Unit 3 Antimicrobials Notes 2025 Jan 24 PDF

Unit 3. Antimicrobials for Controlling Zoonosis (defn): Infectious disease transmitted Infectious Disorders from animal-to-human. Fifty-eight percent of human diseases and 73% percent of emerging...

Unit 3. Antimicrobials for Controlling Zoonosis (defn): Infectious disease transmitted Infectious Disorders from animal-to-human. Fifty-eight percent of human diseases and 73% percent of emerging Historical use of antimicrobials for growth infectious human pathogens are of zoonotic promotion and disease prevention: origin. Many zoonotic diseases involve livestock and companion animals as intermediate vectors. Antimicrobial usage in animal production has become an accepted practice today to minimize Increasing livestock productivity with impact of microbial stressors. Antimicrobials are antimicrobials (Slide 3) divided into four classes: antibiotics, antifungals, antivirals, and antiparasitics. Antimicrobials increase livestock productivity by A) promoting growth, and B) reducing This lecture will primarily emphasize antibiotics production loss to disease. because of their historical popularity. In 2015, 2/3 of global antibiotic production was reportedly A. Promoting growth: At sub-therapeutic used for animal husbandry. concentrations (i.e. 2.5-125 ppm), antimicrobials in animal feed or water are referred to as Global livestock antibiotic usage estimates antimicrobial growth promoters (AGP). AGP (cattle, sheep, chicken and pigs) in 2020 were were first reported to promote animal growth in 99,502 tonnes and have been projected to 1946, and in 1951 they were approved for use in increase by 8% by 2030. The top 5 user countries livestock feed by the US Food and Drug in order include China, Brazil, India, USA, and Administration (FDA). Australia (Mulchandani R et al. 2023 PLOS Global Public Health). There is considerable evidence that AGP effectively improve the growth of pigs and In terms of aquaculture, global estimates of poultry under poor hygiene conditions; this antibiotic usage in 2017 were 11,308 tonnes and especially relevant during early life when risk of are projected to increase 33% by 2030. The top disease is greatest because the neuroendocrine- user countries in order include China, India, immune system is still under-developed. Indonesia and Vietnam (Van Boeckel TP 2020 Scientific Reports 10: 21878) When production systems are modified to improve housing and feed and water quality, As with humans, when animals consume these however, the effectiveness of AGP is less certain, antibiotics, 30 to 90% end up being excreted in and usage may reduce profit margins for feces and urine into the surrounding environment producers. (Singer AC. 2016 Frontiers Microbiol 7: 1728: 1). Summary of AGP previously used in Canadian Driving forces behind antimicrobial usage on livestock production (Slide 4): livestock and companion animals (Slide 2): AGP mechanisms of action (Slide 5): 1. Increasing livestock productivity -producer driven The exact mechanism(s) by which anti- 2. Increasing product quality -consumer driven microbials promote animal growth remain to be 3. Improving product uniformity -food processor determined, and undoubtedly will vary among and consumer driven antimicrobials. 4. Improving animal welfare by reducing disease -consumer and producer driven Understanding these mechanism(s) of action 5. Reducing risk of zoonosis -society driven will be essential for the development of alternative growth promoters in the future. Current research suggests that the mechanism(s) Increasing livestock productivity with of action involve interactions with the a) antimicrobials contd. (Slide 6): microbiome and b) promoting gut immunity. B. Reducing production loss to disease: a) Interactions with the gut microbiota: AGPs may interact with the gut microbiota in the Antimicrobials are sometimes administered to following ways: livestock to prevent disease but are more appropriately used therapeutically to treat sick 1. Inducing subtle changes to microbial livestock and aquaculture species. After livestock populations: recover from illness, they can then be returned to -Optimize nutrient availability for the animal their regular production cycle. -Controls number of pathogens that contribute to subclinical and clinical disease; this may also 2016 US: Usage of approved antimicrobials allow the immune system to respond without (Slide 7): becoming overwhelmed In the US, the following medically important 2. Reducing microbial competition for nutrients antimicrobials were primarily used on food producing animals between 2015-16: 3. Reducing production of microbial metabolites tetracyclines (70%), penicillins (10%), with growth-inhibiting properties, or vice-versa. macrolides (7%), sulfas (4%), aminoglycosides (4%). b) Promoting gut immunity: Therapeutic concentrations of certain antimicrobials appear to Tetracyclines (42%) and ionophores (33%) are reduce gut inflammation and modulate the host the most used of all antimicrobials. immune response (i.e. alter T cell sub- populations). 2016 US: Usage of medically important approved antimicrobials by species (Slide 8): While inflammation is an essential innate host response to pathogenic infection, excessive In the US, the following medically important inflammation may be intentionally triggered by antimicrobials were primarily used in the certain pathogens (i.e. viruses) to evade immune following livestock sectors between 2015-16: detection. cattle > swine > turkey > chicken. The host inflammatory response is also Poultry medically important antibiotic usage physiologically costly for the following reasons: continues to decrease while use of ionophores continues to increase. 1. The energy required for growth is redirected to immune-related protein production US & EU Approved antimicrobials, tolerance levels and their withdrawal times (Slide 9): 2. Pro-inflammatory cytokines (TNFa, IL-1) induce anorexia and muscle catabolism Here is a list of therapeutic antimicrobials, that are currently used in US and EU veterinary 3. Inflammation can damage the gut epithelial medicine; also included are tolerance (residue) barrier, which reduces nutrient absorption and can levels in various tissues, and the required lead to leakage of gut contents, including withdrawal time to ensure that contaminated opportunistic pathogens and their toxins, into livestock products don’t enter the human food sterile host tissues. chain. 2 Tetracyclines: Include various salts of Consequences of antimicrobial usage (Slide tetracycline, oxytetracycline and 10): chlortetracycline, and are often combined with other antimicrobials such as sulfonamides. Three important consequences of antimicrobial Tetracyclins are approved for use in all food usage in livestock production include: animal species including fish. They are used to treat a variety of bacterial infections {i.e. 1. Exposure of consumers to potentially bioactive bacterial enteritis and pneumonia} and drug residues in food products. These drugs can mycoplasma in poultry. affect consumers (i.e. allergy) and their gut microbiota. Penicillins: Many are used as water or feed additives. Examples include Penicillin G and 2. Environmental impact on other species (i.e. procaine. algae, invertebrates and fish) Macrolides: Tylosin used to treat necrotic enteritis 3. The development of antimicrobial resistant in poultry and swine dysentery, erythromycin is (AMR) pathogenic microbes, or AMR used to treat poultry chronic respiratory disease. commensal microbes that may transfer AMR genes to other pathogenic microbes. Sulfonamides: Oral sulfamethazine and sulfachloropyridazine are commonly Antimicrobial resistance (Defn): The ability of administered to calves with diarrhea, although a microorganism to become resistant to the efficacy is limited. Sulfamethazine is also used to growth inhibitory or killing effects of treat porcine septicemia and bacterial pneumonia, antimicrobials. This can severely compromise and Escherichia coli and Pasteurella multocida treatment success against human and/or animal infections (fowl cholera) in turkeys. pathogens. Sulfonamides are occasionally also used to control poultry coccidiosis. Mcr-1 and resistance to colistin (Slide 11): Aminoglycosides: Gentamicin and neomycin are In 2015, while I was at Zhijiang University in the major aminoglycosides used in livestock Hangzhou, China, a group of researchers from production. Often used to treat or control piglet this university isolated an Escherichia coli bacterial enteritis, and bacterial infections in plasmid from pig meat carrying the mcr-1 gene young chickens and turkeys. that confers resistance to a last resort antibiotic, polymyxin-E (colistin), which is used to treat Streptogramins: Virginiamycin is the major Gram-negative bacterial infections (Liu et al. streptogramin used therapeutically to treat 2016 Lancet Infect Dis 16:2:161. poultry, bovine and porcine bacterial enteric diseases. Despite a ban on the use of colistin for animals in China in 2017, this plasmid can be detected in Chloramphenicol: Not approved for food China and US watersheds, and in livestock and producing animals but is approved as a broad- pets around the world. Mcr-1 is now also found in spectrum antimicrobial for companion animals Salmonella spp. suggesting that horizontal (i.e. horses). transfer of the plasmid has occurred. Plasmid (Defn): A small DNA molecule that is physically separated from chromosomal DNA, replicates independently, and is easily mobile across species. 3 Aquaculture at the crossroads of global warming and AMR (Slide 12): A very common mechanism of AMR involves DNA mutations within genes coding enzymes that A meta-analysis of data from 40 countries of metabolize antimicrobials. DNA mutations can different economic status revealed that levels of also modify antimicrobial protein targets, and AMR fish bacterial pathogens correlated with proteins affecting membrane permeability to levels of AMR in human clinical bacteria, as well antimicrobials. as country vulnerability to climate change. Vietnam, India, Pakistan, and Bangladesh 2. Mobile genetic elements (Slide 14): Genetic displayed the highest levels of human and material can be transferred across organisms by aquaculture AMR pathogens and are amongst the the following mechanisms: most vulnerable countries to climate change and rising temperature. (Next time you go shopping 1. Transformation -foreign DNA containing for sea food, look closely where it is coming AMR gene(s) is incorporated into the microbial from!) genome by recombination. Bacteria developing AMR (Slide 13): 2. Transduction -bacteriophages found in wastewater for example, transfer DNA containing How do bacteria become AMR? Bacteria can AMR gene(s) between bacteria. become AMR by 1) developing DNA mutations, or 2) by acquiring mobile genetic elements from Bacteriophage (Defn): A virus that infects a other microorganisms. bacterium. Since many antimicrobials are produced by 3. Conjugation -a bacterial plasmid containing microbes, it is not surprising that microbes also AMR gene(s) is transferred across a small can develop AMR. membrane channel (sex pillus) that can form between bacteria. Examples: -Penicillium spp. -penicillin Misuse/overuse of antimicrobials and -Streptomyces cinnamonensis -monensin development of AMR (ionophore) -Streptomyces virginiae -virginiamycin Human and environmental exposure to drug -Streptomyces erythraea -erythromycin residues and the development of AMR is greatly -Streptomyces aureofaciens -tetracycline increased by the misuse and overuse of -Streptomyces avermitilis- ivermectin (ionophore) antimicrobials. -Streptomyces antibioticus- actinomycin Examples of antimicrobial misuse (Slide 15): 1. DNA mutations: DNA mutations occur randomly across all genomes. However, when -Use of the wrong antimicrobial to treat a disease antimicrobial treatment occurs at sub-therapeutic (i.e. Gm+ versus Gm-, virus versus bacteria) levels, this can trigger genome-wide hypermutations. -Antimicrobial treatment at higher than recommended doses, or refusing to follow Sub-therapeutic antimicrobial use also places recommended withdrawal times, increases human selection pressure on microbial populations, exposure to drug residues meaning that microbes possessing mutations in genes conferring AMR to an individual -Use of banned antimicrobials antimicrobial or related antimicrobials will survive through selective advantage. 4 -Use of poor quality or expired antimicrobials Other drivers of AMR (Slide 19): means that treatment dose is less than expected therapeutic dose ® AMR -Heavy metals (i.e. copper, zinc, cadmium, and arsenic) have also been used as AGPs because -Failure to follow prescribed treatment period ® they possess bactericidal, anthelminthic, and AMR of surviving pathogens fungicidal properties; these and other industrial heavy metals appear to also promote AMR to -Inappropriate treatment of animal waste products antimicrobials. can introduce antimicrobial residues and AMR microbes to soil and aquatic environments (i.e. -Biocides (i.e. disinfectants and surfactants) and use of livestock manure in Asian aquaculture solvents (i.e. octanol, hexane, and toluene) may industry). also promote AMR to antimicrobials. Examples of overuse (Slide 16): -Nitrogen fertilizers can also shift the relative abundance of soil microorganisms supporting the -When antimicrobials are administered to growth of AMR microbes. livestock to prevent disease instead of treating disease ® AMR AMR is now a global problem that crosses agriculture and aquaculture industry sectors and -Fifty percent of all antimicrobials prescribed to is predicted by the World Health Organization people are considered unnecessary. This overuse (WHO) to be “one of the top health challenges and misuse of antimicrobials means that humans facing the 21st century”. can become reservoirs of AMR microbes. If they interact with livestock and companion animals, Can AMR be reversed? AMR microbes and genes can be transferred from human to animal. One strategy to reduce the development and spread of AMR is to limit or suspend use of Conceptual drivers of AMR (Slide 17): antimicrobials. This is a conceptual framework (infograph) The use of antibiotics as AGP has been banned showing the potential contribution of different in Europe and in North America. Food suppliers factors driving AMR, the supporting evidence, including Tyson, McDonalds, Subway, and Taco and weighted impact on the human population Bell appear committed to reduce use of (diameter of bubble). antibiotics in food production, at least for poultry. There is now solid scientific evidence showing The rationale behind the AGP banning strategy that overuse and misuse of antimicrobials on is that it may lower selection pressure, allowing animals is a major contributor to AMR. These microbes that are not AMR, but presumed to be antimicrobials and AMR microbes can be found thriftier, to dominate; however, this may not in animal bedding, down-wind dust particles, always be the case. Regardless of whether or not farm runoff water, river and pond sediments, and AMR is reduced by banning antibiotics as AGP, soil; thus, interaction with other environmental it may at least delay further development and microbes can easily occur. (Slide 18: Typhoon spread of AMR. near Shanghai 2014) 5  has been proposed for animals, but this requires Prolonging use of therapeutic antimicrobials rapid diagnosis of disease, testing for AMR, and (Slide 20): assessment of animal health, so it is highly unrealistic for livestock. The following strategies have been proposed to prolong the use of therapeutic antimicrobials for Monitoring antimicrobial dose: Sub-therapeutic disease treatment. antimicrobial exposure can be avoided by measuring drug pharmacokinetics in real-time. Banning AGPs: This has occurred in Europe and North America but we have no control over their Testing the quality of generic antimicrobials: All use in other countries; this will require consumer commercially available antimicrobials should be education; leadership from international quality tested to ensure efficacy. governing bodies and industry; tighter regulation by government, doctors, veterinarians and Combined antimicrobial therapy: This involves pharmacists; and more rigid testing of animals, using a combination of antimicrobials with animal products and their waste for AMR and different mechanisms of action that a pathogen antimicrobial drug residues (One Health shows no cross-resistance to. Risks: The half-life Approach). of each antimicrobial will vary, and there are likely to be detrimental effects to the host Increasing access to non-medicated feeds: We microbiome. need to provide better access to non-medicated feed options for producers. Using an on-farm biosecurity program: Keep pathogens off the farm and ensure that sick In Asia for example, a feed company will make animals are isolated from other animals to a batch of fish feed for a whole community; these minimize direct and indirect pathogen exposure. people may not be educated and have no voice in the matter of antimicrobial inclusion in the feed. Research Priorities (Slide 21): Restrict antimicrobials: Restricting certain The following is a list of research priorities to antimicrobials for either human, or animal use. deal with AMR. Health Canada now requires that a prescription Develop novel antimicrobials: Most of our be filled out by a veterinarian after visitation for antimicrobial arsenal is > 35 years old. Making the use of medically important antibiotics for new antimicrobials is a huge and often livestock and companion animals. (i.e. Neomycin, unsuccessful financial endeavor that Penicillin G, Erythromycin, Virginiamycin, pharmaceutical companies are reluctant to invest Sulphonamides, Tylosin, Streptomycin, and in without strong financial incentives. Tetracycline/Chlortetracyclene/Oxytetracycline). Ionophores such as monensin and ivermectin can Alternative approaches: Research areas of interest still be purchased over the counter. include, but are not limited to, the following: Antimicrobial cycling: Replacing an -Using other compounds to attenuate bacterial antimicrobial from one class with an virulence (i.e. defenins, alkaline phosphatase) and antimicrobial from another class may be useful disrupt biofilm formation for preventing AMR, but it will likely not reduce -Bacteriophage therapy AMR. -Identification of drug targets to reduce bacterial fitness during the development of AMR Personalized antimicrobial therapy: Targeting a -Gene editing to develop novel targeted pathogen with a pathogen-specific antimicrobial antimicrobials, as opposed to broad-spectrum 6 antimicrobials, or to resensitize pathogens by removing AMR genes -Enhance host immune response prophylactically (i.e. vaccines, immunoceuticals that support normal immune function) -Enhancing animal health via genetic selection -Eco-biological approaches to modify the microbiome (i.e. prebiotics, probiotics) -Enhancing animal health through nutrition (i.e. antioxidants, vitamin D, fatty acids, enzymes, postbiotics (metabolites like SCFAs), selenium, digestible fiber, organic acids, etc.) 7