Denagard® 2% premix (tiamulin hydrogen fumarate) has now been approved in the UK for the treatment of ileitis and colitis, to add to its original claims of swine dysentery treatment and prevention, and as an aid in the control of enzootic pneumonia.

Tiamulin was first described as an effective treatment of ileitis, as long ago as 1981 by a Yorkshire vet, David Jennings, who investigated a case in wasting grower pigs, which were showing some diarrhoea and an occasional mortality. On post-mortem examination, they showed the classical proliferation and thickening of the lower small intestine and some areas of necrosis (dead tissue). Following treatment via the drinking water, the mortality decreased and the incidence of emaciated pigs disappeared. In those days, we could recognise ileitis or proliferative enteropathy, but we had not identified the bacterium involved, Lawsonia intracellularis, nor could we grow it. It was not until the 1990's that Gordon Lawson at Edinburgh University, was able to grow the organism using a cell culture and this lead to further breakthrough work by Steve McOrist, now of Nottingham University, to determine the intra-cellular activity of a number of antimicrobials that could be used to treat the disease (McOrist and others, 1995).

His first artificial infection challenge study in pigs with infected cell-cultures was carried out using tiamulin (McOrist and others, 1996). Pigs were infected orally and placed on medication 2 days before infection (prevention) and seven days after infection (treatment) and the trial was terminated 21 days after infection. He confirmed that tiamulin given in feed was highly effective for both the treatment and prevention of ileitis (see Table 1).

Table 1. Artificial infection challenge trial results (McOrist and others, 1996)

Treatment group	Gross lesions pigs affected (%)	Lesion score ileum (%)	Lesion score caecum (%)
Infected control	86	42	46
Prevention: tiamulin 50ppm -2 to 21 days	0	0	0
Treatment: tiamulin 150ppm 7 to 21 days	0	0	0

More recently, researchers in Minnesota University (Wattanaphansak and others, 2007) tested ten US and EU isolates of L. intracellularis, including the McOrist isolate used in his study and showed that the intracellular minimum inhibitory concentration (MIC) of tiamulin to be 0.125µg/ml. If we look at the estimated concentration of tiamulin in the ileum using a pharmacokinetic model (Burch, 2005), we can see why tiamulin has such a strong therapeutic effect against the organism (see Figure 1) as the ileal contents concentration of tiamulin are substantially higher than the MIC 90 for the organism.

Ileitis remains an important endemic disease in the UK herd, with Mortimer and others (2000) showing 94.6% of farms were positive for the infection in the UK and Ireland, and Quality Meat Scotland (Ward, 2008 - personal communication) has just reported that 91% of Scottish herds are infected. Denagard should be able to play an active and effective role in controlling this disease, especially where some of the older antibiotics may be losing their effect due to resistance development.

Colitis, caused by Brachyspira pilosicoli, is also quite common in the UK and especially in Scotland. It is a similar organism to Brachyspira hyodysenteriae, the cause of swine dysentery, and lives in the same part of the gut - the large intestine or colon. Fortunately, it is not associated with such a severe disease. In the reports from the Veterinary Laboratories Agency for 2006 (VLA, 2007), there were 92 cases of swine dysentery, 84 cases of ileitis and 46 cases of colitis. These infections can come individually or mixed together, especially in grower and finisher pigs. They are hard to differentiate clinically and can be confused with PCV2 enteritis. It is important to differentiate them by culture or PCR test.

Tiamulin achieves high levels in the colon contents, well above the MIC 90s for both B. pilosicoli and B. hyodysenteriae (see Figure 2). B. pilosicoli, as well as causing a milder disease than B. hyodysenteriae, also seems to be more susceptible to tiamulin with an MIC 90 of 0.25 and 2.0µg/ml respectively.

In a series of field trials, Thomson and others (2006) tested tiamulin at 100ppm in feed for 7-10 days in six split batches of 600 high-health pigs. The pigs arrived from the nurseries at about 9 weeks of age (25kg bodyweight) and were kept on the trial farm for a further 6 weeks in 4 large straw-bedded pens before being sent to the final finisher. The pigs were weighed in and again when they left and the feed given was recorded. Tiamulin was used as 8 isolates of B. pilosicoli from the unit had shown good sensitivity. The results are highlighted in Table 2.

Table 2. Trial results of 6 batches of growers treated with tiamulin 100ppm in feed

	Untreated controls	Tiamulin 100ppm	Improvement (%)
Average daily gain (g)	757	880	16.2
FCE	2.03	1.77	12.8
Mortality (%)	1.08	0.91	0.17

When the results were put into a spreadsheet model using feed costs of £220/tonne and Denagard® 2% premix at 5kg/tonne to give 100ppm at £19/tonne, there was a substantial additional margin per pig of £3.13. Although colitis does not cause a high mortality, it can cause a substantial reduction in performance. Overall, Denagard's new claims should prove to be welcome additions to the veterinary surgeon's armoury to fight mixed enteric infections in growing and finishing pigs and improve the productivity and profitability of producers.

References:

Anderson, M.D., Stroh, S.L. and Rogers, S., 1994. Tiamulin (Denagard®) activity in certain swine tissues following oral and intramuscular administration. Proceedings of the American Association of Swine Practitioners Chicago, Illinois, 115-118

Burch, D.G.S., 2005. Pharmacokinetic, pharmacodynamic and clinical correlations relating to the therapy of Lawsonia intracellularis infections, the cause of porcine proliferative enteropathy ('ileitis') in the pig. Pig Journal 56, 25-44

Jennings, D.S., 1981. Intestinal adenomatosis. Pig Veterinary Society Proceedings 7, 61-62

McOrist, S., Mackie, R.A. and Lawson, G., 1995. Antimicrobial susceptibility of Ileal Symbiont intracellularis isolated from pigs with proliferative enteropathy. Journal of Clinical Microbiology 33, 5, 1314-1317

McOrist, S., Smith, S.H., Shearn, M.F.H., Carr, M.M. and Miller, D.J.S., 1996. Treatment and prevention of porcine proliferative enteropathy with oral tiamulin. Veterinary Record 139, 615-618

Mortimer, I., Green, L. and Hodge, A., 2000. Serological prevalence of Lawsonia intracellularis across the UK and Irish pig herds. Proceedings of the 16th International Pig Veterinary Society Congress Melbourne, Australia, 110

Thomson, J.R., Murray, B.P., Henderson, L.E. and Edwards, S.A., 2006. A cost-benefit study on the control of porcine colonic spirochaetosis in a commercial grower unit. Proceedings of the 19th International Pig Veterinary Society Congress Copenhagen, Denmark, Vol. 2, 250

Veterinary Laboratories Agency (VLA), 2007. VIDA Veterinary Investigation Surveillance Report 1998-2006

Wattanaphansak, S., Gebhart, C., Singer, R. and Dau, D., 2007. In vitro testing of antimicrobial agents for Lawsonia intracellularis. Proceedings of the American Association of Swine Veterinarians Orlando, Florida, USA, 255-256

May 2008