Role of the Environment in the Transmission of Antimicrobial

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Critical Review

Role of the environment in the transmission of antimicrobial resistance to humans: A review Patricia Huijbers, Hetty Blaak, Mart C. M. de Jong, Elisabeth A. M. Graat, Christina M. J. E. Vandenbroucke-Grauls, and Ana Maria De Roda Husman Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.5b02566 • Publication Date (Web): 10 Sep 2015 Downloaded from http://pubs.acs.org on September 15, 2015

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Environmental Science & Technology

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Role of the environment in the transmission of antimicrobial resistance to humans: A

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review

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Patricia M.C. Huijbersa,b, Hetty Blaakb,*, Mart C.M. de Jonga, Elisabeth A.M. Graata,

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Christina M.J.E. Vandenbroucke-Graulsc, Ana Maria de Roda Husmanb,d

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a

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(WIAS), Wageningen University, P.O. Box 338, 6700 AH Wageningen, The Netherlands

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b

Quantitative Veterinary Epidemiology Group, Wageningen Institute of Animal Sciences

Centre for Zoonoses and Environmental Microbiology, Centre for Infectious Disease

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Control (CIb), National Institute for Public Health and the Environment (RIVM), P.O. Box 1,

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3720 BA Bilthoven, The Netherlands

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c

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P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

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d

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University, P.O. Box 80178, 3508 TD Utrecht, The Netherlands

Department of Medical Microbiology and Infection Control, VU University Medical Center,

Faculty of Veterinary Medicine, Institute for Risk Assessment Sciences (IRAS), Utrecht

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* Corresponding author

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Address: Hetty Blaak, Centre for Zoonoses and Environmental Microbiology, Centre for

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Infectious Disease Control, National Institute for Public Health and the Environment, P.O.

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Box 1, 3720 BA Bilthoven, The Netherlands

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E-mail: [email protected]

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Telephone: +31 (0)30 2747005

1 ACS Paragon Plus Environment


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Abstract

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To establish a possible role for the natural environment in the transmission of clinically

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relevant AMR bacteria to humans, a literature review was conducted to systematically collect

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and categorize evidence for human exposure to extended-spectrum β-lactamase-producing

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Enterobacteriaceae, methicillin-resistant Staphylococcus aureus, and vancomycin-resistant

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Enterococcus spp. in the environment. In total, 239 datasets adhered to inclusion criteria.

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AMR bacteria were detected at exposure-relevant sites (35/38), including recreational areas,

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drinking water, ambient air, shellfish, and in fresh produce (8/16). More datasets were

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available for environmental compartments (139/157), including wildlife, water, soil, and

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air/dust. Quantitative data from exposure-relevant sites (6/35), and environmental

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compartments (11/139) were scarce. AMR bacteria were detected in the contamination

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sources (66/66) wastewater and manure, and molecular data supporting their transmission

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from wastewater to the environment (1/66) were found. The abundance of AMR bacteria at

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exposure-relevant sites suggests risk for human exposure. Of publications pertaining to both

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environmental and human isolates, however, only one compared isolates from samples that

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had a clear spatial and temporal relationship, and no direct evidence was found for

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transmission to humans through the environment. To what extent the environment, compared

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to the clinical and veterinary domains, contributes to human exposure needs to be quantified.

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AMR bacteria in the environment, including sites relevant for human exposure, originate

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from contamination sources. Intervention strategies targeted at these sources could therefore

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limit emission of AMR bacteria to the environment.

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Keywords: ESBL, MRSA, VRE, soil, water, air, wildlife, wastewater, manure

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Introduction

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The occurrence and spread of antimicrobial resistant (AMR) bacteria are pressing public

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health problems worldwide. Recently, in its first global report on surveillance of

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antimicrobial resistance, the World Health Organization (WHO) reported very high rates of

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resistance in bacteria (e.g. Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus)

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that cause common healthcare-associated and community-acquired infections in people in all

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WHO regions.1 Infections caused by AMR bacteria are associated with excess mortality,

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prolongation of hospital stay, and increased costs.2 In order to formulate effective

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intervention strategies to combat intractable infections caused by AMR bacteria, it is

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important to discern which fraction of the total disease burden and costs are attributable to

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different sources, including animal reservoirs and vehicles such as foods, or the

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environment.3

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Enteric bacteria are introduced into the environment with human and animal feces,

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and people may be exposed to these bacteria through e.g. recreation in contaminated surface

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water, consumption of contaminated drinking water, fresh produce or (shell)fish, and

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inhalation of bioaerosols. Previous studies indicate that the risk of contracting Salmonella

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spp. or Campylobacter spp. in recreational waters is higher than or equal to the risk of

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contracting the organisms through chicken consumption.4,5,6 In the USA, 9% of all outbreaks

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with the pathogenic E. coli O157 are waterborne.7 Based on global WHO risk assessments, it

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was estimated that there are over 120 million cases annually of gastrointestinal disease from

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exposure to coastal waters via recreation or by eating raw or lightly cooked shellfish.8

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Multiple studies have described outbreaks of infections with Enterobacteriaceae associated

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with consumption of fresh produce.9 Examples include the 2011 outbreak of E. coli O104:H4

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associated with sprouts in Europe and Northern America,10 and the 2006 outbreak of E. coli

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O157:H7 associated with spinach in the USA.11



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The natural environment has been identified as a pathway by which transmission of

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AMR bacteria to humans might occur.12 The extent to which this occurs remains unknown,

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however. It is important to establish the relative role of the environment in the transmission

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of AMR bacteria to humans, compared with the spread of AMR bacteria through contact with

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animal carriers, consumption of food of animal origin, (international) travel, and their spread

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in healthcare and community settings. The aim of the current study was to establish a possible

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role for the natural environment, defined as soil, water, air/dust, and wildlife in the

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transmission of clinically relevant AMR bacteria to humans by systematically reviewing the

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peer-reviewed literature. For this purpose, three AMR bacteria were selected: extended-

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spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-Ent), methicillin-

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resistant S. aureus (MRSA), and vancomycin-resistant Enterococcus spp. (VRE).

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Additionally, the contribution of fecal contamination sources (human wastewater and animal

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manure) to the burden of the AMR bacteria in the environment was explored.

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Methods

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Search strategy

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Two databases (Medline and Scopus) were searched on April 10th, 2014 to identify

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publications describing one or more of three AMR bacteria in relation to the environment.

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The bacterial species were selected to represent Gram-negative and Gram-positive species,

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and species of fecal and non-fecal origin. Moreover, each of the bacterial species colonizes

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both animals and humans, has a clinically relevant type of resistance, and is sufficiently

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prevalent in humans and/or animals to anticipate its presence in the environment.

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Accordingly, ESBL-Ent (i.e. E. coli, Enterobacter spp., K. pneumoniae), MRSA, and VRE

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were selected, and carbapenemase-producing Enterobacteriaceae were not selected.


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For the purpose of the present review, environment was defined as natural

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environment (or ‘outdoor’ environment). Consequently, indoor environments such as

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hospitals or livestock housing were excluded. Four environmental compartments were

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distinguished: soil, water, air/dust and wildlife (Figure 1). Wildlife was categorized as an

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environmental compartment because these animals are not treated with antibiotics, and

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carriage of AMR bacteria is most likely explained by uptake from the natural environment

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during foraging and drinking. Wildlife can therefore be considered as an extension of the

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specified environmental compartments, as well as a vehicle for multiplication and spread of

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these bacteria. Within the environmental compartments, sites relevant for human exposure

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were defined and included in the search strategy: recreational areas (i.e. beach sand and

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recreational water), irrigation water, drinking water, urban water (e.g. fountains), shellfish

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and ambient air. Fresh produce i.e. food of plant origin such as vegetables and fruits, may be

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contaminated with AMR bacteria during growth in contaminated soil and/or irrigation with

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contaminated water. Consequently, this was also included as a ‘site’ relevant for human

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exposure. Finally, the main sources of fecal contamination of the environment, wastewater

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and manure, were included in the search strategy. For the purpose of the current study,

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manure was defined as animal feces that is intentionally (e.g. for use as fertilizer) or

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unintentionally (e.g. droppings of free-range animals) introduced into the natural

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environment, or that is stored, presumably for use as fertilizer. Consequently, only

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measurements of AMR bacteria in animal feces introduced in natural environments (e.g. not

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fecal swabs or droppings sampled in stables) were included.

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Combinations of key search terms for AMR bacteria and defined environmental

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compartments, contamination sources and exposure-relevant sites, were used to interrogate

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the online databases (Table 1). Specifically, the titles, abstracts and key words of publications

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included in the online databases were screened for these key search terms.



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Selection criteria

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Two reviewers independently screened titles and abstracts, resulting from the automated

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database search, for exclusion criteria. Publications were excluded if they were in a language

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other than English, Dutch or German, contained non-original research (e.g. reviews), or did

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not investigate the specified compartments or AMR bacteria (Figure 2). Publications solely

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describing resistance genes (i.e. genes encoding ESBL or resistance to methicillin or

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vancomycin), independently of bacterial hosts, were excluded. In case of conflict of opinion

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about inclusion of an article based on title or abstract, this was discussed by both reviewers

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until consensus was reached. Full texts were retrieved for included publications, and for

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publications where the decision for inclusion or exclusion could not be based on the contents

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of title and abstract, or abstracts were not available. Full-texts were further assessed for

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compliance with the inclusion and exclusion criteria (Figure 2A).

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Data extraction

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Study characteristics and data from included publications were extracted and exported to a

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database using a custom-made form. Full details of the extraction fields are available in Table

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S1 (Supporting Information). In case multiple publications described the same or overlapping

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sets of samples or isolates, these publications were considered as one data source i.e. one

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publication. Publications were categorized based on the type of investigated compartment

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(contamination sources, environmental compartments, exposure-relevant sites) and the type

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of AMR bacteria. Individual publications could be included within more than one category.

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To ensure the quality of the dataset, the method used to isolate AMR bacteria was

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assessed. Firstly, it was determined whether selective culture methods were used to detect the

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AMR bacteria. Selective culture was defined as culture (pre-enrichment or direct plating) in


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the presence of relevant antibiotics: 3rd generation cephalosporin-supplemented medium or

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commercial screening medium for the isolation of ESBL-Ent; methicillin-, oxacillin- or

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cefoxitin-supplemented medium or commercial screening medium for MRSA; and

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vancomycin-supplemented medium for VRE. The rationale for this assessment is the lack of

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sensitivity of non-selective culturing methods for the detection of AMR bacteria, and the

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resulting unreliability for drawing conclusions based on the lack of detection when non-

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selective culturing was used. Secondly, it was determined whether the antibiotic resistance

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was confirmed using phenotypic and/or molecular methods. Phenotypic confirmation tests

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deemed valid included: growth of isolates on media containing concentrations equal to or

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above clinical breakpoints, established Minimal Inhibitory Concentrations (MICs) equal or

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above clinical breakpoints or, in the case of disc diffusion assays, inhibition zones smaller

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than clinical breakpoints as described in the Clinical and Laboratory Standards Institute

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(CLSI) guidelines.13 VanB-carrying VRE variants with MICs below the current CLSI break-

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point concentration (32 µg/ml) have been described,14 therefore growth at concentrations >16

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µg/ml was also considered a valid phenotypic confirmation. Polymerase chain reactions

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(PCRs) detecting mecA, and vanA or vanB genes were considered valid molecular tests for

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MRSA and VRE, respectively. For ESBL-Ent, PCRs detecting CTX-M-genes, PCRs

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detecting TEM-, SHV- and OXA-genes in combination with sequencing to establish

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subtypes, or PCRs detecting other ESBL-genes were considered valid molecular confirmation

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tests. Sequencing of TEM-, SHV-, and OXA-genes is required since non-ESBL-encoding

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alleles exist of these genes. Studies in which AMR bacteria were investigated, but not

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detected using only non-selective culture methods, or where resistance of isolates was not

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confirmed appropriately, were excluded from analysis.

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For each publication, it was assessed whether AMR bacteria were enumerated, and

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whether environmental isolates were compared with isolates from fecal contamination



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sources or with human isolates for phenotypic or genetic relatedness. From the perspective of

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the current review, i.e. study of documentation on transmission from the environment to

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humans, and emission from contamination sources to the environment, only comparisons

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between isolates from samples with a spatiotemporal relationship were considered relevant.

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Tests frequently used for establishing relatedness of isolates included: pulsed-field gel

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electrophoresis (PFGE), multilocus sequence typing (MLST), antibiotic resistance profiling,

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Staphylococcus protein A gene (spa)-typing (specifically for MRSA), and PhenePlate (PhP)

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biochemical fingerprinting (specifically for VRE). Additional tests included those identifying

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resistance genes and their genetic environment e.g. identification of ESBL-genotype and

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plasmid characterization for ESBL-Ent, and staphylococcal cassette chromosome SCCmec-

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typing for MRSA.

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Results

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General

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The selection process yielded 241 publications that met the inclusion criteria (Figure 2A), and

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from these publications data were extracted. Fifteen publications described the same or

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overlapping samples or isolates, and these were combined to represent seven publications.

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Some publications described multiple AMR bacteria, environmental compartments,

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contamination sources, and/or exposure-relevant sites. For further study, data from included

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publications were divided into datasets, with each dataset describing one type of AMR

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bacteria (i.e. ESBL-Ent, MRSA, VRE) in combination with one type of environmental

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compartment (i.e. soil, water, air/dust, wildlife), contamination source (i.e. wastewater,

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manure) or fresh produce. The 241 included publications resulted in 312 datasets (Figure 2B).

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After applying the defined quality criteria, 64 datasets were excluded. For 9 datasets, the

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results could not be interpreted due to lack of specification in which of the studied


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compartment(s) AMR bacteria were found. These had not been not excluded earlier in the

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selection process because the publications also contained other, valid datasets. This left 239

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datasets for further study. Details on publications describing these datasets are available in

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Table S2 (Supporting Information). The majority of datasets described wildlife (n=71),

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wastewater (mostly municipal or urban sewage) (n=60), and water (n=56), followed by soil

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(n=25), fresh produce (n=16), manure (n=6), and air/dust (n=5). ESBL-Ent (n=102), and

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VRE (n=88) were described more often compared to MRSA (n=49).

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All continents were represented, however more than half of the datasets described

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isolates collected in Europe (n=139), followed by North America (n=39), Asia (n=38), Africa

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(n=9), South America (n=8), Oceania (n=3), and the Antarctic (n=2). One dataset contained

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isolates that were collected from both Europe and Asia.

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Exposure-relevant sites and fresh produce

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Of 157 datasets concerning environmental compartments (Table 2), 24% (38/157) included

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sites that are relevant for human exposure (Table 3). Of these, almost two thirds were about

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recreational water (n=15), or beach sand (n=12). The remaining datasets were about drinking

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water (n=5), ambient air (n=3), shellfish (n=2), and irrigation water (n=1). No datasets

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pertaining to urban water (e.g. fountains) were identified. Furthermore, 16 datasets concerned

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fresh produce such as vegetables, fruits, sprouts and herbs (Table 3). Overall, AMR bacteria

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were detected in 92% (35/38) of datasets about exposure-relevant sites, and 50% (8/16) of

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datasets about fresh produce.

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Only six datasets concerning exposure-relevant sites included quantitative data on the

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AMR bacteria (Table 4). Five datasets concerned concentrations in recreational areas,

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ranging from 100.1-103 CFU/100ml.15-18 One dataset provided information on concentrations

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in blue mussels, which was

Role of the Environment in the Transmission of Antimicrobial

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