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Addressing the antibiotic resistance and improving the food safety in food supply chain (farm-to-fork) in Southeast Asia
Food Control 108 (2020) 106809
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Addressing the antibiotic resistance and improving the food safety in food supply chain (farm-to-fork) in Southeast Asia
T
Sarina Pradhan Thapa, Smriti Shrestha, Anil Kumar Anal∗ Food Engineering and Bioprocess Technology, Department of Food, Agriculture and Bioresources, Asian Institute of Technology, Pathum Thani, Thailand
A R T I C LE I N FO
A B S T R A C T
Keywords: Antibiotic resistant bacteria Food chain Southeast asia Strategies and regulations
Antibiotics are the compounds widely used to treat bacterial infections in human and variety of agricultural sectors including livestock farming, plants and crops, and aquaculture. However, rampant and uncontrolled use of antibiotics results in the emergence of resistant bacterial strains. Such resistant strains on the food chain possibly increase the risk of antibiotic resistant foodborne pathogens. Antibiotic resistant bacteria can reach human either directly via the contact with the infected animal or indirectly via the food chain through the consumption of contaminated food. Prevalence of antibiotic resistant bacteria in Southeast Asia region threatens the global public health as this region is regarded as a hotspot of antibiotic resistant bacteria. The risk of development of antibiotic resistance can be reduced only with appropriate regulation and policies. However, the lack of appropriate surveillance systems in this region leads to the absence of reliable national data on the level of antibiotics. To counteract the risk of antibiotic resistance, the World Health Organization (WHO) has published the global action plan on antimicrobial resistance which has been adopted by several countries in Southeast Asia.
1. Introduction The natural, semi-synthetic or synthetic compound that can either kill or interfere with the growth of bacteria is known as antibiotic. Wide range of antibiotics is utilized for bacterial infections treatment in humans and animals, used as feed additives or as synthetic growth promoters in animals, aquacultures and other agricultural activities (Ronquillo & Hernandez, 2017). The discovery of penicillin in 1928 and introduction of first antimicrobial sulfonamides in 1930 have opened the gateway of antibiotics applications in human (Davies & Davies, 2010). Further, with the discovery of animal growth promoter chlortetracycline in the 1940s, growth-promoting effects of different antibiotics have been observed (Castanon, 2007; Dibner & Richards, 2005). In the agricultural sector, antibiotics application is associated with the range of benefits including an increase in animal weight, feed efficiency, reproductive efficiency and decrease in morbidity and mortality. In the United States alone, the majority of the antibiotics produced are estimated to be used to treat bacterial infection and promoting the growth in animals (Lipsitch & Samore, 2002). Antibiotic has drastically improved human and animal health, however, over the years effectiveness of antibiotics has decreased leading to the emergence of more vibrant and resistant bacterial strains. The excessive and uncontrolled use of antibiotics is of considerable concerns to public ∗
health, as these drugs can possibly enter the food chain and increase the risk of antimicrobial resistance (AMR) foodborne pathogens (Teale, 2002). More than the use, misuse of antibiotics at large-scale in human and animal medicine, agriculture and aquaculture sectors are linked to the development of resistance in bacteria against the particular antibiotic (Van Boeckel et al., 2015). The antibiotic that once could inhibit a certain type of bacteria, if no longer is effective against the same strain, this situation is known as antibiotic resistance and the bacteria that acquire resistance is known as antibiotic resistant bacteria (ARB). Prevalence of food borne pathogenic bacterial strain resistant to antibiotic has become a serious and prime concern (WHO, 2011). The contamination of food with ARB indicates high risk in public health safety issue (Akbar & Anal, 2015). In the USA alone infection caused by ARB is estimated to cause around 23,000 death annually (CDC, 2013). There is a rise in public health threat with the increase in antibiotic resistance as the available treatment for common infections becomes ineffective (WHO, 2014). Globally, by 2050 annual death of 10 million people are estimated to occur due to ARB with a cumulative economic cost of US$100 trillion (O'Neill, 2016). Approximately 60–80% of antibiotics used for medical practices are estimated to be released from the animal body (Gobel et al., 2005), which further accumulate in the environment when not completely
Corresponding author. Department of Food Agriculture and Bioresources, Asian Institute of Technology, Pathum Thani, 12120, Thailand E-mail addresses: [email protected], [email protected] (A.K. Anal).
https://doi.org/10.1016/j.foodcont.2019.106809 Received 29 June 2019; Received in revised form 2 August 2019; Accepted 5 August 2019 Available online 06 August 2019 0956-7135/ © 2019 Elsevier Ltd. All rights reserved.
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degraded (Lertpaitoonpan, Ong, & Moorman, 2009). Most of the antibiotics are water-soluble and as much as 30–90% of the antibiotics not absorbed by the body gets into the surrounding through excreta or urinal discharge (Li et al., 2018). Release of antibiotic residue into the surroundings is dependent on environmental condition as well as antibiotic properties and bioavailability (Kummerer, 2003). Globally, public health issue is concerned with the increasing prevalence of antibiotic resistance genes (ARGs) in the environment and their possible acquisition by human pathogens (Rossolini, Arena, Pecile, & Pollini, 2014). Similarly, ARGs, that once enter the system, can spread antibiotic resistance to other bacterial cells. Bacteria can attain antibiotic resistance by several mechanisms such as transferring the resistance genes to other non-resistant bacteria through plasmid deoxy ribonucleic acid (DNA) or using other genetic materials including bacteriophages, integrons and transposons (Sivagami, Vignesh, Srinivasan, Divyapriya, & Nambi, 2018).
Fig. 2. The occurrence of antibiotic resistance in bacteria and transfer via humans, animals and foodstuffs.
which target pathogen counteracts with specific resistance system. The antibiotics used in animals, their mode of action and the developed resistance mechanism are summarized in Table 1. Agriculture plants and crops are susceptible to bacterial disease, which are difficult to control and might result in huge financial losses to farmers. With the identification of therapeutic properties of antibiotic to treat human disease, its potential to control plant diseases was recognized. However, in response to the development of antibiotic resistance in human and animal, the emergence of antibiotic resistance has also limited the value of antibiotics in crop protection. In the USA alone, of total antibiotic used, antibiotics used in plant agriculture account for less than 0.5%. The commonly used antibiotics in plants are (1) Streptomycins, (2) Oxytetracyclines, (3) Gentamicins, (4) Oxolinic Acid, (5) Penicillins and (6) Chloramphenicol (McManus, Stockwell, Sundin, & Jones, 2002). In plants, antibiotics are formulated in powder form (17%–20% w/w), dissolved in water to get solution with concentration 50–300 ppm, and finally sprayed in plants (Psallidas & Tsiantos, 2000). The main plant antibiotics, their mode of action and the developed general resistance mechanisms are summarized in Table 2(see Table 3).
2. Transmission routes of antibiotic resistance along the food chain Of the total worldwide antibiotic consumption, agricultural activities account a large proportion (Ronquillo & Hernandez, 2017). Along with disease treatment and prevention in human and animals, antibiotics are applied in large amounts to promote growth in agriculture, livestock, aquaculture and apiculture (Zuccato, Castiglioni, Bagnati, Melis, & Fanelli, 2010). A wide range of bacteria is related to food that is present in all ecological niches including plants, animals, birds, soil, aquatic ecosystems, or, discharge from human sewage, linked to the production and handling of food for consumption (Sørum & L’AbéeLund, 2002). The development of antibiotic resistance and the possible pathway for transmission of ARB along the food chain is shown in Fig. 1. Different research works on antibiotic resistant bacteria have shown the prevalence of ARB in the food of animal origin, livestock, companion animals and in humans (Kirbis & Krizman, 2015). ABR bacteria can reach human either indirectly through the food chain with the ingestion of food contaminated with ARB or directly through the contact with the infected animals (Founou, Founou, & Essack, 2016) (Fig. 2). Both direct or indirect transmission of ARB and ARGs possess high public health risk in developing and least developed countries due to limited food biosecurity and safety measures along the farm-to-fork (Padungtod, Kadohira, & Hill, 2008). However, in developed regions, as the emergence of ARB and ARGs are well maintained along with the food system, indirect contamination of food with antibiotic resistant pathogens are responsible for foodborne infections. The antibiotics are used at large scale in today's modern farming practices in relation to the vast increase and to promote the animal growth, as well as to treat and prevent the infectious diseases (Sivagami et al., 2018). Each antibiotic has its own specific action mechanism to
3. Antibiotic resistant in South East Asia region Inappropriate use of antibiotics is one of the important reason for the emergence of ABR in South East Asia (SEA) region (Holloway, Kotwani, Batmanabane, Puri, & Tisocki, 2017). In the past few decades, SEA has been a center of economic growth, biodiversity as well as the region for the emergence of certain human diseases (Walther et al., 2016). This region has a contribution to the spread of AMR globally as the disease-causing organisms are carried to different parts of the world by international trades and international travelers. A tremendous increase in antimicrobial usage and antimicrobial resistant in SEA region has been reported. Easy access to antimicrobial and antibiotics, lack of appropriate regulation on antimicrobial usage, self-medication and irrational prescription and lack of awareness with regard to AMR are regarded as the leading reasons for the widespread of AMR in SEA (Zellweger et al., 2017). Most of the countries in SEA region are underdeveloping and developing and thus, it has to bear more consequences of AMR compared to developed regions (Sakeena, Bennett, & McLachlan, 2018). However, for this region, the reliable quantitative and qualitative data on antibiotic usage and antimicrobial resistant are lacking. Most of the research is limited to pathogens isolated from animal sources including pigs, poultry and aquaculture from Vietnam, Thailand, and Malaysia. There is even none published data from the rest of the countries of SEA region including Indonesia, Myanmar, and the Philippines (Nhung, Cuong, Thwaites, & Carrique-Mas, 2016). Among the 50 countries with the highest amount of antimicrobial use in animals, the top five countries include Myanmar, Indonesia, Nigeria, Peru followed by Vietnam as recorded in 2010. Indonesia is on
Fig. 1. Schematic representation of the main source of antibiotics and routes of antibiotic resistance along the food chain. 2
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Table 1 Summary of antibiotics used in animals, their mode of action and the developed resistance mechanism. Drugs classification
Mode of action
Resistance Mechanism
Reference
Sulfonamides Sulfadiazine Lincosamides Macrolides,
Interfere with folic acid synthesis Prevent protein production
Sköld (2000) Ungureanu (2010)
Tetracyclines
Inhibit bacterial protein synthesis
Penicillin, Beta Lactamase sensitive, Cephalosporins
Inhibits the formation of peptidoglycans layer of bacterial cell walls
Quinolones, Flouro quinolones
Interfere in DNA replication by binding DNA-gyrase Binds to bacterial 50S ribosomal subunit and interferes with protein synthesis.
Chromosomal resistance; plasmid- borne resistance Target modification; decrease of intracellular antibiotic concentration by active efflux Inducible efflux proteins, Ribosomal protection proteins and tetracycline inactivation by enzymes. Beta Lactamase production mainly changes cell wall proteins so that they cannot bind to penicillin binding proteins. Target-Mediated Quinolone Resistance, Plasmid-Mediated and chromosome Quinolone Resistance Reduce binding affinity of drug due to modification of bacterial and ribosome efflux of macrolides from the bacterial cell.
Macrolides/Azalides Aminoglycosides
the list among the top five nations with the highest expected percentage increase in antimicrobial use by 2030 (Sivaraman & Parady, 2018). Sugiri et al. (2014) reported that 16% of the chicken meat samples from traditional markets of Indonesia were infected with Listeria monocytogenes and most of those isolates exhibited multidrug resistance especially to penicillin, ampicillin, and erythromycin. The different species of Escherichia bacteria isolated from poultry meat from Vietnam, Thailand, and Indonesia showed resistance against antibiotics such as oxytetracycline and fluoroquinolones (Usui et al., 2014). Several studies have been reported for the antimicrobial residues in Vietnamese meat products (Addis & Sisay, 2015; Ngoc Do et al., 2016; Yamaguchi et al., 2015). Nhung et al. (2018) reported on bacterial isolates positive for sulfonamides, tetracyclines, gentamicin/neomycin and β-lactams and macrolides in 357 meat samples (119 chicken, 122 pork and 116 beef) sampled from Hanoi and Dong Thap province, Vietnam. However, non-typhoidal Salmonella isolates showed high levels of AMR against antimicrobial drugs, quinolones and penicillin, which are considered critically important human drugs. Globally, nontyphoidal Salmonella is an important agent of food-borne gastroenteritis (Majowicz et al., 2010). Similarly, In Vietnam, Van, Moutafis, Istivan, Tran, & Coloe, (2007) screened 180 raw food samples including meat and shellfish samples contaminated with Salmonella spp., and Escherichia coli for antibiotic resistance against 15 antibiotics. This study revealed that Salmonella isolates (50.5%) and E. coli isolates (83.8%) were resistant to at least one antibiotic. A study by Abatcha, Effarizah, and Rusul (2018) showed the prevalence of higher rate of Salmonella contamination and ARGs in the fresh food market of Malaysia. The isolated Salmonella species showed the susceptibility to cephalothin (100%) and followed the antibiotic resistance in the order; tetracycline (44.4%), sulfonamides (44.4%), ampicillin (26.7%), chloramphenicol (29.1%) and trimethoprim-sulfamethoxazole (16.6%). Thailand is the major producer and consumer of swine, with 9.51
Chopra and Roberts (2001) Fernandes, Amador, and Prudêncio (2013) Aldred, Kerns, and Osheroff (2014) Dinos (2017)
million pigs raised by about 210,978 households in 2013 (Tantasuparuk and Kunavongkrit, 2014). However, the swine farms of all size in Northern Thailand were observed to be reservoirs of multidrug resistance. This prevalence of AMR is generally affected by the farm size and antimicrobial usage practices on the farm, thereby adding to major AMR transfer along the food chain (Love et al., 2015). In research work by Chanseyha, Sadiq, Cho, and Anal (2018), Escherichia coli (39.17%) and Salmonella (23.33%) isolated from lettuce samples from Thailand and Cambodia showed the presence of beta-lactam and tetracycline resistant genes. The presence of these ARGs indicates a high risk of antibiotic resistant transmission to human, animals and other non-resistant microorganisms. Salmonella and Staphylococcus aureus, prominent food-borne pathogens, were isolated from poultry meat products in Thailand. The isolates were observed to be resistant to at least one antibiotic such that Salmonella (72.72%) and S. aureus (44.73%) showed resistance to tetracycline (Akbar & Anal, 2013). A research study by Sadiq, Tarning, Cho, & Anal, (2017) exhibited the presence of bla CMY and tet (A) genes in E. coli and tet (A) genes from Salmonella enteritidis isolated from beef meat; and tet (B) genes in Salmonella typhimurium isolated from poultry meat samples from Thailand. Southeast Asian countries are popular for traditionally fermented food and in this region, the process for fermenting cereals, meat products, and vegetables are developed. Such fermented foods are highly priced for improved nutritional and organoleptic quality as well as for beneficial microorganisms (Anal, 2019). The fermented food products are classified into five groups including fermented soybean; fish; vegetable; bread and porridges; and alcoholic beverage. Lactic acid bacteria (LAB) are the commonly involved bacteria in these products to a varying extent, having either positive or negative effects (Rhee, Lee, & Lee, 2011). However, different research works have indicated that along with health benefits, fermented foods can act as vehicles of ARB and ARGs to humans and other bacteria (Abriouel, Knapp, Gálvez, & Benomar, 2017). Lactic acid bacteria (LAB) strains, including Lb.
Table 2 Summary of antibiotics used in plants, their mode of action and the developed resistance mechanism. Drug Classification
Mode of action
Resistance mechanism
Reference
Streptomycins
Inhibit protein synthesis by binding irreversibly to bacterial ribosomes Inhibit protein synthesis and matrix metalloproteinases
chromosomal mutation, gene acquisition
Hyun, Kim, Yi, Hwang, and Park (2012) Chopra and Roberts (2001)
Tetracyclines Gentamicins Oxolinic acid Penicillins Chloramphenicol
enzymatic inactivation of tetracycline, efflux, and ribosomal protection acquired mutation in the ribosomal target, activation of Efflux pumps Alteration in the targets of quinolones, and overexpression of efflux pump system production of enzyme beta-lactamase that destroys the beta-lactam ring of penicillin enzymatic inactivation, target site mutation, presence of efflux pumps
Inhibits amino acid incorporation into protein by binding the 30S subunit of the bacterial ribosome Affect interaction with DNA gyrase Inhibits cross-linking activity and prevents new cell wall formation. Inhibits protein synthesis.
3
Garneau-Tsodikova and Labby (2016) Ruiz (2003) Tenover (2006) Fernandez et al. (2012)
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Table 3 Summary of the prevalence of antibiotic resistance in food samples of SEA region. Country
Food/Specimen
Antibiotic Resistant bacteria
Prevalence (%)
References
Thailand
Chicken
ESBL- producing Enterobacteriaceae ESBL- producing E. coli ESBL-producing Klebsiella ESBL- producing Enterobacteriaceae ESBL- producing E. coli ESBL-producing Klebsiella ESBL-producing Klebsiella ESBL-producing Klebsiella ESBL-producing Klebsiella ESBL-producing Klebsiella E. coli Salmonella isolates MDR- E. faecalis MDR-E. coli MDR-E. faecalis MDR- E. coli MDR- E. faecalis ESBL- producing E. coli MDR- Salmonella ESBL-producing Salmonella isolates MDR- Salmonella enterica MDR-Escherichia coli ESBL- producing E. coli
45.4 50 40 53.5 61.5 44.4 66.7 36.4 30.8 20 57.45 46.43 73 91.5 100 62.8 84.5 48.8 98.2 2.4 67.8 75.3 2.4
Boonyasiri et al. (2014)
Pork
Thailand and Cambodia Thailand Vietnam
Fish Beef Bean sprouts Shrimp Green leaf lettuce Chicken
Indonesia Malaysia Thailand and Laos
Chicken Pork
Philippines Thailand and Cambodia
Poultry meat Broilers, pigs and meat
Chanseyha et al. (2018) Usui et al. (2014)
Aliyu, Saleha, Jalila, and Zunita (2016) Sinwat et al. (2016) Calayag, Paclibare, Santos, Bautista, and Rivera (2017) Trongjit, Angkittitrakul, and Chuanchuen (2016)
ESBL, extended spectrum β-lactamase producers. MDR, Multi-Drug Resistant.
With an aim to support the implementation of the WHO's global action plan in the food and agricultural sectors, FAO launched its action plan on antimicrobial resistance O'Neill, 2016–2020. FAO action plan has four focus areas including Awareness, Evidence, Practices, and Governance. These areas which are identified as four main pillars of work on antimicrobial resistance, are strongly interrelated and need to be addressed in parallel (FAO, 2016). The OIE promotes the responsible and prudent application of antimicrobial in terrestrial and aquatic animals to preserve the therapeutic efficacy of antimicrobials. OIE has developed a wide range of international standards and guidelines that provides a framework for responsible use of antimicrobial in terrestrial and aquatic animals along with the surveillance system, monitoring of the quantities applied, and the risk assessment of the emergence or spread of antimicrobial resistant bacteria (OIE, 2015). The OIE strategy assists the Global Action Plan's objectives and reflects the OIE mandate based on four objectives which include (1) improvement in awareness and understanding; (2) improvement in information through research and surveillance; (3) capacity building; and (4) implementation of standards (OIE, 2016). Animals and animal food products, agro-food environments are the common sources of antimicrobial resistant pathogens in developing countries. Further, the lack of adequate surveillance systems leads to absences of reliable national data on the level of antimicrobial resistance in animals (Grace, 2015). Use of antibiotics in the SEA region is extremely high with inadequate policies to encourage appropriate use (Holloway et al., 2017). SEA region is lagging in respect to the implementation of standards to fight antibiotic resistance, along with that lacks appropriate surveillance system, training to farmers and professionals, and the national organization for independent drug regulation (Goutard et al., 2017). It has been estimated to bear 3.24 million days of hospitalization and 38481 deaths per year, and a cost of 0.6% of national GDP due to the antimicrobial resistance in Thailand alone. “Thai National Strategic Plan on Antimicrobial Resistance (2017–2021)” was finalized in 2016 with the aim to reduce morbidity, mortality and the economic impact of antimicrobial resistance. This action plan has set goals to reduce antimicrobial resistance morbidity by 50%; reduce the antimicrobial use in human and animal by 20% and 30% respectively; and to increase public awareness about antimicrobial resistance by 20% (WHO, 2019).
Fermentum, Lb. Plantarum, P. acidilactici, were isolated from Indonesian fermented food products, dadih (fermented milk), bekasam (fermented meat) and tape ketan (fermented rice). All isolated strain showed resistance against chloramphenicol up to the concentration 5 μg/mL and Lb. Plantarum exhibited resistance against erythromycin up to a concentration of 15 μg/mL (Sukmarini, Mustopa, Normawati, & Muzdalifah, 2017). 4. Strategies to mitigate the impact of antibiotic resistant in the south-east asia region Globally, severe health and socio-economic risk have increased with the spread of ARB and ARG in the food chain and have become major public health concerns. This situation has been affecting both developing and developed countries (Padungtod et al., 2008). In developing countries, antibiotic resistant bacterial infection increases the morbidity and mortality rates while in the developed nation it increases the therapeutic costs (Harbarth et al., 2015). Appropriate measures to prevent and control the spread of ARB from farm-to-fork is lacking in most of the developing countries, therefore, it poses a serious risk for global public health. To address the risk of ARB, the “One Health” approach has been endorsed by supranational entities, following the coalition between the World Health Organization (WHO), Food and Agriculture Organization (FAO), and World Organization for Animal Health (OIE) referred as the “Tripartite Alliance”. To counteract the global concerns of antimicrobial resistance, WHO in collaboration with its tripartite partners published the “Global Action Plan on Antimicrobial Resistance” in 2015. Under this global action plan, with an aim to set integrated measures for prevention and containment of antibiotic resistance in the food chain, five strategic objectives have been developed, including (1) increasing awareness on usage of antibiotics and its resistance; (2) improving information through research and surveillance; (3) reduction of diseases; (4) optimization of antibiotic use; and (5) mobilization of resources and research (WHO, 2015). The primary knowledge required to establish integrated surveillance for antibiotic use and antibiotic resistance is provided by a guideline on integrated surveillance of antimicrobial resistance (AGISAR) issued by the WHO (Bordier, Uea-Anuwong, Binot, Hendrikx, & Goutard, 2018). 4
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the level of prevalence of antibiotic resistance in the different food chain. However, the lack of proper policy and guidelines on the regulation of antibiotic usage makes the condition worse. A guideline and action plan from a different organization such as WHO, FAO, OIE provide the primary information needed by countries to establish integrated surveillance of antibiotic use in human, animals, plants, and aquaculture. To reduce the risk of ARB, use of antibiotics needs to be regulated. Surveillance of resistance in humans and food animals is important to measure the long-term effectiveness of any control measure. However, unavailability and lack of implementation of standards hamper the surveillance system. Integrated surveillance system helps to measure and compare the extent of prevalence of antibiotic resistant in the food chain. Though the magnitude of global AMR contributed through the food chain is not clear but it has been documented that if the emergence of ARB and ARG genes can be controlled in basic food production and processing system, it is possible to reduce the risk of foodborne infections.
Following the adoption of the Global Action Plan on Antimicrobial Resistance, Malaysia committed to develop the country's national action plan, “Malaysian Action Plan on Antimicrobial Resistance (MyAPAMR) 2017–2021”. This action plan has four priority areas including (1) public awareness and education, (2) surveillance and research, (3) i prevention and control and (4) appropriate use of antimicrobials (Ministry of Health and Ministry of Agro-Based Industry, Malaysia, 2017). In Malaysia, antibiotics used for disease treatment are regulated by National Pharmaceutical Regulatory Agency (NPRA) under the Ministry of Health (MOH), Malaysia, whereas antibiotics for disease prevention and growth promotion are controlled by the Department of Veterinary Services (DVS) under the Ministry of Agriculture. Based on the list of registered veterinary products by NPRA, out of 688 registered veterinary products, 458 (66.6%) were antibiotics registered for use in livestock as of record in November 2017. In order to regulate the antibiotic resistance, Malaysia has developed policies, termed as (i) Registration of veterinary products: it requires all new veterinary products to registered with NPRA and should fulfil all requirements in respect to quality, safety, efficacy and residue; (ii) Monitoring programme of antibiotic residues: in 2013, DVS has implemented monitoring of veterinary drug residues including antibiotics in animal feed; (iii) Malaysian good agricultural practices: it is a certification scheme for agricultural, livestock and aquaculture sector based on Malaysian Standard; and (iv) Guideline for organic chicken production: in 2014 DVS Malaysia has published a Guideline for Organic Chicken Production to guide the farmers to ensure the product meets the requirement of organic chicken (Hassali, Yann, Verma, Hussain, & Sivaraman, 2018). The rate of antimicrobial resistance is high in Vietnam with thousands of deaths annually due to multi-drug-resistant infections. Since detecting and tracking these infections is key to stop antimicrobial resistance, Vietnam's National Action Plan and antimicrobial resistance surveillance system involves 16 laboratories and six model hospitals. This action plan also includes monitoring the use of antibiotics while encouraging antibiotic stewardship (CDC, 2018). In Vietnam, antimicrobial resistance has been recognized as a major threat in public health, trade, economy and overall sustainable development of the country. Vietnamese Ministry has developed an inter-ministerial strategy to combat antibiotic resistance and an integrated surveillance system for antibiotic resistance as supported by international organizations and cooperation, and in line with international recommendations (Bordier et al., 2018). In 2017, Indonesia has committed to advance “One Health” with collaboration with five ministries joint communique to work together to undertake One Health-drive risk mapping; address the major threat of antimicrobial resistance in Indonesia; raise awareness about the importance of relevance of Zoonoses; clarify, foster and integrate One Health linkage; support and advance One Health coordination; improve the sharing of information (Sivaraman & Parady, 2018).
References Abatcha, M. G., Effarizah, M. E., & Rusul, G. (2018). Prevalence, antimicrobial resistance, resistance genes and class 1 integrons of Salmonella serovars in leafy vegetables, chicken carcasses and related processing environments in Malaysian fresh food markets. Food Control, 91, 170–180. https://doi.org/10.1016/J.FOODCONT.2018. 02.039. Abriouel, H., Knapp, C. W., Gálvez, A., & Benomar, N. (2017). Antibiotic resistance profile of microbes from traditional fermented foods. Fermented Foods in Health and Disease Prevention, 675–704. https://doi.org/10.1016/B978-0-12-802309-9.00029-7. Addis, M., & Sisay, D. (2015). Journal of Tropical Diseases A Review on Major Food Borne Bacterial Illnesses, 3(4)https://doi.org/10.4176/2329891X.1000176. Akbar, A., & Anal, A. K. (2013). Prevalence and antibiogram study of Salmonella and Staphylococcus aureus in poultry meat. Asian Pacific Journal of Tropical Biomedicine, 3(2), 163–168. https://doi.org/10.1016/S2221-1691(13)60043-X. Akbar, A., & Anal, A. K. (2015). Isolation of Salmonella from ready-to-eat poultry meat and evaluation of its survival at low temperature, microwaving and simulated gastric fluids. Journal of Food Science & Technology, 52(5), 3051–3057. https://doi.org/10. 1007/s13197-014-1354-2. Aldred, K. J., Kerns, R. J., & Osheroff, N. (2014). Mechanism of quinolone action and resistance. Biochemistry, 53(10), 1565–1574. https://doi.org/10.1021/bi5000564. Aliyu, A. B., Saleha, A. A., Jalila, A., & Zunita, Z. (2016). Risk factors and spatial distribution of extended spectrum beta-lactamase-producing- Escherichia coli at retail poultry meat markets in Malaysia: A cross-sectional study. BMC Public Health, 16, 699. https://doi.org/10.1186/s12889-016-3377-2. Anal, A. (2019). Quality ingredients and safety concerns for traditional fermented foods and beverages from Asia: A review. Fermentatio, 5(1), 8. https://doi.org/10.3390/ fermentation5010008. Boonyasiri, A., Tangkoskul, T., Seenama, C., Saiyarin, J., Tiengrim, S., & Thamlikitkul, V. (2014). Prevalence of antibiotic resistant bacteria in healthy adults, foods, food animals, and the environment in selected areas in Thailand. Pathogens and Global Health, 108(5), 235–245. https://doi.org/10.1179/2047773214Y.0000000148. Bordier, M., Uea-Anuwong, T., Binot, A., Hendrikx, P., & Goutard, F. L. (2018). Characteristics of one health surveillance systems: A systematic literature review. Preventive Veterinary Medicine. https://doi.org/10.1016/J.PREVETMED.2018.10.005. Calayag, A. M. B., Paclibare, P. A. P., Santos, P. D. M., Bautista, C. A. C., & Rivera, W. L. (2017). Molecular characterization and antimicrobial resistance of Salmonella enterica from swine slaughtered in two different types of Philippine abattoir. Food Microbiology, 65, 51–56. https://doi.org/10.1016/J.FM.2017.01.016. Castanon, J. I. R. (2007). History of the use of antibiotic as growth promoters in European poultry feeds. Poultry Science, 86(11), 2466–2471. https://doi.org/10.3382/ps.200700249. CDC (2013). Antibiotic resistance threats in the United States. 2013 https://www.cdc.gov/ drugresistance/pdf/ar-threats-2013-508.pdf/, Accessed date: 14 May 2019. CDC (2018). Vietnam tracks multi-drug resistant bacteria. https://www.cdc.gov/ globalhealth/security/stories/vietnam-tracks-multi-drug-resistant-bacteria.html/, Accessed date: 27 May 2019. Chanseyha, C., Sadiq, M. B., Cho, T. Z. A., & Anal, A. K. (2018). Prevalence and analysis of antibiotic resistant genes in Escherichia coli and salmonella isolates from green leaf lettuce. Chiang Mai Journal of Science, 45(3), 1274–1286. Chopra, I., & Roberts, M. (2001). Tetracycline antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance. Microbiology and Molecular Biology Reviews: Microbiology and Molecular Biology Reviews, 65(2), 232–260. second page, table of contents https://doi.org/10.1128/MMBR.65.2.232260.2001. Davies, J., & Davies, D. (2010). Origins and evolution of antibiotic resistance. Microbiology and Molecular Biology Reviews, 74(3), 417 LP – 433 https://doi.org/10. 1128/MMBR.00016-10. Dibner, J. J., & Richards, J. D. (2005). Antibiotic growth promoters in agriculture: History and mode of action. Poultry Science, 84(4), 634–643. https://doi.org/10.1093/ps/84.
5. Conclusion The emergence of antibiotic resistance indicates that certain types of antibiotics effective against bacteria will be no longer effective. This rise of ARB and ARGs is linked with excessive and uncontrolled use of antibiotic in the treatment of human disease, and in different agricultural practices. Bacteria develop the antibiotic resistance by several mechanisms and can spread to non-resistant bacteria either through DNA or other genetic matters such as integrons, transposons, and bacteriophages. There is an indirect relation between the prevalence of ARB in food production and transmission through the food chain to the consumer. However, the magnitude of global antimicrobial resistant contributed through the food chain is unclear. Developing countries must bear more consequences of antibiotic resistance than the developed countries. SEA region is regarded as the global hub for antimicrobial resistance. In countries like Thailand, Myanmar, Malaysia, Indonesia, different research works have been conducted to measure 5
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Food Control journal homepage: www.elsevier.com/locate/foodcont
Addressing the antibiotic resistance and improving the food safety in food supply chain (farm-to-fork) in Southeast Asia
T
Sarina Pradhan Thapa, Smriti Shrestha, Anil Kumar Anal∗ Food Engineering and Bioprocess Technology, Department of Food, Agriculture and Bioresources, Asian Institute of Technology, Pathum Thani, Thailand
A R T I C LE I N FO
A B S T R A C T
Keywords: Antibiotic resistant bacteria Food chain Southeast asia Strategies and regulations
Antibiotics are the compounds widely used to treat bacterial infections in human and variety of agricultural sectors including livestock farming, plants and crops, and aquaculture. However, rampant and uncontrolled use of antibiotics results in the emergence of resistant bacterial strains. Such resistant strains on the food chain possibly increase the risk of antibiotic resistant foodborne pathogens. Antibiotic resistant bacteria can reach human either directly via the contact with the infected animal or indirectly via the food chain through the consumption of contaminated food. Prevalence of antibiotic resistant bacteria in Southeast Asia region threatens the global public health as this region is regarded as a hotspot of antibiotic resistant bacteria. The risk of development of antibiotic resistance can be reduced only with appropriate regulation and policies. However, the lack of appropriate surveillance systems in this region leads to the absence of reliable national data on the level of antibiotics. To counteract the risk of antibiotic resistance, the World Health Organization (WHO) has published the global action plan on antimicrobial resistance which has been adopted by several countries in Southeast Asia.
1. Introduction The natural, semi-synthetic or synthetic compound that can either kill or interfere with the growth of bacteria is known as antibiotic. Wide range of antibiotics is utilized for bacterial infections treatment in humans and animals, used as feed additives or as synthetic growth promoters in animals, aquacultures and other agricultural activities (Ronquillo & Hernandez, 2017). The discovery of penicillin in 1928 and introduction of first antimicrobial sulfonamides in 1930 have opened the gateway of antibiotics applications in human (Davies & Davies, 2010). Further, with the discovery of animal growth promoter chlortetracycline in the 1940s, growth-promoting effects of different antibiotics have been observed (Castanon, 2007; Dibner & Richards, 2005). In the agricultural sector, antibiotics application is associated with the range of benefits including an increase in animal weight, feed efficiency, reproductive efficiency and decrease in morbidity and mortality. In the United States alone, the majority of the antibiotics produced are estimated to be used to treat bacterial infection and promoting the growth in animals (Lipsitch & Samore, 2002). Antibiotic has drastically improved human and animal health, however, over the years effectiveness of antibiotics has decreased leading to the emergence of more vibrant and resistant bacterial strains. The excessive and uncontrolled use of antibiotics is of considerable concerns to public ∗
health, as these drugs can possibly enter the food chain and increase the risk of antimicrobial resistance (AMR) foodborne pathogens (Teale, 2002). More than the use, misuse of antibiotics at large-scale in human and animal medicine, agriculture and aquaculture sectors are linked to the development of resistance in bacteria against the particular antibiotic (Van Boeckel et al., 2015). The antibiotic that once could inhibit a certain type of bacteria, if no longer is effective against the same strain, this situation is known as antibiotic resistance and the bacteria that acquire resistance is known as antibiotic resistant bacteria (ARB). Prevalence of food borne pathogenic bacterial strain resistant to antibiotic has become a serious and prime concern (WHO, 2011). The contamination of food with ARB indicates high risk in public health safety issue (Akbar & Anal, 2015). In the USA alone infection caused by ARB is estimated to cause around 23,000 death annually (CDC, 2013). There is a rise in public health threat with the increase in antibiotic resistance as the available treatment for common infections becomes ineffective (WHO, 2014). Globally, by 2050 annual death of 10 million people are estimated to occur due to ARB with a cumulative economic cost of US$100 trillion (O'Neill, 2016). Approximately 60–80% of antibiotics used for medical practices are estimated to be released from the animal body (Gobel et al., 2005), which further accumulate in the environment when not completely
Corresponding author. Department of Food Agriculture and Bioresources, Asian Institute of Technology, Pathum Thani, 12120, Thailand E-mail addresses: [email protected], [email protected] (A.K. Anal).
https://doi.org/10.1016/j.foodcont.2019.106809 Received 29 June 2019; Received in revised form 2 August 2019; Accepted 5 August 2019 Available online 06 August 2019 0956-7135/ © 2019 Elsevier Ltd. All rights reserved.
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degraded (Lertpaitoonpan, Ong, & Moorman, 2009). Most of the antibiotics are water-soluble and as much as 30–90% of the antibiotics not absorbed by the body gets into the surrounding through excreta or urinal discharge (Li et al., 2018). Release of antibiotic residue into the surroundings is dependent on environmental condition as well as antibiotic properties and bioavailability (Kummerer, 2003). Globally, public health issue is concerned with the increasing prevalence of antibiotic resistance genes (ARGs) in the environment and their possible acquisition by human pathogens (Rossolini, Arena, Pecile, & Pollini, 2014). Similarly, ARGs, that once enter the system, can spread antibiotic resistance to other bacterial cells. Bacteria can attain antibiotic resistance by several mechanisms such as transferring the resistance genes to other non-resistant bacteria through plasmid deoxy ribonucleic acid (DNA) or using other genetic materials including bacteriophages, integrons and transposons (Sivagami, Vignesh, Srinivasan, Divyapriya, & Nambi, 2018).
Fig. 2. The occurrence of antibiotic resistance in bacteria and transfer via humans, animals and foodstuffs.
which target pathogen counteracts with specific resistance system. The antibiotics used in animals, their mode of action and the developed resistance mechanism are summarized in Table 1. Agriculture plants and crops are susceptible to bacterial disease, which are difficult to control and might result in huge financial losses to farmers. With the identification of therapeutic properties of antibiotic to treat human disease, its potential to control plant diseases was recognized. However, in response to the development of antibiotic resistance in human and animal, the emergence of antibiotic resistance has also limited the value of antibiotics in crop protection. In the USA alone, of total antibiotic used, antibiotics used in plant agriculture account for less than 0.5%. The commonly used antibiotics in plants are (1) Streptomycins, (2) Oxytetracyclines, (3) Gentamicins, (4) Oxolinic Acid, (5) Penicillins and (6) Chloramphenicol (McManus, Stockwell, Sundin, & Jones, 2002). In plants, antibiotics are formulated in powder form (17%–20% w/w), dissolved in water to get solution with concentration 50–300 ppm, and finally sprayed in plants (Psallidas & Tsiantos, 2000). The main plant antibiotics, their mode of action and the developed general resistance mechanisms are summarized in Table 2(see Table 3).
2. Transmission routes of antibiotic resistance along the food chain Of the total worldwide antibiotic consumption, agricultural activities account a large proportion (Ronquillo & Hernandez, 2017). Along with disease treatment and prevention in human and animals, antibiotics are applied in large amounts to promote growth in agriculture, livestock, aquaculture and apiculture (Zuccato, Castiglioni, Bagnati, Melis, & Fanelli, 2010). A wide range of bacteria is related to food that is present in all ecological niches including plants, animals, birds, soil, aquatic ecosystems, or, discharge from human sewage, linked to the production and handling of food for consumption (Sørum & L’AbéeLund, 2002). The development of antibiotic resistance and the possible pathway for transmission of ARB along the food chain is shown in Fig. 1. Different research works on antibiotic resistant bacteria have shown the prevalence of ARB in the food of animal origin, livestock, companion animals and in humans (Kirbis & Krizman, 2015). ABR bacteria can reach human either indirectly through the food chain with the ingestion of food contaminated with ARB or directly through the contact with the infected animals (Founou, Founou, & Essack, 2016) (Fig. 2). Both direct or indirect transmission of ARB and ARGs possess high public health risk in developing and least developed countries due to limited food biosecurity and safety measures along the farm-to-fork (Padungtod, Kadohira, & Hill, 2008). However, in developed regions, as the emergence of ARB and ARGs are well maintained along with the food system, indirect contamination of food with antibiotic resistant pathogens are responsible for foodborne infections. The antibiotics are used at large scale in today's modern farming practices in relation to the vast increase and to promote the animal growth, as well as to treat and prevent the infectious diseases (Sivagami et al., 2018). Each antibiotic has its own specific action mechanism to
3. Antibiotic resistant in South East Asia region Inappropriate use of antibiotics is one of the important reason for the emergence of ABR in South East Asia (SEA) region (Holloway, Kotwani, Batmanabane, Puri, & Tisocki, 2017). In the past few decades, SEA has been a center of economic growth, biodiversity as well as the region for the emergence of certain human diseases (Walther et al., 2016). This region has a contribution to the spread of AMR globally as the disease-causing organisms are carried to different parts of the world by international trades and international travelers. A tremendous increase in antimicrobial usage and antimicrobial resistant in SEA region has been reported. Easy access to antimicrobial and antibiotics, lack of appropriate regulation on antimicrobial usage, self-medication and irrational prescription and lack of awareness with regard to AMR are regarded as the leading reasons for the widespread of AMR in SEA (Zellweger et al., 2017). Most of the countries in SEA region are underdeveloping and developing and thus, it has to bear more consequences of AMR compared to developed regions (Sakeena, Bennett, & McLachlan, 2018). However, for this region, the reliable quantitative and qualitative data on antibiotic usage and antimicrobial resistant are lacking. Most of the research is limited to pathogens isolated from animal sources including pigs, poultry and aquaculture from Vietnam, Thailand, and Malaysia. There is even none published data from the rest of the countries of SEA region including Indonesia, Myanmar, and the Philippines (Nhung, Cuong, Thwaites, & Carrique-Mas, 2016). Among the 50 countries with the highest amount of antimicrobial use in animals, the top five countries include Myanmar, Indonesia, Nigeria, Peru followed by Vietnam as recorded in 2010. Indonesia is on
Fig. 1. Schematic representation of the main source of antibiotics and routes of antibiotic resistance along the food chain. 2
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Table 1 Summary of antibiotics used in animals, their mode of action and the developed resistance mechanism. Drugs classification
Mode of action
Resistance Mechanism
Reference
Sulfonamides Sulfadiazine Lincosamides Macrolides,
Interfere with folic acid synthesis Prevent protein production
Sköld (2000) Ungureanu (2010)
Tetracyclines
Inhibit bacterial protein synthesis
Penicillin, Beta Lactamase sensitive, Cephalosporins
Inhibits the formation of peptidoglycans layer of bacterial cell walls
Quinolones, Flouro quinolones
Interfere in DNA replication by binding DNA-gyrase Binds to bacterial 50S ribosomal subunit and interferes with protein synthesis.
Chromosomal resistance; plasmid- borne resistance Target modification; decrease of intracellular antibiotic concentration by active efflux Inducible efflux proteins, Ribosomal protection proteins and tetracycline inactivation by enzymes. Beta Lactamase production mainly changes cell wall proteins so that they cannot bind to penicillin binding proteins. Target-Mediated Quinolone Resistance, Plasmid-Mediated and chromosome Quinolone Resistance Reduce binding affinity of drug due to modification of bacterial and ribosome efflux of macrolides from the bacterial cell.
Macrolides/Azalides Aminoglycosides
the list among the top five nations with the highest expected percentage increase in antimicrobial use by 2030 (Sivaraman & Parady, 2018). Sugiri et al. (2014) reported that 16% of the chicken meat samples from traditional markets of Indonesia were infected with Listeria monocytogenes and most of those isolates exhibited multidrug resistance especially to penicillin, ampicillin, and erythromycin. The different species of Escherichia bacteria isolated from poultry meat from Vietnam, Thailand, and Indonesia showed resistance against antibiotics such as oxytetracycline and fluoroquinolones (Usui et al., 2014). Several studies have been reported for the antimicrobial residues in Vietnamese meat products (Addis & Sisay, 2015; Ngoc Do et al., 2016; Yamaguchi et al., 2015). Nhung et al. (2018) reported on bacterial isolates positive for sulfonamides, tetracyclines, gentamicin/neomycin and β-lactams and macrolides in 357 meat samples (119 chicken, 122 pork and 116 beef) sampled from Hanoi and Dong Thap province, Vietnam. However, non-typhoidal Salmonella isolates showed high levels of AMR against antimicrobial drugs, quinolones and penicillin, which are considered critically important human drugs. Globally, nontyphoidal Salmonella is an important agent of food-borne gastroenteritis (Majowicz et al., 2010). Similarly, In Vietnam, Van, Moutafis, Istivan, Tran, & Coloe, (2007) screened 180 raw food samples including meat and shellfish samples contaminated with Salmonella spp., and Escherichia coli for antibiotic resistance against 15 antibiotics. This study revealed that Salmonella isolates (50.5%) and E. coli isolates (83.8%) were resistant to at least one antibiotic. A study by Abatcha, Effarizah, and Rusul (2018) showed the prevalence of higher rate of Salmonella contamination and ARGs in the fresh food market of Malaysia. The isolated Salmonella species showed the susceptibility to cephalothin (100%) and followed the antibiotic resistance in the order; tetracycline (44.4%), sulfonamides (44.4%), ampicillin (26.7%), chloramphenicol (29.1%) and trimethoprim-sulfamethoxazole (16.6%). Thailand is the major producer and consumer of swine, with 9.51
Chopra and Roberts (2001) Fernandes, Amador, and Prudêncio (2013) Aldred, Kerns, and Osheroff (2014) Dinos (2017)
million pigs raised by about 210,978 households in 2013 (Tantasuparuk and Kunavongkrit, 2014). However, the swine farms of all size in Northern Thailand were observed to be reservoirs of multidrug resistance. This prevalence of AMR is generally affected by the farm size and antimicrobial usage practices on the farm, thereby adding to major AMR transfer along the food chain (Love et al., 2015). In research work by Chanseyha, Sadiq, Cho, and Anal (2018), Escherichia coli (39.17%) and Salmonella (23.33%) isolated from lettuce samples from Thailand and Cambodia showed the presence of beta-lactam and tetracycline resistant genes. The presence of these ARGs indicates a high risk of antibiotic resistant transmission to human, animals and other non-resistant microorganisms. Salmonella and Staphylococcus aureus, prominent food-borne pathogens, were isolated from poultry meat products in Thailand. The isolates were observed to be resistant to at least one antibiotic such that Salmonella (72.72%) and S. aureus (44.73%) showed resistance to tetracycline (Akbar & Anal, 2013). A research study by Sadiq, Tarning, Cho, & Anal, (2017) exhibited the presence of bla CMY and tet (A) genes in E. coli and tet (A) genes from Salmonella enteritidis isolated from beef meat; and tet (B) genes in Salmonella typhimurium isolated from poultry meat samples from Thailand. Southeast Asian countries are popular for traditionally fermented food and in this region, the process for fermenting cereals, meat products, and vegetables are developed. Such fermented foods are highly priced for improved nutritional and organoleptic quality as well as for beneficial microorganisms (Anal, 2019). The fermented food products are classified into five groups including fermented soybean; fish; vegetable; bread and porridges; and alcoholic beverage. Lactic acid bacteria (LAB) are the commonly involved bacteria in these products to a varying extent, having either positive or negative effects (Rhee, Lee, & Lee, 2011). However, different research works have indicated that along with health benefits, fermented foods can act as vehicles of ARB and ARGs to humans and other bacteria (Abriouel, Knapp, Gálvez, & Benomar, 2017). Lactic acid bacteria (LAB) strains, including Lb.
Table 2 Summary of antibiotics used in plants, their mode of action and the developed resistance mechanism. Drug Classification
Mode of action
Resistance mechanism
Reference
Streptomycins
Inhibit protein synthesis by binding irreversibly to bacterial ribosomes Inhibit protein synthesis and matrix metalloproteinases
chromosomal mutation, gene acquisition
Hyun, Kim, Yi, Hwang, and Park (2012) Chopra and Roberts (2001)
Tetracyclines Gentamicins Oxolinic acid Penicillins Chloramphenicol
enzymatic inactivation of tetracycline, efflux, and ribosomal protection acquired mutation in the ribosomal target, activation of Efflux pumps Alteration in the targets of quinolones, and overexpression of efflux pump system production of enzyme beta-lactamase that destroys the beta-lactam ring of penicillin enzymatic inactivation, target site mutation, presence of efflux pumps
Inhibits amino acid incorporation into protein by binding the 30S subunit of the bacterial ribosome Affect interaction with DNA gyrase Inhibits cross-linking activity and prevents new cell wall formation. Inhibits protein synthesis.
3
Garneau-Tsodikova and Labby (2016) Ruiz (2003) Tenover (2006) Fernandez et al. (2012)
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Table 3 Summary of the prevalence of antibiotic resistance in food samples of SEA region. Country
Food/Specimen
Antibiotic Resistant bacteria
Prevalence (%)
References
Thailand
Chicken
ESBL- producing Enterobacteriaceae ESBL- producing E. coli ESBL-producing Klebsiella ESBL- producing Enterobacteriaceae ESBL- producing E. coli ESBL-producing Klebsiella ESBL-producing Klebsiella ESBL-producing Klebsiella ESBL-producing Klebsiella ESBL-producing Klebsiella E. coli Salmonella isolates MDR- E. faecalis MDR-E. coli MDR-E. faecalis MDR- E. coli MDR- E. faecalis ESBL- producing E. coli MDR- Salmonella ESBL-producing Salmonella isolates MDR- Salmonella enterica MDR-Escherichia coli ESBL- producing E. coli
45.4 50 40 53.5 61.5 44.4 66.7 36.4 30.8 20 57.45 46.43 73 91.5 100 62.8 84.5 48.8 98.2 2.4 67.8 75.3 2.4
Boonyasiri et al. (2014)
Pork
Thailand and Cambodia Thailand Vietnam
Fish Beef Bean sprouts Shrimp Green leaf lettuce Chicken
Indonesia Malaysia Thailand and Laos
Chicken Pork
Philippines Thailand and Cambodia
Poultry meat Broilers, pigs and meat
Chanseyha et al. (2018) Usui et al. (2014)
Aliyu, Saleha, Jalila, and Zunita (2016) Sinwat et al. (2016) Calayag, Paclibare, Santos, Bautista, and Rivera (2017) Trongjit, Angkittitrakul, and Chuanchuen (2016)
ESBL, extended spectrum β-lactamase producers. MDR, Multi-Drug Resistant.
With an aim to support the implementation of the WHO's global action plan in the food and agricultural sectors, FAO launched its action plan on antimicrobial resistance O'Neill, 2016–2020. FAO action plan has four focus areas including Awareness, Evidence, Practices, and Governance. These areas which are identified as four main pillars of work on antimicrobial resistance, are strongly interrelated and need to be addressed in parallel (FAO, 2016). The OIE promotes the responsible and prudent application of antimicrobial in terrestrial and aquatic animals to preserve the therapeutic efficacy of antimicrobials. OIE has developed a wide range of international standards and guidelines that provides a framework for responsible use of antimicrobial in terrestrial and aquatic animals along with the surveillance system, monitoring of the quantities applied, and the risk assessment of the emergence or spread of antimicrobial resistant bacteria (OIE, 2015). The OIE strategy assists the Global Action Plan's objectives and reflects the OIE mandate based on four objectives which include (1) improvement in awareness and understanding; (2) improvement in information through research and surveillance; (3) capacity building; and (4) implementation of standards (OIE, 2016). Animals and animal food products, agro-food environments are the common sources of antimicrobial resistant pathogens in developing countries. Further, the lack of adequate surveillance systems leads to absences of reliable national data on the level of antimicrobial resistance in animals (Grace, 2015). Use of antibiotics in the SEA region is extremely high with inadequate policies to encourage appropriate use (Holloway et al., 2017). SEA region is lagging in respect to the implementation of standards to fight antibiotic resistance, along with that lacks appropriate surveillance system, training to farmers and professionals, and the national organization for independent drug regulation (Goutard et al., 2017). It has been estimated to bear 3.24 million days of hospitalization and 38481 deaths per year, and a cost of 0.6% of national GDP due to the antimicrobial resistance in Thailand alone. “Thai National Strategic Plan on Antimicrobial Resistance (2017–2021)” was finalized in 2016 with the aim to reduce morbidity, mortality and the economic impact of antimicrobial resistance. This action plan has set goals to reduce antimicrobial resistance morbidity by 50%; reduce the antimicrobial use in human and animal by 20% and 30% respectively; and to increase public awareness about antimicrobial resistance by 20% (WHO, 2019).
Fermentum, Lb. Plantarum, P. acidilactici, were isolated from Indonesian fermented food products, dadih (fermented milk), bekasam (fermented meat) and tape ketan (fermented rice). All isolated strain showed resistance against chloramphenicol up to the concentration 5 μg/mL and Lb. Plantarum exhibited resistance against erythromycin up to a concentration of 15 μg/mL (Sukmarini, Mustopa, Normawati, & Muzdalifah, 2017). 4. Strategies to mitigate the impact of antibiotic resistant in the south-east asia region Globally, severe health and socio-economic risk have increased with the spread of ARB and ARG in the food chain and have become major public health concerns. This situation has been affecting both developing and developed countries (Padungtod et al., 2008). In developing countries, antibiotic resistant bacterial infection increases the morbidity and mortality rates while in the developed nation it increases the therapeutic costs (Harbarth et al., 2015). Appropriate measures to prevent and control the spread of ARB from farm-to-fork is lacking in most of the developing countries, therefore, it poses a serious risk for global public health. To address the risk of ARB, the “One Health” approach has been endorsed by supranational entities, following the coalition between the World Health Organization (WHO), Food and Agriculture Organization (FAO), and World Organization for Animal Health (OIE) referred as the “Tripartite Alliance”. To counteract the global concerns of antimicrobial resistance, WHO in collaboration with its tripartite partners published the “Global Action Plan on Antimicrobial Resistance” in 2015. Under this global action plan, with an aim to set integrated measures for prevention and containment of antibiotic resistance in the food chain, five strategic objectives have been developed, including (1) increasing awareness on usage of antibiotics and its resistance; (2) improving information through research and surveillance; (3) reduction of diseases; (4) optimization of antibiotic use; and (5) mobilization of resources and research (WHO, 2015). The primary knowledge required to establish integrated surveillance for antibiotic use and antibiotic resistance is provided by a guideline on integrated surveillance of antimicrobial resistance (AGISAR) issued by the WHO (Bordier, Uea-Anuwong, Binot, Hendrikx, & Goutard, 2018). 4
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the level of prevalence of antibiotic resistance in the different food chain. However, the lack of proper policy and guidelines on the regulation of antibiotic usage makes the condition worse. A guideline and action plan from a different organization such as WHO, FAO, OIE provide the primary information needed by countries to establish integrated surveillance of antibiotic use in human, animals, plants, and aquaculture. To reduce the risk of ARB, use of antibiotics needs to be regulated. Surveillance of resistance in humans and food animals is important to measure the long-term effectiveness of any control measure. However, unavailability and lack of implementation of standards hamper the surveillance system. Integrated surveillance system helps to measure and compare the extent of prevalence of antibiotic resistant in the food chain. Though the magnitude of global AMR contributed through the food chain is not clear but it has been documented that if the emergence of ARB and ARG genes can be controlled in basic food production and processing system, it is possible to reduce the risk of foodborne infections.
Following the adoption of the Global Action Plan on Antimicrobial Resistance, Malaysia committed to develop the country's national action plan, “Malaysian Action Plan on Antimicrobial Resistance (MyAPAMR) 2017–2021”. This action plan has four priority areas including (1) public awareness and education, (2) surveillance and research, (3) i prevention and control and (4) appropriate use of antimicrobials (Ministry of Health and Ministry of Agro-Based Industry, Malaysia, 2017). In Malaysia, antibiotics used for disease treatment are regulated by National Pharmaceutical Regulatory Agency (NPRA) under the Ministry of Health (MOH), Malaysia, whereas antibiotics for disease prevention and growth promotion are controlled by the Department of Veterinary Services (DVS) under the Ministry of Agriculture. Based on the list of registered veterinary products by NPRA, out of 688 registered veterinary products, 458 (66.6%) were antibiotics registered for use in livestock as of record in November 2017. In order to regulate the antibiotic resistance, Malaysia has developed policies, termed as (i) Registration of veterinary products: it requires all new veterinary products to registered with NPRA and should fulfil all requirements in respect to quality, safety, efficacy and residue; (ii) Monitoring programme of antibiotic residues: in 2013, DVS has implemented monitoring of veterinary drug residues including antibiotics in animal feed; (iii) Malaysian good agricultural practices: it is a certification scheme for agricultural, livestock and aquaculture sector based on Malaysian Standard; and (iv) Guideline for organic chicken production: in 2014 DVS Malaysia has published a Guideline for Organic Chicken Production to guide the farmers to ensure the product meets the requirement of organic chicken (Hassali, Yann, Verma, Hussain, & Sivaraman, 2018). The rate of antimicrobial resistance is high in Vietnam with thousands of deaths annually due to multi-drug-resistant infections. Since detecting and tracking these infections is key to stop antimicrobial resistance, Vietnam's National Action Plan and antimicrobial resistance surveillance system involves 16 laboratories and six model hospitals. This action plan also includes monitoring the use of antibiotics while encouraging antibiotic stewardship (CDC, 2018). In Vietnam, antimicrobial resistance has been recognized as a major threat in public health, trade, economy and overall sustainable development of the country. Vietnamese Ministry has developed an inter-ministerial strategy to combat antibiotic resistance and an integrated surveillance system for antibiotic resistance as supported by international organizations and cooperation, and in line with international recommendations (Bordier et al., 2018). In 2017, Indonesia has committed to advance “One Health” with collaboration with five ministries joint communique to work together to undertake One Health-drive risk mapping; address the major threat of antimicrobial resistance in Indonesia; raise awareness about the importance of relevance of Zoonoses; clarify, foster and integrate One Health linkage; support and advance One Health coordination; improve the sharing of information (Sivaraman & Parady, 2018).
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5. Conclusion The emergence of antibiotic resistance indicates that certain types of antibiotics effective against bacteria will be no longer effective. This rise of ARB and ARGs is linked with excessive and uncontrolled use of antibiotic in the treatment of human disease, and in different agricultural practices. Bacteria develop the antibiotic resistance by several mechanisms and can spread to non-resistant bacteria either through DNA or other genetic matters such as integrons, transposons, and bacteriophages. There is an indirect relation between the prevalence of ARB in food production and transmission through the food chain to the consumer. However, the magnitude of global antimicrobial resistant contributed through the food chain is unclear. Developing countries must bear more consequences of antibiotic resistance than the developed countries. SEA region is regarded as the global hub for antimicrobial resistance. In countries like Thailand, Myanmar, Malaysia, Indonesia, different research works have been conducted to measure 5
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