Abstract
Objectives
Intestinal colonization by ESBL Escherichia coli and its association with community-acquired MDR infections is of great concern. This review determined the worldwide prevalence of human faecal ESBL E. coli carriage and its trend in the community over the past two decades.
Methods
A systematic literature search was conducted using PubMed, EMBASE and Google Scholar to retrieve articles published between 1 January 2000 and 13 February 2020 that contained data on the prevalence of faecal carriage of ESBL E. coli among healthy individuals. A cumulative (for the whole period) meta-analysis was used to estimate the global and regional pooled prevalence rates. Articles were grouped into study periods of 3 years, and subgroup meta-analyses were undertaken to examine the global pooled prevalence over time.
Results
Sixty-two articles covering 29 872 healthy persons were included in this meta-analysis. The cumulative (2003–18) global pooled prevalence of ESBL E. coli intestinal carriage in the community was 16.5% (95% CI 14.3%–18.7%; P < 0.001). The pooled prevalence showed an upward trend, increasing from 2.6% (95% CI 1.6%–4.0%) in 2003–05 to 21.1% (95% CI 15.8%–27.0%) in 2015–18. Over the whole period, the highest carriage rate was observed in South-East Asia (27%; 95% CI 2.9%–51.3%), while the lowest occurred in Europe (6.0%; 95% CI 4.6%–7.5%).
Conclusions
Globally, an 8-fold increase in the intestinal carriage rate of ESBL E. coli in the community has occurred over the past two decades. Prevention of its spread may require new therapeutic and public health strategies.
Introduction
The gut microbiota is a reservoir of antimicrobial resistance genes.1 Among Enterobacteriaceae, Escherichia coli is becoming a major storehouse of ESBL genes, which impart resistance to a number of β-lactam antibiotics.2–4
E. coli, a Gram-negative facultative anaerobe5,6 whose primary habitat is the distal intestines of humans and animals,7,8 is the most common cause of urinary tract infections9 and urosepsis in humans.10 Acquisition of drug resistance genes by E. coli makes the treatment of these infections difficult. For example, ESBL-producing E. coli are resistant to many β-lactam antibiotics, including penicillins, aztreonam and most cephalosporins.11 ESBL E. coli can emerge in the human or animal gut following the use of antibiotics.12,13 Since E. coli are generally transmitted through the faecal–oral route,14 MDR forms of ESBL E. coli are transmissible through contact with humans, animals or the environment, or ingestion of contaminated food or water.15–19 In fact, one study showed that 60% of community-acquired ESBL E. coli were attributable to human to human transmission, whereas food accounted for about 20%.20
The intestinal carriage of ESBL E. coli is usually asymptomatic and persistent.21 However, many studies have shown the association of faecal carriage with ESBL E. coli infections.22–25 Unlike infections with β-lactam-susceptible E. coli, ESBL E. coli infections have poor clinical outcomes. For instance, the mortality rate of ESBL E. coli sepsis (60%) is three times higher than for β-lactam-susceptible strains (20%).26
Two systematic reviews on ESBL Enterobacteriaceae in 2011 and 2016 showed a steady increase in the worldwide community prevalence.27,28 Faecal ESBL E. coli carriage, in particular, has become a global pandemic, which can lead to widespread infections with limited therapeutic options.28 Understanding the current status of this MDR bacterium is critical for developing effective methods for its control, including the prevention of its transmission and decolonization of carriers. The 2016 review27 covered Enterobacteriaceae in general, but did not provide specific details on ESBL E. coli. The meta-analysis presented here highlights the global prevalence and evolution of faecal ESBL E. coli carriage in healthy individuals over the past two decades.
Methods
This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist (Table S1 available as Supplementary data at JAC Online).29
Data sources and search terms
A systematic literature search was conducted in PubMed, EMBASE and Google Scholar to retrieve relevant articles published from 1 January 2000 to 13 February 2020. We used four groups of search terms: (i) Escherichia coli OR E. coli; (ii) extended spectrum β-lactamase OR ESBL; (iii) faecal OR faeces OR stool OR intestinal OR gastrointestinal tract; and (iv) community OR community-acquired. These groups of search terms were then connected by the Boolean operator ‘AND’ to find papers that contained the terms anywhere in the article. The search retrieved 122, 173 and 280 articles indexed in PubMed, EMBASE and Google Scholar, respectively, for further screening (Figure 1). Two authors (Y.B. and W.B.) screened titles and abstracts to select studies. Another author (A.B.) was involved in reaching a consensus for discrepancies.
Figure 1.
Flow chart showing selection of articles for meta-analysis.
Study selection: inclusion and exclusion criteria
Studies that reported the prevalence of ESBL E. coli carriage among healthy individuals of any age group were eligible. A healthy individual was defined as an asymptomatic person who lived in the community or visited a hospital only for a routine wellness check-up, antenatal care, vaccination, pre-international travel screening or for transrectal biopsy screening for prostate cancer. We excluded studies that reported faecal ESBL E. coli prevalence among hospital outpatients, admitted patients, residents of aged-care facilities and household contacts of colonized individuals, as well as studies that analysed non-faecal samples or involved only non-human study subjects. Our analysis included original articles written in English and excluded reviews, retrospective studies, case–control studies and conference abstracts. In addition, we only included studies that confirmed ESBL production with at least the double-disc synergy test (DDST) or PCR, and excluded those studies that relied solely on antibiotic susceptibility testing. Studies that determined the faecal carriage of ESBL Enterobacteriaceae, but did not perform bacterial species identification or did not specify the total number of ESBL E. coli-positive persons, were excluded (Figure 1).
Data extraction and quality control
The main outcome of interest was the prevalence of gastrointestinal colonization by ESBL E. coli in healthy individuals. The prevalence was obtained by dividing the total number of confirmed ESBL E. coli-positive individuals by the total number of individuals screened via stool testing. For each research article, year of study, study design, nature of study participants, method of ESBL confirmation and study location (country and WHO region)30 were recorded and shown in a spreadsheet (Table S2). For studies that took more than a year (e.g. 2012–13), the approximate mean (2013) was taken as the ‘year of study’.
The methodological quality of each study was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies developed by the National Heart, Lung, and Blood Institute of the NIH (Table S3).31
Data analysis
A random-effects meta-analysis using the DerSimonian and Laird method32 was performed to obtain a pooled prevalence and estimate the global trend of faecal ESBL E. coli carriage. Subgroup meta-analyses were performed by grouping studies using the WHO regions30 and 3 year intervals of the study period. The Freeman–Tukey arcsine methodology33 was used to stabilize the variance of raw proportions, and no studies with 0% or 100% proportions were excluded.34 The I2 statistic was the measure of heterogeneity,32 and probability values less than 0.05 at a 95% CI were considered significant. The presence of publication bias was assessed using Egger’s regression test.35 The meta-analysis was performed using OpenMeta (Analyst).36 GraphPad Prism (version 8.0.2, San Diego, CA, USA) was used to create linear regression plots and bar graphs.
Results
Study characteristics and quality assessment
Of the 575 relevant articles produced by the search, 62 were included in our meta-analysis (Figure 1). They comprised 20 prospective and 42 cross-sectional studies deemed to be of fair to good quality. The characteristics and quality assessment of the selected studies are presented in Table S2.
Prevalence of faecal ESBL E. coli carriage in the community
The 62 studies covered a total of 29 872 healthy individuals from the six WHO regions. This gave a global pooled prevalence of ESBL E. coli intestinal carriage in the community of 16.5% (95% CI 14.3%–18.7%) (Figure 2). The highest carriage rates occurred in South-East Asia (27%; 95% CI 2.9%–51.3%), followed by Western Pacific (24.5%; 95% CI 17.6%–31.4%), Africa (21.4%; 95% CI 12.7%–30.1%) and Eastern Mediterranean (20.6%; 95% CI 10.2%–30.1%). The lowest pooled prevalence was reported from European studies (6.0%; 95% CI 4.6%–7.5%) (Figure 2 and Table S2).
Figure 2.
Pooled prevalence of intestinal ESBL E. coli carriage among healthy individuals in six WHO regions.30 E-Mediterranean, Eastern Mediterranean; SE-Asia, South-East Asia; W-Pacific, Western Pacific region.
Looking at the country level, the highest community prevalence was reported from Tanzania (76.3%), followed by Vietnam (75.1%), Laos (70.2%), China (58.5%), Thailand (56.1%), Egypt (45.1%) and Lebanon (38.5%). Australia (with a prevalence of 1.9%) and the USA (at a carriage rate of up to 3.5%) were among countries with the lowest prevalence (Figure S1 and Table S2).
Global trend in prevalence of human intestinal ESBL E. coli carriage
The results of subgroup meta-analyses performed by dividing the study period into 3 year intervals are shown in Figure S2. The pooled prevalence increased steadily from 2.6% (95% CI 1.6–4.0) in 2003–05 to 21.1% (95% CI 15.8%–27.0%) in 2015–18, representing an average increase of 1.2% per year (Figure 3a and Figure S2). Similarly, an estimated projection from linear regression analysis revealed a 1.5% yearly increase, with an estimated global prevalence of just under 30% in 2020 (P = 0.021) (Figure 3b).
Figure 3.
Global trend in faecal ESBL E. coli carriage among healthy individuals. (a) Pooled prevalence showing a clear increase from one 3 year interval to another. (b) A simple linear regression plot depicting the trend of carriage (1.5% rise per year, P = 0.021).
Discussion
We studied the intestinal carriage of MDR ESBL E. coli among healthy people as it has very significant clinical and public health implications.37,38 Healthy carriers may develop serious urinary, intra-abdominal or bloodstream infections at some point in their lifetime.22 Mortality rates following ESBL E. coli infections are generally high,26 and last-resort carbapenems are the only reliable treatment options.38 Even mild urinary tract infections have a tendency to become recurrent, leading to increased morbidity.39,40 From a public health perspective, human to human transmission of ESBL E. coli and its extensive spread throughout the world is a great concern.37 Clonal and plasmid-mediated spread are responsible for the increasing global incidence of MDR E. coli, as seen, for example, with the pandemic E. coli ST131 clone and the blaCTX-M plasmid.37,41 Furthermore, the possible horizontal transfer of ESBL genes to other flora within the human gut is another concern.21
Using a 15 year pooled prevalence, this study found that at least a sixth (16.5%) of the world’s population is colonized by ESBL E. coli. Subgroup meta-analysis by every 3 years of the study period showed an increasing trend, with a much higher carriage rate in recent years. For example, the pooled prevalence for the period 2015–18 was 21.1% (95% CI 15.8%–27.0%). This is almost a 3-fold increase when compared with the pooled prevalence of 10 years earlier [7.8% (95% CI 2.2%–13.3%) in 2006–08)] and an 8-fold increase from 2003 to 2005 [2.6% (95% CI 1.6%–4.0%)]. The global pooled prevalence in our study is higher than that reported by Karanika et al., who found a 14% global pooled prevalence for the intestinal carriage of ESBL Enterobacteriaceae (E. coli, Klebsiella pneumoniae, etc.) among healthy people.27 However, Karanika et al. considered studies conducted between 1978 and 2015, so missing 2015–18, which our analysis showed was a period of further increase in prevalence. A study by Woerther et al. also showed an increasing trend of ESBL Enterobacteriaceae between 2002 and 2011 in each of the six WHO regions.30
By WHO region,30 the pooled prevalence was highest in South-East Asia, whereas Europe and the Americas had the lowest carriage. These relative estimates concurred with those presented by Karanika et al., who showed the highest prevalence rate in South-East Asia (46%; 95% CI 29%–63%) and the lowest prevalence rates in the Americas [North (2%; 95% CI 0%–5%) and South (3%; 95% CI 0%–7%)] and Europe [central (3%; 95% CI 1%–5%), northern (4%; 95% CI 2%–6%) and southern (6%; 95% CI 1%–12%)].27 Differences in the regional carriage rates compared with our study are most probably due to variation in the study periods and methods (inclusion and exclusion criteria). For instance, our study determined carriage rates specific for ESBL E. coli and we included only those confirmed by at least DDST or PCR.
There could be several explanations for the successful worldwide spread of ESBL E. coli. The first, and most likely, is a high transmission rate, as seen in the rates of ESBL E. coli colonization among travellers. A Swiss study recruited 170 Swiss travellers to South Asia (India, Bhutan, Nepal and Sri Lanka) who initially were negative for ESBL E. coli upon pre-travel stool screening. Surprisingly, on return, 118/170 (70%) of these travellers were found to have been colonized with ESBL E. coli (86% among travellers to India).42 A Danish study also reported a >90% colonization rate among travellers to India.43 Second, the faecal titre of ESBL E. coli was high among colonized humans (102–108 cfu/g of stool)44 and animals (103–107 cfu/g of stool).45,46 This high faecal ESBL E. coli titre among carriers could relate to the documented high rate of human to human transmission related to poor post-toilet hygiene. Hence, effective faeco-oral transmission seems to be the main driving factor for the increasing worldwide prevalence.
Our findings suggest that the presence of MDR ESBL E. coli is dramatically increasing outside the hospital setting. This is concerning, given the risk of persistent intestinal carriage,21 as well as the possible horizontal transfer of ESBL genes to other flora within the human gut.47–49 In addition, because ESBL E. coli are resistant to most of the available antibiotics, our findings signal that the world could be heading toward the worst phase of a ‘post-antibiotic era’, where common infections that used to be easily treated will no longer respond to currently existing medications. Since E. coli is a common cause of urinary tract infections, sepsis and neonatal meningitis, increasing prevalence of ESBL E. coli has significant clinical implications, with an anticipated increase in morbidity and mortality. With antimicrobial resistance projected to become the number one killer of humans by 2050,50 ESBL E. coli could become one of the main culprits. The WHO’s global antimicrobial resistance surveillance system (GLASS) has already been monitoring the resistance profile of E. coli from blood and urine samples obtained during routine clinical care since 2015.51 However, since ESBL E. coli is no longer restricted to the hospital setting, and given the high community carriage shown by our results, we believe control strategies by the WHO and other organizations would be better informed by including monitoring of faecal carriage of ESBL E. coli among healthy individuals.
A strength of this review is in following a strict inclusion criterion on the method of ESBL E. coli detection. In addition, we used subgroup meta-analysis to show the temporal pattern. It is important to note, however, that the study also had several limitations. First, it determined the pooled prevalence in each WHO region,30 which may lead to an overestimation or underestimation of the prevalence for certain member countries, and the findings need careful interpretation. For example, a 9.9% pooled prevalence in the Americas was mainly contributed to by the high carriage rate in South America, not the USA. Second, there were a limited number of studies in certain locations, such as Africa, South-East Asia, North America and Australia. This might have overestimated or underestimated the prevalence in these areas. Third, the review only considered articles published in English, and relevant data published in other languages may have been missed. Finally, the varying time periods of studies from different WHO regions30 might have underestimated or overestimated the regional cumulative prevalence and the global trend.
Conclusions
The intestinal carriage of MDR ESBL E. coli showed a high and increasing prevalence among healthy individuals worldwide. Based on the findings, we recommend that the WHO and other institutions should consider a community stool ESBL E. coli surveillance scheme and implement preventive measures to address its community spread.
Acknowledgements
Special thanks to Yohannes Gishen for his valuable support.
Funding
This study was conducted as part of our routine work.
Transparency declarations
None to declare.
Supplementary data
Tables S1 to S3 and Figures S1 and S2 are available as Supplementary data at JAC Online.
Data sharing
All data are available in the manuscript or the supplementary materials.
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