Articles
Import and spread of extended-spectrum β-lactamase-producing Enterobacteriaceae by international travellers (COMBAT study): a prospective, multicentre cohort study

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Summary

Background

International travel contributes to the dissemination of antimicrobial resistance. We investigated the acquisition of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) during international travel, with a focus on predictive factors for acquisition, duration of colonisation, and probability of onward transmission.

Methods

Within the prospective, multicentre COMBAT study, 2001 Dutch travellers and 215 non-travelling household members were enrolled. Faecal samples and questionnaires on demographics, illnesses, and behaviour were collected before travel and immediately and 1, 3, 6, and 12 months after return. Samples were screened for the presence of ESBL-E. In post-travel samples, ESBL genes were sequenced and PCR with specific primers for plasmid-encoded β-lactamase enzymes TEM, SHV, and CTX-M group 1, 2, 8, 9, and 25 was used to confirm the presence of ESBL genes in follow-up samples. Multivariable regression analyses and mathematical modelling were used to identify predictors for acquisition and sustained carriage, and to determine household transmission rates. This study is registered with ClinicalTrials.gov, number NCT01676974.

Findings

633 (34·3%) of 1847 travellers who were ESBL negative before travel and had available samples after return had acquired ESBL-E during international travel (95% CI 32·1–36·5), with the highest number of acquisitions being among those who travelled to southern Asia in 136 of 181 (75·1%, 95% CI 68·4–80·9). Important predictors for acquisition of ESBL-E were antibiotic use during travel (adjusted odds ratio 2·69, 95% CI 1·79–4·05), traveller's diarrhoea that persisted after return (2·31, 1·42–3·76), and pre-existing chronic bowel disease (2·10, 1·13–3·90). The median duration of colonisation after travel was 30 days (95% CI 29–33). 65 (11·3%) of 577 remained colonised at 12 months. CTX-M enzyme group 9 ESBLs were associated with a significantly increased risk of sustained carriage (median duration 75 days, 95% CI 48–102, p=0·0001). Onward transmission was found in 13 (7·7%) of 168 household members. The probability of transmitting ESBL-E to another household member was 12% (95% CI 5–18).

Interpretation

Acquisition and spread of ESBL-E during and after international travel was substantial and worrisome. Travellers to areas with a high risk of ESBL-E acquisition should be viewed as potential carriers of ESBL-E for up to 12 months after return.

Funding

Netherlands Organisation for Health Research and Development (ZonMw).

Introduction

Antimicrobial resistance constitutes an increasingly important human health hazard worldwide.1 The use of antibiotics in human beings and food animals is a well established driving force behind increasing resistance.2 Given the enormous growth of international tourism, from 25 million travellers in 1950 to 1·133 billion in 2014,3 international travel might also contribute substantially to the rise in resistance because resistant bacteria or bacterial mobile genetic elements carrying resistance genes (eg, plasmids) may be rapidly transported between regions.4 An important part of antimicrobial resistance genes is found on plasmids and codes for extended-spectrum β lactamase enzymes ([ESBLs] eg, TEM, SHV, and CTX-M) and carbapenemases that confer resistance to most β-lactam antibiotics.2, 4 Additionally, ESBL-producing Enterobacteriaceae (ESBL-E) and carbapenemase-producing Enterobacteriaceae (CPE) are typically resistant to multiple other antibiotic classes, which leaves few to no effective antimicrobial agents for prevention and treatment of infections.4, 5

Previous studies have reported frequent acquisition of ESBL-E associated with various predictors and sporadic acquisition of CPE among international travellers.6, 7, 8, 9, 10 However, data on ESBL-E colonisation after travel and assessment of associated predictors for sustained carriage and onward transmission within households are very limited. Such data are needed to establish the public health risk of the introduction and spread of antimicrobial resistance by travellers, and the potential needs and measures to monitor or manage these risks. Identifying individuals at risk of ESBL-E carriage enables appropriate measures to be taken to prevent introduction and spread of ESBL-E or CPE and for empirical adjustment of antibiotic treatment in individuals to optimise clinical care. We investigated the acquisition of ESBL-E during international travel, the associated predictive factors for acquisition, duration of colonisation, and onward transmission to household members.

Research in context

Evidence before this study

We searched PubMed on Aug 17, 2015, with the search terms “Gram negative bacteria”, “Enterobacteriaceae”, “Escherichia”, ”Klebsiella”, ”Salmonella”, “Shigella”, “Yersinia”, “travel”, “tourist”, “tourism”, “turista”, “aviation”, “air transport”, “airport”, “resistance”, “colonisation”, “antibiotic”, “susceptibility”, “carriage”, and “carrier”. We did a systematic review and identified 11 eligible studies. We updated this search on April 14, 2016, and found no new prospective studies. The results of the 11 prospective cohort studies showed high acquisition rates of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) among travellers who had returned from southern Asia and northern Africa. Four travellers who visited India acquired carbapenemase-producing Enterobacteriaceae (CPE). However, whether antibiotic use and traveller's diarrhoea are predictors for ESBL-E acquisition was unclear. Moreover, these studies did not sufficiently address duration of ESBL-E carriage among travellers or onward transmission within households. One study asked travellers to provide stool samples up to 12 months after return, but duration of carriage was defined by ESBL phenotype. One other study looked at household transmission, but because only 11 household contacts were included, no reliable conclusion could be inferred about the risk of household transmission.

Added value of this study

In this large-scale, longitudinal cohort study, we followed up travellers and their non-travelling household members for up to 12 months after travel. The large sample size meant that we could investigate ESBL-E acquisition among travellers who had returned from a large number of countries across the world, including those such as Uganda, for which community carriage rates of ESBL-E were previously unknown. We identified several predictors (some new) for ESBL-E acquisition, including factors specific to subregions. Moreover, we were able to ascertain duration of ESBL-E carriage and associated resistance genes, identify predictors for sustained colonisation, and to model transmission rates mathematically within households.

Implications of all the available evidence

High frequencies of ESBL-E acquisition during travel, subsequent sustained carriage, and evidence of onward transmission within households show that travellers contribute to the emergence and spread of ESBL-E on a global scale. Active screening for ESBL-E and CPE and adjustment of empirical antimicrobial therapy should be considered for returning travellers at increased risk of ESBL-E carriage. However, implications for infection prevention and antibiotic treatment policies will differ locally because the degree of consequence of acquisition and spread of ESBL-E by travellers is highly dependent on local ESBL-E prevalence in the country of origin.

Section snippets

Study design and participants

The study design and methods have been described in detail elsewhere.11 Briefly, we did a multicentre, longitudinal, prospective cohort study involving travellers who were followed up from 1–3 weeks before travel departure until 12 months after return. To study household transmission, we also assessed non-travelling household members in the same period.

Eligible participants were adults (age ≥18 years) planning to travel for at least 1 week and up to 3 months. They were recruited at three

Results

2737 travellers were screened for eligibility, of whom 2001 were included in the study (appendix), with median age 50·5 years (IQR 32·8–60·7) and good health before travelling in most (table 1). 49 travellers were lost to follow-up.

The main purpose for travel was tourism (1655 [84·2%] of 1965 travellers) and the median travel duration was 20 days (IQR 15·0–25·0; table 1). The subregions most frequently visited were southeast Asia (n=650), eastern Africa (n=287), South America (n=228), and

Discussion

Results from this large cohort study of travellers indicated that the risk of ESBL-E acquisition during travel is high, especially during travel to Asia and northern Africa. 11·3% of travellers who acquired EBSL-E remained colonised at 12 months after return, and the estimated probability of onward transmission within households was 12%. Other important predictors for ESBL-E acquisition during travel were antibiotic use, traveller's diarrhoea that persisted after return, and pre-existing

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