investigate whether travelabroad more than a year earlier or antibiotic use more than a yearearlier are risk factors for colonization. Furthermore we did not col-lect data on the use of proton-pump inhibitors, found to be a riskfactor for faecal carriage in the Amsterdam 2011 communitystudy (aOR 1.9)3 and the rural study.25 Since CTX-M ESBLPE arenow widely established in the English general population we werenot surprised to find that many cases were not directly attributableto travel abroad in the last year.

Most of our prevalence estimates come from a weighted ana-lysis that weighted participants by ethnic group, age group andsex. Should our participants be unrepresentative in respect of anyother variable then prevalence estimates for the general popula-tion could be biased. The risk of such a bias is compounded by thelow response rate (4%) and variation in response rate in the differ-ent groups.

Implications

Faecal colonization with ESBLPE usually precedes an ESBLPE infec-tion when it occurs7,8 so we believe that this study, showing CTX-MESBLPE to be established in the general population of England andthe prevalence of colonization to be considerably higher amongsome sections of the general population, has implications forempirical prescribing for all infections typically caused byEnterobacteriaceae, and that antimicrobial guidance should re-flect our findings.49 The population that is most relevant to anyconclusions about empirical antibiotic prescribing is the populationof those who have infections likely caused by Enterobacteriaceaeand are seen by clinicians. We haven’t studied this population butwe believe that a high prevalence estimate for a section of thegeneral population can be used to inform on the likely prevalenceof those from the same section of the general population whoseek treatment for infections likely caused by Enterobacteriaceae.When selecting empirical treatment for uncomplicated UTIwe suggest that clinicians should consider the risk of ESBLPE,noting recent travel, country of birth and region of origin,especially South Asia (India, Pakistan, Bangladesh, Sri Lanka orNepal). Nitrofurantoin, which has greater activity against ESBLPE,



is preferable to trimethoprim as an empirical agent in most casesof acute uncomplicated UTI.49 Although nitrofurantoin will still beappropriate for most patients with acute uncomplicated UTI, in pa-tients belonging to a section of the population that has a particu-larly high risk of ESBLPE carriage it may be preferable to obtainmicrobiology specimens before starting antibiotics. This might in-clude those born in South Asia and in patients who have travelledto South Asia in the last year. Empirical antimicrobials prescribedfor ‘sepsis’50 should always include an antimicrobial agent thattreats ESBLPE.51

Previous studies of the length of faecal colonization withESBLPE have been in patients who have attended a travel clinicand have acquired colonization abroad. There is wide variation inthe estimates of the percentage still colonized, from 4.8%52 to14.3%10 of travellers with faecal ESBLPE colonization at 6 months,and from 2.2%52 to 11.3%10 at 12 months. We need to understandthe length of carriage and transmission in the general population,which may be different; this would be best investigated in a longi-tudinal study in a typical population. Prospective or case–controlstudies designed to look at the risk of UTI or future infections inthose with ESBLPE faecal colonization are needed. To improve ourunderstanding of evolving risk groups for ESBLPE infections, wesuggest enhanced or periodic antimicrobial resistance surveillanceshould be extended to patients with uncomplicated infections(to reduce spectrum bias),6 and data collection should include eth-nic group, age and sex of the patient. If feasible to do so, we alsosuggest collecting: country of birth, recent travel history, ethnicorigins, occupation and use of antibiotics and antacids in thelast year.

A study of healthcare domestics’ colonization with ESBLPE com-pared with other healthcare workers, and possibly patients, isneeded as their numbers in our study were small, and there arelarge numbers of domestics working in healthcare with the poten-tial to transfer ESBLPE. Additionally, domestics receive less trainingabout infection prevention and control than other healthcareworkers, as they have no direct role in hands-on patient care.

According to our results the prevalence of CPE in the generalpopulation is still very low, and therefore efforts to reduce UKhealthcare transmission of CPE are worthwhile and could help todelay the inevitable expansion of these genes into the generalpopulation.

AcknowledgementsWe thank all the individuals who returned stool samples and question-naires; without you we could not have done this study. We wish to thank:Andre Charlett for all his help with the statistical interpretation and ad-vice on the paper; Rahim Shabbir for building the Access database;Katherine Butler and Eileen Hamilton for administrative support; the GPpractice staff; Primary Research network staff; ethics committees;Research Support Unit in Gloucester, especially Mark Walker; ElizabethCoates, Head of research governance at PHE; communications teams atPHE and radio stations who advertised the project; and Mike Nelson.

FundingThe report is based on independent research commissioned and fundedby the NIHR Policy Research Programme (Ref.041/0038S).

Transparency declarationsNone to declare.

Author contributionsC. A. M. M. (Principal Investigator) led the writing of the grant applicationand protocol, was involved in the literature review, contributed to the de-sign of the questionnaire, led the project steering group and led the writ-ing of the manuscript. D. M. L. (Project Manager Mar–Jul 2014 and fromApr 2015) was involved in practice and patient recruitment, data collec-tion and data management, was a steering group member and helpedwrite the manuscript. L. X.-M. (Clinical Scientist) was a grant co-applicantand was involved in study design and laboratory supervision, supportedlaboratory data management, was a steering group member and con-tributed to the writing of the manuscript. D. N.-S. (Research Assistant)was involved in ethics application, practice and participant recruitmentand data collection and entry, was a steering group member and com-mented on and agreed the final manuscript. K.-T. C. (Research Scientist)was involved in laboratory work, recording and data entry and agreedthe final manuscript. T. N. (Statistician) was a grant co-applicant, wasinvolved in study design, practice and participant selection, data man-agement and data analysis, was a steering group member and contrib-uted to the writing of and agreed the final manuscript. H. L. T.(Epidemiologist) was a grant co-applicant, was involved in study andquestionnaire design and data interpretation, was a steering group mem-ber and commented on and agreed the final manuscript. M. T. was a grantco-applicant, was involved in study and questionnaire design, was a steer-ing group member, was primary care lead, was involved in practice selec-tion and commented on and agreed the final manuscript. A. A.-B.(Research Scientist) was involved in laboratory work and data cleaning andagreed the final manuscript. K. T. (Unit Administrator) was involved in par-ticipant recruitment and liaison and data collection and entry and agreedthe final manuscript. S. Sh. (Research Scientist) was involved in laboratorywork and data collection and agreed the final manuscript. S. M. (ResearchScientist) was involved in laboratory work and data collection and agreedthe final manuscript. S. Sm. was a grant co-applicant and was involved instudy design, was a steering group member and commented on andagreed the final manuscript. L. C. (Project Manager Oct 2014–Mar 2015)was involved in organizing distribution of sample kits and data manage-ment and agreed the final manuscript. P. M. H. was a grant co-applicantand was involved in literature review, study design, questionnaire design,laboratory supervision and data interpretation, was a steering group mem-ber and contributed to the writing of and agreed the final manuscript.

DisclaimerThe views expressed in the publication are those of the authors and notnecessarily those of the NHS, the NIHR, the Department of Health, ‘arms’length bodies or other government departments.

Supplementary dataThe questionnaire is available as Figure S1 at JAC Online.

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