Valnemulin (Econor®) has been reintroduced in the UK and the rest of the EU following the lifting of the suspension of its marketing authorisation by the EU Commission, in response to the unanimous recommendation of the Committee for Veterinary Medicinal Products, their scientific advisory committee. This was excellent news for farmers and their veterinarians and marked the return of an essential weapon to their dwindling antimicrobial armoury.
Econor® was launched in 1999 for the treatment and prevention of swine dysentery and enzootic pneumonia. It was proving highly effective in the control of swine dysentery, in particular where other older products were failing due to tolerance or even resistance and also in mixed infectious diarrhoeas of growing pigs associated with Brachyspira hyodysenteriae, B. pilosicoli and Lawsonia intracellularis where it was also shown to be highly active. (See graph 1 and 2).
Graph 1. Comparison of Econor's antimicrobial activity against Brachyspira species
(Source: Dunser and Schweighardt, 1998)
Graph 2. Comparison of Econor's activity against Lawsonia intracellularis
(Source: McOrist and others, 1995 and 1998)
In combination with chlortetracycline (Aurogran®) it was offering a broad-spectrum control of many infections found in the MIRD (mycoplasma induced respiratory disease) complex such as M. hyopneumoniae, Pasteurella multocida and Actinobacillus pleuropneumoniae and gave the best lung lesion control in comparison with a number of other commonly used medications such as tilmicosin, lincomycin and chlortetracycline and a combination of penicillin, chlortetracycline and sulphadimidine. (See graph 3).
Graph 3. Comparison of lung lesions (%) following a MIRD challenge and treatment
(Source: Stipkovits and others, 2001) Key - products plus numbers equals ppm in feed
The product was suspended in October 2000 following a series of reported suspected adverse reactions when used in Scandinavia. Thirty five (97%) of the cases were in Denmark, Sweden and Finland and one case was reported in Ireland. No other cases were reported in the rest of the EU or particularly in the UK. In the meantime it has continued to be used in Eastern Europe, Asia and South America and development work has continued in the US without any reported incidents.
Pigs appeared to react typically 2-6 days after the introduction of feed containing Econor and the most commonly affected pigs were 6-7 weeks of age. They would show signs of a high temperature, depression, reduction of appetite and stiffness and pain when they moved. This is common at this age associated with a number of infections e.g. Glässer's disease caused by Haemophilus parasuis. Occasionally some developed oedema of the eyelids and skin, similar to bowel oedema caused by E. coli and also erythema (reddening) of the head, perineum, which extended onto the back. Responses to removal of the feed and treatment by injection with an antibiotic such as amoxycillin were rapid and recovery was almost complete in 24-48 hours instead of 5 days if untreated, suggesting there was an infectious component in the reaction.
A number of studies were set up to look at the regional difference between Scandinavia and the rest of the EU, to reproduce the condition and try to investigate the possible cause and to try to eliminate factors one by one.
There was a definite geographic link because of the high prevalence of the reactions in Scandinavia. From an epidemiological survey of nearly 200 farms in the EU, a genetic link was made to Danish and Swedish Landrace and their crossbreds. It was also interesting that breed structure is still mainly intact in most countries, in spite of international breeding companies and the core genetics in a country remained distinct.
What was different about the Scandinavian pig? In Denmark they still have to castrate pigs to maintain the high quality of meat for export because they are susceptible to 'boar taint'. Danish pigs appear to have metabolic enzyme pathway deficiency in the liver (cytochrome P450 oxidase 2A), which metabolises skatole, the cause of boar taint. Valnemulin, the active substance of Econor is metabolised by a similar enzyme pathway the CYP 3A system and is thought to competitively block that pathway. It was found that the CYP 2A deficiency is the genetic marker for the Econor adverse reaction. A study showed that endotoxin derived from E. coli gave a prolonged temperature and clinical response when injected into Danish reaction-susceptible pigs in comparison with French non-susceptible pigs and the response was doubled when the Danish pigs were medicated with valnemulin. Endotoxins are metabolised and destroyed in the liver, like many toxic substances such as alcohol but the precise route for endotoxins has not been described. It is suspected that the CYP 2A and CYP 3A enzyme pathways are involved, so when they are deficient or blocked by valnemulin then endotoxins may not be destroyed and circulate in the bloodstream causing the clinical signs previously described.
These findings overall confirm a geographic and genetic link to the reaction and support the theory that endotoxins from concurrent infections play a crucial role in the reaction.
As a result, Econor's label now advises to use extreme care in pigs of Scandinavian origin, particularly the Danish and Swedish Landrace breeds and their crossbreeds.
The return of Econor in the EU and UK in particular, is an additional support to veterinarians and farmers in their fight against swine dysentery and enzootic pneumonia and new claims are being sought against colitis (B. pilosicoli) and ileitis (L. intracellularis) as well. Econor now has a one day withdrawal period for all its formulations so may be used in fattening pigs right up to the day before slaughter. In combination with chlortetracycline, Econor also offers a broad-spectrum economic approach to combating mixed respiratory infections of the MIRD complex, although statutory withdrawal periods apply.
References:
McOrist, S. Mackie, R.A. and Lawson, G.H.K. (1995) Antimicrobial susceptibility of ileal symbiont intracellularis isolated from pigs with proliferative enteropathy. Journal of Clinical Microbiology 33, 5, 1314-1317
McOrist (1998) In-vitro and in-life studies of efficacy of valnemulin for proliferative enteropathy (ileitis). Proceedings of the 15th International Pig Veterinary Society Congress Birmingham, England, 3, p 114
Stipkovits, L., Miller, D., Glavits, R., Fodor, L. and Burch, D. (2001) 'Treatment of pigs experimentally infected with Mycoplasma hyopneumoniae, Pasteurella multocida and Actinobacillus pleuropneumoniae with various antibiotics.' Canadian Journal of Veterinary Research 65, 213-222.
Dunser, M. and Schweighardt, H. (1998) Antimicrobial susceptibility testing for Econor, Tiamutin and Lincomycin against Brachyspira hyodysenteriae and weakly beta-haemolytic intestinal spirochaetes. Proceedings of the 15th International Pig Veterinary Society Congress Birmingham, England, 3, p 140
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