The emergence and spread of antibiotic resistance have created a growing global threat. Because the use of antibiotics in any form resistance occurs, it is important to minimize the use of these antibiotics both in animals and human treatment -a goal that depends on eliminating inappropriate uses and finding other means of preventing infections. In Animal and Human medicine, strategies can include reducing health care-associated infections, limiting the unnecessary use of antibiotics, ensuring the use of those antibiotics effective against a narrow spectrum of bacteria whenever possible and increasing the use of appropriate vaccines.
On March 08, 2023, The International Poultry Council (IPC) at a program during VIV Asia in Bangkok, Thailand was pleased to announce eight private-sector organizations that have recognized the importance of responsible antimicrobial use and are endorsing the council’s antimicrobial use stewardship principles. These international leaders, representing over15% percent of the global broiler production, include six associations and two companies and together they represent a collective effort in reducing reliance on antimicrobials globally. These organizations were recognized as leaders for adopting the antimicrobial use stewardship principles and serve as an example for others that want to make a tangible impact on global health security. Therefore it is time to think for alternatives to antibiotics in animal production.
Alternative products play a crucial role in allowing farmers and veterinarians to reduce the use of antibiotics. Vaccines are among the most promising and widely used of these alternatives, but pre- and probiotics and other innovative products are also in use are currently being recommended. Many of these have been shown to simultaneously prevent infection and improve animal performance, such as growth rate or egg production, etc. However, the efficacy of alternative products tends to be variable across individual livestock operations and with the disease status of herds/ flocks, and is often affected by external factors such as weather or feed composition. More research is needed to understand exactly why efficacy is so variable and to ensure optimized use, but this is complicated by the fact that the mechanism of action (i.e., the molecular processes that generate the desired effect) for many alternative products is not well understood. These alternative products should be considered as one part of a comprehensive herd or flock health management program aimed primarily at the prevention of diseases, rather than curing of infections. This paper aims to provide an overview of the options available to reduce the need for antibiotics in animal agriculture through the use of non-antibiotic alternative products and strict biosecurity practices restricting the enter of infection.
What are the Alternative Strategies to Antibiotics?
The most important ways to prevent antibiotic resistance are:
- Minimise unnecessary prescribing and overprescribing of antibiotics. This occurs when people expect doctors to prescribe antibiotics for a viral illness (antibiotics do not work against viruses) or when antibiotics are prescribed for conditions that do not require them.
- Complete the entire course of any prescribed antibiotic so that it can be fully effective and not breed resistance.
- Use of appropriate Vaccines to control the occurrence of infections.
- Supplementation of alternative products to reduce or prevent use of antibiotics(such as Enzymes, Organic acids, Probiotics, Prebiotics, Synbiotics, Postbiotics and Phytobiotics).
- Practice good hygieneand biosecurity measures such as hand-washing and use appropriate infection control procedures.
As the public health concerns of antibiotic resistance and the resulting withdrawal of antibiotics from prophylactic uses started happening in recent years, a dire need for alternative strategies has sparked in the production animal industry. Many researchers seek the potential of various natural and synthetic molecules in fighting bacterial infections, weighing their efficacy and cost-effectiveness on the scale. Probiotics, Prebiotics, Synbiotics, Postbiotics, Organic acids, Vaccinations, Innate immune stimulation, and improving biosecurity are at the forefront of these alternatives. Although these strategies may not have shown consistent efficiency throughout research, combinations of two or more approaches have exhibited proficiency.
Withdrawal of antibiotics in poultry
Withdrawal of antibiotics from poultry feed have created the need for alternatives that would influence improvement of health and production traits of chickens and safety for human consumption of poultry products. Since antibiotic use is diminishing because of concerns such as the emergence of antibiotic-resistant bacteria, alternative strategies have become valuable in the control of infections. Recent advances in research identified several possible replacement therapies. Researchers are focusing on finding a replacement to treat bacterial infections that can devastate flock health.
What is an alternative to antibiotic in poultry feed?
The natural alternatives to antibiotics includes:Enzymes, Probiotics, Prebiotics, Symbiotics, Organic acids, Immunostimulants, and Phytogenic (Phytobiotics) including herbs, botanicals, essential oils, and oleoresins are the most common feed additives that acquired popularity in poultry industry(fig.1)
The nutrients for the multiplication and growth of bacteria in the intestinal tract are derived largely from dietary components, which are either not digested by digestive enzymes or absorbed so slowly that the bacteria in host guts compete for them. Addition of enzymes not only influence the absorption of nutrients but also produce nutrients for specific populations of bacteria through their action. Therefore, their use has a direct impact on the microfloral populations. The most widely used feed enzymes are mixture of a variety of glycanases, and the single-using degrading enzyme is phytase.
Inclusion of the enzyme phytase in animal diets aids in the digestion of phytate to inositol and inorganic phosphate. This is usually done because the phosphorus from cereal grains cannot be digested by poultry without phytase addition. The addition of phytase in poultry diets is economical because it efficiently utilizes phosphorus, which is regarded as the most expensive mineral in poultry production. It is essential to include fiber and starch digesting enzymes in poultry diets as they assist in digesting non-starch polysaccharides. Xylanase and β-glucanase addition to poultry diets improve feed conversion ratio, digestibility, growth performance, and nutrient utilization and reduce wet litter. The inclusion of enzymes in livestock diets is of great benefit not only to the animal through improved health, nutrient utilization, and growth but to the farmer also through reduced cost and increased returns.
Short chain fatty acids such as formic, acetic, propionic and butyric acid and other carboxylic acids such as lactic, malic, tartaric, Fumaric, and citric acid have been most commonly used in the poultry industry because their chemical and physical properties are applicable to poultry diets.
Dietary organic acids have gained great attention because of their antimicrobial activity against pathogenic bacteria and the fact that these compounds can induce a pH reduction in the gastrointestinal tract (GIT), which can improve nutrient utilization in poultry diets.
The organic acidshelp to enhance digestibility of energy and protein contents of the feed and reduction of microbial pathogens, improving the immunity, lowering the infection level, and reducing the ammonia and other harmful metabolites.
Probiotics are live microorganisms including bacteria (i.e., Lactobacillus acidophilus) and yeast that are commonly supplemented in poultry feed to improve animal well-being through a variety of mechanisms. Probiotics have a variety of functions in host, which are mainly triggered by their outer membrane composition and metabolic outputs. Some of the bacterial probiotics are several Lactobacillus species, Bifidobacterium, Bacillus and Enterococcus.Yeast or fungal probiotics are added to feed such as Saccharomyces cervisiae ), Aspergillus oryzae . Candida pintolopsiiand Saccharomycesthat caused positive effects on the performance and gut health.
Necrotic enteritis is an acute infection caused by the bacteria C. perfingens. Intestinal damage in poultry allows the bacteria, which is a normal inhabitant of the intestinal tract, to attach, proliferate and produce toxins.The bio -therapeutic uses a combination of genetic engineering and synthetic biology techniques such as Probiotics are commonly used alternative to antibioticsagainst C. perfringens and necrotic enteritis.It effectively decreases mortality by 40-70% against C. perfringens. In addition, birds that were administered the live therapeutics showed improved feed conversion ratio.Further the research suggests that the bio therapeutic will work against other poultry diseases, including coccidiosis and avian influenza.
There are also certain adverse effects reported contradictory to the positive effects. However, multiple reports depict the positive enteric health effects of probiotics in improving intestinal integrity and mentioning that they could be a great alternative to antibiotics in the poultry industry.
The mechanism of action of probiotics consists of: 1) Competitive exclusion 2) Maintaining dysbiosis 3) antagonism and 4) Immunomodulation (fig.3and 4)
According to FAO, prebiotics is defined as non-digestible food ingredients that benefit the host. They selectively stimulate the growth and activity of bacteria in the colon and thereby improve host health. They are supplying a substrate for beneficial microorganisms in the gastrointestinal tract. Although the previous definition has focused only on few carbohydrates, researchers have redefined prebiotics, including various oligosaccharides containing varying carbon lengths, and collectively designated them as non-digestible oligosaccharides. Different molecules such as fructooligosaccharides, galactooligosaccharides,mannanoligosaccharides, inulin, and isomaltooligosaccharide are among the non-digestible oligosaccharides that have beneficial properties as prebiotics.
Reports suggested that certain non-digestible oligosaccharides such as fructose oligosaccharides, inulin-type fructans, and mannanoligosaccharides can modulate gastrointestinal microbiota by increasing the Lactobacillus population while reducing harmful pathogens such as E.coli and Clostridium perfringens.
Synbiotics are mixtures of probiotics and prebiotics. Synbiotics have always been an attractive choice for promoting the health of the gut microbiome, as they combine friendly bacteria, along with an appropriate food source for good bacteria, in one supplement. Studies have shown the beneficial effects of Synbiotics on reducing harmful bacteria such as Campylobacter jejuni and Salmonella typhimurium. Addition of symbiotic supplementation in drinking water helps to influence a healthy microbiota and improved immune response in the intestines of laying hens during a Salmonella challenge.
Postbiotics is a product recently introduced into the poultry industry and are mainly derived from Lactobacillus, Bifidobacterium, Streptococcus, and Faecalibacterium species. The Postbiotics are derived from Aspergillus oryzae, a fungi largely used to ferment rice and soybeans in East Asia.Feeding a Postbiotics derived from Aspergillus oryzae (AO) can improve layer performance, productivity and egg qualityas well as reduce mortality. Their properties including anti-inflammatory, immunomodulatory, antiobesogenic, antihypertensive, hypocholesterolemic, antiproliferative, hepatoprotective, and antioxidant led to the improvement of host health through enhancing several physiological functions.
The use of antibiotics promotes drug-resistant pathogens, leading to dysbiosis. Antimicrobial peptides (AMPs) a possible replacement for poultry antibiotics. AMPs are part of the immune system of every living organism. AMPs can target and kill a broad spectrum of pathogens and bacteria, including medically important antibiotic-resistant strains, without toxicity against animal cells. They can be formulated as additives in feed or water, topical products and for in ova injection. Like conventional antibiotics, AMPs do not trigger resistance to medically important drugs and don’t persist in meat or wastewater, which could make them a safe alternative to preventing and treating bacterial diseases in the post-antibiotic era.
The non-ribosomal AMPs, mainly produced by bacteria, are synthesized by peptide synthetases and structural modifications. They include gramicidin, polymyxin, bacitracin, and sugar-peptide. Polymyxin is from B. polymyxin, playing bactericidal effect by destroying the bacterial cell membranes. It is effective against many Gram-negative bacteria, such as P. aeruginosa, E. coli, Klebsiella Antimicrobial peptides are classified into two categories, non-ribosomally synthesized Antimicrobial peptides(AMPs )and ribosomally synthesized AMPs, according to the peptide synthesis mechanismpneumoniae, Haemophillus, and Salmonella(fig5).
Phytogenics, a group of natural growth promoters used as a feed additives andare another possible alternative to antibiotics. They are mainly something that is made from a raw extraction of plants and that are shown to have an effect on growth promotion. Recent studies show Phytogenics like chili powder, black pepper, ginger, turmeric, garlic, cinnamon, ginger and rosemary can positively impact both growth performance and antimicrobial effects in broilers. They are available as an oil, powder or liquid, depending on the plant extraction. These growth promoters can provide antimicrobial, anti-inflammatory, anti-diarrheal, hepatoprotective and diuretic qualities, depending on the plant used and the final product extracted. Phytogenics could improve welfare by decreasing environmental stress, morbidity and mortality.
Vaccines as Alternatives to antibiotics
Many bacterial infections are major health problems worldwide, in poultry and treatment of many of these infectious diseases is becoming increasingly difficult due to the development of antibiotic resistance, which is a major threat. Prophylactic vaccines against these bacterial pathogens are urgently needed.Traditional vaccines are generally classified into live-attenuated and inactivated/killed vaccines. Bacterin is a suspension of killed or weakened bacteria used as a vaccine. Live-attenuated bacteria, replicating transiently in the host, are capable of expressing a full repertoire of antigens. Common vaccines available for bacterial infections in poultry are, Salmonella spp, E.coli, Fowl cholera, Mycoplasmal infections (fig6.)
Immunomodulators mainly immunostimulants, are able to non-specifically enhance the innate immune function and to improve the host’s resistance to diseases. The use of immunotherapy in infectious diseases may resulting in modulating the immune response to a microbe (e.g., by using cytokines and cytokine inhibitors), modifying a specific antigen-based response (e.g., using interferons) and minimizing end-organ damage using non-specific anti-inflammatory agents (e.g., steroids); β-Glucans, bacterial products, and plant constituents could directly initiate activation of innate defense mechanisms acting on receptors and triggering intracellular gene(s) that may result in the production of antimicrobial molecules(table1)
Table 1. Classification of immunostimulants.
|1||Mineral substances||Selenium, Zinc etc.|
|2||Vitamins||Vitamin A,E,C etc.|
|3||Amino acids||Arginine, leucine, Ubenemex,etc.|
|4||Chinese Herbal Medicines||Astrgalus,Echinacea,etc,|
|5||Plant polysaccharides||Astrgalus polysaccharide, lentinan, algal polysaccharide, polyposaligosaccharide,chitosan etc.|
|7||Microbial preparations||BCGvaccine,Corynebacterium seedings,Lactobacillus,CholeratoxinBsubunit,Mycobacterium pheli, muroetsin, Prodigiiosin etc.|
|8||Immunologic adjuvants||Aluminumadjuvant,propolis, liposome, Freund’s adjuvent|
|9||Hormones and hormone like substances||Growth hormone,|
|10||Nucleic acids preparations||Polynucleotide, immune ribonucleic acid,etc.|
|12||Chemical synthetics||Levomesole.cimitidine, sodium huttuyfonate,imiquimod,ubenemex,tilorone,polinosinicacid|
|13||Bacterial extracts||B-Glucan, peptidoglycan, liposaccharides etc.|
|14||Biological(cytokines)||Interferon, transfer factor, interleukin, immune globulin etc.|
|15||Others||Beepollan,bursaextracts,globulin,heatshock protein,polyIC glycyrrhizin etc.|
Bacteriophages, endolysins, and hydrolases
Bacteriophages are highly species-specific viruses that kill bacteria by the producing endolysins and the subsequent lysis of the bacterial cells. Bacteriophages can be considered safe antibiotic alternatives as they exhibit no activity against animal and plant cells.Phages most likely will never replace antibiotics completely; however, they will be valuable in the treatment of infections caused by multidrug resistant bacteria. Antibiotics will still remain the main treatment for the majority of infections, especially the acute ones, for a long time.
Endolysins and lysozymes
Endolysins and lysozymes are hydrolases. Hydrolases are enzymes that degrade peptidoglycans, the main building block of the bacterial cell wall, and thereby kill bacteria. The hydrolases can be derived from a number of different sources, including bacteriophages, as well as animals, plants, bacteria, and insects, with varying specificity for target bacteria.
Lysozymes and autolysins
Lysozymes and autolysins are hydrolases generated by eukaryotic organisms (i.e., animals and plants) and bacteria, respectively. In humans, lysozymes are an important component of the innate immune system and naturally present in the skin and secreted into saliva, urine, milk, and other bodily fluids.157 Lysozymes in particular tend to have activity against a broad spectrum of bacteria and are known to effectively break down the carbohydrate component of peptidoglycan layer of bacteria. They are also known to be effective against viruses and other pathogens.158 Lysozymes and autolysins are promising alternatives to antibiotics, although they share many of the limitations discussed under endolysins.
There is a growing demand for poultry and by-products due to an increase in the human population globally. Farmers utilize feed additives and antibiotics to enhance growth and alleviate diseases to meet this increasing demand for meat and meat products. Although antibiotic use as growth promoters (AGPs) in the livestock industry has brought about a positive increase in production, the industry has also been negatively affected by the development of bacteria resistant to antibiotics and the presence of chemical residues in meat and excreta. Thishasrisen a concern as this poses a health risk in humans. Resistant bacteria can be transmitted to humans by consuming meat from antibiotic-fed animals or environmental spread from animal wastes. Therefore, action is required to curb this issue by addition of alternatives that have the potential to replace antibiotics for food safety, health, and environmental reasons.