Antimicrobial Resistance in Agriculture: Perspective, Policy and Mitigation

Antimicrobial Resistance in Agriculture

Perspective, Policy and Mitigation

Indranil Samanta

Department of Veterinary Microbiology, West Bengal University of Animal and Fishery Sciences, Kolkata, India

Samiran Bandyopadhyay

ICAR-Indian Veterinary Research Institute-Eastern Regional Station, Kolkata, India

Table of Contents

Cover image

Title page

Copyright

Foreword

Preface

Chapter 1. History of antimicrobial resistance

Definition

History of chemotherapy

Discovery of antimicrobials/antibiotics and individual scientific contributions

Emergence of antibiotic-resistant bacteria historical perspective

Chapter 2. Use of antimicrobials and antibiotics in livestock, poultry, fishery and agriculture

Use of antibiotics in animals and aquaculture – purpose and objective

Recent trends of antibiotic usage – global scenario

Details of the antimicrobials used in poultry

Details of the antimicrobials used in pigs

Details of the antimicrobials used in bovine

Details of the antimicrobials used in aquaculture

AMU in agriculture – current and future possible impacts

Chapter 3. The emergence of antimicrobial-resistant bacteria in livestock, poultry and agriculture

Overview of antimicrobial use in animals

Resistant pathogens in livestock and poultry sector

Resistant pathogens in agriculture sector

Dissemination

Preventive strategy

Chapter 4. Emergence of antimicrobial resistant bacteria in aquaculture

Background

AMR in open and closed system aquaculture

AMR in integrated fish farming

Spread of antimicrobial resistance in fish pathogens

Role of probiotics in AMR in the aquatic system

Environment impact of AMR in aquaculture and its abatement

Chapter 5. Emergence of antimicrobial-resistant bacteria in environment

Background

Drivers and pathways

Regulators

Prevention and control strategies

Chapter 6. β-Lactamase

Overview, mechanism and diversity of β-Lactamase

ESBLs – origin and present status

Detection of β-lactamase production

Therapeutic strategies

Chapter 7. Carbapenem resistance

Carbapenem resistance – types and mechanism

Detection of carbapenem resistance

Spread in animals

Therapeutic strategies

Chapter 8. Resistance to fluoroquinolones

Overview

Resistance mechanism

Present status

Detection

Therapeutic strategies

Chapter 9. Resistance to aminoglycoside, tetracycline and macrolides

Aminoglycoside resistance

Resistance mechanism

Status in animals

Detection

Therapeutic strategies

Tetracycline resistance

Diagnosis

Macrolide resistance

Resistance mechanism

Status in animals

Detection of macrolide and lincosamide resistance

Strategies

Chapter 10. Colistin resistance

Overview

Colistin resistance mechanism

Spread and status in animals

Detection of colistin resistance

Detection of molecular mechanism of colistin resistance

Therapeutic strategy

Chapter 11. Antifungal resistance

Overview

Mechanism of antifungal resistance

Detection techniques

Status present

Chapter 12. Biofilm formation and persister cells

Background

Formation of biofilm

Types of biofilm

Biofilm and drug resistance

Biofilm and infection

Overview of persistence/drug tolerance

Mechanism of persistence or drug tolerance

Dormancy and persistence

Present status

Detection of biofilm formation

Therapeutic strategies in biofilm

How to overcome persistence

Chapter 13. Characteristics of antimicrobial resistance among microorganisms of concern to animal, fish and human health: Salmonella

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 14. Klebsiella

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 15. Escherichia coli

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 16. Staphylococcus

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Virulence factors

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 17. Streptococcus

Properties of genus

Antigenic characteristics

Toxins and virulence factors produced

Virulence factors

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 18. Actinobacillus

Properties of genus

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 19. Campylobacter

Properties of genus

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 20. Clostridium

Properties of the genus

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Rifamycin (rifampicin) resistance

Chapter 21. Pasteurella and Mannheimia

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Characteristics of antimicrobial resistance

β-Lactam resistance

Tetracycline resistance

Macrolide resistance

Aminoglycoside resistance

Quinolone resistance

Sulphonamide and trimethoprim resistance

Chloramphenicol and florfenicol resistance

Chapter 22. Vibrio

Properties

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 23. Pseudomonas

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 24. Aeromonas

Properties

Antigenic characteristics

Transmission

Toxins and virulence factors

Diagnosis

Characteristics of antimicrobial resistance

Chapter 25. Mycobacterium

Properties

Genome

Antigenic characteristics

Toxins and virulence factors produced

Transmission

Diagnosis

Characteristics of antimicrobial resistance

Chapter 26. Candida

Properties

Antigenic characteristics

Virulence factors

Transmission

Diagnosis

Laboratory examination

Characteristics of antifungal resistance

Chapter 27. Others

Chlamydia

Estrella lausannensis

Parachlamydia acanthamoebae

Bacteroides fragilis

Aspergillus fumigatus

Cryptococcus neoformans

Scedosporium spp.

Chapter 28. Cross-resistance between biocides and antimicrobials

Classification of biocides

Use of biocides in animal farm, agricultural field and fishery sector

How biocides work

Mechanism of resistance against biocides

Cross-resistance, co-resistance and co-regulation between biocides and antimicrobials

Chapter 29. Antimicrobial stewardship

Definition

Necessity

Approaches and techniques

Pitfalls

WHO list of priority antimicrobial-resistant pathogens

International guidelines to minimize antimicrobial resistance

Chapter 30. Alternative antiinfective therapy

Bacteriophage therapy

Enzybiotics

Phytobiotics and essential oils

Nanomaterial-based antiinfective particles

Others

Chapter 31. Immunotherapy

Cellular immunotherapy

Immunomodulation

Vaccination

Chapter 32. Antimicrobial resistance: one health approach

Definition of one health concept

History of one health concept development

Antimicrobial resistance as a one health issue

Integrated antimicrobial intake and antimicrobial resistance surveillance

Challenges of one health approach

Index

Copyright

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Foreword

The global community has been articulating serious concerns on the impact of antimicrobial resistance (AMR) on human development. AMR is considered as the most important challenge to human efforts in controlling communicable diseases. In an unprecedented way, the United Nations General Assembly has taken a serious note of burgeoning challenge of AMR and called upon all countries to initiate concerted actions to contain emergence and spread of AMR.

Recent report projects AMR causing 10 million deaths annually and wiping off a massive cumulative US$ 100 trillion from economy by 2050 as consequence of inaction to contain AMR. This report also estimates that mortality due to AMR shall exceed those due to cancers and road accidents put together. Moreover, most of these deaths will be in developing countries creating greater impact on health and economy. Data from the World Bank reveal that global exports will see a decrease of up to 3.5%, livestock production will diminish by 7.5% and additional health care–related costs will be staggering US$ 1 trillion by 2050.

Inextricable co-existence of human beings with animals, plants and environment since time immemorial has been both beneficial and malefic to human kind. Animals and plants sustain human life and are essential for food security for the growing human population. An ever-increasing and an unstoppable number of human infectious diseases arise from animals. A large part (60%) of all human infectious disease are transmitted from animals, 75% of all emerging infectious diseases originate from animals. Several pandemics in current millennium including severe acute respiratory syndrome, middle-east respiratory syndrome, influenza H5N1, influenza H1N1 and influenza H7N9 have animals as their sources. Around 1.67 million viruses are estimated to be enzootic with up to 50% of these having the potential to invade humans under conducive environment including deforestation and damage to local ecosystem.

The close and continuous contacts between humans and animals make the latter as a critical reservoir of infectious diseases to humans. One of the major drivers of AMR – perceived as the biggest challenge in global efforts to control communicable diseases – is the humongous irrational use of antimicrobial agents in the animal health sector, especially the use of antimicrobial agents for growth promotion of the animals.

The transmission of resistant pathogens and genes from animals to humans is a complex process influenced by several factors. The dynamics at human–animal interface require better understanding to facilitate institution of efficient control measures. It also requires close collaboration between human health, animal health and environment sectors in true spirit of One Health.

One Health is a validated, integrated and holistic approach that is being advocated by the World Health Organization (WHO), the Food and Agriculture Organization of the United Nations (FAO) and the World Organization for Animal Health (OIE) for combating health threats to humans and animals through human–animal–plant–environment interface. One Health concept warrants multisectoral, multidisciplinary, multiinstitutional and multilocation coordination, communication and collaboration to attain optimal health for people, domestic animals, wildlife, plants and environment. This makes it a complex philosophy with inherent barriers in successful implementation at the country level where silo and sector-specific approaches have been in vogue and well established.

It is heartening to note that this book aims to provide evidence-based information on various aspects of AMR in agriculture and their perceived impact on human health. The valuable information provided in this document may be utilized by policymakers and various groups of experts including academic and research personals engaged in zoonotic infection, veterinary microbiologists, veterinary medicine, medical microbiology and industrial microbiology, along with all veterinary and medical practitioners.

The book provides updated information encompassing all the genera of livestock and fish-originated pathogenic bacteria associated with AMR.

I am sure that the contents of this book shall be immensely helpful for not only academicians but also for progressive practitioners who wish to provide better care and management, and in the process, contributing to containment of AMR.

Dr Rajesh Bhatia

Former Director Communicable Diseases.

WHO Regional Office for South East Asia Region and

Former Regional Technical Adviser, AMR.

FAO Regional Office for Asia-Pacific.

New Delhi.

Preface

Antimicrobials have served as the most potent therapeutic agent for the last two to three decades saving the human and animal life. It is because of antibiotics we could have reduced the catastrophic effects of two World Wars that changed the human civilization in a significant way. Unfortunately, the infectious diseases are again returning back more intensely and threatening the human civilization as we failed to preserve the efficacy of antimicrobials. The United Nations has given the issue a parallel status to AIDS/tuberculosis to be discussed in the 71st UN General Assembly in New York in 2016. Antimicrobial resistance (AMR) is truly a ‘One Health mega-concern’ because it has three functional domains such as animals, human and environment. The resistance genes generated in the commensal or pathogens in animals or human can be transferred between them during the exchange of microbial pool. The resistant bugs become untreatable, as antimicrobials used in animals or human are mostly the same molecule and thus the resistance generated in one can affect the others. Tackling the resistance issue with One Health approach thus increases the therapeutic life span of the antibiotics. The World Health Organization (WHO) in collaboration with the Food and Agricultural Organization (FAO) and the World Organization for Animal Health (OIE) developed several joint strategies to combat the problem. Excess antibiotics are released in the environment through different excretory systems of the animals and human. Other than livestock and poultry manure, antibiotic residues from the pharmaceutical industry, human hospitals and agricultural fields are also the major sources of environmental contamination. The accumulated antibiotics contribute to the resistance gene pool present in the environmental bacteria. Thus the AMR is also considered as an ecological problem. The pollution with antibiotics is more pronounced in low- and middle-income countries because of lack of rigorous enforcement of the environmental protection laws. Furthermore, with the rising concern of AMR, global gross domestic product is anticipated to fall by 3.5%, causing around 28   million people to be slipped under poverty.

The authors felt a need for a comprehensive book to cover all the pertinent issues such as emergence of AMR in livestock, poultry, fishery, agriculture and the environment, as well as the approaches to tackle the issue. The book encompasses the biological properties, genome, antigenic characteristics, toxins and virulence factors, transmission, diagnosis and mechanism of AMR in all the bacterial genera associated with livestock, poultry and fishery. In the other part of the book, the authors narrated mechanism of cross-resistance with biocides, approaches, techniques and pitfalls of antimicrobial stewardship, alternative antiinfective therapy such as bacteriophage therapy, use of enzybiotics, phytobiotics, essential oils, nanomaterials, cellular immunotherapy, immunomodulators and vaccines. Moreover, how to tackle the problem with One Health approach and what are the challenges ahead to successfully combat AMR are incorporated.

We hope the book will cater the need by providing the basic and updated knowledge in AMR domain to the scientists/researchers, students, policymakers and all those common people who like to save our mother earth from the most devastating calamity. Any suggestions from any corner for the betterment of the book will be generously accepted.

Indranil Samanta

Samiran Bandyopadhyay

Kolkata

27 May 2019

Chapter 1

History of antimicrobial resistance

Abstract

This chapter describes definition of antimicrobials and antibiotics, history of chemotherapy, discovery of antibiotics, individual scientific contributions and emergence of antibiotic-resistant bacteria with a historical perspective.

Keywords

Antibiotic; Antimicrobial; Domagk; Ehrlich; Fleming; Swann Report

Definition

History of chemotherapy

Discovery of antimicrobials/antibiotics and individual scientific contributions

Emergence of antibiotic-resistant bacteria historical perspective

References

Definition

• Antimicrobial: Any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of a microorganism but causes little or no damage to the host. It is a broader term and it can be classified into several groups according to the type of microbes on which it acts such as antibiotics (bacteria), antivirals (virus), antifungals (mould and yeast) and antiparasitic (malaria agent). On the basis of mode of action, antimicrobials are either microbicidal (lysis of microbes) or microbistatic (growth inhibition).

• Antibiotic: Low molecular weight substance produced by a microbe that at little concentrations inhibits or kills other bacteria.

History of chemotherapy

First evidence of chemotherapy was noticed in 1899 when Emmerich and Löw prepared extract from Pseudomonas aeruginosa (pyocyanase). The extract was found active against pathogenic bacteria although was toxic to the human cells. During the prechemotherapy (preantibiotic) era, case fatality rate of Staphylococcus- or Streptococcus-associated pneumonia, endocarditis and bacteraemia was 40%–97% (Newman et al., 1954). In First World War (1914–18), 70% of wound infections were treated with amputation as no antibiotic was available (Hirsch, 2008).

Paul Ehrlich (1854–1915, Germany) during his work with dyes noticed that specific aniline dyes can kill a specific group of microbes, not the others. Based on the idea of specificity, Ehrlich began his quest for magic bullet during 1904 to treat syphilis (sexually transmitted disease caused by Treponema pallidum). In Europe and United States, the syphilis was treated with mercury and arsenical compounds which had acute toxicity and poor efficacy. Paul Ehrlich and Alfred Bertheim identified the chemical structure of atoxyl, a less toxic arsenical drug used to treat African sleeping sickness. They started to synthesize numerous derivatives of atoxyl and the arsphenamine derivative (compound 606, Salvarsan) was found effective against syphilis in experimental rabbits, followed by limited human trials (Ehrlich and Halta, 1910). The era of chemotherapy thus began and Ehrlich was awarded with Nobel Prize in 1908 along with Metchnikoff. With the discovery of more antimicrobials (Table 1.1) and their introduction into the clinical practices such as sulphonamides (1935), penicillin (1941), streptomycin (1943), para-aminosalicylic acid (1944) and isoniazid (1952), the annual mortality rate due to infectious diseases decreased rapidly (Armstrong et al., 1999).

Discovery of antimicrobials/antibiotics and individual scientific contributions

William Roberts (1874) observed that Penicillium glaucum (a mould) can inhibit the growth of bacteria. John Tyndall also noted similar observations 2   years later (Roberts, 1874). Alexander Fleming (1881–1955, United Kingdom) discovered the first antibiotic penicillin in 1928. He observed that growth of Staphylococcus aureus was inhibited by a contaminant blue mould (Penicillium) in culture dishes. The observation was converted to the concept that certain microbes produce diffusible substances that can inhibit the growth of other microorganisms. Fleming faced difficulties in purification of the substance extracted from the mould and the substance was unstable. After a decade, the Oxford team led by Howard Florey and Ernest Chain purified the substance (Chain et al., 1940). Penicillin was introduced into the clinical practice during 1940 and as a wonder drug it saved several lives during Second World War. Fleming, Chain and Florey were awarded with the Nobel Prize in 1945. Identification of core structure (6-aminopenicillanic acid) paved the way for development of numerous derivatives such as penicillinase-resistant penicillins (methicillin, oxacillin, nafcillin), aminopenicillins (ampicillin, amoxicillin, bacampicillin), carboxypenicillins (carbenicillin, ticarcillin) and ureidopenicillins (mezlocillin, azlocillin, piperacillin) (Wright, 1999).

Table 1.1

Josef Klarer and Fritz Mietzsch (chemists of Bayer AG, Germany) first synthesized sulphonamide chrysoidine (KI-730, Prontosil), which was tested by Gerhard Domagk for antibacterial activity in animal models (Domagk, 1935). Prontosil was later confirmed as prodrug and its active component sulphanilamide was found to possess antibacterial activity, especially against streptococci. The sulphanilamide compounds were previously used in dye industry and the patent was already expired. Owing to off-patent nature and low production cost, numerous derivatives of sulphanilamide were developed by different companies. Introduction of sulpha drugs into the clinical practice reduced mortality by 2%–3% and increased life expectancy by 0.4–0.7 years (Jayachandran et al., 2010).

René Dubos (1939) first isolated tyrocidine (mixture of cyclic and linear polypeptide) having antibacterial activities (Lipmann et al., 1970). Gause and Brazhnikova (1944) extracted gramicidin S from Brevibacillus brevis and confirmed its antibacterial activities.

Discovery of other major antimicrobials and individual scientific contributions are described in Table 1.1.

Emergence of antibiotic-resistant bacteria historical perspective

Therapy with antibiotics fails when applied to resistant bacteria and it generates worse prognosis. The choice of antibiotic also becomes limited to treat multidrug-resistant organisms. As consequence, major medical advancements such as complex surgery, transplantation and chemotherapy are compromised (Hawkey, 2008). Annual mortality rate due to resistant bacteria is 50,000 each year across Europe and the United States alone, which will reach up to 10 million throughout the world by 2050 (O'Neill, 2014). The resistance is associated with increased resource utilization and cost because of prolonged hospital stay, use of mechanical ventilation, need for intensive care and invasive devices, excess surgery, additional isolation room and gloves, aprons, etc., need for postacute care and loss of man day (Friedman et al., 2016).

Few bacteria are intrinsically resistant to certain groups of antibiotics (e.g., Pseudomonas), whereas others develop resistance during therapy or contact with an antibiotic. The resistance gene can be transmitted through mobile genetic elements such as plasmids, integrons, etc., to other susceptible group of bacteria present in the gut or the environment. Transfer of resistant bacteria to human is a complex and multifactorial issue consisting of foods, water and probably all of the environmental components (Prescott, 2014). Details of resistance mechanism against different antibiotics generated in major bacterial species associated with livestock, poultry, fishery and environment are described in the following chapters. The resistance to antimicrobials is although an evolutionary conserved natural process and is not a new entity. Existence of natural product antibiotics was detected during 2 billion–40 million years ago, which indicates the similar ancient existence of the antibiotic resistance (Hall and Barlow, 2004). The metagenomic analysis of ancient DNA from Beringian permafrost sediments revealed the presence of antibiotic resistance genes against β-lactam, tetracycline and glycopeptides (D'Costa et al., 2011).

Emergence of penicillin-resistant Staphylococcus began in human patients during mid-1940s after the introduction of penicillin (Kirby, 1944). The penicillinase was detected although even before the clinical uses of penicillin (Bolhofer et al., 1960). Penicillin-resistant Staphylococcus became pandemic during 1950–60 with the spread of a specific Staphylococcus clone (phage-type 80/81) (Blair and Carr, 1960). It was followed by the generation of resistance to tetracycline and macrolides in 1950s. Introduction of methicillin (penicillinase-resistant) although cleared the phage type 80/81 from the population, methicillin-resistant S. aureus (MRSA) appeared in 1961 (Barber, 1961). The earliest MRSA strain (COL) was reported from three human patients in Colindale, United Kingdom (Jevons, 1961). Penicillin-resistant Streptococcus pneumoniae strains appeared in the community during late 1970s. Fig. 1.1 describes history of major antibiotic discovery and associated development of resistance.

Figure 1.1 History of antibiotic discovery and associated development of antibiotic resistance.

One of the first reports of antibiotic resistance in livestock was detected in coliform bacteria in turkeys experimentally fed with streptomycin (Starr and Reynolds, 1951). Subsequent studies detected correlation between dietary intake of tetracycline and the generation of antibiotic-resistant streptococci in chicken (Barnes, 1958; Elliott and Barnes, 1959). First report of MRSA infection in animals was obtained from Belgium, which was associated with clinical mastitis in dairy cattle (Devriese et al., 1972).

The first recommendation to prohibit the subtherapeutic use of antibiotics in poultry was discussed in British Parliament during 1969, known as Swann Report (Britain and Swann, 1969). In the United States, the debate to ban the subtherapeutic usage of antibiotics in livestock and poultry began with the Council for Agricultural Science and Technology report (1981). World Health Organization (2000) recommended phase out prohibition of those antibiotics as growth promoters, which are also used in human therapy. Sweden (1986) and Denmark (avoparcin, 1995) are the first countries to ban the subtherapeutic use of antibiotics in livestock and poultry. In 1997, European Union (EU) banned the use of avoparcin as growth promoter in all the member countries. In 1999, EU banned certain antibiotics in livestock and poultry, which are commonly used in human such as tylosin, spiramycin, bacitracin and virginiamycin.

References

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Barber M. Methicillin-resistant staphylococci.  Journal of Clinical Pathology . 1961;14(4):385.

Barnes E.M. The effect of antibiotic supplements on the faecal Streptococci (Lancefield group D) of poultry.  British Veterinary Journal . 1958;114:333–344.

Blair J.E, Carr M. Distribution of phage groups of Staphylococcus aureus in the years 1927 through 1947.  Science . 1960;132(3435):1247–1248.

Bolhofer W.A, Sheehan J.C, Abrams E.L. Totally synthetic penicillins.  Journal of the American Chemical Society . 1960;82(13):3437–3441.

Britain G, Swann S.M.M. Report of the joint committee on the use of antibiotics in animal husbandry and veterinary medicine.  HM Stationery Office . 1969.

Chain E, Florey H.W, Gardner A.D, Heatley N.G, Jennings M.A, Orr-Ewing J, Sanders A.G.Penicillin as a chemotherapeutic agent.  The Lancet . 1940;236(6104):226–228.

Council for Agricultural Science and Technology.  Antibiotics in Animal Feeds . Ames, IA: CAST; 1981 Report 88.

D'Costa V.M, King C.E, Kalan L, Morar M, Sung W.W, Schwarz C, Froese D, Zazula G, Calmels F, Debruyne R, Golding G.B.Antibiotic resistance is ancient.  Nature . 2011;477(7365):457.

Devriese L.A, Damme L.V, Fameree L. Methicillin (Cloxacillin)-resistant Staphylococcus aureus strains isolated from bovine mastitis cases.  Zoonoses and Public Health . 1972;19(7):598–605.

Domagk G. Ein beitrag zur chemotherapie der bakteriellen infektionen.  DMW-Deutsche Medizinische Wochenschrift . 1935;61(07):250–253.

Ehrlich P, Halta S.  Die Experimentelle Chemotherapie der Spirillosen . vol. 8. Berlin: Julius Springer; 1910.

Elliott S.D, Barnes E.M. Changes in serological type and antibiotic resistance of Lancefield group D Streptococci in chickens receiving dietary chlortetracycline.  Microbiology . 1959;20(2):426–433.

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Friedman N.D, Temkin E, Carmeli Y. The negative impact of antibiotic resistance.  Clinical Microbiology and Infection . 2016;22(5):416–422.

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Chapter 2

Use of antimicrobials and antibiotics in livestock, poultry, fishery and agriculture

Abstract

The use of antimicrobials in food-producing animals, especially for growth promotion, has become a hotly debated issue nowadays. In line with the global action plan on AMR, World Health Organization unambiguously recommended discontinuing the use of medically important antibiotics in food animals to preserve the efficacy of antimicrobials critical for human health. Truly speaking, there is a lack of sufficient evidence to link antimicrobials use (AMU) in agriculture with development-resistant bugs in human beings. But then again, use of or exposure to antimicrobials is undeniably the single most important driver for the development of AMR, and with reports of bad bugs coming from animals and aquaculture, need for immediate action to curb AMU in agriculture is more pressing than ever. This chapter tries to elucidate different perspectives of AMU in livestock and aquaculture and possible impacts of AMU in agriculture.

Keywords

AMR; AMU; Aquaculture; Growth promoter; Pig; Poultry

Use of antibiotics in animals and aquaculture – purpose and objective

Recent trends of antibiotic usage – global scenario

Details of the antimicrobials used in poultry

Details of the antimicrobials used in pigs

Details of the antimicrobials used in bovine

Details of the antimicrobials used in aquaculture

AMU in agriculture – current and future possible impacts

References

Use of antibiotics in animals and aquaculture – purpose and objective

There is no denying that livestock sector across the globe has witnessed a stupendous growth with a gradual but steady shift towards intensive farming practices, in recent years, only to meet the ever-increasing demand for animal protein for the growing world population. Increasing animal density, overcrowding, rapid urbanization, and deforestation, shrinkage of arable or grazing land – all are crucial to bringing a drastic and often irreversible change in the ecosystem, thereby rising infections and health problems in animals. As a consequence, the use of antibiotics has also been increased as the food animals in such environment demand aggressive health management that their production performance is maintained and preserved (Guardabassi, 2013; Magouras et al., 2017). Nevertheless, little information is available regarding the quality and quantity of antibiotic prescribed in animal sector, particularly in the developing and underdeveloped countries and that constitutes the major barrier for successful implementation of the antibiotic stewardship programme. In many countries, the surveillance system to monitor the antibiotic consumption, particularly in agriculture and animal sector, is not strong enough or nonfunctional. Even in many developed countries, such monitoring system started to function in full strength very recently. Thus, inadequacy of reliable data and the paucity of information are the major deterrent to provide an illustration of antimicrobials use (AMU) and in agriculture, animals and aquaculture sector.

Broadly, antibiotics are used in livestock or food animals for three purposes (Magouras et al., 2017; Van Boeckel et al., 2015; Landers et al., 2012):

(1) Therapeutic or curative treatment: This is conducted for the treatment of sick/diseased animals, to be particular, of animals exhibiting obvious clinical symptoms.

(2) Control treatment or metaphylaxis: Usually after the occurrence of disease/infection in a part of a group/herd or flock, this treatment protocol is followed with an objective to reduce the spread of infection to other animals at risk and also to reduce morbidity in animals already incubating the disease (Done et al., 2015; Checkley et al., 2010; Baptiste and Kyvsgaard, 2017).

(3) Prophylactic or preventive treatment: This is followed in an animal or a group of animals, before onset or indication of any clinical sign of infectious disease to prevent such occurrence (Checkley et al., 2010; Baptiste and Kyvsgaard, 2017).

(4) Nutritional treatment: In intensive livestock farming, it is not unusual to use antibiotic or antimicrobial agents as a growth promoter when antibiotics are used in subtherapeutic concentration. It is believed to improve feed conversion ratio by affecting the gut flora (Lee et al., 2012; Dibner and Richards, 2005).

Roughly, there are three avenues of antimicrobial uses in animals without any identifiable infectious illness. Landers et al., 2012, illustrated such nontherapeutic use of antibiotics using the data available for AMU in food animals in the United States (Landers et al., 2012). While 16% of the lactating dairy cattle in the United States were reported to receive antibiotics for clinical mastitis, the intramammary antimicrobial infusion was advocated for almost all dairy cattle as a prophylactic measure in the form of penicillin or other β-lactam drugs. In a similar way, about 10% of the beef feedlot cattle received antibiotic despite being healthy to prevent respiratory illness. About 42% of beef calves were reported to be treated with macrolide – tylosin to prevent liver abscess. Tylosin and tetracyclines were common antibiotics used as feed additives in 88% of the growing pigs in the United States for preventive or growth promotion purpose. Data suggested superfluous use of antibiotics in agriculture intended for nontherapeutic consumption. In the United States, about 74% of farm-animal received antibiotics in feed and 21% in drinking water (Anonymous, 2017). More importantly, the report stated that the sale of medically important antibiotics was three times higher in the animal sector than in human beings. In China, approximately 46% of 210,000 tons of antimicrobial produced was intended for consumption in animals (Li, 2017). Preventive use of antibiotics is not only intended for animals at risk but also during the impending stress of the animals because of weaning, prolonged transportation, confinement or over congestion (Anonymous, 2013a). There is no established recommendation for such prophylactic or metaphylactic use of antibiotic and concerned farm manager or veterinarians use their own dose or duration schedule based on his own experience. Many times, such nontherapeutic use is overseen by the concerned veterinarian. Thus, region-wise variation may be noted for this kind of nontherapeutic use of antibiotics.

For production purpose, the antibiotics are given in feed or water to promote faster growth. However, there is little scientific understanding of how antibiotics increase FCR (feed conversion ratio) and promote growth. It is thought that antibiotics in subtherapeutic dose modulate the gut microbiome, body metabolism, and adiposity resulting in higher body mass (Costa et al., 2017; Hughes and Heritage, 2004). Reduction of gastrointestinal infection is believed to mask the effect of catabolic hormone leading to increased body weight. Moreover, the effect of such growth promoter being more conspicuous in sick animals than in the healthy animals had led to the presumption that such growth promotion in animals was possibly mediated by reduction of infection burden (Hughes and Heritage, 2004). With burgeoning evidence of antimicrobial resistance in food animals, however, the use of antibiotics as growth promoter has no longer been permitted by the FDA since January 2017 (Siegner, 2019). They implemented a voluntary plan for the livestock industry to phase out such use for growth promotion. European countries also took such an initiative to curb the use of antibiotics in food animals, long before. Use of antibiotics as growth promoter was first prohibited by Sweden in 1986 followed by Denmark, the United Kingdom and other countries. All these countries have their own mechanism and monitoring system to review the trend of antimicrobial resistance and use in animals.

Recent trends of antibiotic usage – global scenario

In the human sector, few studies were conducted to reflect the global picture of antibiotic usage. Global Point Prevalence Survey (Global-PPS) of Antimicrobial Consumption and Resistance was conducted in 2015 to assess the international prevalence of antimicrobial use and resistance, with an emphasis on countries with low resources, support and expertise. The study based on data from 303 hospitals in 53 countries including 8 lower-middle-income and 17 upper-middle-income countries revealed that 34.4% of the inpatients of adult wards received at least one antimicrobial. The most frequently prescribed antimicrobials include penicillins with β-lactamase inhibitors, third-generation cephalosporins and fluoroquinolones in the most part of the globe. However, in Latin America, west and central Asia, carbapenems were most frequently prescribed. The study further pointed out the inherent weakness in the antimicrobial-consumption monitoring system in lower- and middle-income countries because of unavailability of proper tools to appraise antibiotic prescribing in hospitals, even in the human sector (Versporten et al., 2018). From such an observation, we can easily assume the status of such monitoring system in the animal sector in those countries. Very recently, the global trend in antimicrobial consumption in food animals was illustrated by Boeckel and co-workers (Van Boeckel et al., 2015). The workers estimated global average annual consumption of antimicrobials per kilogram of animal produced was 45   mg/kg, 148   mg/kg, and 172   mg/kg, for cattle, chicken, and pigs, respectively. Global consumption of antibiotic was projected to rise by 67% to reach 105,596 (±3605) tons in 2030 from 63,151 (±1560) tons in 2010. Although 66% of such drastic increase was attributed to the increased number of animals for food production, about 34% was only due to the shift towards intensive farming practices, particularly in middle-income countries. Asia alone is likely to see a 46% increase in antimicrobial consumption by 2030 to reach 51,851 tons, representing 82% of the current global antimicrobial consumption in food animals. This is possibly because of increased antibiotic consumption in the poultry and piggery sector where the same is expected to grow by 129% and 124%, respectively, by 2030. In a revised estimate, the authors predicted an approximate increase of 53% in global antimicrobial consumption in food-producing animals between 2013 (131,109 tons) and 2030 (200,235 tons) (Van Boeckel et al., 2017). Only in the BRICS countries, antibiotic consumption in food animals is expected to rise by 99% by 2030. The problem is likely to be more intense in low- and middle-income countries where the demand of animal-source protein is anticipated to be higher, about 725% increase in demand for poultry consumption being projected only in South Asia (Schar et al., 2018). In all, it is no less than a wake-up call for us to take initiatives to optimize the use of antibiotics in food animals so as to preserve their efficacy.

The exact data on AMU in food animals are not available from all countries. However, the sporadic figures are quite alarming. In 2012, in the United States, the AMU in food animals (32.2 million pounds/14.6 million kg) was more than four times higher than that in human (7.25 million pounds/3.29 million kg). Of all the antimicrobials sold for use in animals, majority belonged to tetracycline (12,439,729 pounds), penicillin (1,940,424 pounds), macrolides (1,284,931 pounds), sulphur drugs (817,958 pounds), aminoglycosides (473,761 pounds), lincosamides (419,100 pounds) and cephalosporins (58,667 pounds) and other compounds such as aminocoumarins, amphenicols, diaminopyrimidines, fluoroquinolones, glycolipids, pleuromutilins, polypeptides, quinoxalines and streptogramins (in total, 3,330,237 pounds). Most of these antibiotics (94%) sold for use in food animals were intended to be delivered through feed formulation or water; only 4% of the antibiotics were sold to be used in the injectable form. More importantly, many of these antimicrobials including those which are also considered to be highly or critically important in human medicine (macrolides, streptogramins and tetracyclines) were possibly sold over the counter without any prescription or veterinary oversight. Furthermore, the FDA report reads that nearly 70% of the 25 million pounds of medically important antibiotics sold for any purpose was consumed by food-producing animals (Basri, 2017). Of this, 43% was intended for use in cattle, 37% intended for use in swine, 9% intended for use in turkeys, 6% intended for use in chickens and 4% intended for use in other species/unknown. In the United States, medically important antibiotics approved for use in both food and nonfood-producing species include ceftiofur, lincomycin, ampicillin, penicillin, polymyxin B, sulfamethazine, chlortetracycline and oxytetracycline, which constituted about 60% of the domestic sales of all antimicrobials approved for use in food-producing animals (in 2016). The highest distribution and sell was recorded for tetracycline (70%), followed by penicillins (10%), macrolides (7%), sulfonamides (4%), aminoglycosides (4%), lincosamides (2%), fluoroquinolones (≤1%) and cephalosporins (<1%). Among these antibiotics, while cephalosporin was mostly intended for use in cattle (80%), lincosamide (83%) and macrolide (61%) were intended for swine. About 72% of these antibiotics were designed for use as a feed additive, 23% to be in the water and only 5% was to be used by injection, intramammary, oral and topical route. The nonmedically important drugs, which accounted for 40% of the domestic sales of all antimicrobials approved for use in food-producing animals, were mostly comprised of ionophores. Of antimicrobials belonging this group, 55% were intended for use in cattle, 30% intended for use in chickens, 8% intended for use in swine and 7% intended for use in turkeys, as the FDA report stated. In total, 13,983,016   kg of the antimicrobial active ingredient was sold and distributed for use in food animals in the United States in 2016, of which medically important antibiotics shared 8,361,740   kg and nonmedically important class shared 5,621,276   kg. Timeline analysis during past 10 years (2009–16) showed a marginal increase (9%) in sales and distribution (domestic and export) of antimicrobials approved for use in food-producing animals; nevertheless, it decreased by 10% in 2016 when compared with that in 2015. A recent report given by the Natural Resources Defense Council in 2018 indicated that nearly 27.1% of all medically important antibiotics sold in the United States are used in piggery sector despite the initiative taken by the FDA to ban the use of antibiotics as a growth promoter in January 2017 (Wallinga, 2018). This is in stark contrast to data revealed from Denmark and the Netherlands where antibiotic use in pig production has fallen by 27% and 57%, respectively, since 2009.

During 2017, total quantity of active ingredient of antibiotic sold was about 282 tonnes, of which 72% was indicated for animal consumption in the United Kingdom. Thus, the consumption in animals has recorded a decrease of 35% from 2013 (436 tonnes) as per the report published by UK-VARSS 2017 (Peter Borriello, 2017). In animals, total sale of antibiotics was about 37   mg/kg when adjusted for animal population, which is a substantial drop from what sold in 2013 (40%). Species-wise, the majority of the antibiotics sold were indicated for use in pig and poultry (52%) followed by cattle (5.6%) and fish (1.2%). About 9.5% of the antibiotics were sold for use in nonfood animals. Among the various class of antibiotics sold during that period, tetracycline represented the major proportion (∼37%) followed by β-lactams (∼28%), trimethoprim/sulphonamides (11%), aminoglycosides (8.5%), macrolides (8.15%) and other antibiotics. In spite of the ban on antibiotic as a growth promoter, the premix route of administration remained the most common, accounting for 38% of all antibiotics sold in 2017. Nevertheless, the sale of critically important antibiotic (CIA) was reduced by 52%, since 2013. Antibiotic usage was about 131   mg/kg in pig production in 2017 and the total use was mostly represented by tetracycline (45%) followed by penicillins (17%), trimethoprim/sulphonamides (16%), macrolides (12%) and others. In comparison to 2015 (278   mg/kg), antibiotic use was dropped by more than 50% in 2017.

Since its inception in 1995, Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) is instrumental to monitor trends in resistance among bacteria from animals, food and human, to monitor the consumption of antimicrobial agents, to determine the association between consumption and occurrence of resistance and to model transmission of resistance from animals to humans. Following discontinuation of antibiotics as growth promoter during 1994–99 in Denmark, the total antibiotic consumption in animals was decreased by 49% in 2016 than that in 1994, and as per the recent report of DANMAP-2016, the total antibiotic consumption in animals was estimated to about 104.4 tonnes active compound. Majority of the antibiotics was used in pigs (75%), followed by bovine (12%), fur animals (5%), poultry (2%), fish (2%), pet animals and horses (1% each) (Birgitte Borck and Korsgaard, 2016). For the piggery sector, the antibiotic consumption was decreased by 27% from 2009 to 2016 with a reduction in the use of tetracycline, pleuromutilin, and β-lactamase sensitive penicillin. Use of tetracycline alone dropped by 35% during this period, the report said. The use of CIA such as fluoroquinolone and cephalosporins was negligible in 2016 in Denmark. In contrast, use of colistin in pigs was increased by more than twofold during this span (864   Kg in 2016 from 409   Kg in 2009) – which may have potential public health implication as colistin is considered as last resort for treating human patients with carbapenem-resistant infection. Antibiotic consumption was considerably dropped also in cattle during this period. Interestingly, there was no record of the use of fluoroquinolone and approximately 11   kg of cephalosporins was used, of which higher generation cephalosporin constituted only negligible proportion. Use of cephalosporins was decreased by 83% in 2016 when compared with that in 2008. Importantly, use of intramammary antibiotic infusion was also restricted with initiatives from the Danish Agriculture and Food Council. In general, antibiotic consumption is low in the poultry sector in Denmark possibly because of the very high level of biosecurity in Danish poultry farms. Tetracycline and amoxicillin were the more frequently used antimicrobials in poultry in Denmark, as indicated in the report of DANMAP, 2016.

Swedish Antimicrobial Resistance Monitoring Programme (SVARM) has also been operational to monitor the use of antibiotics in animals, since long. The recent report from SVARM revealed that about 10,310   kg of antibiotics was sold for animals in 2017 against 16,364   kg in 2008 and this 37% drop in antibiotic sell could be attributed to the stringent antibiotic stewardship programme in Sweden, which restricted the use of CIA in the animal sector with increasing awareness among the prescribers. Sales of the CIAs such as cephalosporins, fluoroquinolones and colistin were dropped by 89%, 84% and 46%, respectively, since 2008 (OlssonAspevall, 2017).

There are sporadic reports on the use of antibiotics in animals from different countries. In 2013, Chinese Academy of Science reported that 162,000 tons of antibiotics are consumed in China each year, of which 52% was intended for food animals (Yu et al., 2019). The large-scale antibiotic consumption could be attributed to the pork industry in China. The situation is alarming as a recent report from China predicted that typical swine farms with the feedstock of 10,000 pigs could release about 4.0   ±   1.3×10¹⁷ gene copies of ARGs (antibiotic resistance genes) per day (Zhang et al., 2019). Again, Krishnaswamy et al., 2015 reported that about 38.5 million kg [84.9 million lbs] of antimicrobials were used in China's production of swine and poultry in 2012. While slightly more than 4.5 million kg [9.9 million lbs] of antimicrobials were used in poultry production, the figure is about 34 million kg [75 million lbs] in pigs. Group-wise, tetracycline and coccidiostats were frequently used in pigs and poultry, respectively (Krishnaswamy et al., 2015). In 2016, Chinese authority pushed for a reduction in antibiotic use in the animal sector and set a target to be achieved by 2020. Like in China, pig (392–423 mg/kg) industry was found to be the highest consumer of antibiotics in Japan, followed by beef cattle (45–67   mg/kg), broiler chickens (44–63   mg/kg) and dairy cattle (33–49   mg/kg). In 2013, 780.88 tons of active ingredients were sold for animal consumption of which tetracycline constituted the largest share (43.5%–46.2%). However, the medically important drugs such as third-generation cephalosporins and fluoroquinolones accounted for less than 1% of overall sales (Anonymous, 2017).

Details of the antimicrobials used in poultry

The use of antimicrobials in food-producing animals, especially in poultry, is a highly debated issue in current days. Other than its use in the treatment of the sick birds, antibiotics are also used in for a prophylactic or metaphylactic purpose and its use as a growth promoter is highly controversial. Birds have their unique physiological properties to impact drug absorption and distribution (Landoni and Albarellos, 2015). The crop of chicken influences the temporal pattern of drug absorption because of its acidic pH (4.5) and for being the storehouse of bacteria such as Lactobacillus spp. Tetracycline groups of drugs generally precipitated in crops of pigeons (pH 6.3) or turkeys (pH 6); however, in chickens, such precipitation is not common, thanks to the acidic pH. Conversely, the flora of chicken crop may interfere with the absorption of antibiotics belonging to macrolide–lincosamide–streptogramin (MLS) groups. In adult chicken, intestinal flora also contains a large number of Lactobacillus spp. In addition, efflux pumps (P-glycoprotein) and cytochrome P-450 enzyme (especially CYP3A), the enzymes responsible for the biotransformation of many drugs including antimicrobials in the enterocytes, reduce the bioavailability of many antimicrobials such as fluoroquinolones, oxytetracycline, doxycycline and MLS either because of rapid metabolism or interference in their absorption. Bioavailability of drugs in poultry is always compromised because of reduced glomerular filtration rate combined with low or absent tubular reabsorption.

In an effort to ensure rational use of antibiotic in the broiler industry, British Poultry Council's (BPC) antibiotic stewardship has been in place, since 2011 in the United Kingdom. About 82% of the total antibiotics used in poultry meat sector in the United Kingdom in 2016 were contributed by amoxicillin (44%) and tetracycline (38%). A number of measures taken up under this programme including a complete ban on colistin use (in 2016), stoppage of prophylactic use of antibiotics and use of fluoroquinolone and macrolides only as last resort – all resulted in 71% reduction in the total use of antibiotics from 2012 to 2016 (Anonymous, 2019). This pointed out the importance of stewardship programme in reducing the unnecessary use of antibiotics (Table 2.1).

Table 2.1

¹  Banned in India since 2018

Details of the antimicrobials used in pigs

For pigs, antibiotic consumption is relatively higher in pork-eating countries. In OECD countries, antimicrobial consumption per population correction unit (PCU) is much higher in pigs (172   mg/PCU) and poultry (148 mg/PCU) than in cattle (45 mg/PCU) (Gonzalez Ronquillo and Angeles Hernandez, 2017). In 2015, total AMU in the UK pig industry was about 200 tonnes, i.e., 260   mg per kg PCU – five times higher than in Denmark (46   mg/kg PCU) and the Netherlands (53   mg/kg PCU) and about 25 times higher than in Sweden (11   mg/kg PCU) (Rose and Nunan, 2016). In low- and middle-income countries, AMU was greatest in chickens (138 doses/1000 animal-days [interquartile range (IQR) 91.1–438.3]), followed by swine (40.2 [IQR 8.5–120.4]) and dairy cattle (10.0 [IQR 5.5–13.6]). However, for per kg of meat produced, AMU was the highest in swine, followed by chickens and cattle (Cuong et al., 2018). China is the largest producer and consumer of pig, and use of antibiotics in pig rearing in China has remained a much discussed and debated issue since the detection of plasmid-mediated colistin resistance gene (mcr-1) linked by many to the use of colistin as a feed additive in the porcine ration. Various studies indicated the use of antibiotics as feed additives in the majority of the pig rations, and prophylactically, antibiotics are often given to the herd rather than to the individual animal (Anonymous, 2013b). Apart from it, antibiotics are also used for the treatment of diseases such as enzootic pneumonia, Streptococcus suis, mycoplasma infections and swine dysentery (Table 2.2).

Details of the antimicrobials used in bovine

In dairy cattle, antibiotics are mostly used for the treatment of infections of which mastitis obviously comes first. In mastitis, antibiotics are often used prophylactically in the form of intramammary infusion, as dry cow therapy. Apart from it, antibiotics are often prescribed in metritis through the systemic or intrauterine application. Other bacterial diseases also warrant the need for antibiotics. In the face of outbreaks, farmers in consultation with veterinarians often prefer to keep their unaffected stocks under antibiotic therapy to prevent the spread of infection among healthy stocks. Some viral infection also requires antibiotic therapy to keep away the secondary infections. The most crucial factor which is frequently overlooked by the farmers or veterinary doctors is the actual body weight of the animal while prescribing or dispensing the antibiotics. Particularly at the field, body weight is often determined based on visual estimation, which is erroneous and eventually leads to overdosing/underdosing of the drugs. Such underdosed application runs the risk of being ineffective to cure the animals. On the other hand, overdosing may lead to toxicity. Besides, the resistant pathogens are likely to survive and propagate in more number in such cases. Therefore, antibiotics in bovines should always be given with adequate care such as to ensure proper dosing and duration. However, in feedlot cattle intended for beef production, antibiotics are given in premix feed often with an intention to increase FCR and body weight (Table 2.3).

Details of the antimicrobials used in aquaculture

As is the case in terrestrial animals, aquaculture has also been shifted towards intensification to meet the ever-increasing demand for human need. In parallel, the need for antibiotics is also increasing as a part of an aggressive disease management strategy. A survey conducted by the FAO in different countries revealed that 60 different veterinary medicine ingredients including 26 antibiotics are used in aquaculture. The antibiotics used in aquaculture belonged to a diverse group – β-lactam, nitrofurans, phenicols, macrolides, quinolones, sulphonamides, rifampicin and tetracycline. Studies conducted by the FAO revealed that oxytetracycline is the most frequently used antibiotic in aquaculture. The workers further emphasized that besides prophylactic uses, antibiotics are abused or overused because of improper diagnosis (Gonzalez Ronquillo and Angeles Hernandez, 2017). The use of antimicrobials is mainly intended for various fish diseases such as cold water diseases rainbow trout fry syndrome, bacterial kidney disease, enteric redmouth disease, furunculosis, piscirickettsiosis, bacterial gill disease, vibriosis, epitheliocystis, tenacibaculosis, rainbow trout gastroenteritis, red mark syndrome or cold water strawberry disease, etc. (Sekkin and Kum, 2011). Although data on the kind of antibiotics used in different countries are not available, most of the counties including many European countries use at least two CIAs in fish farming – tetracyclines and oxolinic acid, a third-generation quinolone. Studies pointed out wide variation in AMU ranging from 1   g per metric ton of production in Norway to 700   g per metric ton in Vietnam depending on the local or national regulation and government policies in this sector (Towers, 2014). An appreciable body of evidence suggested the metaphylactic use of antibiotics in aquaculture which is largely debated because it requires protracted antibiotic therapy in subtherapeutic concentration in the healthy fishes along with sick one, which is ineffective to completely clear out the infection, and the drug resistance is more likely to emerge (Towers, 2014) (Table 2.4).

Table 2.2

∗  Banned in the United States in 2016.

b  Banned in India in 2018.

Table 2.3

a  Extra-label use of aminoglycosides is prohibited in many countries for its propensity to accumulate in the kidney for a lasting period.

Table 2.4

AMU in agriculture – current and future possible impacts

Although the use of an antimicrobial is regarded as the most important and crucial driver for the emergence of AMR, it is not very easy to understand and decipher how the use of antimicrobial in agriculture can impact human health. Moreover, we are yet to quantify the share of resistance burden of the public health that could be attributed to AMU in agriculture.

Landers et al., 2012, rightly, pointed out various complex interaction of elements in the physical environment (e.g., air, soil and water), social exchanges (e.g., between animals within a herd, farmers and animals, and domestic poultry and migratory birds), in processing steps (e.g., farming activities, transportation and storage) and in human use patterns (e.g., food