Biomedical Research

DOI: 10.4066/biomedicalresearch.52-18-583

Abstract

The progressive increase of antibiotic resistance poses an alarming threat on public health worldwide. Although antibiotic resistance is a problem of human health, a one health approach to tackling antibiotic resistance is required, due to the effect of animal and environment on human health. To exactly estimate the impact of animal and environment on the spread of antibiotic resistance in human, scientific evidence with high quality is required. Molecular analysis of antibiotic-resistant bacteria through high-resolution, such as whole-genome sequencing, is suitable for obtaining credible evidence in examining the transmission of strains or genetic mobile elements responsible for antibiotic resistance among human, animal, and environment. In this paper, we discuss many observational studies using the whole-genome sequencing on various isolates collected from human, animal, and environment. These analyses suggest that more extensive surveillance based on whole-genome sequencing is required to accurately assess the potential threat of animal and environment on the spread of antibiotic resistance in human and that the effort to overcome various limitations in obtaining higher quality evidence is required.

Keywords

Antibiotic resistance, One health approach, Whole-genome sequencing, Animal, Environment

Introduction

From the first introduction in the market of a commercial antibiotic, antibiotics have been used in veterinary medicine as well as human medicine [1]. In addition to therapeutic purposes, antibiotics administered to food animals have been also used as growth-promoting agents to obtain sufficient amount of food [2]. Antibiotics for non-therapeutic purpose are generally supplied to food animals through feeding at very low concentrations for a long time [3,4]. Such antibiotic usage is known to be a dangerous practice, because antibiotics at low concentrations are able to generate selective pressure which could enrich antibiotic-resistant bacterial populations [5,6]. Therefore, antimicrobial growth promoters were banned in many European countries and the United States [4,7], but clinically important antibiotics are still being fed to food animals for growth promotion in some countries [3,4]. Several antibiotics have been used only in veterinary medicine, but some of them are structurally very similar to clinically important antimicrobial agents, such as fluoroquinolones and macrolides [8]. Most of commercial antibiotics have been used in both human and veterinary diseases for a long time [4]. These indiscriminate uses of antibiotics in livestock settings have caused the emergence of antimicrobial resistance.

Antimicrobial resistance has been considered a one health issue [9]. One health is an emerging concept that the human health is connected to the health of animal and environment. There is general scientific consensus that the use of antibiotics in veterinary medicine exerts selective pressure for the emergence of antimicrobial resistance in human [10]. Antimicrobialresistant bacteria selected by antibiotic use in veterinary medicine could spread to humans through foods, direct contact with animals, or environmental pathways [10,11]. However, to know why the recent antibiotic resistance crisis requires One Health approach, scientific evidence with high quality is required. Molecular analysis of antibiotic-resistant bacteria through high-resolution, such as whole-genome sequencing, has scientific merits in the elucidation of the connection between human health and animal (or environmental) health [12-14].

A recent study performed by Alicia et al. reported a retrospective, whole-genome sequencing study analyzing 288 Salmonella enterica serotype Typhimurium isolates obtained between 1911 and 1969 from 31 countries and from various sources, including human, animal, and food [15]. They showed the existence of ampicillin-resistant S. enterica serotype Typhimurium strains in human beings before ampicillin was released to the market. The authors suggested that the nonclinical use of narrow-spectrum penicillins, such as penicillin G, may exert selective pressure on the emergence of ampicillin-resistance S. enterica serotype Typhimurium in human. Based on this assumption, they highlighted the need for a One Health approach. To understand the connection between human health and animal (or environmental) health, we analysed all reported whole-genome sequencing studies examining the effect of animal and environment on antibiotic resistance of human. The analysis results suggest the following important aspects: (i) requirement for more extensive and observational evidences for the transmission of various strains or genetic mobile elements responsible for antibiotic resistance among human, animal, and environment; (ii) requirement for Randomized Controlled Trials (RCTs).

Observational Evidences for the Transmission of Antibiotic Resistance among Human, Animal, and Environment

There are many observational studies using the whole-genome sequencing tool to analyse the possibility of the transmission of genetic mobile elements or strains responsible for antibiotic resistance among human, animal, and environment (Table 1). The whole genome sequencing studies showed that the same antibiotic-resistant foodborne and zoonotic pathogens, such as S. enterica, Staphylococcus aureus, and Campylobacter sp., are detected in both human and animals [16-28]. For example, cefoxitin-resistant S. enterica serovar Heidelberg strains with 0 to 4 Single Nucleotide Variations (SNVs) (i.e. almost genetically identical strains) are identified in human, abattoir poultry, and retail poultry isolates [18]. This result suggests that the transmission of cefoxitin-resistant S. enterica serovar Heidelberg strains among human, abattoir poultry, and retail poultry sources may happen. The clonal transmission of opportunistic pathogens, such as Escherichia coli, Klebsiella pneumoniae, and Clostridium difficile, was also detected [29-38]. The whole genome sequencing of C. difficile strains, which are a commensal organism and a pathogen in both human and animal [39], showed that C. difficile isolates with identical (no SNP differences) and almost identical (less than two SNP differences) are detected in both farmers and pigs in the Netherlands [34]. Many β-lactam-resistant E. coli strains identified in human samples were also detected in animals [29,31,35-38] and environment [35,40,41]. These results indicate the complex transmission of β-lactam-resistant E. coli strains among human, animal, and environment.

In addition to the clonal transmission, the transmission of mobile genetic elements responsible for resistance of various antibiotics, such as β-lactam, colistin, and tetracycline, was also detected (Table 1). Colistin has been used in veterinary medicine for the prevention of infections and growth promotion for a long time, but it recently remains one of the last-resort drugs to treat infections caused by multidrugresistant gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, E. coli, and K. pneumoniae [42]. Since a first report for the presence of the mcr-1 gene responsible for plasmid-mediated colistin resistance in commensal E. coli isolated in pig farms in China [43], the mcr genes have been reported among various bacterial pathogens worldwide [42]. Many reports showed that the same plasmids containing the mcr genes are detected in E. coli isolates from human and animals [44-51]. For example, some colistin-resistant E. coli strains isolated from commercial chicken meat in Brazil carried an IncX4 plasmid containing the mcr-1 gene [47] and the sequence of this plasmid showed 100% identity to that of another IncX4 plasmid (pICBEC72Hmcr), which is detected in a colistin-resistant E. coli strain isolated from human in Brazil [52]. Notably, two IncX4 plasmids originating from environmental samples in Germany were almost identical to the pICBEC72Hmcr plasmid [53]. These results suggest that the mcr-1-containing IncX4 plasmids may be globally distributed in human, animal, and environment.

Table 1. Observational studies analyzing the possibility for the transmission of strains or genetic mobile elements responsible for antibiotic resistance among human, animal, and environment through whole genome sequencing.

Scope for Further Studies

First, observational studies using whole-genome sequencing showed that the clonal transmission between human and animal is investigated in several antibiotic-resistant bacteria, including foodborne or zoonotic pathogens and commensal bacteria. However, these investigations are focused on several bacteria, such as S. aureus, E. coli, and S. enterica. It is required to examine whether the clonal transmission of other clinically important bacteria between human and animal is possible or not. To accurately assess public health impacts of antibiotic resistance in animal and environment, the continued monitoring based on whole-genome sequencing of bacterial isolates in human, animal, food and environmental sources is required. The study of Alicia et al. showed the existence of ampicillin-resistant S. enterica serotype Typhimurium strains in human beings before ampicillin were released to the market. The authors suggest that the non-clinical use of narrowspectrum penicillins, such as penicillin G, may exert selective pressure on the emergence of ampicillin-resistance S. enterica serotype Typhimurium in human. This result underlines the importance of One Health approaches and the merit of wholegenome sequencing. Therefore, the retrospective, wholegenome sequencing analysis of a large number of isolates collected from human, animal, or environment have to be continued.

Second, because observational studies provide low quality evidence, RCTs are needed for high quality evidence [54]. Many RCTs evaluating the effect of antimicrobial agents and probiotics on human health have provided high quality evidence on their effectiveness and safety [55-57]. However, there is no RCT to evaluate the transmission of antibioticresistant strains or genetic mobile elements between animal and human [58]. RCTs evaluating the transmission of antibiotic resistance from animal or environment to human are generally not feasible [59]. Nevertheless, the effort to overcome various limitations in obtaining high quality evidence is required, due to the overwhelming and urgent threat of antibiotic resistance on public health. In conclusion, these efforts will provide an important scientific basis for exactly estimating the impact of animal and environment on the spread of antibiotic resistance in human.

Conflict of Interests

The authors declare that they have no competing interests.

Acknowledgments

This work was supported by research grants from the Bio and Medical Technology Development Program of the NRF funded by the MSIT (numbers NRF-2017M3A9E4078014 and NRF-2017M3A9E4078017); the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (numbers NRF-2017R1A2B4002315 and NRF-2016R1C1B2010308); and the Research of Korea Centers for Disease Control and Prevention (number 2017NER5404-00).

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