Reducing antibiotic resistance; what to expect from feed additives?

Friday, February 22, 2019

Reducing antibiotic resistance; what to expect from feed additives?

Tim Goossens, PhD, Global Scientific & Technical Manager and Daniel Ramírez, MVZ, Global Sales Manager; Health by Nutrition, Adisseo



Microorganisms, such as bacteria, fungi and parasites, can develop resistance against antimicrobial substances, such as antibiotics, antifungals and anthelminthics. As a results, these antimicrobial substances become ineffective in limiting the growth of resistant microorganisms. The occurrence of antimicrobial resistance (AMR) is not a new phenomenon; in fact, it is a natural selection process that has been going on for billions of years. In recent years, however, microorganisms have been isolated that have developed AMR against a wide range of medically important drugs. As such, these 'superbugs' become an increasing threat to human healthcare.

The misuse and overuse of antimicrobials is accelerating this process. While it is recognized that the human use of antibiotics is the largest contributor to AMR in human pathogens, the over-use in intensively-produced farm animals is now believed to play a considerable role in this global problem as well. For this reason, governmental administrations and food animal producing organizations worldwide are looking into the possibility to reduce antimicrobial use, either as veterinary drug or as antimicrobial growth promoter (AGP), in animal production.

In this context, special attention is given to several strategies aiming to minimizing the need to apply antibiotics to food animals, such as an increased focus on veterinary support, biosecurity measures, production management and nutritional interventions, such as the use of functional feed additives. Indeed, certain feed additives can have a beneficial effect on gut health in animals, and can mitigate the damage caused by intestinal pathogens, thereby reducing the need to routinely use veterinary drugs applied to tackle enteric infections. In addition, gut health will stimulate animal performance in general, and additives that strengthen the digestive tract can therefore be employed as part of a strategy replacing AGPs.

However, in order to correctly evaluate the potential of gut health promoting additives as alternatives to antibiotics, it should be pointed out that the characteristics of both groups of active molecules are very different, which has consequences to their proper application. Often, when animal producers are faced with the need or the wish to reduce AGP supplementation for the first time, they are looking for ways to remove the antibiotics in the feed, just to replace them by other active ingredients which they hope will have the same effect. Similarly, some producers that want to minimize veterinary interventions, might try to apply feed additives as a way to cure an upcoming disease, expecting they will act in similar ways as drug. These approaches, however, deny the fact that additives have a different mode of action compared to AGPs/antibiotics, and that knowledge of these mechanisms is needed to correctly use those additives, as well as to have realistic expectations on their potential.

To illustrate this, in Figure 1, some of the modes of action of AGPs and gut health promoting feed additives are listed. Both classes of compounds can be said to have the same goal: improving intestinal health and function, thereby increasing animal performance. AGPs are hypothesized to do so by directly affecting the intestinal microbiota, and perhaps by having anti-inflammatory properties. The additives, on the other hand, can have different working mechanisms; typically, some of them are overlapping with those of AGPs, while others are distinctive. Some coated butyrate products, for instance, will have a direct or indirect effect on intestinal microbial species (see below), but often without directly killing them, or inhibiting their growth, as antibiotics do. Butyrate has also strong anti-inflammatory properties, while it also has the potential to trigger several physiological pathways, when it is delivered throughout the entire intestinal tract by means of a coating that sets butyrate free gradually after ingestion (ADIMIX®Precision, a Precision Delivery Coated Butyrate, PDCB). Intestinally-delivered butyrate can trigger signaling pathways which are not (or less) activated by antibiotics: for instance, it can fortify the epithelial lining of the digestive tract, it can increase the secretion of digestive fluids, and it might be used by other organs, such as the liver, as energy source and as modulator of metabolic and detoxification processes.

The fact that AGPs and PDCB have underlying modes of action that are partially similar and partially distinct, means that PDCB can be used to reduce dependency on AGPs: both products can be used in combination with each other, or, when the use of AGPs is forbidden or needs to be restricted, PDCB will be needed to fill this void, for example by mitigating the effect of pathogenic intestinal bacteria, albeit via a different route.

Below, some examples are given on how researching different application of PDCB can shed light on how this product can be employed to support animal health and production in a production context where less antibiotics are used.

In a model for necrotic enteritis in broilers, for instance, supplementing challenged birds with PDCB had limited effects on the enumeration of Clostridium perfringens in the intestinal tract. However, PDCB-treatment birds had lower necrotic lesion scores (Figure 2). These results are in line with the hypothesis that PDCB doesn’t have a direct bacteriostatic effect against Clostridium, but that it prevents or repairs intestinal epithelial damage, thereby limiting nutrient loss and inflammation and as such restricting conditions that would favour the intestinal overgrowth of Clostridium in later life stages.

Similarly, PDCB can restrict the colonization of Campylobacter and Salmonella in the intestinal tract of production animals, but it cannot be used as an antibiotic drug to be applied in the final production stage, to wipe out these zoonotic pathogens just before the animals are slaughtered. This is demonstrated by an experiment, where 0 or 3 kg/T of PDCB was added to several feeds of broilers infected with Campylobacter jejuni in the growing stage (Figure 3). When PDCB was added to all feeds, or from the moment onwards that birds where orally infected, caecal Campylobacter loads where significantly reduced compared to birds from the control treatment. However, inclusion of PDCB in only the starter feed and/or the finisher feed had a less profound impact on caecal Campylobacter counts (Figure 4). These results demonstrate that PDCB, in addition to its effects on animal performance, can be of value in a program reducing zoonotic pathogens, but that it is not a 'quick fix' to be applied during the end of production, exerting a specific antibacterial effect.

In conclusion, antibiotics, whether applied as drugs or AGPs, most likely exert a specific and direct effect on enteric bacteria. The downside of this approach is that bacteria can build up resistance against certain drugs, jeopardizing future treatment of humans and animals with antibiotics. Functional feed additives such as PDCB, on the other hand, do not cure acute bacterial challenges, but prepare the gastro-intestinal tract of animals as good as possible to overcome negative consequences of certain diseases in a later life stage. As many of the effects of feed additives on bacteria are indirect, or modulate their virulence pathways, rather than having a specific bacteriostatic effect, the chances of building up resistance against these components is much less likely to happen. As such, feed additives can be a safer way of raising animals without AGPs, while they can also optimize intestinal integrity, thereby helping in reducing the need for veterinary application of antibiotics.

These examples also demonstrate that additives can never by a 'quick-fix', as replacer of antibiotics without careful consideration as to how the application of these products should be implemented in a production context that acknowledges that reducing dependency on antibiotics requires a multifaceted management approach. We believe that we, as feed additive producer, can be a valuable partners in these discussions, as our considerable knowledge and experience in the potential of our products allow to us to advise on the optimal use of our products, so that they can be part of real-life solutions for our customers.


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Article made possible through the contribution of Tim Goossens, Daniel Ramírez and Adisseo