Zinc oxide, a possible alternative to antibiotics?

At weaning, piglets often suffer from digestive disorders and growth retardation caused by changes to their diet and stress related to their being grouped into batches of animals of similar age (batching). To avoid these problems and thereby limit the losses they cause, a large proportion of animals systematically receive a preventive antibiotic treatment in the form of medicated feed (containing colistin, or colistin sometimes in combination with another antibiotic).

As an alternative to these antibiotics, some European countries already authorise the use of high doses of zinc oxide (ZnO) in the diet of piglets, in the form of medicated premix, during this weaning period. There is currently no such authorisation in France.

Antimicrobial resistance is recognised as a major problem at international level in terms of both human and animal health, with the emergence, selection and growing spread of strains of bacteria resistant to antibiotics. The development of alternatives to antibiotics is therefore one of the measures being considered to combat this phenomenon, in particular by "EcoAntibio 2017", the national plan to reduce the risk of antibiotic resistance in veterinary medicine. 

In this context, the Agency received a formal request from the French Ministry of Agriculture to conduct a risk-benefit assessment of the use of zinc oxide in the diet of piglets (its efficacy for animals, and risk to humans, animals and the environment) and to issue an opinion on the value of using this treatment to reduce the risk of antimicrobial resistance.

ANSES’s work

To carry out this work, the Agency set up a dedicated group of experts with complementary skills. This working group reported to the Expert Committees (CES) on "Feed" and "Animal Health” and to the French Commission for Veterinary Medicinal Products (CNMV). It reviewed the available scientific data on: 

• weaning and the digestive disorders that can develop in piglets during this period;
• the effects of zinc oxide on these disorders;
• the chemical characteristics of zinc oxide and the risks it could pose to humans and animals; 
• the conditions of use for zinc oxide and the risks it could pose to the environment;
• bacterial resistance to antibiotics used to treat piglets and to zinc oxide.

The Agency also compiled an initial inventory of alternatives to antibiotics in post-weaning piglets.

Conclusions

This work indicated that the efficacy of zinc oxide in preventing moderate post-weaning diarrhoea in piglets was demonstrated at a dose of 3100 ppm⁽¹⁾ and for a maximum period of 14 days, but this dosage still needs to be optimised. Zinc oxide can therefore be regarded as a means of preventing these digestive disorders. However, its efficacy in preventing serious forms or oedema disease and its efficacy when digestive disorders are established, have not to date been documented.

The assessment of the environmental risk associated with the use of zinc oxide as a medicated premix (spreading slurry from post-weaning piglets) indicates a toxic risk for the different environmental compartments (sediment, water and soil). The level of impact depends on the context of use, specifically the type of farm and the level of zinc in the diet throughout the rearing period. 

Phenomena of bacterial resistance to zinc and cross-resistance or co-selection of bacterial resistance to certain antibiotics have been described in the literature, but it is impossible to anticipate how they will develop if zinc oxide is used.

The use of antibiotics such as colistin is still an effective practice with regard to established bacterial digestive infections. However it should be noted that resistance to colistin is an emerging phenomenon in pig farming, even though the level is currently low.

No comparison of the efficacy of zinc oxide with that of colistin in controlling post-weaning diarrhoea has yet been documented. It was therefore not possible to assess the comparative benefits of colistin and zinc oxide.

In terms of quantitative risk assessment, comparing the risks associated with the use of colistin and those of zinc oxide appears difficult in the present state of knowledge, due among other things to the major scientific uncertainties concerning the development of resistance to colistin and changing phenomena of bacterial resistance to zinc or co-selection of antibiotic resistance in the short and medium term.

Many other alternatives to antibiotics for controlling digestive disorders at weaning are being studied, and although some are promising, their use presupposes a scientific validation of their efficacy. However, it is likely that most of these alternatives will not be sufficient in the event of infection with highly pathogenic strains.

Recommendations

Based on this work, the Agency considers that with regard to the environmental risk associated with the use of zinc oxide as a medicated premix in post-weaning piglets, management measures to offset this risk must be considered. The first is to only use zinc oxide in farms with fattening units, and which do not treat the slurry before application. In addition, in these farms, other management measures should also be proposed to reduce zinc emissions into the environment. 

Considering the fact that the demonstrated efficacy of zinc oxide in the case of severe digestive disorders and oedema disease or established diarrhoea has not been documented, the Agency states that the use of antibiotics, and colistin in particular, in these situations cannot be excluded. It emphasises, however, that colistin should be used prudently and accompanied by monitoring for bacterial resistance.

ANSES states that any authorisation of zinc oxide as a medicated premix for post-weaning piglets should be accompanied by the establishment of a system for monitoring resistance to zinc, cross-resistance or co-selection of resistance to certain antibiotics, as well as annual monitoring of amounts used at national level.

The Agency also states that marketing authorisation applications for medicated premixes based on zinc oxide should include evidence substantiating:

• the precise indication, in terms of the targeted conditions and alleged mode of action (prevention/treatment);
• the dosage;
• the environmental risk.

Finally, ANSES emphasises that although it was able to conduct an intrinsic risk-benefit assessment of the zinc oxide product for its use in the context of digestive diseases in post-weaning piglets, it was not able to compare this usage to that of antibiotics (including colistin):

• the comparative benefit could not be established: comparing the efficacy of the two product types requires field trials using both compounds, which have thus far not been carried out;
• the comparative risk was not studied: this approach was confronted firstly with the difficulty of comparing a predominantly environmental risk with a risk of antimicrobial resistance, and secondly with the fact that such a comparative approach requires non-scientific criteria to be taken into account, whether they be economic, political or sociological. 

It seems that this overall comparative approach is actually the responsibility of the risk manager, when considering the options and making the final decision.

⁽¹⁾ parts per million