Introduction

Antimicrobial resistance (AMR), is the phenomenon by which microorganisms ability to resist the antibiotics’ effect and propagate in the presence of drugs that were effective against them, rendering treatments ineffective.1 The use of antibiotics, which were discovered over 70 years ago, has led to significant advancements in public and animal well-being and agriculture. However, throughout history, the emergence of resistant microbes has continuously challenged these medical innovations. This indicates that antimicrobial resistance is a natural, ancient, and widespread occurrence among bacteria in any biological system.2

Furthermore, it is worth noting that many antimicrobial substances share chemical similarities with naturally occurring compounds. Remarkably, genes responsible for AMR have been discovered from the permafrost, suggesting they existed long before humans developed the ability to produce antibacterial chemicals and use them on a large scale. Thus, the occurrence of AMR within bacterial populations can be considered a largely predictable phenomenon.3 Nevertheless, recent research focusing on modern commensal microbial genomes found in environment and humans has unveiled a significantly higher abundance of genes of antimicrobial-resistance than previously acknowledged. This finding suggests that various factors facilitate the rise and propagation of drug resistant bacteria.4

AMR was not created by humans, but rather promoted by applying evolutionary pressure on the ecosystem. The maintenance and distribution of resistance within bacterial populations depend on the organism’s lifestyle and the genomic root for resistance. AMR can be inherent, mutation-allied, or attained through horizontal gene handover between organisms.3 Bacteria can overcome the effect of one or more antimicrobial classes through either intrinsic, meaning it is naturally present in the bacteria or acquired (through transformation, transduction, or conjugation of mobile genetic elements like transposons and plasmids enabling numerous resistant genes incorporation into the genome or plasmid of receiver microbe) mechanisms.5 In the past few decades, pharmaceutical companies have decreased their interest in antibiotic research and development due to snags in clinical improvement and monitoring of scientific and financial subjects. Clinical evaluation of the effectiveness of new antimicrobials is problematic and expensive owing to the absence of rapid diagnostic tests, particularly when directing Gram-negative multidrug-resistant bacteria.6

Antimicrobial-resistant organisms are a major health crisis causing over 700,000 deaths annually across the globe, anticipated to increase to 10 million by 2050.7 AMR is a rising concern, especially in developing countries and is anticipated to upsurge in the coming years due to higher antimicrobial utilization in public and veterinary care. Antimicrobials are used for livestock farming at a significantly higher rate, 73–100% extra antimicrobials than human medicine, driven by a growing middle class’s demand for animal-based protein.8 According to a report by the antimicrobial resistance collaborators, E. coli was the leading cause of death associated with resistance to antimicrobial drugs in 2019 followed by Staphylococcus aureus, then by Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. These pathogens were responsible for approximately 929,000 deaths directly attributed to AMR globally and a total of 3.57 (2·62–4·78) million deaths owing to AMR with higher 27.3 (20.9–35.3) demises apiece 100,000 individuals in the Western part of Sub-Saharan Africa.8

A momentous increase in microbes resistant to one or more antibiotics is posing a great threat to the effectiveness of life-saving antibiotics worldwide. This necessitates the urgent need to identify the microbes that require more attention for drug development, given the severe consequences of multidrug resistance and the limited introduction of new drugs. WHO has prioritized certain pathogens based on their critical, high, and medium priorities. Critical-priority bacteria include Acinetobacter baumannii and Pseudomonas aeruginosa resistant against carbapenem, and Enterobacteriaceae resistant against carbapenem and third-generation cephalosporin.9 High-precedence bacteria include enterococcus faecium resistant against vancomycin, helicobacter pylori resistant against clarithromycin, and staphylococcus aureus resistant against methicillin, and shigella spp. resistant against fluoroquinolone, campylobacter spp. resistant against fluoroquinolone, Haemophilus influenzae resistant against ampicillin, and streptococcus pneumoniae resistant against penicillin (Figure 1).10

Figure 1 Final ranking of antibiotic-resistant bacteria. Reprinted from Lancet Infect Dis. 18(3), Tacconelli E, Carrara E, Savoldi A, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 318–327, Copyright 2018, with permission from Elsevier.9 In the above figure, Mean (SD) pathogen weights derived by the software from the survey participants’ preferences and the segments represent the contribution of each criterion to each pathogen’s final weight.

Abbreviations: PNS, penicillin non-susceptible; 3GCR, third-generation cephalosporin resistant; CR, carbapenem resistant; MR, methicillin resistant; VR, vancomycin resistant; ClaR, clarithromycin resistant; FQR, fluoroquinolone resistant; AmpR, ampicillin resistant.

One health concept involves understanding the biological elements related to the evolution of AMR, including microorganisms, vectors, host organisms, environments, and cultural and socioeconomic factors that aid its spread. AMR is considered a significant one-health problem.11 Unification of the environment and human and animal territories play a role in the rise, progress, and blowout of AMR, posing a peril to human wellbeing. Resistance can spread across different microbiomes and alter bacterial population genetics, potentially altering the genetic makeup and population dynamics of microbiomes. Changes in habitats, such as contamination by antibiotics or antibiotic-resistant microbes can affect the assemblies of bacterial populations and hasten the propagation of AMR among the microbiomes.12

Genes responsible for AMR are carried by mobile genetic elements (MGEs) that can move among different species and clones of bacterial. These MGEs are present in various environments including human, animal, nourishment, mess, water and soil, forming the interconnected microbiome ecosystem. The proximity of densely populated areas with a high concentration of vertebrate animals increases the likelihood of frequent interactions and merging of microbiomes, leading to the spread of AMR.13,14 The decline in diversity and increase in interactions between animals and humans may lead to a repeated merging of similar types of microorganisms and the exchange of genes between microorganisms. This highlights the significance of One health in contending AMR, as AMR involves complex interactions among humans, animals and the milieu, providing various routes for the spread of drug residues and resistant bacteria.15

Statement of Problem

There are the latest research findings, insights, and recommendations regarding the distribution of antimicrobial resistance within humans, animals, the environment and wildlife and associated contributing factors and preventive measures. Therefore, there is a need for a comprehensive review that encompasses the contribution of humans, animals, the environment and wildlife for the propagation of antimicrobial resistance and preventive approaches in the One Health framework.

Objective of the Review

The current review aimed to overview an impression of the potential causes of the antimicrobial resistance spread and preventive measures from a One Health perspective.

Review Methodology

The manuscripts used for the current review were searched from reputable journals and Google Scholar by using keywords and phrases like antimicrobial resistance; antimicrobial resistance and one health; AMR and drug misuse and overuse in humans or animals; AMR and environment; antimicrobial resistance in the public settings and antimicrobial resistance in the wildlife; antimicrobial resistance and agrichemicals and preventive measure of antimicrobial resistance. Additionally, I have searched in Google Scholar by formulating sentences based on the specific ideas I was exploring. During the review, all possible efforts were made to use the most recent information.

Potential Causes of the Spread of Antimicrobial Resistance from One Health Perspective

AMR is influenced by factors like human practices (antimicrobial overuse and misuse, insufficient infection deterrence, and lack of awareness); animal-related practices (widespread antibiotic use in livestock and aquaculture, transmission through food chains and direct contact); environmental factors (release of antibiotics and resistant bacteria into water bodies, soil, and waste systems) and wildlife-related factors (transmission through contact with wildlife and habitat encroachment).16

Human-Related Causes of Antimicrobial Resistance Inappropriate Antimicrobial Use in Human Medicine

Excessive and inappropriate use of antibiotics has played a significant role in the worldwide problem of antibiotic resistance. The available evidence indicates that our heavy reliance on antibiotics, along with the interconnected relationship between human health, animal farming, and animal health, has led to the emergence and dissemination of drug resistant bacteria and other organisms. This has resulted in a global epidemic where many commonly used antibiotics are becoming less effective in treating infections.17

The overuse of drugs, including self-medication, dispensing antibiotics without prescriptions, over-prescription, patients’ prospects and liability pressure, can cause the development of drug resistance. These practices promote the survival and proliferation of germs that are resistant to antimicrobials by destroying the susceptible ones, leading to the emergence of AMR. While antimicrobials can kill certain disease-causing germs, they also eliminate beneficial germs that protect our bodies from infections. As a result, the remaining antimicrobial-resistant microorganisms survive and multiply, carrying resistance traits in their DNA that can be transferred to other microorganisms. Unnecessary use of broad-spectrum antibiotics owing to the delayed or inaccurate identification of the etiology of the ailment further fuels the problem of AMR.18,19

There is an association between the use of certain antibiotics and resistance to antibiotics in which increased antibiotic use often increases antibiotic resistance, reducing antibiotic use will also reduce antibiotic resistance to some extent. Higher infection rates are seen in patients infected with bacteria resistant to bacteria from environments with high levels of antibiotics and multidrug-resistant (MDR) strains. The disease is treated more like an infection. Antibiotic use upsurges the menace of selection of resistant bacteria in the normal microbiota and raises the probability of the emergence and spread of resistant microbes when used longer.8

Although antibiotic resistance is seen as a result of antibiotic use, the interaction between these two factors is not a linear relationship. Both changes are involved in microbial antibiotics, and the development of drug resistance and the interaction between them is complex. From an epidemiological perspective, the occurrence, abundance and spread of AMR are influenced by many factors.20 According to21 the overprescribing of antibiotics is a significant issue, particularly in primary care settings mainly for infections caused by viruses. This in turn leads patients to re-attend medical facilities more frequently and use antibiotics excessively for self-limiting conditions, where they are not truly necessary. This refers to the act of using antibiotics inappropriately or too frequently, which can result in modifications/selection pressure within the bacteria which render the bacteria resistant to the antibiotics.

Microbes can mutate spontaneously or as a result of encounters with certain drugs, enabling them to amend or circumvent antimicrobial targets. Bacteria can undergo mutations that alter their cell walls or the enzymes responsible for breaking down antibiotics, for example; viruses can mutate to evade antiviral agents designed to target their replication cycle, while parasites can alter their metabolic pathways to avoid antiparasitic agents.22 Mutations or exchanges of genes horizontally upshot in a selection of variants in naturally sensitive bacterial populations with reduced antibiotic susceptibility. Additionally, mutations or genes responsible for resistance accrue in specific strains or clones of pathogenic bacteria and can subsist even when there are numerous drugs. In this process, the same antibiotic can select different microbial isolates resistant to more than one drug and different antimicrobials can also select microbes resistant to one drug (Figure 2).23

Figure 2 Mutant selection window (MSW) and mutant prevention concentration (MPC). Figure 2. illustrates that when the concentration of an antimicrobial is between the minimum inhibitory concentration (MIC) and the (MPC), there is a selection pressure that promotes the persistence of a population of resistant microbes. As the concentration exceeds the MPC, the selection of resistant mutants is unlikely, and the susceptible population is eradicated. Conversely, when the concentration is below the MIC, there is no effect on both the susceptible and resistant subpopulations.

Another example shows that antibiotic overuse is a key contributive aspect to the development of antibiotic-resistant microbes like S. aureus resistant to methicillin and multidrug-resistant tuberculosis.24 Likewise, therapeutic and prophylactic excessive use of antiviral drugs such as oseltamivir (Tamiflu) for influenza facilitates the development of drug resistant influenza strains, including the H1N1pdm09 strain.25 Moreover, inducible genes, such as erythromycin resistance methylase (erm) genes, are present within mycobacteria and S. aureus which are synthesized only in the presence of certain types of antibiotics, resulting in the bacteria quickly developing resistance to those specific antibiotics.26

Inapt antimicrobial use in the community is identified as a foremost factor contributing to the development and propagation of MDR organisms that pose a solemn peril to public health.27 This occurs as the drug kills off the susceptible bacteria, leaving the resistant ones to grow unrestricted Antimicrobial misuse can happen in numerous customs, for example, taking antibiotics to relief viral infections like influenza, flu, or COVID-19.28 Besides, underutilization of antibiotics, ie, not appropriately prescribed or not taken as per the recommended dosage, can result in ineffective treatment outcomes and repeated infections. This, in turn, may necessitate the utilization of more antibiotics, which further fuel the rise and dissemination of AMR.29 As documented by,30 in the Southeast Asian region there is widespread usage of antibiotics without prescriptions from physicians (self-medication with antibiotics), increasing the likelihood of improper drug usage and subsequent appearance and distribution of drug-resistant microorganisms.

Another example demonstrates that S. aureus resistant to methicillin is also resistant to beta-lactams. However, S. aureus susceptible to methicillin remains vulnerable to cephalosporin like cefuroxime as well as beta-lactams containing beta-lactamase inhibitors like amoxicillin/clavulanate. It is imperative to consider that the use of these antimicrobials (cephalosporins, amoxicillin/clavulanate) possibly encourage resistance against methicillin via co-selection (Figure 3).17

Figure 3 Antibiotic selection pressure leads to methicillin-resistance. Figure 3, depicts that exposure to amoxicillin-clavulanate may allow the emergence of methicillin-resistant S. aureus (MRSA) over methicillin-sensitive S. aureus (MSSA). Similarly, exposure to other antibiotics (cephalosporins, clindamycin, macrolides, fluoroquinolones and fusidic acid) to which MRSA is more likely to be resistant compared to MSSA may also favor the emergence of MRSA.

Furthermore, the improper utilization of antibiotics, which includes the usage of broad-spectrum antibiotics that eliminate both harmful and beneficial bacteria within the body, can also actively contribute to the rise of AMR. Such antibiotic practices create an environment favorable growth of resistant bacteria by disrupting the normal bacterial flora. Consequently, the resistant bacteria are provided with an opportunity to multiply and spread.31 It is instigated that, the utilization of second-line antimicrobials such as macrolides and second-generation cephalosporins, in cases of acute self-limiting infections or infections that can be effectively treated by commonly used first-line antimicrobials like amoxicillin or penicillin alone, can generate selective pressure on microbes which inturn cause AMR.17

Under-prescription of antibiotics culminates in the administration and presence of subtherapeutic drug concentration in the body which in turn endorses the rise of AMR by favoring genetic modifications. Fluctuations in gene expression induced by antibiotics can result in increased virulence of bacteria and augmented mutagenesis and horizontal genetic transfer which further promote AMR and its spread among microbial populations.32 For instance, lower concentrations of drugs have been found to cause strain diversification in organisms like P. aeruginosa. Secondly, piperacillin and/or tazobactam at concentrations lower than MIC actuates wide genomic alteration in Bacteroides fragilis.33

The organisms created antimicrobial resistance in over said strategies spread to the environment and other non-human creatures through different implies. For instance, besides intestine organisms, which contain a wide cluster of resistance determinants, antimicrobials devoured by people are discharged into the environment in pee and fecal material contained in treated wastewater and sludge applied to the land.34 Past this, anthropogenic contamination presents antibiotic-resistant microbes (ARM) and antibiotic resistance genomes (ARGs) to the healthy setting, and resistance genomes that initially existed in natural microbes can be exchanged, by parallel genome exchange, to the microbes infecting humans.35 For instance, an investigation by Nepal et al34 demonstrated that the presence of resistance genes in crAssphage, a bacteriophage that’s uncommonly plenteous in and particular to human feces without clear signs of selection within the environment through the crAssphage arrangements is an indicator of human stool defilement.

Inadequate Sanitation and Hygiene in the Public Settings

The destitute cleanliness and failure to take after disease avoidance and control measures have played a critical part in the spread and expansion of antibiotic-resistant microbe strains. Hospitals, in particular, have risen as noteworthy reservoirs of these resistant microbes. This will be ascribed to the recurrent and extensive use of drugs within hospitals and the nearness of patients, which creates more opportunities for the transmission of these microbes. Eventually, these variables contribute to the proceeded engendering and spread of microbial strains resistant to different antibiotics which inflict a serious risk to public wellbeing.36

Streptococcus-pyogenes resistant to sulfonamide was identified within public clinical settings in early the 19, S. pyogenes resistant to penicillin was noted in the 1940s and MDR microbes were reported in the 1950s.37 In certain occasions, the extent of patient-to-patient transmission is directly proportional to the extent of hospital environment contamination (Figure 4). Furthermore, inadequate sanitation of the health facility environment favours the persistence of these microbes in the environment (Figure 4).38 Each day, thousands of staff, visitors and patients from diverse parts reach hospitals, each harboring a set of the microbiome of diverse genotypes and phenotypes on their on/inside their bodies as well as clothing. Microbes can disseminate in case health settings do not practice satisfactory sanitary strategies and protocols to keep up setting hygiene and culminate in further development and spread of AMR.36

Moreover, the improperly released hospital water and effluents spread the antimicrobial-resistant organisms and antimicrobial-resistant genes to and encourage their event within the adjacent environment, and their procurement by humans and animals when uncovered in the environment (Figure 4).39 Hence, the presentation of diverse visitors and patients harboring diverse organisms with resistant genes besides insufficient sanitation and cleansing part in the spread of AMR from one place to another, humans and animals.40 In a study conducted in Vietnam, it was found that 83% of E. coli isolates from hospital wastewater showed resistance to at least one antibiotic, and 32% showed resistance to multiple drugs advocating that hospitals play a role in the spread of AMR. Another study in a Chinese teaching hospital investigated the transmission of MRSA in a pancreatic surgery ward and revealed the presence of MRSA (specifically the ST5-MRSA-II-T311 clone) in 20 strains isolated from both the environment and patients. This also instigates that the hospital environment and lack of proper hand hygiene could be risk factors for AMR spread.41

Figure 4 Schematic flow of antibiotic resistance from hotspots of evolution. Reprinted from Kraemer SA, Ramachandran A, Perron GG. Antibiotic pollution in the environment: from microbial ecology to public policy. Microorganisms. 2019;7(6):180. Creative Commons.42

Notes: Antibiotic-resistant bacteria (ARBs) and antibiotic resistance genes (ARGs) from hotspots of evolution (hospital) transmit (red circles) to the environment (green circles) through sludge and different vectors (blue circles).

Beyond this, after being discharged into the environment, resistant bacteria can reside on plants and be ingested by animals (Figure 4). Once inside the animals’ gut, they transfer the resistant gene, which then alters the structure of the microbiome community since gut contains different microorganisms.43 This renders the gastrointestinal tract an important source of ARGs that can be exchanged between strains of identical or dissimilar species through various mechanisms like phagocytic transduction, plasmid transfer, and natural transformation, which int urn shed in feces.44 According to45 some of the most common nosocomial infection-related pathogens with higher AMR, such as A. baumannii, S. aureus, P. aeruginosa and Enterobacteriaceae (E. Coli, K. pneumoniae), and are persevere in the hospital setting for an extended period.

It is shown that water bodies around the world massively reserve clinically significant antibiotic-resistant organisms and it is mainly attributed to defilement by anthropogenic discharges. Thus, the role of natural recreational waters in the acquisition and transmission of AMR is an area of increasing interest. It is demonstrated that bathing waters contain AMR organisms including Enterobacteriaceae producing New Delhi metallo-beta-lactamase (NDM) and E. coli resistant to cephalosporin.46 Due to the nature of swimming pools as public spaces for recreation, the likelihood of transmission of antimicrobial-resistant microorganisms through various contact points like the eyes, skin, nostrils, oral cavity, anus and vagina is high. A study conducted in central Ohio of the United States found that a significant proportion, 96%, of P. aeruginosa isolates obtained from swimming pools and hot tubs were resistant to multiple drugs.47 Another investigation from Zaria, Nigeria, reported recreational water to contain E. coli and K. pneumoniae strains harboring extended spectrum beta-lactamase genes (TEM, SHV and CTX-M).48

The other public settings with a high likelihood of spreading antimicrobial resistance include buses, railway stations, subway trains, and crowded university or school classrooms due to their high population density. This overcrowding hones the dissemination of different species of microbes with a great variety of general makeup and genetic exchange among them.40 Research conducted in Guangzhou, China depicted the presence of MRSA in railway and coach stations. Out of the samples collected, 39.21% tested positive for staphylococci, with 1.58% being identified as MRSA and 75.84% as multidrug-resistant staphylococci. These findings instigate that railways act as a hotspot for the distribution of MRSA between humans, the environment, and animals, and vice versa.49 Furthermore, an investigation in Chinese public buildings on airborne S. aureus, including MRSA, revealed varying levels of MRSA concentrations. The study reported mean total and respirable concentrations of airborne MRSA in different places, such as 24 and 17 CFU/m3 in university classrooms, 20 and 13 CFU/m3 in kindergarten, 3 and 16 CFU/m3 in the hotel, and 33 and 20 CFU/m3 in the movie theater. This study further supports the idea that public settings have a noteworthy contribution to the propagation of AMR.50

The aforementioned public settings comprise surfaces that are touched by many people carrying different resistant microbes to different antibiotics, which leads to the genetic allotment among microbes and becoming resistant to different drugs. Surfaces frequently touched by hands can act as a means of transmitting AMR from one individual to another if someone directly touches these surfaces or if bacteria on their skin is transferred to a surface and then touched by others.40 Furthermore, in crowded public places, the transmission of resistant bacteria can occur through different methods including the release of bacteria into the air from the skin, inhaling contaminated aerosols, or consuming tainted food.51

Using Antibiotic-Incorporated Cosmetics and Detergents, and Biocides

Everyday grooming and hygiene products like lotions, creams, shampoos, soaps, shower gels, toothpaste, and fragrances contain additives to preserve the product and have disinfection properties. However, these additives can enter ecosystems where they come into contact with microbial communities, potentially promoting the spread of resistance.52 Active substances found in many household detergents and cosmetics can contribute to antibiotic resistance. For example, triclocarban and triclosan, broad-spectrum antibacterial compounds found in a variety of cosmetic products, have been shown to contribute to AMR and promote the growth of resistant to both biocides and antibiotics. The low solubility of these compounds worsens contamination as they tend to build up and stay in surface waters and sediments for extended periods.53 Additionally, exposure to triclosan has led to the discovery of mutations in the enoyl-acyl carrier protein reductase gene in vulnerable bacteria, thereby to the presence of of genes responsible for AMR. It can facilitate the selection of cross-resistant and multidrug-resistant genes, thereby aiding in the spread of ARGs and portable genomic elements in bacterial communities.54

Biocides like chlorine, iodine, alcohols, etc., commonly found in disinfectants, are used to control infections in critical healthcare settings and are now being marketed for home use.55 Scientific studies have shown that the use and improper use of products containing biocides can potentially lead to antibiotic resistance in bacteria. Additionally, bacteria that are tolerant to biocides have been found to also possess resistance to antibiotics.56 This is due to that, biocides and antibiotics may show some resemblances in their mode of action and common mechanisms of microbial insusceptibility may work.57 Factors including the concentration of the biocide, contact time, pH, temperature, the presence of organic matter or other substances, and the characteristics of the microbes or entities being targeted can influence the effectiveness of biocides and aid in development resistance.58

For instance, an investigation on E. coli has shown that from 40 strains evolved in sub-inhibitory, constant concentrations of ten widespread biocides, 17 (43%) have low vulnerability to therapeutically pertinent antibiotics.59 High-touch and disinfected areas like office desks, ATM machines, public toilets, doorknobs and faucets as well as sinks are the risky areas where microbes develop biocide-induced resistance and transmit to humans.60

Animal-Related Causes of the Spread of Antimicrobial Resistance

Animals have an undeniable contribution to AMR spread as human antimicrobials are used in animals as a growth promotor and therapeutically, which has a significant effect on the development of AMR.61 Other variables that facilitate the dissemination of AMR in animals include globalization, worldwide travel and exchange, and contact with wildlife.62 Meanwhile, the misuse or overuse of antimicrobials in animal production has driven different ABR and ARGs, which can be exchanged among animals, the environment and people.63 These ARB and ARGs that emerged in farms can be transmitted to people through direct or backhanded contact with animals, manure, or products, and inhalation of bioaerosol that harbors them.39,64

Prophylactic and Therapeutic Antimicrobial Misuse in Animals and Antimicrobial Resistant Microbe and Resistance Gene in Animal-Derived Food

Antimicrobials prescribed for and crucial for human medicine are used in animals, including pets, aquaculture, apiculture, and farm animals, both prophylactically and therapeutically at higher rates.65 Antimicrobials misuse in animals and resultant AMR is a growing problem worldwide, affecting not only humans but also livestock along the entire food chain in almost every country.16 Genes responsible for antimicrobial resistance and drug resistant bacteria can spread from food-producing animals to people via close contact or consumption of animal products, especially if they are not handled or cooked properly. The United States centers for disease control and prevention estimates that approximately 1 in 5 cases of resistant infections are linked to pathogen found in animals and food of animal origin.66 Furthermore, the presence of drug resistant microbes and drug residue in animal waste is the main source of environmental AMR then humans through direct defilement and stimulation respectively.67 From the environment, animals get these resistant microorganisms through various routes and animals’ guts and tissue harbor a high population of ARB which is further disseminated to the environment as well as to humans and vice-versa.14 These pathogens access humans through handling and ingesting contaminated food items, or contact with animals, as well as through fishing in or drinking defiled water.62

Beyond this, extra-label use of antimicrobial ends in the higher or lower absorption, distribution, or excretion of the antimicrobial active principle. These are also related to the fact as the animal size increases, the ratio of body surface area to body weight decreases, resulting in slower physiological processes compared to smaller animals. These factors collectively influence the way drugs are absorbed, distributed, metabolized, and eliminated in different species.68 Administering antibiotics that are not efficient against the bacteria recorded on the label, or when the dose on the label is inadequate (due to AMR), upshots in unnecessary antibiotic exposure and fairing AMR.69 For instance, antibiotics including penicillins, lincosamides, quinolones, and combinations of sulfonamides with trimethoprim are used for most cases in animals without confirmatory diagnosis.70

It is crucial to note that consumers can potentially come into contact with or consume animal products carrying resistant bacteria, which adds to their exposure to such microorganisms.71 In a study on consumer exposure to antimicrobial-resistant bacteria in food at the Swiss retail level, it was found that out of 38,362 bacteria isolates and 122,438 samples of food tested, 22.9% of the bacterial isolates and 24.6% of the samples were identified as AMR positive. A significant portion of the samples (61.5%) and bacteria (70.2%) were discovered in meat products like cuts, ground pieces, or meatballs. These meat products also comprised the highest percentage (88.7%) of samples with AMR and the majority (60.1%) of AMR-positive bacteria detected. ARB includes enterococcus, campylobacter, salmonella, vibrio spp., listeria and Escherichia coli were isolated from animal products.65 Demonstrating that livestock products including meat, eggs and milk have been proven to be a key route of extraintestinal MDR pathogens, especially for E. coli and Salmonella, posing a potential health risk to consumers.72 For instance,73 reported that out of 152 Salmonella isolates from retail foods of animals, 92.8% of bacteria were MDR.

Furthermore,74 identified coagulase-negative staphylococcus (39.1%), followed by S. aureus (17.2%), S. hyicus (14.1%), S. intermedius (9.4%), and E. coli (9.4%) in cow, camels, and goats milk. E. coli isolates from both cows and goats were MDR against spectinomycin, vancomycin, doxycycline, ceftriaxone and penicillin. S. aureus isolates from all milk have MDR to penicillin G, spectinomycin, and clindamycin. In another investigation in Swiss, Enterobacteriaceae like Citrobacter, Cronobacter, Enterobacter, Klebsiella, and Shigella, E. coli and Salmonella were isolated from most types of milk, cheese, meat, plant and seafood products with a predominance of raw meat origin, particularly of beef, and poultry origin. These bacteria harbor blaACC, blaCMY, blaCTX, blaDHA, blaFOX, blaOXA, blaOXY, blaSHV, or blaTEM variants resistant to aminoglycosides, cephalosporins and penicillins.65

Presence of Antimicrobial Residue in Food of Animal Origin and Animals’ Excreta

Intensive production methods, which involve keeping large numbers of animals in small spaces under stressful conditions, have increased the risk of infectious diseases, necessitating antibiotics to combat them. Likewise, over time, antibiotics started being used extensively at lower doses for preventative and growth-promoting purposes in farm animals.75 Recently, antibiotic consumption in cattle and poultry has risen at an extraordinary rate globally, which is expected to rise further by 67% by the year 2030 in rapidly polluting and developing countries of the world.76

The use of antibiotics in animals can lead to the presence of antibiotic residues in food products like chicken, meat, milk, and eggs. These residues can still be present even after cooking the food, as the cooking heat may not eliminate all the antibiotic residues77 and pose a significant risk of public exposure when consuming animal originated food.78 Many veterinary drug dispensers lack sufficient knowledge about animal illnesses, drug usage, withdrawal periods, side effects, and proper methods of administration. This lack lack of adherence to withdrawal time for drugs used in animals, particularly concerning livestock products like milk and meat consumed by humans important cause for the presence of drug residue.79 These subinhibitory or sublethal concentrations of antibiotics present in food can enter the human body when consumed, either in raw or cooked form. Microbes within the human body are exposed to these concentrations, which can stimulate the development of various resistance mechanisms against the antibiotics present in the feed.35 In addition to this, sub-MIC of antimicrobials have been observed to potentially enhance the frequency of conjugation, which ultimately results in the transfer of genetic material through plasmids, facilitating the spread of antibiotic resistance by mechanism.80

For instance, an investigation by81 sub-MIC concentration different drugs on the handover of ARGs carried in the plasmid to Escherichia coli from K. pneumoniae. The study utilized K. pneumoniae strain SW1780 with plasmid carried MDR gene PSW1780-KPC as the donor strain, and Escherichia coli strain J53 as the recipient. They treated K. pneumoniae SW1780 with subinhibitory concentrations of ciprofloxacin, amikacin, meropenem and cefotaxime. The study demonstrated a substantial increase in the resistance gene handover frequencies upon treatment of K. pneumoniae SW1780 with these subinhibitory concentrations of the above antibiotics.

Antibiotic residues are significantly shed in to and disposed of with farm waste, which poses selection pressure on the environmental microbes. Several antimicrobials administered to the animals are poorly absorbed from the gut of the animals, and as much as 90% of the main antimicrobial active compound is excreted in urine and up to 75% in feces,82 quantities varying among animal species. Animal waste containing such residue is applied to the land and, in turn, contaminates air, water, and soils near both storage and field application sites. There AMR emerged, as microbes were found everywhere and exposed to sub-MIC.83

For instance, tetracyclines, are among the most frequently used antibiotics in poultry farming owing to their broad spectrum action, for prophylactic, therapeutic, or growth promotion roles.84 However, due to poor absorption, active ingredients of tetracyclines can accumulate in muscle, feces and urine. In an investigation by Mahmoud et al85 in Egypt in broiler farms, high concentrations of chlortetracycline 6.05μg/g and 5.9μg/g and oxytetracycline 2.47μg/g and 1.33μg/g was recovered from chicken litter and droppings, respectively. Slightly lower amounts of tetracycline and doxycycline were found: 1.9 μg/g in litter and 0.46 μg/g in droppings for tetracycline, and 0.87 μg/g and 0.02 μg/g for doxycycline.

Antimicrobial Resistant Microbe and Resistance Gene in Animals’ Excreta

Irrational use (like under prescription, lower frequency, inappropriate route) of antimicrobials in animals results in the development of AMR in organisms inhabiting animals’ gut and on their body surface.86 These organisms advance and spread to the people and environment through direct contact and fecal defilement. Gut antibiotic-resistant microbes are excreted in defecation and can spread within the environment and conceivably enter other animals and farmworkers.71 Antibiotics not only affect pathogenic bacteria but also affect the resident microbiota making animal gut rich with ARM and ARGs associated with microbial pathogenicity and diversity.87 This defilement permits the simple selection and exchange of genes related to antimicrobial resistance inside the microbial community of that specific environment. As a result, these ARGs can be transmitted to people and other situations through the utilization of a sullied diet and introduction to squander materials individually.63 For instance, 210 fecal samples were collected from farm animals and the farmer and analyzed the spread of MCR-associated with plasmids among E. coli by multiplex PCR, 18,4 and 1 colistin-resistant E. coli isolates carrying mcr-1 (including 13) with 33 virulence factors were isolated from calves, pigs and farmer respectively and. This instigates that, mcr-1 gene was transferred from the calf to the farmer, thus farm is a reservoir of ARB with zoonotic potential.88

It is demonstrated that farm animals are a reservoir of ARB (such as E. coli, K. pneumonia, Salmonella, S. aureus, etc.) and ARGs that reaches peoples via close contact with farm animals.64 Farm bioaerosols generated during farming practices have also been regarded as a reservoir of ARB and ARGs can be inhaled into the respiratory tract of animals and humans.89 Another author,90 demonstrated that animal waste and slaughterhouses are a reservoir of MDR bacteria, indicating an occupational risk to workers. In addition to this, ARB and ARGs from animal bioaerosols could easily be transmitted from animal farms to the environmental dust through the natural wind.91 AMR persists in animal wastes since animal waste contains resistant pathogens and stable antimicrobial agents.92 Geographic clustering of large-scale livestock farms is highly associated with pollution of soils and irrigation water transferring to and the presence of antimicrobial-resistant bacteria in the food crops, fruits, and vegetables and subsequent transmission to humans upon consumption.93 Fertilization of soil by raw animal squander (fertilizer) or discharge of farmhouse squander into streams are chief route of spread of ARGs and AMR organisms in new fruit and vegetables and aquatic food (Figure 5).62 People acquire these AMR organisms and ARGs as they consume plant-derived foods, especially those eaten raw and aquatic food (Figure 5).94

Figure 5 Spread of ARB and ARGs from animal faeces to the environment and human health. Reprinted from Iwu CD, Korsten L, Okoh AI. The incidence of antibiotic resistance within and beyond the agricultural ecosystem: a concern for public health. MicrobiologyOpen. 2020;9(9):e1035. © 2020 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd. Creative Commons.32

Use of Antimicrobials as a Feed Additive in Livestock

Antibiotics are extensively used in animal farming as feed additives to enhance the utilization of nutrients, promote growth and improve overall animal productivity at concentrations lower than the therapeutic dose.95 These antibiotics inflict selection pressure triggering the synthesis of resistant genes in the bacteria and creating a suitable environment for the emergence of AMR since sub-therapeutic antibiotic doses are applied to the feed.61 Furthermore, as mentioned earlier in this document, residual antimicrobial substances can accumulate in animal tissues such as beef, pork, and poultry, as well as in products like eggs and milk which reach microbes in humans.77 In certain instances, contact with sub-MIC of antibiotics can lead to the production of reactive oxygen species. This can potentially contribute to an escalation in mutation rates and the emergence of multidrug-resistant mutants. Additionally, antibiotics in animal feedstuff can hasten the handover of genes through bacteriophages, thereby promoting the dissemination of ARGs. It is worth mentioning that sub-MIC of antibiotics also foster exchange of gene horizontally, a chief means responsible for the exchange of ARGs.32

Environment-Related Cause of the Spread of Antimicrobial Resistance Environment as a Source of Naturally Existing ARG and AMRM for Human and Animal Pathogens

With respect to the take-up of novel resistance components, water, soil and other environments with profoundly variable biological specialties give an unmatched genetic pool with differing qualities that incredibly surpasses that of the human and domestic animal microbiota.96 Indeed, the most striking feature of the environmental microbiome is, that it is incredibly diverse, offering a wide array of genes that pathogens may acquire to counteract antibiotic effects.42 Antibiotic resistance genes are thought to originate from environmental bacteria that produce and release antibacterial substances to impact other microbes they compete with for resources.97 The recent discovery of antibiotic resistance genes in ancient permafrost sediments suggests that AMR existed naturally even earlier than the use of modern antibiotics. This natural resistance may have contributed appearance and dissemination of AMR in disease-causing microbes showing that milieu is the main source of drug resistant microorganisms.98

Most ARGs did not solely originate in clinical or agricultural sceneries, instead, they evolved in the natural environment where naturally occurring antibiotics derived from soil bacteria and fungi existed. These antibiotics, like penicillin, streptomycin, tetracycline, and chloramphenicol, allowed bacteria to compete for limited resources.40 Since antibiotic-producing microorganisms are comparable to other microorganisms they compete with, there’s a chance they can be hurt by the harmful metabolic compounds created by others. To safeguard themselves, they have evolved defense mechanisms.99 ARGs likely came from antibiotic-secreting microbes and entered into other bacteria through horizontal gene transfer. AMR can also arise from mutations in target sites or pre-existing genes that encode enzymes or are transported via efflux pumps, eventually becoming resistance mechanisms.40

Improper Disposal of Unused and Expired Antimicrobials

Indecorous disposal and/or handling of unused drugs is one of the pathways through which antibiotics can disseminate in the water and other parts of the environment where microorganisms can encounter through various ways such as the release of sewage from urban, industry, animal husbandry, plant production and household.100 The rise in antibiotic use is repeatedly associated with the free availability, accessibility, and incongruous use of antibiotics and the reason for developing antibiotic resistance.101

Many products that are given to patients or clients are not fully used, resulting in large amounts of unused or expired medicines. This has become a global issue that has caught the attention of policymakers, healthcare professionals, pharmaceutical companies, and the general community.102 Improper disposal of pharmaceuticals is a significant issue because users often lack knowledge about proper disposal methods, leading them to flush or throw away their unused and expired medication. This in turn ends up in landfills, water supplies and drains that lead to contamination of the environment.103 This subinhibitory or sublethal concentration in the expired medicines and the containers or in unexpired ones but deteriorated by environmental factors triggers environmental microbes to develop all possible resistance machinery against the antibiotics.104

Environmental Contamination by Wastes from Public Settings, Animal Farms and Pharmaceutical Industries

Wastewater contains diverse contaminants including pharmaceuticals, personal care products, disinfectants, and pesticides, collected from residences, industries, and medical facilities by urban wastewater systems (Figure 6).105 These antibiotics and related chemical constituents in the wastewater pose a foremost health risk owing to their ability to persuade AMR since their microorganism comes in contact with those substances.106 Different studies showed that wastewaters are hotspot reservoirs for both antimicrobials and clinically relevant antimicrobial-resistant bacteria and resistance genes demonstrating that wastewater is a significant vehicle for the AMR spread.107 As mentioned earlier in this manuscript, these AMR microbes and ARGs spread to the environment, animals and humans through different direct or indirect contact and food chains (Figure 6).62,94

Figure 6 Transmission pathways of AMRM and ARGs from wastewater hotspots to the other environment, animals and humans. Reprinted from J Environ Chem Eng; 8(1), Gwenzi W, Musiyiwa K, Mangori L. Sources, behaviour and health risks of antimicrobial resistance genes in wastewaters: a hotspot reservoir. 102220, Copyright 2020, with permission from Elsevier.110

Long-term use of manure and waste as fertilizer can lead to plants absorbing antibiotics from treated soil, contaminated water, or raw manure. This can expose humans to lower concentrations of antibiotics throughout the food chain.108 In vegetables like forage, corn, wheat, and peanuts, there is a possibility of them absorbing and storing antibiotics when they are fertilized with animal manure instigating that antibiotics present in the manure can be taken up by these crops and retained within their tissues (Figure 7). These low concentration antibiotics can increase development and persistence of ARGs in human and animal pathogens.109

Furthermore, AMR microorganisms and ARGs in the wastewater and raw manure can also be transferred to plants. These microorganisms inhabit the intercellular spaces or cells of various tissues and organs of healthy plants at a certain stage, or all stages, and are called plant endophytes. These AMR microbes and ARGs are obtained by humans and animals in the food chain (Figure 7).111 Another author112 it was found that the endophytic bacteria present in celery, Chinese cabbage, and cucumber plants, which were cultivated using chicken manure, exhibited a notable level of antibiotic resistance. Among the antibiotics tested, the bacteria showed the highest rate of resistance against cefalexin.

Figure 7 Transmission loop of AMRM and ARG among agronomic production, plants, animals, and human systems. Reprinted from Yan Z, Xiong C, Liu H, et al. Sustainable agricultural practices contribute significantly to one health. J Sustain Agric Environ. 2022;1(3):165–176. © 2022 The Authors. Journal of Sustainable Agriculture and Environment published by Global Initiative of Crop Microbiome and Sustainable Agriculture and John Wiley & Sons Australia, Ltd. Creative Commons.111 AMR microorganism and ARG in wastewater, raw manure, or contaminated water adds to the leaf and flowers (the nectar and pollens), fruits, and seeds phyllosphere microbiomes and reach humans via raw foods.

The burial service industry, involving thanatopraxy care, burial and incineration may be flourishing worldwide commerce and closely connected to well-being care including in the arrangement, capacity, transport and consequent burial in cemeteries.113 In societies around the world, the predominance of infectious and incessant maladies caused by hurtful microorganisms incredibly contributes to human sickness and mortality. To combat these infections, different therapeutic drugs such as antimicrobial, antiretrovirals, and antifungals are utilized based on the particular pathogens included.114

In another way, as someone passes away, the process of thanatopraxy care including the use of embalming fluids containing various synthetic substances like personal care products, pharmaceuticals, antimicrobials, disinfectants, colognes and moisturizers provoke and/or disseminate AMR.113 Wastewaters from funeral parlors and leachates from cemeteries/gravesites may also serve as a hotspot reservoir of ARGs. In addition is shown that cemeteries contribute to groundwater contamination by non-steroidal anti-inflammatory drugs/analgesics (salicylic acid, nimesulide) and psychiatric drugs (carbamazepine, fluoxetine).115

Human cadavers can potentially contain traces of pharmaceuticals, particularly antibiotics administered during treatment for various infections, contributing to the development of AMR. Consequently, solid waste materials like used bandages, wipes, and gloves, as well as wastewater and airborne particles from facilities involved in thanatopraxy, may carry a diverse range of pharmaceuticals, AMR bacteria, and ARGs (Figure 8).116 Moreover, the interment and possible decay of human bodies in cemeteries result in the discharge of leachates containing medications, resistant microbes, and ARGs to the surroundings (Figure 8).117

Figure 8 General routes of transmission of AMR microbes and ARG