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Unique Breeding Schemes in Denmark and Sweden May Be Factor in Mystery ADRs
Of the 36 adverse drug reactions linked to the swine antibiotic Econorâ (valnemulin) in the EU between November 1999 and September 2000, 34 of them - or more than 94% - occurred in Denmark and Sweden. One was reported in Finland and another in Ireland. Overall, incidence of adverse drug reactions, or ADRs, in these countries ranged from 0.03% to 1.76% of all pigs treated.
According to the product's manufacturer, Novartis Animal Health, Inc., Basel, Switzerland, no reactions were reported in the rest of the EU, nor have any similar reactions been reported in more than 2 years of continuous use in Eastern Europe, Latin America or the Pacific Rim.
What is so unique about the pigs and pig production in Denmark and Sweden that makes them more sensitive to Econor?
Initially, scientists thought the ADRs might be linked to nutritional programmes or interactions with other feed ingredients unique to these countries. Since then, however, investigators have trained their sights on the breeding programmes used in Denmark and Sweden and, more specifically, the deficiency of an enzyme that could slow metabolic processes in the liver.
This deficiency, in turn, might make pigs, particularly young ones, more sensitive to Econor. Symptoms associated with these reactions include raised temperature, oedema of the nose and eyelids, weakness, and depression for 3 to 4 days. Mortality rate in affected herds ranged from 0.7% in Sweden to 1.2% in Denmark.
Unique genetic traits
For decades, breeders in Denmark have fine tuned their breeding programmes to create an optimum balance of litter size, weight gain, meat quality and carcass leanness to meet the needs of their strong export market, which accounts for 80 % of the country's total pig production. But along the way, some unique metabolic traits may have also developed.
For example, looking to optimise carcass leanness, Danish researchers have conducted numerous studies focusing on the male pig's ability to metabolise compounds responsible for "boar taint" in meat. In the process, they identified a sub-group of pigs in Denmark that was deficient in the enzyme CYP2A P450. This deficiency can slow the metabolic processes of the liver in swine and, in turn, make pigs more susceptible to ADRs.
Recent research led by Dr. Christian Friis, Royal Veterinary and Agricultural University, looked at the possibility that a similar metabolic deficient pathway might be involved in the adverse reactions associated with Econor.
"Pigs that reacted adversely to Econor showed a deficiency of the CYP2A P450 enzyme," adds Dr. Paul Ripley, an R&D veterinarian with Novartis Animal Health who led the ADR investigation. "We can't say for certain whether this deficiency occurred before or after the reaction, but evidence suggests that a CYP2A P450 deficiency is associated with an adverse reaction to Econor, as it follows a pattern within certain litters."
Scientists are still conducting studies to identify the exact cause of the problem. In the meantime, statistics and circumstantial evidence strongly suggest that ADRs seen in Denmark and Sweden may be unique to pigs bred for those markets. Specialists do not expect this phenomenon to spill over to other markets, unless the pigs being raised are of Scandinavian origin.
"We have kept our Landrace breeding lines isolated and thoroughly tested for many years," says Peter Høgedal, a consulting Danish veterinarian actively involved in this investigation.
This intensive testing programme of more than 100,000 progeny per year allows Denmark to produce high quality pigs that meet the demands of the export market ¾ and to keep their herd's genetics isolated through careful management of pig lines.
Høgedal agrees that the answer is not simple or clear cut. "The pigs involved in testing are crossbred market pigs with Landrace, Yorkshire, Duroc and Hampshire breeding - not simply pure Landrace."
Solving the puzzle
Whether the entire answer or a piece of the puzzle, genetics do seem to be playing a major role. Econor safety studies involving seven EU countries and nearly 200 farms across Belgium, Denmark, Germany, Ireland, Spain, Sweden and the UK looked at potential risk factors, including pig management, husbandry, disease patterns, drug usage and genetics.
"The studies concluded that there was a correlation with breeds found in Denmark and Sweden," says Ripley. "It also concluded that the observations were not those of a new disease or previously undetected toxic effects."
Animal husbandry and environment have also been crossed off the suspect list. "Husbandry issues in pig raising and basic feedstuffs are fairly uniform throughout the EU," stresses Høgedal, which rules against many environmental variables.
Disease pressure
In some cases, disease pressure may have contributed to Econor reactions on some Danish and Swedish farms. According to Ripley, pigs from herds with heavy Gram-negative bacteria pressure may be at greater risk.
"Pigs from a susceptible herd reacted much more strongly to an artificial E. coli endotoxin challenge," notes Ripley. "This suggests that high Gram-negative bacterial burden may be a mechanism for the observed effect of an Econor reaction."
The pig farms with high levels of Gram-negative bacteria are also more likely to utilize Econor earlier in their feeding programmes to help control disease in young pigs less than 7 weeks of age. A pig's metabolic capacity is not considered mature until 7 weeks of age.
"We want an answer for pig producers as to why some pigs react and others don't", stresses Ripley. "But for now, it appears that the problem is limited to pigs of Scandinavian origin."
Commitment to safety
Novartis Animal Health has approached this question with serious study and thorough testing to ensure safe and responsible use of the Econor product.
Multiple, on-farm trials including herds with previously identified reactions were conducted in Denmark. These trials incorporated daily observation of both treated and untreated pigs by practising veterinarians. Further laboratory testing and tissue evaluation is being conducted at the Royal Veterinary and Agricultural University, Copenhagen.
"The ultimate answer would be to identify a genetic marker linked to the ADRs," says Ripley.
"While we may not reach this goal, we are finding and documenting valuable information for pig producers," he adds.
In the meantime, Novartis Animal Health has added an advisory note to the Econor label noting that ADRs appear to be "mainly associated with breed mixes that include Danish and/or Swedish Landrace" and that "extreme care should be taken" when using Econor in "pigs of Scandinavian origin," especially Danish and Swedish Landrace breeds and their crossbreeds.
"Between the product's proven safety record in other markets and the relicensing of the product by the European Commission, we feel strongly that veterinarians and producers in the EU can use Econor with a high degree of confidence and success," says Dr. Ulrich Klein, a professional service veterinarian with Novartis Animal Health.
"Our market research shows that the EU pig industry urgently needs a new antibiotic for enteric and respiratory disease - one that has not shown resistance and one that is not used in human medicine. Only Econor meets those criteria."
For more information about Econor, contact the company at Novartis Animal Health, Inc., WRO 1032.3.41/AH 6.4, CH-4002, Basel, Switzerland. Tel: +41-61-697-7851.
