Many of you will have read that the Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency (EMA) announced in December 2016 that in their opinion they found the risk/benefit balance was unfavourable for the therapeutic use of zinc oxide and that all products containing zinc oxide should have their marketing authorisations removed. This was a major surprise as CVMP had only approved it in November 2015.
So what had changed in the meantime? France and the Netherlands did not want zinc oxide to be used in their countries, primarily due to the potential risk of environmental contamination of soils and potential run off into waterways. So they brought the referral back to the EMA under Article 35 of Directive 2001/82/EC. Denmark also demonstrated that soil concentrations of zinc were increasing in their country and calculations showed, especially in acid and sandy soils, zinc levels had exceeded the predicted no-effect concentrations (PNECs) and might be on the point of becoming a ‘toxic hazard’. Denmark produces 32 million weaners per year in a relatively small country. If the production of weaners is compared with the number of human beings in the population with 5.5 million people, it works out at a ratio of 5.8: 1. In comparison in the EU it is a ratio of 0.5: 1 so Denmark produces over 11 times more weaners than the EU average. They consume over 500 tonnes of zinc oxide and on a calculation of consumption over a 14 day medication period at 3100ppm, it would appear that 32 million weaner doses are consumed, or 100% are treated. In the UK, we estimate between 70-90% of weaners are treated, because not all pigs are medicated for just 14 days, some is used to prevent oedema disease. The UK ratio is 0.17:1, well below the EU average. In one study in the UK, zinc soil levels were shown to be falling, especially where the land was grazed or crops were grown, so zinc concentrations in soil can be utilised too.
Zinc also binds to components in the soil so the International Zinc Association have examined the Danish soil report and stated that they had not followed EU guidelines while doing their assessments and predictions. The concentrations can be divided by a factor of 3, because of the binding of zinc to soil, so-called ‘aging,’ which reduces its bioavailability. Their conclusion was, ‘therefore the scientific analyses used were simply not in line with the EU Zn Risk Assessment Report and should not be considered correct or valid’.
So on one side of the balance is environmental issues and also there are perceived risks from co-selection of resistance genes found in methicillin-resistant Staphylococcus aureus (MRSA). Most LA MRSA CC398s are also zinc resistant as well as methicillin resistant and tetracycline resistant also. The Danish pig industry has come in for a lot of bad publicity related to MRSA and the sudden increase in human cases of colonisation and infection from a few in 2004 to 1277 in 2014. However, 85-89% of these are associated with pig farmers, their families and other workers with pigs, e.g. vets and slaughter house workers. The incidence of MRSA in Danish herds has risen from approximately 3% to 68% over these 10 years. Some scientists feel this is due to the use of zinc oxide. This does not make sense, as the MRSA has to get from one farm to another. It is basically clonal and the czrC gene is chromosomal along with the methicillin resistant gene mecA. So it is the bacteria that have to be spread from farm to farm probably by an infected pig (boar/gilt/weaner – or man/fomite) and colonise the next herd. There is some debate over the extent of co-selection on farm caused by zinc once it has infected a farm. One Danish study did show an increase in nasal MRSA count from approximately 165 to 230, a 40% increase but tetracyclines increased the number from 90 to 340 or 278%, several times more than the zinc oxide. Another Canadian study using nasal swabs showed an increase in pigs infected with MRSA by 6 fold in the low zinc group and a 6.5 fold increase in the high zinc group. Both studies show that there was an increase in MRSA in the nose after weaning but in both studies it declined over the next two weeks. This suggests that the increase may be partially due to post-weaning stress and dysbacteriosis in the nasal microbiome as well as in the gut microbiome and once immunity develops, it subsides, even in the presence of zinc oxide. The co-selection may increase the numbers of MRSA for a short period but then they decline.
The other side of the balance is efficacy. There are a large number of dose-titration studies and efficacy studies showing that therapeutic levels of zinc oxide of 1500ppm and above have a very strong effect on preventing post-weaning enteritis and diarrhoea. Inclusion levels of 1000ppm and below show no effect on preventing diarrhoea or improving growth. In a recent review by a UK colleague of 5 field cases, he showed that when zinc oxide was removed from the diet, mortality increased on average by 3%, 30% of the pigs started having diarrhoea, the growth rate dropped by 20% and they had to use antibiotics to try to control it. The mortality in the bowel oedema case was much higher. Is it surprising that nearly 90-100% of pig farmers like to use zinc oxide in feed, if they are allowed to do so?
Rather than ban the use of zinc oxide in the EU, surely some compromise can be reached. The zinc levels in soil and water should be checked or monitored to see what is happening and not just in one country, which is not representative of the EU. If they are concerned about the use of zinc oxide in herds with MRSA, then this use can be controlled on a national basis.
From a veterinary perspective, it would be disastrous at this time to remove zinc oxide from those countries that depend on it and either do not have environmental concerns or do not have MRSA in their pig herds. It can only increase the risks associated with antibiotic resistance from the direct use of antibiotics at a time when we are trying to reduce their use. It is hoped the CVMP, will reverse their opinion this month or the European Commission will postpone a final decision, so that the environmental issues can be examined in more Member States, using an agreed methodology of assessment and confirm whether it is a real hazard or not. I suspect only France, Netherlands and Denmark might be ‘affected’ and all the other 25 Member States are not.