DAIRY FARMING AND EMERGING ANTIMICROBIAL RESISTANCE

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DAIRY FARMING AND EMERGING ANTIMICROBIAL RESISTANCE

Das T1 and Das NK2

1Scientist, ICAR-DFMD, Bhubaneswar

2BVO, Bisoi, Mayurbhanj, FARD, Government of Odisha

Corresponding author E mail id: tarenisahoo@gmail.com

Abstract

Demand for dairy and dairy products are increasing due to uprising human population.  Non-prudent therapeutic and non-therapeutic use of antimicrobials in surging dairy sectors leads to selective evolutionary pressure and rapid development and dissemination of antimicrobial resistance (AMR) across the globe. AMR is a multifaceted problem and an emerging threat to human health, animal health and ecosystem. Rising AMR interferes with effective treatment resulting in treatment failure of previously treatable diseases and high economic burden on society. National action plan on AMR and Global action plan by WHO are formulated to tackle AMR. Improving animal health, good management practices, increased use of ethnoveterinary practices, prudent use of antibiotics, ensuing withdrawal period following antibiotic treatment and treatment of waste from dairy farming will reduce development and dissemination of AMR.

Keywords: AMR, dairy farming, impact, India, strategies

Importance of dairy farming

Due to budding global human population, demand on animal protein is growing. According to the United Nations, the world population is projected to reach 8.5 billion in 2030, 9.7 billion in 2050 and 11.2 billion by 2100. About 4.7 billion (61%) global population lives in Asia and 1.39 billion (18%) lives in India which is one of the most populous countries in the world (https://www.un.org/en/desa/world-population). About 6 billion people worldwide consume milk and milk products. World milk production is increased by 1.6% in 2018 (838 Mt) and in India, production is increased by 3.0% (174Mt) (OECD-FAO, 2019). World milk production is expected to grow 1.7% per annum and is expected to reach 981 Mt. by 2028 and developing country like India is expected to contribute significantly to the world’s growing milk production. Per capita consumption of fresh dairy product is expected to grow by 1% annually (OECD-FAO, 2019). Mostly in developing country like India, demand for dairy and dairy product is rising due to rising population, changing food habit, rising per capita income, urbanization etc. India is having world’s largest population of dairy animals (more than 300 million bovines) with 187 million tons milk production. Livestock sector contributes to 4.11% to India’s GDP and dairy sector contributes most important share (67%) to total livestock output (https://www.dailypioneer.com ). This dairy farming plays an important role in socioeconomic development of many rural families. About 8.4 million small and marginal farmers per year depend on dairy for their livelihood (https://www.dailypioneer.com ). In India, due to increased urban population, peri urban small holder dairy farms play important role in milk production and food security (Chauhan et al., 2018).

Antimicrobials use in dairy farming

In order to enhance livestock and poultry production for continuous supply of sufficient amount of high quality and low-cost animal protein to the expanding human population, antimicrobials (AMs) are used regularly in modern animal production practices for maintaining health, preventing and treating diseases, enhancing productivity, reducing rumen fermentation and emission of methane gases from livestock and prevention of water eutrophication for aquatic animals. Routine and wide spread use, misuse and overuse of antimicrobials leads to selective evolutionary pressure and rapid development of antimicrobial resistance and faster spreading across the globe among humans, animals and environment. The food animals like pig, poultry, dairy etc. are source of AMR pathogens. Continuous use of antibiotics in dairy sector as growth promotor, therapeutic and prophylactic leads to AMR development and dissemination to public sector and environment. AMR is now considered as emerging public health crisis.

Dairy animals are important source of healthy food consumed globally by all age groups. Various animal diseases are major impediment to the growth of dairy industry and milk production by causing morbidity and mortality. In these animals’ antimicrobials are used to treat and prevent mastitis, metritis and lameness.  Mastitis is one of the most common infectious diseases affecting milk quality and quantity. In developing country like India, where infectious disease burden is very high and health care facilities are poor, substantial quantity of antimicrobials are used to combat impact of various pathogens. Subtherapeutic doses and suboptimal concentration of antibiotics in these animals lead to development of AMR. Various factors leading to AMR in these dairy animals are unrestricted availability of antimicrobials, self-treatment by farmers, low level of knowledge of farmers about antibiotics, shortage of veterinarians, increased informal prescribers, improper diagnosis, lack of proper laboratory facility, incorrect treatment duration, improper or unchecked antimicrobial use and dosage, unnecessary use of expensive drugs, use of low cost antibiotics by small dairy farmers, lack of awareness programme on antibiotics use, easy availability and east access to antibiotics, lack of regulations related to non-therapeutic use of antibiotics, lack of knowledge regarding antibiotics withdrawal period, selling of milk from cows treated with antibiotics, poor disease surveillance, monitoring, control and prevention measures etc. (Chauhan et al., 2018; Sharma et al., 2018; Broom and Doron, 2020; Farrell et al., 2021).

Surplus dairy calves or male calves born on dairy farm are also a major source of AMR pathogens. Inadequate colostrum practices, feed and water deprivation, long distance transport, poor biosecurity and intensive housing in these surplus dairy calves make them susceptible to various infectious diseases and subsequent use of antimicrobials and development of antimicrobial resistance (Vinaya Mohan et al., 2022).

In livestock production system, large amounts of antibiotics (63,151 tons in 2010) are used globally and is projected to reach 200,235 tons by 2030 (Van Boeckel et al., 2017) which is one of the drivers for AMR development. In India, 3% of global antimicrobials are used in food animals. India is having highest numbers of dairy animals mostly raised by small scale farmers and is considered as hot spot for AMR (Mutua et al., 2020).  In the US, 16% lactating dairy animals receive antibiotic therapy annually for clinical mastitis and all animals receive intramammary antibiotic therapy for future mastitis prevention (Landers et al., 2012).

Development of antimicrobial resistance

Microorganisms acquire antimicrobial resistance through mutation of existing genes or and acquiring AMR genes from environment or from other microbes through phages, plasmids and transposons resulting proliferation of AMR traits and making antibiotics ineffective. The various mechanisms associated with development of AMR are alteration in antibiotic target site, modification or alteration of antibiotics, altering antibiotic metabolic pathways and by minimizing influx and maximizing efflux of antibiotics (McManus, 1997; Sharma et al., 2018).

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Antimicrobial resistance has been detected in various bacterial pathogens infecting dairy animals like multi drug resistant (MDR) Staphylococcus aureus, vancomycin resistant Staphylococcus aureus (VRSA) and methicillin resistant Staphylococcus aureus (MRSA), Escherichia coli, Mycobacterium tuberculosis complex (MTBC), Streptococcus agalactiae, Streptococcus uberis, Klebsiella pneumoniae, Listeria monocytogens, Ceftiofur resistant and MDR Salmonella, Vibrio cholerae, Campylobacter jejuni, Enterococcus, Acrobacter  etc. isolated from milk, manure pit, faces, farm slurry, drinking water supply, bedding materials of dairy farms in different parts of world. These are leading cause of human food borne illness. In the USA dairy farm, there is increasing reports of extended spectrum β-lactamase producing (ESBLs) Enterobacteriaceae (ESBLs-E. coli and ESBLs-Klebsiella species) due to extensive use of third generation cephalosporins (Gelalcha and Dego, 2022).  In Canadian dairy farm, extended spectrum β-lactamase/ AmpC producing E. coli were found resistant to tetracycline, sulfisozaxole and streptomycin (Masse et al., 2021). In Bangladesh dairy farms, 84.2% E. coli isolated from clinical mastitis were multidrug resistance and highest resistance was observed against amoxicillin, ampicillin and tetracycline (Bag et al., 2021).  In Jordan, 26% of tested milk samples were positive for mecA MRSA and all isolates were resistant to penicillin, oxacillin and cefoxitin (Obaidat et al., 2018).  Tahoun et al., in 2017 reported 88% of L. monocytogenes isolated from raw milk, milking machine and hand swabs of dairy farm workers were multidrug resistance and most virulent isolates were resistant to tetracycline, clindamycin and rifampicin.  In a study conducted in Punjab, highest proportion of AMR genes were detected in farm slurry and milk and commensal E. coli and Klebsiella were found to be reservoirs of AMR genes leading to environ mental pollution (Jindal et al., 2021). Baker et al., 2022 reported that wastes from dairy production farm are major source of AMR genes and bacteria which can contaminate environment and transmitted to humans. Annually and globally, 3 billion tons waste manure is produced from 265 million dairy cows. In US dairy farm, waste milk fed to calves was found to be a major source of antimicrobial residues and multidrug resistant E. coli which may enhance selection and dissemination of resistant bacteria (Tempini et al., 2018). In South Africa, out of 17% environmental substrate of three dairy farms were MTBC positive, 47.3% were isoniazid resistance and 16.4% were MDR (Ntloko et al., 2021).

Spread and Negative impact of antimicrobial resistance

Humans come in contact with AMR pathogens directly from food animals or indirectly from contact with resistance organism from environment as a result of contamination of soil and water with antimicrobial residues or AMR genes or AMR pathogens as a result of antibiotic use in food animals.  Direct effects of antimicrobial use in humans are AMR microbes’ colonization, infection and outbreak of various AMR diseases and induction of AMR in normal microbial flora. Indirect effects are dissemination of resistant in the environment through animal mobilization, transfer and incorporation of resistant gene from animal to human pathogens, contamination of soil and water through animal wastes containing AMR genes and pathogens and subsequent alteration in human flora etc. (Landers et al., 2012; Laconi et al., 2021). The rising Indian pharmaceutical industries discharge AMs contaminated wastes into the environment and different microbes coming in contact with these new unused antimicrobial residues develop AMR. At the United State dairies, antibiotic resistance genes were found more frequently in faces and soil from dairy calves and heifers than from hospitals, lactation and dry pens. Also soil from dairy calves’ pen had most antibiotic resistant E. coli followed by heifer pen soil and hospital pen soil (Liu et al., 2019). Changes in environmental microflora may hamper recycling of ecosystem carbon and nutrients and affect planetary health. AMR is a severe emerging threat to global health and food security which is growing at alarming rate. The adverse effects of AMR are increased disease severity, increased risk of complications, increased case fatality rate (MRSA), increased death (Carbapenem resistant K. pneumoniae), delay in treatment, treatment failure (ESBL producing Klebsiella pneumoniae), use of expensive medicines, longer hospital stays, increased stay in intensive care unit, increased resource utilization, higher medical costs and increased economic burden and higher cost associated with implementation of AMR infection control measures in healthcare units. It is estimated that additional 10,000 to 40, 000 US$ is required to treat patient with MDR infection. (Friedman et al., 2015). As per WHO, the world economy will lose USD 210 trillion by 2050 due to drug resistant pathogen infection. As antibiotics are less effective, it is tougher to treat pneumonia, TB, gonorrhea, salmonellosis, food poisoning etc. and difficult to carry out organ transplantation, surgery, chemotherapy etc. In USA, about 38.7% and 50.9% pathogens causing after surgery infection are resistant to most standard antibiotics (Friedman et al., 2015).  About 3.7% of new TB cases and 20% of previously treatable TB cases are now globally caused by isoniazid and rifampicin resistant TB (Llor and Bjerrum, 2014).  Also, antibiotic overprescribing is associated with various adverse effects like allergic reaction, gastrointestinal problems, hepatotoxicity, neurological problems etc. apart from AMR. About 48 million people per year affected with food borne illness and every year pathogens like Campylobacter, Salmonella and Shigella cause 742,000 antimicrobial resistant infection as per CDC estimate. Currently, about 700,000 deaths annually are attributable to multi drug resistant pathogen and will rise to 10 million by 2050 without proper action plans (Robinson et al., 2016). The MDR TB and extensive drug resistance TB are responsible for 200,000 deaths per year.  It is estimated that 214,000 neonatal deaths due to drug resistant sepsis occurring globally and India is one of the world’s five countries with highest recorded neonatal deaths. In Asia, by 2050, there will be 4.7 million deaths due to drug resistant pathogens if AMR is not mitigated (Mendelson and Matsoso, 2015).

Strategies to control AMR

AMR is a critical global health issues that affect human, animal and environmental health. In order to reduce selection pressure and disrupt transmission of AMR genes and microbes, actions are required at global level. In 2011, AMR was considered first time as serious public health threat by WHO. One meeting was conducted in 2011 in Jaipur (Jaipur declaration on AMR), India by WHO-South-East Asia member countries for prevention and control of AMR to improve animal health (WHO, 2011). A Tripartite alliance was formed between WHO, FAO and OIE in 2015 with one health approach to publish global action plans (GAP) including understanding of AMR through increased surveillance and research. The global action plans include improved awareness and understanding of AMR, increased research and surveillance to enhance knowledge, to reduce incidence of infection, to optimize use of antimicrobials in veterinary and public sector and to increase investment in new medicine, vaccine, diagnostics etc. (Mendelson and Matsoso, 2015).  World antimicrobial awareness week is celebrated from 18-24 November every year to increase global awareness and to encourage best practices among general population, healthcare workers and policy makers in order to mitigate generation and spread of antimicrobial genes and pathogens.

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The Government of India has taken various measures to tackle AMR like National Programme on AMR containment in 2012-2017, National Action Plan (NAP) on AMR in 2017 according to WHO GAP, AMR surveillance network in 2013, AMR research and international collaboration etc.( https://pib.gov.in ).

Development of new and potent antimicrobial with improved spectrum of activity can mitigate AMR. But the development of new antimicrobial is very slow and challenging as compared to alarming rise of AMR. Thus, it is very crucial to develop new alternate management strategies to curb AMR. Prior vaccination is important strategy helps in reducing severity of disease, pathogen shedding and increases pathogen threshold load required for infection. Vaccination also induces herd immunity.  Quiroga et al., 2022 developed novel proteo-liposome based vaccine against E. coli mastitis with notable results. Inactivated polyvalent mastitis vaccine comprising of S. aureus, S. uberis and E. coli had been synthesized and successfully evaluated (Shah et al., 2022).  Different vaccines are available against different animal protozoa and ticks. In field condition, domestic animals are regularly vaccinated against Foot Mouth Disease, black quarter, hemorrhagic septicemia, PPR etc. to prevent any future disease incidence. Alternative therapies which inhibit microbial growth and regulate microbial virulence can be used.  Different ethnomedicinal plants are documented for curing FMD, anthrax, diarrhea, dysentery, wound, fracture, lactational problems in animals.  Phytocompounds like tea tree oil can be used against bovine mastitis. Different plant derived antimicrobial compound can be used as alternative drug line to treat different bacterial infections like organo-Sulphur compound of Allium sativum can be used against Campylobacteria.  Extracts of stem bark of African medicinal plant Tieghemella heckelii were found effective against MRSA (Kipre et al., 2017).  Probiotics can be used as an alternative to antibiotics for growth promotion and enteric microbial health in dairy animals. Probiotics also have antagonistic effect MDR E. coli, MDR Pseudomonas aeruginosa, MDR Shigella, mastitis causing Staphylococcus species etc. (Sharma et al., 2018). Antimicrobial peptides like lactoferricin from bovine mammary gland and esculentin-1-21 from frog skin were found potent against bovine mastitis pathogens. (Islas‐Rodrìguez et al., 2009; Sharma et al., 2018). Bacteriophage and quorum quenchers can be used to lyse the bacteria or to attenuate bacterial virulence respectively instead of antibiotics. Different nanoparticles have different antimicrobial activities. They can be used against bacterial and fungal pathogens and to treat bovine mastitis. Kalikska et al., 2019 described use of silver and copper nanoparticles for treatment of bovine mastitis in dairy industry. Immunostimulants like selenium, zinc, vitamins, plant polysaccharides, bacterial extracts, hormones, cytokines etc.  can be used to enhance immunocompetence and disease resistance in animals.

Three significant areas for antimicrobial usage in dairy farms are udder health (mastitis), uterine health (metritis and retained placenta) and replacement calf health for treatment of respiratory and gastrointestinal diseases (Gerber et al., 2021). Thus, good management in these areas will prevent or decrease future disease incidences, antimicrobial use and development of antimicrobial resistance. Different managemental strategies include preventing mastitis, routine microbial culture and antibiotic sensitivity test of cows with clinical and subclinical mastitis, treating animals at right time to prevent transmission of pathogens, good hygiene and biosecurity of dairy animals and surroundings, good hygiene during milking, improving hygiene and sanitation during calving and obstetrics, preventing metabolic diseases weakening animal’s immunity like hypocalcemia, ketosis etc. and improving calf health and calf management like refining colostrum supply and calf feeding, providing mineral and vitamin supplement, vaccination, deworming, proper housing, improving barn hygiene etc. (Gerber et al., 2021).

Other effective measures to prevent or to reduce AMs usage and AMR development in Indian conditions include enhancing quality veterinary resources, enhancing antimicrobial usage awareness among field veterinarians, para veterinarians, farmers, physicians, drug dealers or distributors, pharmacists etc., discouraging non-prescribed AMs use and self-treatment by farmers, strengthening laboratory facility to diagnose diseases and to carry out antimicrobial sensitivity tests, imposing regulations and policies for AMs usage and distribution, prohibiting use of antibiotics as growth promoters, alerting farmers to strictly follow withdrawal period rules following AMs treatment to prevent AMs residue contaminated milk to enter into food chain for human use and calf feeding (Chauhan et al., 2018). Rapid field-testing kits are under development which can help field veterinarian to select correct antibiotics for treatment of mastitis (https://www.thecattlesite.com).

Wastes from dairy production farms are major source of AMs residues, AMR genes and AMR microbes. Dairy manure treatment like composting, anaerobic digestion and storage of manure along with prudent and responsible use of antibiotics, avoiding use of critically important human antimicrobials in animals and use of short half-life AMs will reduce concentration of antimicrobial residues, AMR genes and bacteria in manure (Oliver and Gooch, 2017). In a preliminary study, microwave heating of dairy manure for 30 to 330s at 2450 MHz frequencies found to reduce AMR genes by 2 folds in less than one minute (Luo et al., 2021) which can be used to reduce dissemination of AMR genes in the environment.

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