In this issue:
- Redux: drench combinations vs drench rotations
- Contagious yawning in sheep
Combinations vs drench rotation to delay resistance
The article reported that, to delay the onset of anthelmintic resistance, using combinations (of unrelated drench actives) was vastly superior to using single active drenches sequentially (drench A for an extended time, then drench B) or rotation, for example, annually. It was also stated that the results of this modelling broadly confirm the results of other models developed in Australia, New Zealand and elsewhere over the last 20 years. (In the following, emphases (bolding) are mine. – Ed.)
In June 2011, Dobson and others reported the results of a study which addressed the best ways of using the new active monepantel (Zolvix) as well as existing actives. A multi-species model (Haemonchus, Trichostrongylus and Teladorsagia) was used to simulate worm burdens and selection for drench resistance in sheep in two winter rainfall zones (Kojonup (Western Australia, WA), Hamilton (Victoria, VIC),) and two summer rainfall zones (Glen Innes and Armidale (New South Wales, NSW).
To test the effect of refugia, 0,1,4,7 or 10 % of sheep were left untreated (UT). Drench regimens explored were (1) monepantel (MPL) + benzimidazole (BZ) + levamisole (LEV) +abamectin (ABA) used in combination/concurrently, or (2) MPL rotated with BZ+LEV+ABA, or (3) MPL rotated with moxidectin (MOX), or (4) MPL rotated with BZ+LEV+ABA and MOX. So, 20 different treatment regimens were modelled in each region.
For both WA and Vic, using MOX+COM 0%UT, i.e., using MOX+BZ+LEV+ABA in combination, and leaving none-untreated, scored the best in both worm control and resistance management. For northern NSW, MOX+COM 0%UT scored best on resistance management, but was narrowly beaten by 4 other regimens (each of which included MOX and also a combination) on worm control. (Resistance was assumed to be emerging for MOX and ABA (3% resistance alleles) (the situation now-2016-is different!-Ed) and common for BZ+LEV (40% resistance alleles).
Arguably MOX+COM 0%UT would have scored highest as well for worm control in northern NSW if worm control was optimised, as outlined in WormBoss-Your Program.
The authors concluded that “in general, the model predicted that leaving more than 4% of adults untreated did not sufficiently delay the development of anthelmintic resistance to justify the increased production risk from such a strategy.(But in other studies, leaving some undrenched – with caveats – gets a tick). The choice of a drug rotation strategy had an equal or larger effect on nematode control, and selection for resistance, than leaving 1–10% of adults untreated”. I might add it also showed the superiority of combinations.
Barnes and others (1995) used a model simulating Trichostrongylus colubriformis in sheep at Armidale NSW. They found that, using ‘mixtures’ (i.e. using two unrelated drugs simultaneously, with individual drug efficacies at either 10, 50 or 99%), little (further) resistance developed over 20 years, whereas substantial resistance developed with each of the rotation strategies. Resistance developed more rapidly if it was determined by a single rather than two or more genes Resistance developed fastest if it was dominant. Leaving a proportion untreated delayed resistance, but at the expense of worm control. Also in their simulation, it was found that, without grazing management, heavy reliance on drugs rapidly leads to very high levels of resistance and lamb death. (Sage advice from the Terrific Trio).
Sangster in 2001, in a general discussion (covering a range of hosts and parasites), outlined in Table 4 of that paper, lists these measures to slow or deal with resistance: monitor resistance and use effective drugs, reduce reliance on chemicals (especially where there are (parasite) survivors; reduce the number of infective stages (i.e. control exposure); use effective drugs at full dose rates; do not use suppressive treatment regimens; rotate between chemical groups; monitor and treat when thresholds are reached; maintain a refugium (e.g. by leaving some untreated; or delaying the move to a very clean paddock after drenching); use short-acting drugs; and, finally: “ the use of combinations has been predicted to be the most effective way of delaying resistance”… evidence comes from models of parasites as diverse malaria, ticks, helminths… (so) use combinations of drugs with different modes of action, against which there is no resistance (optimal, but often unachievable in the real world. – Ed), and which have the same elimination half lives.”
Smith in 1990 modelled the evolution of anthelmintic resistance in a direct life cycle nematode parasite and reported that the model suggested that alternating or sequential use of anthelmintics with different modes of action may be a less effective resistance management strategy than administering the same drugs simultaneously. Smith stated that there was general agreement that infrequent treatments which targeted just those animals at particular risk would impede development of resistance, but that there could be production penalties. As to various drug strategies, he said the literature was replete with conflicting opinions, with some advising the use of one drug until it became ineffective, then switching to another (sequential use); still others suggested slow rotation of alternate drugs; and finally some (including Dash in 1986, and Anderson, Martin and Jarrett, in 1989), recommending using mixtures of anthelmintics.
There has been a growing acceptance of the value of using drugs in combination, but at the same time the idea that rotation of drugs has significant value in delaying resistance in nematodes of sheep still enjoys considerable favour, despite the paucity of supporting evidence. Lewis Kahn has thought that one paper might have been thought to provide evidence. That reported a study by Donald and others (1980) in which oxfendazole-resistance Teladorsagia (Ostertagia) in sheep was then exposed to selection with levamisole. Progeny of survivors of levamisole treatment(s) showed reduced resistance to oxfendazole, suggesting that levamisole selected against benzimidazole resistance. From this it was suggested that alternation in the use of different drugs could delay the development of resistance.
It has also been suggested that the recommendation to rotate drugs when controlling nematodes in sheep has largely been extrapolated from studies in insects (??).
So, the recent article by Lewis Kahn is a salutary reminder.
To repeat his main points:
Rotation between different drench groups does relatively little to slow development of drench resistance and should not replace these three highly effective practices:
- use products most effective on your property
- use multi-active (combination) products
- use short-acting products
Moving (rotating) to a different drench (or combination of drenches) as an ‘exit’ drench can be of value:
- at the end of the protection period of a persistent drench.
- when sheep are exiting a paddock which was a low worm-risk paddock into which the sheep were drenched and moved earlier, for example pre-lambing, ewes, or lambs at weaning.
According to the Laurenson modelling, a relatively small benefit (compared to using combinations) from drench rotation can also accrue if rotational grazing is practised as well.
All of the above should part of a complete program, as outlined in WormBoss programs, for example, which also, apart from drenching, deal with:
- controlling exposure to infective larvae – though grazing management.
- reducing vulnerability of animals – through nutrition and genetics.
- maintaining sufficient worms in refugia.
As Bartram and others (2012) say, using combinations is not a panacea.
Barnes EH, Dobson RJ, Barger IA, 1995. Worm control and anthelmintic resistance: adventures with a model. Parasitology Today. 1995 Feb;11(2):56-63.
(Also see Bartram and others, 2012. The role of combination anthelmintic formulations in the sustainable control of sheep nematodes. Veterinary Parasitology.)
Dobson RJ, Barnes EH, Tyrrell KL, Hosking BC, Larsen JWA, Besier RB, Love S, Rolfe P and Bailey JN, 2011. A multi-species model to assess the effect of refugia on worm control and anthelmintic resistance in sheep grazing systems. Australian Veterinary Journal Volume 89, No 6, June 2011
(Also see this paper by Dobson et al in May 2011; Minimising the development of anthelmintic resistance, and optimising the use of the novel anthelmintic monepantel, for the sustainable control of nematode parasites in Australian sheep grazing systems. Australian Veterinary Journal Volume 89, No 6, June 2011).
Leathwick DM, 2011.Modelling the benefits of a new class of anthelmintic in combination
Vet. Parasitol. (2011) http://dx.doi.org/10.1016/j.vetpar.2011.11.050
Leathwick DM, Hosking BC, Bisset SA and McKay CH, 2009.Managing anthelmintic resistance: is it feasible in New Zealand to delay the emergence of resistance to a new anthelmintic class? N. Z. Vet. J., 57 (2009), pp. 181–192)
Sangster N, 2001. Managing parasiticide resistance. Veterinary Parasitology 98 (2001) 89–109.
(Also see: Sangster N and Dobson R, 2002. Anthelmintic resistance. In: Lee, DL, ed. The Biology of Nematodes, London: Harwood Academic Publishers, 2002; 531-567).
Smith G, 1990. A mathematical model for the evolutions of anthelmintic resistance in a direct life cycle nematode parasite. International Journal of Parasitology. 1990 Nov;20(7):913-21.
David J. Bartram, Dave M. Leathwick, Mike A. Taylor, Thomas Geurdend, Steven J. Maedere, 2012. The role of combination anthelmintic formulations in the sustainable control of sheep nematodes. Veterinary Parasitology, Volume 186, Issues 3–4, 25 May 2012, Pages 151–158. http://dx.doi.org/10.1016/j.vetpar.2011.11.030 http://www.sciencedirect.com/science/article/pii/S030440171100762X
Abstract below, but read the full review:
Combinations of anthelmintics with a similar spectrum of activity and different mechanisms of action and resistance are widely available in several regions of the world for the control of sheep nematodes. There are two main justifications for the use of such combinations: (1) to enable the effective control of nematodes in the presence of single or multiple drug resistance, and (2) to slow the development of resistance to the component anthelmintic classes. Computer model simulations of sheep nematode populations indicate that the ability of combinations to slow the development of resistance is maximised if certain prerequisite criteria are met, the most important of which appear to concern the opportunity for survival of susceptible nematodes in refugia and the pre-existing levels of resistance to each of the anthelmintics in the combination. Combinations slow the development of a resistant parasite population by reducing the number of resistant genotypes which survive treatment, because multiple alleles conferring resistance to all the component anthelmintic classes must be present in the same parasite for survival. Individuals carrying multiple resistance alleles are rarer than those carrying single resistance alleles. This enhanced efficacy leads to greater dilution of resistant genotypes by the unselected parasites in refugia, thus reducing the proportion of resistant parasites available to reproduce with other resistant adults that have survived treatment. Concerns over the use of anthelmintic combinations include the potential to select for resistance to multiple anthelmintic classes concurrently if there are insufficient parasites in refugia; the potential for shared mechanisms of resistance between chemical classes; and the pre-existing frequency of resistance alleles may be too high on some farms to warrant the introduction of certain combinations. In conclusion, anthelmintic combinations can play an important role in resistance management. However, they are not a panacea and should always be used in accordance with contemporary principles for sustainable anthelmintic use.
For those who like pictures:
Contagious yawning in sheep
Now for something different, and in no way connected to the above:
(Thanks Dr Hatcher)
SL, Armidale, 2016-10-28