Antimicrobial Resistance: A Serious Threat to Human, Animal and Environmental Health

Antimicrobial Resistance: A Serious Threat to Human, Animal and Environmental Health

Anil Kumar Mishra, K Gururaj, Rajpal Diwakar and Nitika Sharma

Introduction

Antimicrobial resistance (AMR) is a state or condition when a pathogen (especially bacterium) develops the ability to survive exposure to antimicrobial agent/s designed to kill them or stop their growth. In other words, the ability of microorganisms (especially bacteria) to resist treatment by antimicrobial/s is called antimicrobial resistance (Laloučková and Skřivanová, 2018). AMR is posing a serious threat to human, animal and environmental health worldwide. The problem of AMR is increasing day by day, and now we can say that we are living in an era of AMR. The continuous increase in AMR and little progress in developments of new antimicrobials are posing major threat to human and animal health, which causes a higher rate of treatment failure, increased infection rate, enhanced severity of infection, and a rising occurrence of infections that would otherwise not have emerged in animals and humans (Honert et al, 2018). We are moving towards ‘post-antibiotic era’, where the diseases caused by the resistant microbes would become untreatable with commonly available antimicrobials (Capita et al., 2016). Due to AMR, around 7 lacs people die every year and it is estimated that approximately 10 million lives will be lost by 2050 (Taneja & Sharma, 2019). AMR alone kills more people than that of cancer and road traffic accidents combined together (O’Neill, 2016). AMR would decrease the gross domestic product and the livestock population of the globe by 2-3.5 percent and 3-8 percent, respectively by 2050 (O’Neill, 2014). In economic term, the world would lose USD100 trillion by 2050 (O’Neill, 2014). The global rise of AMR has attracted the attention of World Health Organization (WHO) and several other stakeholders such as The World Organisation for Animal Health (OIE), Centers for Disease Control and Prevention (CDC, USA), Indian Council of Medical Research (ICMR, India), Indian Council of Agricultural Research (ICAR, India) etc.  Many countries including India have framed their ‘National Action Plans’ to control/prevent AMR. ICAR is also working on AMR in collaboration with Food and Agriculture Organization (FAO) under the programme entitled “ICAR-FAO Network Programme on ‘Indian Network for Fishery and Animals Antimicrobial Resistance (INFAAR)”. It is obvious that sincere efforts are being taken against this common and dangerous enemy of humans, animals and environment all over world. It is well established fact that AMR is a multi-faceted problem and its containment requires multi-pronged approach (Taneja & Sharma, 2019). That is why; the One Health approach is gaining momentum, which highlights importance of the inter-relatedness among human health, animal health and environmental health.  Like other countries, the problem of AMR in the above sectors is increasing at an alarming rate in the past 20-30 years (Kahn, 2017). For the effective control and prevention of AMR, it is important that due consideration must be given to animal as well as environmental health. Most of the scientific reports focus on AMR related to human health whereas research work on AMR with special reference to animal health and environmental health is largely remained neglected so far (WHO, 2016). In India, there is lack of sufficient research work on AMR. Of the 2152 scientific articles published by Indian researchers on AMR, 48.3% (1040/2152) were on humans, whereas only 4.2% (90/2152) on environment and 3.3% (70/2152) on animals, and 0.5% (11/2152) on One Health. The environmental factors/conditions that drive AMR, varies considerably amongst various geographical areas of the world. Hence, guidelines or directions issued to contain AMR by one country/region may not be applicable to other country/region. In this article, we will discuss causes and mechanism of AMR, principal health-threatening bacteria and guidelines/directions to contain AMR.

Causes of AMR

• Selective Pressure: Upon treatment with an antimicrobial, microbes are generally killed, and if, they carry resistance genes, they survive. The population of such strains increases very fast and their progenies quickly become the dominant type amongst the microbial population.
• Mutation: In general, the microorganisms divide rapidly, and adapt quickly to new environmental conditions. During the division, mutations may occur, and few of them may help an individual microbe to resist the antimicrobial therapy.
• Gene Transfer: Microbes that have drug-resistant genes may transfer these genes to other bacteria via several ways. Non-resistant microbes receive the new gene/s, and become resistant to antimicrobial/s. Thereafter, the resistant microbes multiply and thrive.
• Inappropriate Use: Underdosing, overdosing, improper time interval between the therapeutic doses and inappropriate duration of treatment may induce AMR.
• Inadequate Diagnosis: Due to incomplete or imperfect or wrong diagnosis, a clinician may prescribe a wrong antimicrobial or a broad-spectrum antimicrobial when use of a specific antimicrobial might be better. These conditions may lead to selective pressure, and in turn, it may enhance AMR.
• Antimicrobials as growth promotor or as feed additive: When antimicrobials are used as growth promotor or as feed additive, there is heavy probability of development of AMR amongst the microbial pathogens present in the environment, animals and humans.
• Antimicrobials as contaminants in the environment and food/feed/fodder: Currently, almost all environmental entities (water, soil etc.), food, fodder, feed etc. contaminated with antimicrobials, which causes emergence of AMR amongst the microbial pathogens present in the environment, animals and humans.

Principal Health-Threatening Bacteria

Currently, there are no commercially available antibiotics at disposal that do not show any resistance pattern against at least a single microorganism (Cushine and Lamb, 2011). The WHO identified the following drug-resistant bacteria that pose the greatest threat to human health:

1. Carbapenem resistant Acinetobacter baumannii
2. Carbapenem resistant Pseudomonas aeruginosa
3. Extended-spectrumβ-lactamase-producing (carbapenem resistant) bacteria of Enterobacteriaceae
4. Vancomycin resistant Enterococcus faecium
5. Methicillin/Vancomycin resistant Staphylococcus aureus
6. Clarithromycin resistant Helicobacter pylori
7. Campylobacter
8. Fluoroquinolone resistant Salmonellae
9. Cephalosporin/Fluoroquinolone resistant Neisseria gonorrhoeae
10. Penicillin-non-susceptible Streptococcus pneumoniae
11. Ampicillin resistant Haemophilus influenzae
12. Fluoroquinolone resistant Shigella

Emergence of resistance to multiple antimicrobial agents in pathogenic microbes has aggravated the problem of AMR to an extreme level, as there are fewer, or even sometimes no, effective antimicrobial agents available for treatment against the infections caused by the above pathogens (Magiorakos et al, 2012). This group contains multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) isolates/strains of microorganisms, especially bacteria (Magiorakos et al, 2012). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR (microorganisms) was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories (Magiorakos et al, 2012). The emergence of MDR bacteria is responsible for 15.5% hospital born infections in the world (Mulani et al, 2013). A group of bacteria which is called ESKAPE pathogens are responsible for majority of nosocomial infections, and are capable of “escaping” the biocidal action of antimicrobial agents (Navidinia, 2016). The term “ESKAPE” contains six bacterial pathogens with growing multidrug resistance and virulence: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. (Rice, 2008). The WHO has included these pathogens in the list of drug-resistant bacteria that pose the greatest threat to human health (Tacconelli et al, 2018). WHO describes three categories of bacterial pathogens namely critical, high and medium priority, according to the urgency for development of new antibiotics (Mulani et al, 2019). Carbapenem resistant A. baumannii, P. aeruginosa, extended spectrum b-lactamase (ESBL) or carbapenem resistant K. pneumoniae and Enterobacter spp. are grouped in the critical priority list of pathogens. Vancomycin resistant E. faecium (VRE) and methicillin/vancomycin resistant S. aureus (MRSA and VRSA) are kept in the list of high priority group. Clarithromycin resistant Helicobacter pylori, Campylobacter spp., Fluoroquinolone resistant Salmonellae, Cephalosporin/Fluoroquinolone resistant Neisseria gonorrhoeae, Penicillin-non-susceptible Streptococcus pneumoniae, Ampicillin resistant Haemophilus influenzae, Fluoroquinolone resistant Shigella spp.  come under the list of medium priority.

Mechanisms of AMR

The microorganisms show following types of resistance to antimicrobials (Cesur and Demiröz, 2013):

1. Natural or Intrensic or Structural Resistance
2. Acquired Resistance

Natural Resistance: Natural resistance is caused by the structural characteristics of bacteria and it is not associated with the use of antibiotics. It has no hereditary property, and develops as result of the natural or structural resistance (Cesur and Demiröz, 2013). Mycoplasma, Ureaplasma and L-form of bacteria which are wall-less in nature, and are naturally resistant to beta-lactam antibiotics, because these antibiotics inhibit synthesis of the cell-wall.

Acquired Resistance: This type of the resistance occurs due to change in genetic material of the microorganism, which may be chromosomal or extrachromosomal (plasmid, transposon etc.) in origin. Chromosomal resistance arises due to mutations in bacterial chromosome (spontaneous). Various physical and chemical factors may induce mutations leading to structural changes in bacterial cells. Chromosomal resistance generally does not pose serious threat to health of man, animals and environment (Yüce, 2001). Extrachromosomal resistance is caused by change in genetic material of extra-chromosomal origin such as plasmids etc. Transduction (via bacteriophages), transformation, conjugation and transposition are the mechanisms, which are responsible for extrachromosomal resistance. This type of resistance (MDR/XDR/PDR) poses severe threat to all three health sectors (human, animal and environment).

Challenges of AMR in India

India has been referred to as ‘the AMR capital of the world’ (Chaudhry et al, 2017). Emergence of MDR, XDR and PDR organisms are posing therapeutic challenges. Consumption of antibiotics has been increased excessively due to illiteracy, wide availability of illegitimate antimicrobials, lack of adequate knowledge regarding the rational use of antibiotics etc (Bate et al, 2009; Goswami et al, 2013). Lack of awareness about infectious diseases of humans and animals amongst the common people and inaccessibility to healthcare (both animals and man) lead to self-prescription of antimicrobial agents without any professional knowledge regarding the dose and duration of treatment (Morgan et al, 2011). Due to inaccessibility to healthcare, general public is trapped by quacks, which use antimicrobials indiscriminately along with under dosing, over dosing, improper time interval between two doses and improper duration of the therapy. Due to lack of proper diagnostic facilities for identifying the pathogen and its drug susceptibility, the registered medical as well as veterinary practitioners prescribe the broad-spectrum high-end antimicrobials, which may induce AMR amongst the pathogens. Poor availability of doctors (veterinary/medical) as well as paramedical staff and lack of infection, prevention and control guidelines are helping in the spread of resistant pathogens in public, animals and environment (Swaminathan et al, 2017). Easy availability of over-the-counter antibiotics/antimicrobials has further aggravated the problem of AMR (Bate et al, 2009). The pharma companies generate excessive waste containing antimicrobials and due to lack of strict regulations, the antimicrobials reach the water bodies/soil with waste and this contamination of water bodies/soil serves as a continuous source of AMR in the environment, humans and animals (Lundborg et al, 2017).

Initiatives for Containment of AMR

AMR was recognized as a serious public health threat by WHO in 2011 (World Health Organization, 2011). “Jaipur Declaration” was announced to take intensive measures on AMR in the meeting organized by The South East Asian Regional Office (SEARO) at Jaipur, Rajasthan (India) in 2011. The WHO in 2014 reported that AMR was rampant in India with the extraordinary rates. The collaborative efforts were initiated after this report by India and WHO; the Indian Medical Association (IMA) launched an awareness programme to train the doctors, and sensitize the common people (Jha, 2014). In 2015, WHO projected the concept of One Health to fight against AMR and a Global Action Plan was launched (WHO, 2017). India and other member countries agreed to frame their own National Action Plans (NAPs) for AMR by 2017. The Government of India framed its own NAP in 2017 having six strategic priorities. Each strategic priority is comprised of the defined interventions, activities and outputs, the fulfilment of which is delineated by a timeline projected for the next five years, that is, 2017-2021. To prevent the rampant over the counter sale of antimicrobials, the Central Drugs Standard Control Organization implemented Schedule H1 in India in 2014, which includes only few selected antimicrobial groups (Laxminarayan et al, 2016). In June 2017, the Food Safety and Standards Authority of India (FSSAI) published the list of maximum residue levels for antimicrobials in foods prepared from animal, poultry and fish, by which the sale of food having higher amount of antimicrobials can be checked (FSSAI, 2017). Indian Council of Medical Research (ICMR) and the National Centre for Disease Control (NCDC) launched AMR surveillance networks in 2013 and 2014, respectively (Swaminathan et al, 2017). ICMR and NCDC in collaboration with Centers for Disease Control and Prevention (CDC), USA initiated a systematic assessment of the prevailing Infection, Prevention and Control practices in India for drafting new guidelines for preventing healthcare-associated infections. Regarding AMR issue, the National Health Policy-2017 issued the following statement- ‘a rapid standardization of guidelines regarding antibiotic use, limiting the use of antibiotics as OTC medications, banning or restricting the use of antibiotics as growth promoters in animal livestock, and pharmacovigilance including prescription audits inclusive of antibiotic usage-in the hospital and community’ (MoHFW, 2017). ICAR in collaboration with FAO launched Network Programme on ‘Indian Network for Fishery and Animals Antimicrobial Resistance (INFAAR)” in 2018. ICAR institutes (Animal Science and Fishery Institutes) and State Agricultural/Veterinary Universities are participating in this programme. Currently, Staphylococcus and E. coli are being targeted for AMR in animals under INFAAR.

General Guidelines/Future Directions

• Dissemination of information on AMR to the masses at the community level must be done. Educational bodies, non‑governmental organizations (NGOs), healthcare settings etc. may play important role in creating awareness amongst common people.
• Strict regulations must be formulated and implemented for management of the effluents having antimicrobials from pharmaceutical companies as well as healthcare establishments. The violators must be punished without any delay or fail.
• Likewise, strict regulations must be framed and implemented for the use of antimicrobial agents in food animals, fish, food, feed etc.
• Sale of over the counter (OTC) antimicrobials must be regulated and monitored. Without the valid prescription, the sale must be prohibited. Harsh legal action must be taken against the offenders.
• Mechanism or system must be developed at all healthcare settings to ensure judicious/rational use of antimicrobials (the appropriate indications, the appropriate dosage, proper way, proper duration and proper interval).
• Harsh punishments must be given to quacks who prescribe antibiotics/antimicrobials for humans as well as animals in a very haphazard way.
• One Health approach must be followed to tackle AMR: A multisectoral and multidisciplinary approach with combined efforts and supervision is required to tackle AMR.
• Research on developing new antibiotics/antimicrobials must be continued and accelerated. Likewise, scientific work on developing alternatives to antimicrobials/antibiotics must be continued and accelerated.

References

https://www.pashudhanpraharee.com/antimicrobial-resistance-amr-a-global-threat-to-livestock-and-human-health/

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 https://www.who.int/news-room/fact-sheets/detail/antimicrobial-resistance

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