Antimicrobial: Uses and Risks

Antimicrobial: Uses and Risks

Flourage, M. Rady¹ & Asmaa, A. El gendy²

¹Mycology Department, Animal Health Research Institute, ARC. Egypt.

²Bacteriology Department, Animal Health Research Institute, ARC. Egypt

ABSTRACT:

An antimicrobial agent is a naturally occurring, semi-synthetic, or synthesized chemical that at doses attainable, demonstrates antimicrobial action and contains molecules that are effective against bacteria, viruses, , and fungi that either kill or prevent the growth of microorganisms.           

Antimicrobials are efficient at limiting, preventing, or eliminating the growth of microorganisms in both humans and animals and their answerable use avoids the development, persistence, and dissemination of resistant microorganisms.

Veterinarians must be aware of which and how antibiotics to use in food animals must also be made regarding human health and the environmental impact.

Illegal and excessive use of antimicrobials in livestock breeding has major harmful effects, such as leaving residues in animal products and posing a risk to humans.

The most obvious reasons for undesired residue are long-acting medications, overdosing, and not adhering to the withdrawal phase. Regulations concerning antimicrobial residual limits should strictly adhere to withdrawal periods.

1. INTRODUCTION:

              An antimicrobial agent is a natural or synthetic a compound that is selectively lethal to organisms, such as bacteria, fungi, helminthes, parasites, and rickettsia, without having a detrimental effect on the host (Graham, 2023; Lalchhandama, 2021).

             Antibiotics were considered "miracle drugs" when they were first discovered in 1928, revolutionizing modern medicine. Antibiotics have made major advances in medical healthcare, in addition to being used to treat infectious disorders, major operations, organ transplants, and cancer chemotherapy would not be achievable without them (Shaw et al., 2020).

             Antibiotics have recently contributed significantly to economic expansion by improving healthcare, reducing mortality, and raising animal productivity.  Even so, the widespread consumption of antimicrobial agents has driven bacterial resistance more serious, led to ineffective treatments, enhanced morbidity rates, and raised medical expenses. (Bunduki et al., 2024; Gulumbe et al., 2023; Watkins and Bonomo, 2020).

             The World Health Organization, the Centre for Disease Control and Prevention, and the European Centre for Disease Prevention and Control have all warned about the growing threat of resistant bacteria (World Health Organization, 2024; Cobar and Cobar, 2024). WHO promotes more intensive antibiotic controls in veterinary practices, particularly those essential for human medicine, while the CDC and ECDC promote an overall Health strategy that considers human, animal, and environmental health (Mercy et al., 2024; Catteau et al., 2024). These organizations motivate better stewardship practices, increased monitoring and decreased use of antibiotics in animals to prevent the spread of antimicrobial-resistant diseases (Vekemans et al., 2021).

                Antibiotics can have side effects similar to all medications, thus they should be used only when necessary. Guidelines for antibiotic use rank among the most critical public health challenges in modern healthcare. Every year, antibiotics prevent millions of deaths from potentially fatal bacterial illnesses, and there is a growing proof regarding the advantages of administering antibiotics as a preventive measure. (Keenan et al., 2018; Porco et al., 2009).

          However, there is strong evidence that the use of antibiotics raises the prevalence of antibiotic resistance in the community (Goossens et al.,2005 & Skalet et al., 2010), The percentage of infections that are resistant to drugs is rising, that cannot treat, and ultimately to a lowering of our antimicrobial arsenal (Wi et al.,2017; O’Neill J.2016).

          Polyenes, nystatin, kanamycin, and amphotericin B-deoxycholate (AmB) were the first antifungal medications used in 1950. Until today, Am B has been considered a hallmark in treating invasive systemic fungal infections. However, AmB's effectiveness was linked to serious side effects, which prompted the creation of new antifungal medications such as azoles, pyrimidine antimetabolites, mitotic inhibitors, ally amines, and echinocandins (Anália et al., 2023).

          The scarcity of potent medications for antifungal therapy makes it more difficult to control fungal diseases. Conventional antifungal drugs may also result in cytotoxicity, which affects the liver and kidneys and produces reactive oxygen species. In addition, more instances of fungus resistance to azole classes like fluconazole, itraconazole, voriconazole, or posaconazole have been reported (Jong et al., 2020).

2. Classification of antimicrobial

               Most approaches to classification have two basic categories: the first is based on chemical structure, and the second is based on mode of action. A systematic and practical classification system based primarily on chemical structure characteristics has been developed, which includes tetracycline, beta-lactams, aminoglycosides, fosfomycin, macrolides, quinolones, sulphonamides, Glycopeptides and polymyxin. Another valuable classification is based on the specific mechanism of action and it will be discussed in details (Wang, 2023; Sahoo & Banik 2020)

 2.1.   Classification of antibiotics

 2.1.1.   Classification according to chemical Structure

              Β-lactam antibiotics, including penicillin, cephalosporins, carbapenems, and aztreonam, are the most prevalent class. Penicillins are classified into several subclasses, including natural, penicillinase-resistant penicillin (methicillin and oxacillin, nafcillin), aminopenicillins (amoxicillin and ampicillin), and anti pseudomonal and extended-spectrum penicillin (piperacillin, ticarcillin). Tazobactam, clavulanic acid, and sulbactam are β-lactamase inhibitors that, when combined with β-lactam antibiotics, inhibit the bacterial enzyme targeted against the medicine, hence enhancing its antibacterial activity. Other antibiotic classes include lincosamide, vancomycin, teicoplanin, kanamycin, macrolide, tetracycline, aminoglycoside, fluoroquinolone, and sulfonamide. (Lima et al. 2020; Kim et al. 2023)

2.1.2. Classification according to the mode of action

2.1.2.1 Suppression of Protein synthesis

             Tetracycline, penicillin, erythromycin, lincomycin, puromycin, chloramphenicol, and streptomycin are all bacterial protein synthesis inhibitors. Mitochondria have a protein synthesis/photosynthesizing mechanism similar to the rickettsia and chloroplasts of blue-green algae. Bacterial death occurs when the cell is unable to produce certain proteins needed for different cellular processes. (Singhal et al., 2023).

                Several protein synthesis inhibitors modify and interfere with the synchronized movement of ribosomal subunits during tRNA and mRNA translocation on the ribosome, or by engaging with the elongation factors EF-G and EF-Tu, which have roles in ribosomal subunit movement and aminoacyl-tRNA retention. Furthermore, protein synthesis inhibitors such as oxazolidinone and tetracycline have bacteriostatic properties because they impair the termination of translation. In contrast to bacteriostatic antibiotics, bactericidal drugs also limit protein synthesis. The majority of these agents' actions are connected to the block of initiation or the earliest phases of protein synthesis, as opposed to the block in the step of elongation, which is characteristic of bacteriostatic agents and those that do not inhibit bacterial protein synthesis. (Anandabaskar  2021).

2.1.2.2. Nucleic acid synthesis inhibitors

                Mechanisms Compounds hinder bacterial DNA replication, which is a key target. Quinolones are the favoured drug for targeting DNA gyrase, but TB antibiotics are equally effective in targeting topoisomerase IV. Folate synthesis antagonists are used to prevent and cure UTIs. The mechanisms of action involve inhibiting the synthesis of tetrahydrofolic acid, which is required for microbe growth. The therapy of UTIs concentrates on the broad-spectrum nature. We classified the medications according to their methods of action: sulfonamides, trimethoprim, a combination of the two, and minocycline. Bacteriostatic sulfonamides are used as first-line antibiotics for UTIs, with medications that target other ribosome structures such as rifampin (RNA polymerase) and levofloxacin (gyrase and topoisomerase) (Spencer and Panda 2023). An exploratory screening research was planned to maximise coverage, hence minocycline and doxycycline were included. Furthermore, these two medicines exhibit broad-spectrum antifungal efficacy (Peloquin and Davies 2021)

2.1.2.3 Cell wall synthesis inhibitors

              Because bacterial peptidoglycan differs from the cell walls of higher animal and plant cells, its chemical structure is well understood. The efficacy of beta-lactam antibiotics in maintaining peptidoglycan production underscores the significance of their irreducibility. The greater number of medicines used to treat gram-positive organisms than gram-negative rods are related to this subgroup's lower permeability. (Frei et al., 2023).

2.1.2.4 Alteration of cell membrane action

            Impairment of Cell Membrane Function, leading to cytoplasmic membrane lysis and cell leakage. Both Gram-positive and Gram-negative bacteria rely heavily on lipids in their cell membranes. These lipid phospholipids have a hydrophilic head (and two hydrophobic fatty acid chains that repel water. The fundamental distinctions between the two cell membrane types are the presence or lack of teichoic acid and lipopolysaccharide (LPS). In Gram-positive bacteria, the cytoplasmic (inner) membrane is tightly connected with a thick peptidoglycan layer. Gram-negative organisms, on the other hand, have a thick peptidoglycan layer between the cytoplasmic and lipopolysaccharide (outer) membranes, which are likewise made up of a phospholipid bilayer. (Szlasa et al., 2020)

                 Phospholipids, teichoic acid, and lipopolysaccharides are essential for bacterial integrity because they regulate the cell membrane's selective permeability. For example, peptidoglycan contains d-amino acids and amino sugar polymers, is linked together by short peptide cross-links, is made up of long-chain hydrophilic glycan strands (N-acetyl glucosamine and N-acetyl muramic acid, which are folded in an alternating sequence), and contains repeating pentapeptide units. These features, which are key components of the bacterial cell wall, help to shape the cytoplasmic membrane by increasing curvature. Bacteria that perform these activities because of phospholipids, teichoic acid, and lipopolysaccharide, which make a selective permeabilized membrane, die (Zheng et al., 2024).

2.1.2.5 Suppression of metabolic pathways

            Some antibiotics suppress metabolite production via repression mechanisms. Folic acid biosynthesis, isoprenoid biosynthesis, and fatty acid biosynthesis are all inhibited processes. It is critical to understand how antibiotics disrupt with the metabolic pathways that contribute to a bacterium's ability to grow, so we have included the main concepts that may aid in demonstrating the mechanisms of all antibiotics that block metabolism. Though it is not always available to define the steps in a bacterium's metabolic pathway that are being inhibited by an antibiotic, these closure points are frequently useful in evaluating the spectrum of antimicrobial action of such drugs.( Alavi and Hamblin 2023)

                 A complete comprehension of the mechanisms of action of antimicrobial that interact with bacteria's metabolic pathways may aid in determining the efficacy of current medicines against resistant species.As novel techniques to mounting a defence against newly emergent resistant strains of bacteria are developed, it may be possible to establish the spectrum of actions they can do for a given agent by understanding how such compounds cause bacterial cell destruction. (Uddin et al., 2021).

2.2. Antifungal Drug Classification and Mechanism of Action.

2.2.1. Azoles

                 Among the antifungal drug classes, azoles are the most widely prescribed . The mechanism behind the action of azoles involves debilitating the fungal membrane, as identified: The ERG11 gene expresses 14-lanosterol demethylase, which transforms lanosterol to ergosterol in the fungal cellular membrane. The binding region of this enzyme contains an iron iron protoporphyrina substance . Because azoles bound to iron, they interfere with the process of biosynthesis of ergosterol. 14-methyl sterols can accumulate and alter the stability, permeability, and activity of the membrane and the enzymes that interact with it when ergosterol synthesis is suppressed. (Cowen et al., 2025).

                 Miconaz, clotrimazole, econazole, ketoconazole, tioconazole, and sulconazole are some of the well-known examples of the first imidazole-based azoles to be developed. Luliconazole is the most recent imidazole to be licensed for topical treatment of dermatophytosis. Triazole-based therapeutics with a wider range of action like, fluconazole and itraconazole, were later created. Triazoles are utilised for both systematic and local infections, however imidazoles are mostly used for fungal infections of the mucosal. (Sanglard and Coste, 2016)

2.2.2 Polyenes

                   Streptomyces is the original source of polyenes, which are macrolides and amphipathic chemical compounds (Vandeputte et al., 2012). Ergosterol is bound by polyenes, which results in gaps in the plasma membrane. Cell death results from the compromised membrane integrity and ionic imbalance. (Sanglard et al., 2009).

                The three main polyenes are natamycin, nystatin, and amphotericin B (AmpB). In systemic invasive fungal infections, AmpB is mostly effective against species of Aspergillus, Candida, and Cryptococcus. However, because of their poor absorption, natamycin and nystatin are effective for topical infections. (Lemke et al., 2005).

2.2.3 Pyrimidine Analogs

                 Pyrimidine analogues 5-fluorocytosine and 5-fluorouracil are synthetic counterparts of the nucleotide cytosine (5-FU).  Pyrimidine analogue 5-fluorocytosine is converted to cytotidine deaminase into 5-FU, which prevents DNA replication or protein synthesis, which both impair cellular function. These therapeutic alternatives possess anti-Candida and anti-Cryptococcus activities. 5-FC's rapid absorption contributes to its high bioavailability. (Sanglard et al., 2009: Lemke et al., 2005).

2.2.4 Allylamines, Thiocarbamates and Morpholines

               Thiocarbamates and allylamines are quite efficient against dermatophytes, although they are only moderately effective against yeast. Thiocarbamates and allylamines may be able to bind to the enzyme more easily due to their naphthalene ring (Polak, 1990). Their interactions with the mammals’ enzyme that synthesises cholesterol have been limited. Morpholine amorolfine is a topically antifungal drug used to treat onychomycosis by blocking the enzymes 7, 8-isomerase and 14-reductase, which are involved in ergosterol production. Morpholines that block the ERG24 and ERG2 pathways that control the synthesis of ergosterol include fenpropimorph and amorolfine, whereas allylamines and thiocarbamates only impact the ERG1 gene. Terbinafine is one of the allylamines, and tolnaftate is one of the thiocarbamates.  (Mercer, 1991: Haria 1995)

2.2.5 Echinocandins

Echinocandins non-competitively block the enzyme 1, 3-β-D-glucan synthase, which is essential for β-glucan production in the fungi cell wall. Cellular wall stress results from failure in the biosynthesis of cell wall components, which compromises fungal cells' structural integrity (Shapiro et al., 2011) Echinocandins-treated cells consequently show thicker cell walls, higher osmotic sensitivity, pseudo hyphae growth and development, lower sterol levels, and separation defects.(Ghannoum and Rice1999). Since these medications target a particular cell wall synthesis pathway that is limited to fungal cells, they are commonly non-toxic to mammalian cells (Perlin  2011).

3. Uses of antimicrobial agents in animal

                Therapy, metaphylaxis, prophylaxis, and growth promotion were the four ways in which substances with antimicrobial activity were used in animals. American Food and Drug Administration reported that Eighty percent of antimicrobials are used for managing livestock that produces animal-based food items (Rahman et al., 2021).

          The use of antimicrobial medications in animals continues to support the growth of more robust, healthy animals with lower rates of disease, morbidity, and mortality as well as the production of large amounts of nutritious and affordable food for human consumption (Oliver et al., 2011). Furthermore, as livestock manufacturing processes change from extensive to intensive developed production, the early use of antibiotics in animals is exploited for food production. (Steinfeld, 2004).

            Antibiotics are acknowledged as contributing to increase life spans in the 20th century as a result of a decrease in mortality from infectious diseases (Adedeji, 2016).

                The antimicrobial growth promoter contains various chemotherapeutic agents that can be utilized to increase body weight gain, feed conversion efficiency, and general health. Due to growing need for improved productivity, the animal industry is becoming more in favour of the professional use of antimicrobial growth promoters. AGP is supplied at a very low dose, changing the bacterial composition and amount in animal bodies in a way that reduces the incidence of certain diseases and infections (Chirag et al., 2011).

              For necrotic enteritis in broilers, prophylactic treatment has been shown to be beneficial in lowering pathogen challenge and disease as well as improving animal health and welfare. (Lanckriet et al., 2010). And bovine respiratory disease (Schunich et al., 2002).

          Additionally, there is convincing evidence that metaphylaxis significantly lessens the effects of bovine respiratory illness and ewe lameness (Sargison & Scott 2011), and diarrhea in newly born calves (Lorenz et al., 2011). Selective metaphylaxis is predicted to become more prevalent as diagnostic capacity increases. (González-Martín et al., 2011).

          There is mounting evidence that a reduced capacity to select resistant bacteria could be an additional advantage of metaphylactic use of antimicrobial drugs. Because there is less bacterial inoculum in the early stages of the disease so there is less chance that resistance mutations will exist in this smaller bacterial population. (Cantón & Morosini 2011).

 3.1. Uses of antibiotics in veterinary medicine

  3.1.1. Uses of antibiotics in Producing Animals

               In addition to their medicinal, metaphylactic, and preventative uses, antibiotics are also utilized as growth boosters in animals raised for food. In order to increase growth and production efficiency, the latter entails gradually introducing sub-therapeutic doses of medications into ration or water (Canton et al., 2021).                

            Animals are frequently given fewer doses of antibiotics for growth promotion than for medical purposes. However, because it repeatedly exposes bacteria to sublethal doses of the antibiotic, such a strategy is more likely to significantly influence the emergence of antimicrobial resistance since it encourages the selection and retention of resistance traits. Additionally, coccidiosis, a prevalent parasite disease in chicken, is prevented by prophylactic administration of antimicrobials including ionophores and sulfonamides, which are frequently employed as coccidiostats.  By 2030, Oceania, North America, and Europe are expected to have the lowest percentage increases in antibiotic sales (3.1%, 4.3%, and 6.7%, respectively), while Africa is expected to have the largest growth in antibiotic consumption (37%). Asia was the largest antibiotic consumer in both 2017 and 2030, and its consumption is predicted to rise by 10.3% by 2030, accounting for 68% of  the global antibiotic use in 2017. (Tiseo et al., 2020).

              Antibiotics have been used more often for non-therapeutic uses in food animals over the years than for medicinal uses. According to estimates, 50–80% of medications generated in most industrialized nations are used by cattle alone (Cully et al., 2014).

               Antibiotics are a crucial component of the fishing industry. Four primary factors influence the effectiveness of antibiotics in controlling fish diseases: (1) the bacterial component itself, (2) the bacterial strains' sensitivity and/or resistance to the selected antibiotic, (3) the appropriate dosage and treatment intervals, and (4) other stressors. Antibiotics do not treat treated fish directly; instead, they help a fish's immune response fight off germs by limiting bacterial population in the fish (Castro et al., 2008).

3.1.2. Pet Animals

               Over use of medications, particularly antibiotics, in pet therapy is more frequent than in food-raised animals. Guidelines governing the extra-label use of medications vary greatly between nations; for instance, extra-label administration of medications, particularly antibiotics, to companion animals is permitted in the United States, but it is highly restricted in Europe (Papich 2021).

               Overall, the prescription of antibiotics was related to 29.2% of veterinarian evaluations for dogs and cats. The largest rate of prescriptions was found in referral clinics (31.4%), followed by general care practices (26.4%) and private shelters (12.0%). More dogs than cats and more hospitalized patients than outpatient clinics received antibiotic prescriptions. The most common reasons for prescribing antibiotics were skin, gastrointestinal, surgical, ophthalmic, urinary, and respiratory illnesses. The duration of post procedure prophylactic antibiotic prescriptions was equal to that of prescriptions meant to treat infections, and there was a high rate of antibiotic administration for clean operations. Many veterinary professional organizations discourage the use of peri- and postsurgical prophylaxis, the majority of routine clean procedures when following aseptic technique, in accordance with the principles of judicious AU (Granick and Beaudoin 2025).

3.2. Uses of antifungal

                    Fungal infections can be systemic and sometimes fatal (such as blastomycosis, cryptococcosis, histoplasmosis, and coccidioidomycosis) or mainly superficial and bothersome (such as dermatophytosis). Clinically significant dimorphic fungi, at an average temperature 25°C grow like mould in vitro, but in a host, they mimic yeast as in Histoplasma capsulatum, Sporothrix schenckii, and Rhinosporidium. Polyenes, azoles, allylamines, nucleoside analogues, and echinocandins are the five main types of systemic antifungal medicines. The two classes most frequently utilized in veterinary medicine are polyenes and azoles. Most systemic antifungals prescribed are off-label because there are very few medications licensed for veterinary use in the United States, practically all of which are topical treatment (Melissia 2024).

                  Antifungal medications are an important part of today's medical care of mycoses and are a pharmacologically varied category of medications. Despite substantial advancements in antimycotic pharmacology, notably the mortality rate from common invasive fungal illnesses has remained high over the preceding three decades: Aspergillus fumigatus (around 50 to 90%), Candida albicans (20 to 40%), and Cryptococcus neoformans (nearly 20 to 70%). (Lai et al 2008 & Park et al., 2009).

               Antifungal drugs' practical uses and therapeutic regimens have demonstrated efficacy in the prevention and control of fungal diseases in feline, canine, equine and swine (Rochette et al., 2003).

4. Routes of administration:

          Antimicrobials can be administered orally for local action in the GIT, for absorption and systemic activity, topically, or intramammary at the infection site. They can also be administered parenteral to avoid GIT, such as via intravenous, intramuscular (IM), or subcutaneous injection (Gail et al., 2021).

          The intramuscular route has been quite common in ruminants and swine, although it can occasionally result in tissue injury, high residue concentrations, and extended sensitivity of the active component or its formulation (Benedict 2011).

           The subcutaneous injection was quickly and widely adopted after it was discovered that this technique of giving antimicrobial drugs was associated with pharmacokinetics that were not significantly different from those following intramuscular injection and that it caused the least amount of tissue irritation and limited financial losses associated with trimming at slaughter (Van Donkersgoed et al., 2000).

           When considering water medication, it is critical to know the average water consumption in order to estimate the antimicrobial agent's absorption rate. Factors impacting poultry water consumption: (Fairchild & Ritz 2009), pigs, and beef cattle (National Research Council (NRC) 2000) comprise feed composition, activity level, ambient temperature of the water, sanitation, water palatable qualities, activity level, age growth stage, and, especially for poultry, lighting program. Additionally, the variety and management of drinkers may result in varying amounts of wastewater. (Torrey et al., 2008).

          One of the most extensively used practices in the world is the administration of antimicrobial drugs in feed, which should be done in compliance with proper animal feeding practices (Codex Alimentarius Commission (CAC) 2004). The drug is often added to the final ration for bigger groups of animals, but it may be top-dressed in the feed for smaller groups. The medicated feed may be administered as a dry loose mix, granules mash, or crumble. (Schofield 2005).

          Fluconazole, ketoconazole, itraconazole, terbinafine and griseofulvin are used as oral antifungals, whereas azoles, ciclopirox oleamine, terbinafine are topically used (Madhuri et al., 2021).

          Before the widespread use of acridine dyes in the current century of antimicrobial medicines, mastitis was one of the most costly infections that animals might suffer. It is crucial to understand that lactating and dry cow products are two very different kinds of intramammary preparations with unique formulation properties. They are either long-acting or quick-acting (Heikkilä 2012).

5. Possible risks of extensive antimicrobial abuse:

 5.1. Transfer of antimicrobial resistance between animals and humans

             The reluctant use of antibiotics has subsequently led to an increase in antimicrobial resistance, and the use of antibiotics in pet and food-producing animals has propagated resistant microbes. The worldwide distribution of resistance is complex, and it may be improved by variables other than the total amount of antibiotics used.(Alice et al., 2023)

             Growth-promoting antibiotics (GPAs) have been requested to be banned by many organization such as the World Health Organization, the American Medical Association, and the American Public Health Association since Antibiotic-resistant microorganisms proliferate as a result of their usage. On the other hand, industries believe that their elimination will significantly raise manufacturing costs and is unlikely to reduce the danger of antibiotic-resistant diseases in humans. (Smith 2002& Casewell et al., 2003).

            Antimicrobial resistance is one of the greatest challenges to human health worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) kills more Americans annually than suicide, pneumonia, AIDS, and neurological disorders (Infectious Diseases Society of America 2011).

           Antibiotic resistance among microorganisms in animal habitats has increased due to the improper use of antibiotics as growth promoters, or as for infection control and treatment in farm animal. Human beings can be subjected to the reservoir of resistance through consuming food and direct or indirect interaction. By directly generating harmful health consequences or by passing on the resistance genes to other infectious agents resistant bacteria can result in diseases that are more difficult to treat and have higher rates of fatality and morbidity (Economou and Gousia, 2015; Nayem, 2022).  

            Antibiotic resistance is one of the major threats to human health in the 21st century as a result of due to mutations in the bacterial genome bacterial that impair antibiotics' efficacy. According to the UK Government-commission assessment on Antimicrobial Resistance, it may kill 10 million people yearly by 2050 (O'Neill, 2016).

            The miss-use of antibiotics in the human, animal, and environmental sectors, as well as the spread of bacterial resistance genes within these sectors , are some of the factors that contribute to ABR. Antibiotics used to treat human bacterial illnesses are given to animals. Given the significance and interdependence of human, animal, and environmental variables in antibiotic resistance (McEwen and Collignon, 2018).

            It is estimated that strains resistant to isoniazid and rifampicin represent 20% of TB cases that have already received treatment and 3.7% of new cases. These anti-tuberculosis therapies have been beneficial against tuberculosis for several decades, but their current efficacy is limited. Nowadays, only 50% of cases of multidrug-resistant tuberculosis are effectively treated with currently available antibiotics. (World Health Organization, 2014).

          GLASS initiated a global collaborative effort to consolidate the information already available on antifungal-resistant infections in response to the growing concern about antifungal-resistant diseases. Although largely out of the public’s view, fungi are significant contributors to human disease and mortality, and resistance to antifungal medications is an issue, as it is for antibiotic drugs. One of the greatest challenges in combating the rise of fungus resistant to antifungals is a global data shortage (World Health Organization 2019).

          Antifungal drug resistance can be classified into two categories: acquired (secondary) resistance, which arises as a result of exposure to a particular factor, typically an antifungal drug or its structural analogue, and intrinsic (primary) resistance, which is genetically encoded and linked to fungal species regardless of drug exposure. (Ben-Ami & Kontoyiannis2021).

5.2. Antimicrobial residues in foodstuff:

               Antimicrobial usage in animals may result in drug residues in many animal  food products . The spread of antibiotic-resistant bacteria to humans, immunopathological effects, sensitivities, DNA mutation, gentamicin-induced kidney failure, hepatic damage fertility problems, chloramphenicol-induced bone marrow toxicity, and even cancer risk (sulphamethazine, oxytetracycline, furazolidone) are just a few of the detrimental effects that these residues may cause. The most significant adverse effect of antibiotic residues is transmission of antibiotic-resistant bacteria to people (Merve Bacanlı & Nurşen Başaran, 2019).

             Antibiotics are typically used primarily for the management of infections in animals as well as for stimulating growth. But while the residues and byproducts have a number of adverse consequences on the human body such as (mutations, destroying the bone marrow, and affecting the reproductive organs), they also have a wider negative impact on the surroundings. (Fritz  & Heide 2021).

5.3. Drug hypersensitivity reaction

             A sensitised patient's immune-mediated reaction to a medicine is known as drug hypersensitivity, whereas drug allergy is limited to IgE-mediated reactions. Drug allergies can manifest as asthma, dermal reaction and latent hypersensitivity response to medication that appear to be more commonly associated with antibiotics, particularly Penicillin. Sensitized people may experience an allergic reaction to penicillin residues in milk (Demoly & Romano, 2005).

              Penicillin was known to cause hypersensitivity in about 10% but it was less clear how much of an animal population was hypersensitive to the antibiotic. In exceptional cases, impairment of the liver can arise from a specific allergenic response to hepatic cells impacted by macrolides over time. Rarely, exposure to chloramphenicol residues in food results in fatal blood dyscrasia (Settepani, 1984).

            Antifungal hypersensitivity reactions can be categorized based on the clinical phenotype and latency (immediate or delayed). There have been reports of fast reactions that are associated with both immunoglobulin-Emediated reactions and immunoglobulin-E mediated mast cells induction, but the majority of cases documented, are delayed T-cell-mediated reactions of various severity (Ana et al., 2021).

5.4. Modification of the normal intestinal bacteria

             Intestinal bacteria serve as a barrier to keep pathogenic foreign pathogens away. Antimicrobial might negatively affect the total number of microbial community or destroy a certain significant species. Gastrointestinal disorders may result from the broad-spectrum antibiotics' detrimental effects on various types of intestinal flora. This effect has been observed when vancomycin, nitroimidazole, and metronidazole have been used in individuals as well as when flunixin, streptomycin, and tylosin have been used in animals. (Beyene, 2016).

          The maintenance of host health is greatly influenced by their gastrointestinal flora. Antibiotics have enormous effects on the host through the gut microbiota, which can impact many physiological functions, such as immune regulation, metabolic activity, and ultimately general wellness  (Dhrati et al., 2022)

          Antibiotics greatly alter the gut microbiota, limiting the number of bacterial species that beneficial for the host's health while promoting the growth of possible infections (Tony Rochegüe et al., 2021)

          After the trial, the intestinal microbiota composition of the fluconazole-treated mice was significantly changed. However, fluconazole decreased the diversity of the bacterial flora while having no effect on the relative quantity of bacteria. (Xing et al., 2021). 

          Gastrointestinal microbiota development and colonisation in childhood are affected by the presence of antibiotic residues (Chen et al., 2022). Furthermore, neurological conditions like bulimia depression, Alzheimer's disease, irritable bowel syndrome, and Parkinson's disorder are brought on by compromising the healthy balance of intestinal flora. ( Piñeiro & Cerniglia, 2021). 

5.5. Carcinogenic effect

             A substance's ability to cause cancer is referred to having carcinogenic activity. The collaboration with or covalent binding of carcinogenic residues to a variety of Proteins, as well genetic material (DNA), ribonucleic acid (RNA), carbohydrates, phospholipids, and other cytoplasmic compounds have been associated with dormant oncogenic activity (Beyene, 2016). Chloramphenicol was found to be genotoxic and potentially carcinogenic by the Joint FAO/WHO Expert Committee on Food Additives (Anon, 2002; Demoly & Romano, 2005 ;Nisha, 2008).

5.6. Teratogenic effect

             Any medication or agent that disrupts the foetus or embryo at an important early stage in development is referred to as a teratogen. Consequently, a congenital abnormality affects the organism's ability to function effectively and maintain its structural stability (Beyene, 2016). During early stage of pregnancy, administration of anthelmintic, benzimidazole results in embryo toxic and teratogenic effect.

            While azoles, ciclopirox oleamine, and terbinafine are applied topically, fluconazole, ketoconazole, itraconazole, terbinafine, and griseofulvin are taken orally as antifungals. Oral antifungals have been linked to spontaneous abortions and genetic disorders in the embryo (Madhuri et al., 2021).

6. CONCLUSION

              The treatment and prevention of diseases brought on by a variety of microorganisms, such as bacteria, viruses, and fungi, depend significantly on antimicrobials. However, there are a number of serious issues brought about by the growing and frequently inappropriate use of antibiotics, especially when it comes to antimicrobial resistance (AMR). The aforementioned situation poses a significant risk to public health and is also a developing worldwide emergency that makes managing infectious diseases more difficult, prolongs illness, and raises death rates.

              Furthermore, it is inconceivable to dismiss how antibiotic residues affect the environment and human health. When people eat food that has been contaminated, drug residues from animal products—such as meat, milk, and eggs can accumulate up in their organs over time. Prolonged exposure to these residues has been associated with a number of negative outcomes, such as allergic reactions, disturbances of the human microbiome, and more severe long-term impacts like teratogenicity (the capacity to cause birth defects) and carcinogenicity (the potential to generate cancer). These dangers show that stricter regulations are required, including making sure that medications used in animal husbandry have sufficient withdrawal times and improving food safety procedures.

             Researchers must keep highlighting the significance of using antibiotics responsibly, incorporate resistance monitoring techniques, and encourage the creation of alternative treatment alternatives in order to reduce these dangers. In order to protect public health and the effectiveness of current treatments, it is imperative to address the intricate interactions between antimicrobial use, resistance development, and environmental contamination.