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Antimicrobial Resistance: The Silent Pandemic

Edited by Eldrian Tho.


Background

Antimicrobial resistance (AMR), one of the top 10 global public health threats as declared by WHO (2021) which is often associated with prolonged hospital stays, treatment failure and increased mortality. According to CDC (2022), antimicrobial-resistant infections such as the increasingly multidrug-resistant ESKAPEE pathogens, carbapenem-resistant Enterobacterales (CRE), ESBL-producing Enterobacterales and methicillin-resistant Staphylococcus aureus (MRSA) have accounted for approximately 5 million deaths in 2019. Looking at the terrible deaths and detrimental effects of the antimicrobial-resistant bacteria, have you ever thought of their ubiquity in our surroundings or even inside us, hiding among our microbiomes?


Emergence and transmission of resistance

Bacteria display resistance to antimicrobials through several mechanisms such as alteration of the binding sites for antimicrobial agents, upregulation of the enzymes that inactivate the antimicrobial agents, alteration of the entry for antimicrobial agents and upregulation of the efflux pumps that expel the antimicrobial agents from the bacterial cells (Tenover 2006). Some bacteria are intrinsically resistant to certain antimicrobials while the others might acquire genetic materials that confer resistance through horizontal gene transfer (HGT) namely transposition, transduction and conjugation (Reygaert 2018). In addition, the bacteria might develop resistance through mutations as a natural evolutionary process in response to antimicrobial exposure (Holmes et al. 2016). Of those, horizontal gene transfer via mobile genetic elements is perhaps the most worrying as it may cause rapid transmission of AMR even between different species of bacteria. This ability of bacteria to rapidly exchange their genetic material easily has also made AMR an urgent One Health and global health issue. From a global health perspective, there is a globalization of the ARGs in this globalization era as well where the transmission may occur via global interchange of goods by human travellers and migration of animals (Hernando-Amado et al. 2019). An example of this would be the dissemination of mcr-1 gene, a plasmid-mediated colistin-resistant gene that was first isolated in China from raw meat to other countries such as Malaysia, Thailand, France and the UK (Liu et al. 2016, Zhi et al. 2016).


Figure 1: Transmission of genetic materials between microorganisms. Source: Holmes et al. (2016)


Antimicrobial resistance from a One Health perspective

According to WHO (2017), ‘One Health’ is an integrated, unifying approach to balance and optimize the health of people, animals and the environment which involve multiple sectors, disciplines and communities at varying levels. It is relevant to discuss the issue of AMR from a One Health perspective as apart from humans, antimicrobials are also used in animals and plants for therapeutic purposes, growth promotion and as prophylaxis (McEwen and Collignon 2018). In fact, the latter two are often pinpointed to be important drivers of AMR as the administration of antimicrobials for prolonged period at a subtherapeutic dose favour the selection and spread of resistant bacteria within and between the groups of animals as well as to humans through contaminated food or other environmental pathways such as soil and water (McEwen and Collignon 2018, Robinson et al. 2016). Indeed, beyond public health, AMR also impacts the agricultural sector.


Furthermore, there is evidence on circulation of antimicrobial resistance genes (ARGs) among the microbiomes of humans, animals and the environment due to the interconnectedness and interdependence between each of the sectors, which makes AMR a quintessential One Health issue. In a metagenome-wide cross-sectional study, acquired antimicrobial resistance gene pools (resistome) of human gut in farm and slaughterhouse workers was found to be influenced by animal resistome, suggesting the livestock-associated resistome acquisition (Van Gompel et al. 2020). On the other hand, the environment, especially the wastewater treatment plants, agriculture and aquaculture operation sites are considered genetic hotspots for gene exchange and proliferation of antimicrobial-resistant bacteria (Kim and Cha 2021). Following this, interconnection between the environment and human gut resistome was also elucidated in one study (Sun et al. 2020). Interestingly, there are studies showing that animal resistome, environmental resistome and human gut resistome share the similar ARGs with human pathogens, emphasizing the importance of microbiome in the emergence of clinical ARGs (Sommer et al. 2009, Forsberg et al. 2012).


Figure 2: One Health. Source: Malaysia One Health Antimicrobial Resistance (2021)


A One Health approach in combating antimicrobial resistance

To address the complex and challenging issue of AMR, WHO has adopted a global action plan on antimicrobial resistance with 5 main objectives: (i) improve awareness and understanding of AMR through effective communication, education and training (ii) strengthen the knowledge and evidence base through surveillance and research (iii) reduce incidence of infection through effective sanitation, hygiene and infection prevention measures (iv) optimize the use of antimicrobial medicines in human and animal health (v) develop the economic case for sustainable investment that takes account of the needs of all countries and to increase investment in new medicines, diagnostic tools, vaccines and other interventions (WHO 2016). In agreement with the 5 pillars, some recommended approaches to cope with AMR include outreach programs for farmers, improvement in medical and pharmaceutical curriculum, antimicrobial consumption monitoring, surveillance on burden of AMR, policies for antimicrobial use and control measures to improve food and water quality (Aslam et al. 2021).


Efforts being made to control the issue of AMR include a ‘Tricycle protocol’ on global AMR surveillance of ESBL-producing E. coli established by the tripartite collaboration among World Health Organization (WHO), Food and Agriculture Organization (FAO) and Organization for Animal Health (OIE) (WHO 2021). This Global Tricycle Surveillance aims to estimate the prevalence of AMR, as indicated by ESBL-producing E. coli in humans, food chain and the environment over time, to understand the paths of dissemination of AMR as well as to identify specific risk factors associated with it (WHO 2021).


Conclusion

As such, AMR is not only a global health, but also a One Health issue that requires multidisciplinary collaboration between healthcare professionals, veterinarians, agricultural workers and policymakers. Following the advancement in metagenomics and sequencing techniques, it is believed that the transmission of ARGs in different domains of One Health could be better understood and relevant policies can be proposed to tackle the widespread dissemination of ARGs. Indeed, all of us can play a role in stopping this silent pandemic by practicing good hygiene and ensuring the biosecurity of food and water.

 

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