INTRODUCTION

The importance of the occurrence of bacterial resistance to antimicrobials (AMR) and its impact on health, especially public health, is increasingly being discussed. The estimates published by MURRAY, et al. (2020) point to an indirect role for antibiotic-resistant bacteria in the deaths of around 4.95 million people. The cases in which death was directly caused by an antibiotic-resistant infection amounted to 1.27 million people in the same study.

Most of the discussions on the subject focus precisely on the impact of AMR, especially in hospital environments, on human health. As far as veterinary medicine is concerned, part of the responsibility lies with the use of antibiotics in farm animals in their various modes of use (therapeutic, preventive, growth control or promotion), even though there is no scientific proof of a possible causal relationship between their use in farm animals and the occurrence of AMR in human isolates.

Regardless of the above scenarios, one aspect that has been little explored and deserves attention from the animal production sector is the impact of AMR on the sector itself, i.e., on animal health. This text will cover the main impacts of AMR on farm animals, with a special focus on poultry and pigs, and good practices that, once implemented, help to reduce the occurrence of AMR, as well as some concepts related to the subject.

BACTERIAL RESISTANCE TO ANTIMICROBIALS

It is important to establish some concepts and mechanisms on the subject before we delve into the possible impacts and strategies for reducing the occurrence of AMR.

AMR is the ability of bacteria to survive and multiply even in the presence of antimicrobial agents that would normally be effective in inhibiting their growth or killing them. Resistance can be Natural or Intrinsic, when microorganisms are naturally resistant to certain types of antimicrobials due to their inherent structural or metabolic characteristics. This type of resistance is part of the bacteria’s normal genetic profile and is not acquired from other bacteria. Resistance can also be Acquired, when a bacterium that was initially sensitive to an antimicrobial becomes resistant.

The main mechanisms involved in the resistance acquired by bacteria are associated with:

1. Target modification: Bacteria can alter the antimicrobial’s target site, making it less effective.
2. Production of Destructive Enzymes: Some bacteria produce enzymes that can inactivate antimicrobials.
3. Efflux Pumps: These are transport systems that bacteria use to expel antimicrobials from inside the cell. This reduces the concentration of the drug inside the bacterial cell to a non-lethal level.
4. Permeability Barriers: Some bacteria can alter their cell membranes, making it difficult for antimicrobials to enter.
5. DNA Repair Mechanisms: Bacteria have DNA repair mechanisms that can correct the alterations caused by certain antimicrobials, such as those that induce the formation of free radicals to damage bacterial DNA.
6. Horizontal Gene Transfer: Bacteria can acquire resistance genes from other bacteria through processes such as conjugation, transformation or transduction. This can include the exchange of plasmids, which are small pieces of DNA that carry resistance genes.

These resistance mechanisms can occur alone or in combination, making some bacteria extremely resistant to a wide range of antimicrobials.

It is important to note that the use of antimicrobials does not generate resistance per se, but acts as a selective agent that favors the survival and spread of already resistant bacterial strains. In a population of bacteria, there may be some cells that, through mutation or the acquisition of resistance genes, are able to survive in the presence of an antimicrobial. When this medicine is used, it acts on the sensitive bacteria, but the resistant ones survive and multiply. Thus, the use of antimicrobials acts as a filter that selects resistant strains.

Another aspect to consider is that the frequent and/or inappropriate use of antibiotics (such as low doses, incomplete or prolonged treatments and use in unnecessary situations) creates an environment where resistant bacteria have a significant advantage to survive and proliferate.

PRACTICAL IMPACTS OF ANTIMICROBIAL RESISTANCE IN ANIMAL PRODUCTION

AMR in animal production is a complex issue with profound and multifaceted impacts. Firstly, the increasing difficulty in developing new antibiotics, coupled with the prioritization of these for human use, leaves veterinary medicine in a delicate situation. The optimistic long-term outlook suggests that the same antimicrobials that already exist will be available, which could severely limit the treatment options available for bacterial diseases in animals.

This scenario is exacerbated when the prevalence of resistant bacteria increases, making the treatment of bacterial diseases more complex and less effective. Infections that would previously have been easily controlled are now more severe and persistent. This not only increases the suffering of the affected animals, but also puts additional pressure on veterinarians, who must find ways to effectively treat these diseases while fulfilling their duty to look after animal health and welfare.

When resistant infections affect herds or farms, the consequences can be serious. There is an increase in mortality rates, which represents a direct loss for producers. In addition, the remaining animals often have lower growth rates, which ultimately reduces overall production efficiency. These factors combined result in a significant economic impact for the industry, with higher treatment costs and lower returns on investments.

In addition, antimicrobial resistance challenges traditional methods of managing herds and farms. Producers may have to invest more in preventative measures, such as improvements in hygiene, nutrition and environmental management to reduce the incidence of disease. Such changes can require significant investment and alterations to established practices, which can be a challenge.

GOOD PRACTICES FOR REDUCING ANTIMICROBIAL RESISTANCE IN ANIMAL PRODUCTION

In view of what has been discussed so far, it is clear that some measures must be taken to reduce the incidence of antimicrobial resistance in order to preserve the antibiotics still available for the treatment of bacterial diseases in farm animals. These measures can be summarized in an approach of prudent use of antibiotics.

The World Health Organization (WHO) has drawn up a Guide to the Use of Antibiotics Important for Human Medicine in Production Animals. This guide, as the title suggests, focuses on guidelines for the preservation of antibiotics that are important in human medicine and presents four recommendations and good practices that can be applied towards prudent use for this purpose: Reduction in the total volume of antibiotics used; No use of antibiotics as growth promoters; No preventive use of antibiotics; Reserving, as a last resort, the use of critically important antibiotics for human medicine for disease control and very high priority antibiotics critically important for human medicine for the treatment of diseases.

When we consider the scenario of the prudent use of antibiotics from the perspective of veterinary medicine, for veterinary medicine and more precisely for poultry and pigs, we can work on four fronts that have the potential to generate results with a major impact on the preservation of the molecules available today:

No use of antibiotics as growth promoters (APC)

As seen above, the frequent and/or inappropriate use of antibiotics (such as low doses, incomplete or prolonged treatments and use in unnecessary situations) is an aggravating factor in increasing the selection pressure for resistant bacteria. The use of APC generates a double-fault – a dose below and a period of use above the recommended use of the antibiotic – with the sole aim of improving animal performance. From a technical point of view, this is more than enough to justify not using APC. However, for a long time the economic aspect justified the use of PCAs – better performance (feed conversion and/or weight gain) at relatively low costs. Even so, it is now possible to obtain zootechnical results equivalent to those obtained with the use of APCs through the use of alternative products and, in many cases, at similar costs, which makes the withdrawal of APCs viable.

Use of clinical and laboratory resources

Also mentioned above is the need (and duty of the veterinarian) to preserve the health and well-being of animals by using antibiotics to treat bacterial diseases. However, in this respect, all available resources should be used to properly diagnose the organic condition of the animals, as well as which antibiotic is most suitable and/or effective in each case. This approach necessarily involves carrying out clinical and laboratory assessments for a correct diagnosis, implementing and evaluating constant health monitoring and carrying out antibiograms. Through these strategies, it is possible to clearly identify the microorganism involved in the infection and which antibiotics are effective against the identified bacteria. Once a monitoring program has been established, including antibiograms, it is possible to monitor the behavior of each molecule available to the production system over time. This includes antibiotics in use and those that, for whatever reason, are not in use during a given period.

Prioritize the use of alternatives to antibiotics

Not using antibiotics is also a way of reducing the selection pressure for resistant isolates. In this case, the most obvious approach is to replace the APCs with alternative products. However, especially in the case of enteric diseases or disorders such as bacterial infections, dysbiosis or non-specific enteritis, it is possible to use alternative products to antibiotics for treatment, at least as a first coping strategy. Infections in other organs or tissues or even systemic infections can be more difficult to treat with alternative products, which justifies the use of antibiotics as an immediate strategy, always considering what has already been discussed in the previous topic.

In addition to mitigating the occurrence of antibiotic resistance, the use of alternative products for the treatment of enteric diseases or disorders has another important advantage, which is the least possible negative impact on the intestinal microbiota, promoting a more favorable condition for the recovery of animals to their original healthy state.

Rotate molecules in the field

The rotation of antibiotic molecules, or antibiotic cycling, is an advanced drug management strategy in animal production that seeks to reduce the risk of antimicrobial resistance developing. This approach involves programmed alternation between different classes of antibiotics to treat specific infections at certain times. The idea is that by changing the type of selective pressure applied to bacterial populations, you can prevent them from adapting and developing resistance to a particular antibiotic.

This strategy must be carefully planned and based on robust scientific evidence. This includes understanding the pharmacodynamics and pharmacokinetics of different antibiotics, as well as knowledge of local and regional resistance trends. Antibiotic rotation is not a universal solution and must be adapted to the specific circumstances of each herd or farm. In addition, it must be implemented in conjunction with other animal health management practices, such as biosecurity measures, vaccination and proper nutritional management.

It is vital that producers work closely with animal health veterinarians to develop and monitor antibiotic rotation programs to develop and monitor antibiotic rotation programs. Continuous evaluation of the effectiveness of these programs is crucial, as is the readiness to adjust them as necessary. This approach, when well implemented, can contribute significantly to the sustainability of animal production and the overall health of herds.

FINAL CONSIDERATIONS

Management related to the occurrence of AMR in production animal herds must be a constant concern and here we present some points related to this topic, with an emphasis on the impacts of AMR on animal production, as well as some good practices to reduce its occurrence.

However, it should be emphasized that the best way to reduce the occurrence of AMR is to reduce the need for and effective use of antibiotics and that, in this respect, preventing the occurrence of disease is the most effective way to guarantee this reduction. In this sense, the establishment, implementation and execution of a robust biosecurity program plays a fundamental role in the effectiveness of any other actions aimed at reducing the occurrence of AMR, including those presented here.

REFERENCES

Ø         ALTERTHUM, F. Mecanismo de Ação dos Antibacterianos e Mecanismos de Resistência. In: TRABULSI, L. R. & ALTERTHUM, F. Microbiology. 6 ed. p.79-85. São Paulo: Atheneu. 2015.

Ø         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.

Ø         MURRAY, C. J. L.; et al. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. LANCET. 399:629-655. 2022.

Ø         WHO. WHO Guidelines on use of medically important antimicrobials in food-producing animal. World Health Organization. 2017.

Ø         RAUBER, R. H. Avian Influenza ant the Brazilian poultry production: Current situation and prevention strategies. GERMAN JOURNAL OF VETERINARY RESEARCH. 3(4):13-19. 2023.

Ø         WOAH. Annual Report on Antimicrobial Agents Intended for Use in Animals – 7th Report. Paris: World Organisation for Animal Health. 133p. 2022.

Ø         WOAH. Antimicrobial Resistance. Available at https://www.woah.org/en/what-we-do/global-initiatives/antimicrobial-resistance/. Accessed on January 09, 2024.

 

By: Ricardo Hummes Rauber, DVM MSc PhD
Animal Health Consultant – [email protected]
Vetinova – Strategic Animal Health