The pun in the article title is intentional. The intention is to bring immediate reflection on the reasons for using the therapeutic strategy with zinc oxide (ZnO) and the impacts of its possible withdrawal. It’s not a question to be answered. But rather an invitation to understand why the withdrawal of ZnO (and antibiotic growth promoters) is an opportunity to improve the production system.

In the background, we have the endless discussion about antimicrobial resistance and the role of intensive animal production in this scenario. Although there is no clear scientific evidence that the use of antibiotics by the animal production chain is involved in the occurrence of resistant or multidrug-resistant bacteria in hospital environments, when we evaluated the document “WHO Guidelines on Use of Medically Important Antimicrobials in Food-Producing Animals” published by the World Health Organization (WHO) in 2017, we observed a set of four recommendations and good practices for the use of antimicrobials in animal production:

1. Reduction in the total volume of antibiotics used;
2. No use of antibiotics as growth promoters;
3. Failure to use antibiotics preventively (in the absence of illness);
4. Reserve, as a last resort, the use of critically important antibiotics for human medicine for control of disease and very high priority antibiotics critically important for human medicine for the diseases treatment.

The WHO itself, in the same document, recognizes that the evidence available to support the recommendations is of low (recommendations 1 to 3) and very low (recommendation 4) quality. However, when talking about the use of antibiotics at doses below the minimum inhibitory concentration and for prolonged periods, as is the case with growth promoters, it makes sense to at least consider the application of recommendation 2.

Frequently present in intensive pig production, Post-weaning Diarrhea is a disorder that occurs in piglets a few days after weaning. This is an especially critical phase for the animal, which goes through a number of transitions that have an impact on changes in gastrointestinal and physiological dynamics, such as the switch from a highly digestible and rich in protective substances liquid diet, breast milk, to a solid diet with entirely non-digestible compounds and without the protection of antibodies and cytokines present in breast milk. In addition, stressful situations are present at this stage, such as the animals adapting to the new facilities, defining the social hierarchy in the flock, mixing with animals from other origins, vaccination procedures, among others. These changes trigger changes in the gastrointestinal tract (GIT) that favor the adhesion, colonization and multiplication of pathogenic bacteria in the intestine, especially E. coli.

ZnO has been used widely and successfully in recent decades as a way of treating enteric conditions after weaning. The therapy consists of using doses of around 2,500 ppm of Zn in the piglets’ diets, while the dose to meet the nutritional requirements of the phase is no more than 150 ppm. However, two points emerge with importance in the discussions surrounding a possible restriction on the use of therapeutic ZnO:

1. The environmental impact of excess levels of zinc in the diet, since the mineral is not absorbed in the intestine and is, therefore, eliminated through the feces, thus representing a great potential for contamination of the soil and other natural resources.
2. Reports of the development of resistance to certain antimicrobials in bacterial populations in animals subjected to this type of mineral use.

After a risk-benefit analysis, evaluating the points listed above, in June 2017, the European Medicines Agency (EMA) decided to withdraw authorizations for the marketing of oral veterinary products with ZnO in their composition, within a maximum period of 5 years. The decision is valid for the member states of the European Union. However, the fact that the restriction is based on two relevant points from the point of view of the chain’s sustainability (antimicrobial resistance and the environment), generates the need to discuss the issue, with a special focus on the alternatives to be implemented in the event of a possible restriction on the therapeutic use of ZnO in Brazil, either due to internal regulations or to meet the needs of an importing market.

With regard to the production system itself, some actions are fundamental to achieving success in the withdrawal of therapeutic use of ZnO and are centered on a robust Biosecurity program that includes isolation procedures, traffic control, sanitation, quarantine, medication, vaccination, monitoring, eradication, audits, education and a contingency plan.

With a special focus on pig farming, it is worth reinforcing the following actions in a biosecurity program:

1. Structuring the production chain to reduce the number of origins and accommodations considering health pyramids and clustering.
2. Definition of a vaccination program suited to the reality of the farm or region, including the choice of agents and strains, type of vaccine, route of application, number of doses and the essential precautions for transporting, storing and applying the vaccines.
3. Quality of the water supplied to the animals. Observe both the microbiological and physical-chemical quality of the water. Generally speaking, the microbiological quality of water is guaranteed through compulsory chlorination, with levels of around 3 ppm of free chlorine at the point of water consumption furthest from the chlorination point. As far as physical-chemical quality is concerned, both the hardness and pH of the water should be observed and corrected whenever possible. Remember that water with a slightly acidic pH (between 5.0 and 6.5) is ideal from an animal health point of view, as it favors the presentation of chlorine in the form of hypochlorous acid, which is the active form against microorganisms.
4. The process of cleaning and disinfecting the facilities and equipment must be carried out carefully, removing all organic matter from the facilities, including gutters and waste bins. An effective detergent should be used for the cleaning process and, at the end, with the facilities and equipment dry, a disinfectant should be applied, chosen according to the farm’s sanitary situation.
5. For the cleaning and disinfection process to be fully carried out, another point to be observed and planned is the accommodation in the all-in-all-out system, allowing the complete emptying of the installation.

As previously mentioned, the main risk factors for the occurrence of post-weaning diarrhea are caused, directly or indirectly, by an imbalance in the intestinal microbiota, leading to a predominance of potentially pathogenic bacteria and triggering the characteristic clinical picture. With this in mind, strategies need to be established to promote a greater balance in the intestinal microbiota and an overlap of potentially beneficial microorganisms over pathogenic ones.

One action to implement is to avoid the prophylactic use of antibiotics in piglets, both pre- and post-weaning. It should be remembered that even bacteria with a beneficial profile for the host are susceptible to most of the antibiotics used. The preventive use of an antibiotic can be one of the triggers for a more significant imbalance in the intestinal microbiota.

The use of products with the potential to modulate the microbiota and/or control pathogenic bacteria in the GIT, both via feed and drinking water, is also a strategy that can be applied to replace the therapeutic use of ZnO. We can group the main products with this purpose or action profile as follows:

• Probiotics: are single or mixed cultures of live microorganisms which, when administered in adequate quantities, confer a health benefit on the host. In general, probiotics act by 1) modulating or balancing the enteric microbiota, 2) maintaining epithelial homeostasis and/or 3) modulating immune responses in the intestine.
• Prebiotics: usually defined as non-viable components of the diet that confer health benefits to the host, associated with modulation of the microbiota. They act 1) directly on the enteric microbiota and/or 2) on the intestinal wall, regulating its homeostasis.
• Symbiotics: these are products made by combining probiotics and prebiotics in such a way that both act synergistically.
• Phytogenics or plant extracts: these are bioactive compounds derived from plants, which can be natural or synthetic. This group includes a large number of compounds that can have different modes of action. In general, they act 1) directly on pathogenic microorganisms through their antimicrobial properties and/or by stimulating beneficial microorganisms, 2) through their antioxidant and anti-inflammatory properties, 3) through their digestive properties and/or 4) by acting on the homeostasis of the intestinal wall.
• Organic Acids: chemically, they can be described as simple monocarboxylic acids or carboxylic acids linked to a hydroxyl group. In addition to being widely distributed in nature, they are produced in the intestinal lumen of animals through the fermentation of carbohydrates by the microbiota. Its action is predominantly due to 1) direct antibacterial action and/or 2) maintenance of epithelial homeostasis.
• Enzymes: these are biologically active proteins that facilitate the chemical breakdown of nutrients into smaller compounds that are easier to digest and absorb. Normally dealt with and discussed from the point of view of animal nutrition, because they improve the digestibility and availability of nutrients for the host, their action as a modulator of the microbiota is indirect, based on reducing the availability of nutrients for use by the microorganisms in the intestinal lumen.

It is not possible to establish an universal standard program for this purpose. It is necessary to assess the challenges of each farm or group of farms in the same region or integration in order to establish a customized program. However, it is possible to state that, in order to effectively control post-weaning diarrhea in a scenario without the use of therapeutic ZnO, it is necessary to draw up a program that includes compounds representing two or more of the groups mentioned above, in addition to the aforementioned biosecurity actions and the non-use of preventive antibiotics.

It is evident that, although we are not immediately subject to the withdrawal of therapeutic ZnO from pig production in Brazil, we have an interesting opportunity to further improve the Brazilian production system from the point of view of biosecurity and preventing the occurrence of post-weaning diarrhea and other enteric diseases, by acting on the primary causes of these problems.

 

REFERENCES

• BONETTI, A.; TUGNOLI, B.; PIVA, A.; GRILLI, E. Towards Zero Zinc Oxide: Feeding Strategies to Manage Post-Weaning Diarrhea in Piglets. ANIMALS. 11:642. 2021.
• BURCH, D. The role of zinc in piglet health. PIG PROGRESS. Available online: https://www.pigprogress.net/home/the-role-of-zinc-in-piglet-health/ Accessed on May 16, 2022.
• Questions and answers on veterinary medicinal products containing zinc oxide to be administered orally to food-producing species. EMA/394961/2017. European Medicines Agency. 2017.
• GADDE, U.; KIM, W. H.; OH, S. T.; LILLEHOJ, H. S. Alternatives to antibiotics for maximizing growth performance and feed efficiency in poultry: a review. ANIMAL HEALTH RESEARCH REVIEWS. 18(1):26-45. 2017.
• MADEC, F.; BRIDOUX, N.; BOUNAIX, S.; JESTIN, A. Measurement of digestive disorders in the piglet at weaning and related risk factors. PREVENTIVE VETERINARY MEDICINE. 35:53-72. 1998.
• WHO Guidelines on use of medically important antimicrobials in food-producing animal. World Health Organization. 2017.
• PLUSKE, J. R. Feed- and feed additives-related aspects of gut health and development in weanling pigs. JOURNAL OF ANIMAL SCIENCE AND BIOTECHNOLOGY. 4:1. 2013.
• SLIFIERZ, M. J.; FRIENDSHIP, R.; WEESE, J. S. Zinc Oxide Therapy Increases Prevalence and Persistence of Methicillin-Resistant Staphylococcus aureus in Pigs: A Randomized Controlled Trial. ZOONOSES AND PUBLIC HEALTH. 62:301-308. 2015.
• VAHJEN, W.; PIETRUSZYNSKA, D.; STARKE, I. C.; ZENTEK, J. High dietary zinc supplementation increases the occurrence of tetracycline and sulfonamide resistance genes in the intestine of weaned pigs. GUT PATHOGENS. 7:23. 2015.

 

Ricardo Hummes Rauber, DVM MSc PhD
Vetinova – Strategic Animal Health