Similarly, adding a novel constituent active to an anthelmintic combination product that includes

existing constituent actives, as opposed to using it alone or in rotation in areas where resistance already exists, should not predispose it to a more rapid selection for evolution of parasite resistance as demonstrated in recent modeling and empirical studies (Dobson et al., 2011a, Dobson et al., 2011b, Leathwick, 2012 and Leathwick et Bcl-2 inhibitor al., 2012). Proof of efficacy of combinations against existing resistant parasite isolates in dose-determination experiments will alleviate this concern to some extent, although only field use will reliably reveal if selection of a resistance mechanism that crosses anthelmintic classes can occur in nematode populations following the use of a new drug. As noted above, few farmers test selleck chemicals for AR (Lawrence et al., 2007, Dobson et al., 2011a and Morgan et al., 2012). Under these circumstances, a concern is that fixed-dose combination anthelmintic products could mask the development of resistance. This may be considered a technology transfer

or compliance problem that does not change the conclusions from modeling studies that resistance will be substantially delayed by administering anthelmintic combination products in comparison to rotation or sequential use strategies of single-constituent active products (Smith, 1990, Barnes et al., 1995 and Leathwick, 2012). Fixed-dose combination anthelmintic products appear to slow the development of resistance because they afford the highest possible kill of nematodes (Bartram et al., 2012). Parasites that survive one constituent active in the combination are killed by the other constituent active(s); individual parasites that possess two distinct R-alleles, each of which is present in the population at very low frequencies, will initially be very rare. However,

the use of anthelmintic combination products does not eliminate the significant risk for resistance posed by dosing strategies that allow livestock to graze clean (low contamination) pastures after treatment. This tuclazepam practice readily selects for resistant populations as the parasites that survive the treatment become the major source of subsequent contamination on these pastures (LeJambre, 1978, Cawthorne and Whitehead, 1983, Michel, 1985, Taylor and Hunt, 1988 and Taylor and Hunt, 1989). This concern is obviously more acute if resistance to one of the constituent actives in the combination product is already present and unsuitable treatment regimes are implemented. The benefits of maintaining a population of nematodes in refugia, as a means of slowing the development of drug resistance, were first advanced by Martin et al. (1981) and should not be underestimated; van Wyk (2001) and Dobson et al. (2001) proposed that refugia could be the most important factor in determining the rate at which AR develops.