Reprinted from The TEVA Remuda, Spring 2010.

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1 Reprinted from The TEVA Remuda, Spring Texas Equine Veterinary Association P.O. Box 1038 Canyon, TX (806) Cyathostomins, Anthelmintic Resistance & Selective Deworming in Adult Horses Hoyt Cheramie, DVM, MS, DACVS Manager, Large Animal Veterinary Services Merial Limited Introduction Pick up any horse magazine from the last three years, and you ll likely find an article about the growing concern over equine parasite resistance. Several veterinary articles have appeared over the same time as well. Yet, equine anthelmintic resistance is not new.(1) In fact, the first report of cyathostomin (small strongyle) resistance in horses was in 1958(2), and numerous reports of benzimidazole (BZD) and pyrantel salts (PYR) resistance have been published since then.(3-10) What s changed is an increased reporting of ascarid resistance world-wide(11-15), suspected cyathostomin resistance in Europe and South America(16,17), and decreased cyathostomin egg reappearance rates (ERP)(7,14,15) to the avermectin/milbemycin class (AM; ivermectin, moxidectin; also known as macrocyclic lactones) of anthelmintics. These recent reports, along with the notion that it is unlikely that any new anthelmintic classes will be developed and marketed for horses in the foreseeable future, necessitates that veterinarians become educated in the latest knowledge on parasite biology and control practices and regain an active role in the design and monitoring of equine parasite control strategies.(18,19) Most horse owners continue to follow recommendations based on interval treatment proposed in the mid 1960s. The program involved treatment of every horse on the premises every 8 weeks throughout the entire year with rotation of the currently available anthelmintic classes. At that time, thiabendazole, a BZD anthelmintic, was the basis of the rotation, and the target parasite in adult horses was large strongyles. Thiabendazole has not been available for many years, and large strongyles, along with verminous arteritis colic, have virtually been eradicated on most wellmanaged horse farms(13,20). Horses acquire only partial immunity to cyathostomins(21) and they have now become the primary target parasite in adult horses(22). Tapeworms, bots, and large strongyles by virtue of their potential pathogenicity should be considered worthy of specific targeting in an effective parasite control program(18). The remaining equine parasites, stomach spirurid worms (Habronema muscae and Draschia megastoma), pinworms, Onchocerca, Trichostrongylus axei, Dictyocaulus arnfeldi, and Strongyloides westeri would be expected to be controlled in a properly designed program that targets the main group of parasites(18). In certain areas such, as the desert southwest where some of the lesser parasites like Habronema, Draschia and Ocnhocerca may remain quite common, case-by case treatment may be warranted. Ascarids (Parascaris equorum) are the most important parasite of foals but the adult horse parasites identified above also may be significant in some cases.

2 Cyathostomin Biology There are more than 40 species of cyathostomins described in horses with species comprising > 90% and about 3 species of those accounting for 70-80% of the worm burden.(10,23,24) Cyathostomins have a direct, nonmigratory life cycle.(25) Luminal adults undergo sexual reproduction with the females releasing eggs that are shed in the feces and hatch under favorable conditions (~43-85 F) into first stage larvae (L1). The L1 undergo 2 moults in the feces under appropriate conditions (no larval development occurs at <42 F or >100 F (26)) which may take as little as one to two weeks to several months resulting in infective L3. Larval development is directly related to environmental temperature, so as the temperature increases within the cited range, so does the rate of larval development. The L3 leave the fecal pat and move onto pasture to await ingestion. The L3 do not feed as they retain the L2 cuticle giving them a double cuticle layer. L3 die fairly quickly at temperatures >90 F but tolerate cold temperatures well.(27) After ingestion, the L3 penetrate the mucosal lining of the large intestine, encyst, develop into L4, and then emerge through the intestinal mucosa into the lumen. Subsequent development into L5 and maturation to adults complete the life cycle. In some horses, L3 enter a state of hypobiosis which can last from months to years. It is generally thought that these hypobiotic L3 invoke minimal inflammatory responses by the horse and induce few clinical symptoms.(28) The trigger(s) to induce this hypobiotic state may include host immunity, cold conditioning of pasture L3, and population density of parasites in the horse.(29) This phenomenon can lead to burdens of several million mucosal stage larvae in horses showing negative or low fecal egg counts.(30) If mucosal larvae emerge in large numbers (several million), the accumulated excretory and secretory products are released creating intense foci of mucosal inflammation and a colitis syndrome known as larval cyathostominosis.(22) This condition is rare in adult well-fed, immune competent horses. Adult cyathostomins feed on organic material within the ingesta, live adjacent to the mucosa and have no significant pathogenic effects., Anthelmintic Resistance and Refugia Anthelmintic resistance is defined as when there is a greater frequency of individuals within a population able to tolerate doses of a compound than in a normal population of the same species and is heritable.(31) As cited above, cyathostomin anthelmintic resistance in the US has become significant and widespread to BZD and this applies to a lesser degree to PYR, leaving AM as the only wholly effective class of anthelmintic for adult cyathostomin control.(8,18,32) Although decreased ERP is of concern, it is not ubiquitous, and oral ivermectin has recently been reported to be as effective as when first released.(33) Understanding anthelmintic resistance and preventing it from developing further are key to developing a rational parasite control program that ensures healthy horses and promotes continued drug efficacy in the future. The basic principal behind anthelmintic resistance development in nematodes is the accumulation of certain genetic alleles in the parasite population over time that render the parasites less susceptible.(35) The presence of these resistance-conferring mutations are likely present within a given parasite population at the time of first drug exposure.(25) Anthelmintic treatment is a powerful selector of resistance alleles; susceptible worms are killed, but resistant ones survive and reproduce.(37) This effect is perpetuated through excessive selection pressure (repeated frequent exposure), under-dosing, and long-term exposure to less than therapeutic levels.(25,36) Currently, the most important factor in limiting development of anthelmintic resistance is thought to be preservation of refugia.(10,37,38) Refugia refers to the parasite population not exposed to the drug at the time of treatment.(39) Refugia consist mainly of eggs and larvae on pasture, certain stages in treated horses (depending on drug and dose), and those in horses left untreated.(35) Cyathostomins in refugia provide a pool of genetically drug-sensitive genes.

3 Selective Deworming To limit the development of widespread parasite resistance, especially AM resistance, experts agree we need to reassess the goals of a parasite-control program.(18,19,28,39) While in the past the goal may have been to eliminate all parasites in all horses, the new goal is to maintain the health of horses while simultaneously maintaining the effectiveness of the anthelmintics currently available for as long as possible. Horses evolved with their intestinal worms, and certain numbers of cyathostomins are thought not to cause significant health impairment but rather help to stimulate immunity that serves to protect the horse from the establishment of a more serious worm burden.(18) The level of egg shedding is variable among individuals but remains constant in an individual and is related to the host s inherent immunity.(33,34,40) About 20-30% of horses shed about 80% of all eggs.(18,41) Selective deworming by targeting horses that shed the majority of eggs and are responsible for the bulk of pasture contamination was first reported by Gomez and Georgi in 1991.(41) This concept selectively targets high shedding horses for more frequent anthelmintic treatment and reduces the number of treatments in moderate and low shedders. Fecal egg counts (FEC) using the McMaster (or other suitable quantitative) method are performed easily on horses housed together to determine shedding level, and the horses are categorized as low (<200 Eggs Per Gram (EPG)), moderate (200 to 500 EPG), or high (> 500 EPG) shedders.(18,19,28) FEC should be performed after ideal time periods to reduce the suppression effect of the last anthelmintic treatment (ivermectin 12 weeks, moxidectin 16 weeks, BZD/PYR 10 weeks).(personal communication Kaplan 2010) Low shedding horses would be dewormed 2 times per year, moderate shedders 3-4 times per year and high shedders 4-5 times per year.(18,28) Because the majority of horses would be dewormed less frequently, it is imperative to determine that the anthelmintic chosen is still effective on the given farm by performing a fecal egg count reduction test (FECRT). FECRT is performed in all horses 3 yr of age with >200 EPG in small herds.(28) If there are large groups, a representative sample of 6-10 horses may be chosen. Successful FECRT will identify the anthelmintic classes to which the resident cyathostomins are resistant or susceptible. For BZD and PYR, FECR of >90% is considered satisfactory, but for AM, 95% FECR is the minimum acceptable level.(28) Deworming is unnecessary in all geographic regions during the period that comprises the unfavorable season for cyathostome transmission.(28) In the southern US with hot summers, parasite transmission is largely prevented; thus, nematode parasites are greatly reduced by the climate and the need for anthelmintics is negligible. Unnecessary treatment during this period also would diminish refugia.(30) In the northern US the harsh winters greatly reduce pasture transmission, as well. Some areas across the middle states may have both occur. The local environment also determines whether transmission is likely to occur. Because small strongyles are almost exclusively transmitted on pastures, a horse housed on shavings bedding in a stall most of the day and a dry lot when turned out has a significantly reduced risk of contaminating other horses or becoming re-infected with cyathostomins.(28) Additional environmental management techniques need to be considered. Rotating pastures, rotating species of animals when possible, composting of manure before spreading on grazing pastures, manure removal, and dragging/harrowing pastures only when appropriate are nonchemical-based ways of helping to reduce transmission of parasites.(19,25)

4 Summary It has become clear that continuing the status quo in parasite control will select for greater anthelmintic resistance and old-style programs are, in fact, increasing that risk. The goal should be to keep horses healthy and not to kill all the worms in every horse, every time. Equine practitioners need to become proactive in implementing parasite control programs aimed at minimizing pasture contamination and decreasing transmission as it is the larval stages of nearly all nematodes that are generally most pathogenic. The concept of selective deworming while maintaining a susceptible refugia has become key to fostering the long-term efficacy of the anthelmintics currently effective on a given farm and should be considered viable basis for developing an overall parasite control program. If the past has taught us anything, it is that if we do not change what we are doing now, we may not have the opportunity to change in the future. 1. Lyons ET, Tolliver SC. Some historic aspects of small strongyles and ascarids in equids featuring drug resistance with notes on ovids: Emphasis on research at the University of Kentucky. Agriculture Experiment Station, University of Kentucky College of Agriculture, SR- 102, Monograph, Poynter D, Hughes DL. Phenothiazine and piperazine, an efficient anthelmintic mixture for horses. Veterinary Record 70: , Drudge JH, Lyons ET. Newer developments in helminth control and Stongylus vulgaris research. Proceedings, 11 th Annual Meeting, American Association of Equine Practitioners, Miami Beach, Florida, pp , Round MC, Simpson DJ, Haselden CS, Glendinnings ES, Baskerville RE. Horse strongyles tolerance to anthelmintics. Veterinary Record 80: , Chapman MR, Klei TR, French DD. Identification of thiabendazole-resistant cyathostome species in Louisiana. Veterinary Parasitology 39: , Lyons ET, Tolliver SC, Drudge JH, Collins, Swerczek TW. Continuance of studies of Population-S benzimidazole-resistant small strongyles in a Shetland pony herd in Kentucky: Effect of pyrantel pamoate ( ). Veterinary Parasitology 94: , Little D, Flowers JR, Hammerberg BH, Gardner SY. Management of drug-resistant cyathostominosis on a breeding farm in central North Carolina. Equine Veterinary Journal 35: , Kaplan RM, Klei TR, Lyons, ET, Lester G, Courtney CH, French DD, Tolliver SC, Vidyashankar AN, Zhao Y. Prevalence of anthelmintic-resistant cyathostomes on horse farms. Journal American Veterinary Medical Association 225: , Lyons ET, Tolliver SC, Collins SS. Study (1991 to 2001) of drug-resistant Population-B strongyles in critical tests in horses in Kentucky at the termination of a 40-year investigation. Parasitology Research 101: , Kaplan RM. Anthelmintic resistance in nematodes of horses. Veterinary Research 33: , Hearn FPD, Peregrine AS. Identification of foals infected with Parascaris equorum apparently resistant to ivermectin. Journal American Veterinary Medical Association 223: , Lyons ET, Tolliver SC, Collins SS. Field studies on endoparasites of Thoroughbred foals on seven farms in central Kentucky in Parasitology Research 98: , Craig TM, Diamond PL, Ferwerda MS, Thompson JA. Evidence of ivermectin resistance by Parascaris equorum on a Texas horse farm. Journal Equine Veterinary Science 27:67-71, Lyons, ET, Tolliver SC, Ionita M, Lewellen A, Collins SS. Field studies indicating reduced activity of ivermectin on small strongyles in horses on a farm in central Kentucky. Parasitology Research 103: , von Samson-Himmelstjerna G, Fritzen B, Demeler J, Schürmann S, Rohn K, Schnieder T, Epe C. Cases of reduced cyathostomin egg-reappearance period and failure of Parascaris equorum egg count reduction following ivermectin treatment as well as survey on pyrantel efficacy on German horse farms. Veterinary Parasitology 144:74-78, Trawford AF, Burden F, Hodgkinson JE. Suspected moxidectin resistance in cyathostomes in two donkey herds at the Donkey Sanctuary, UK (United Kingdom). Proceedings, 20 th International Conference World Association Advancement Veterinary Parasitology, Christ Church, New Zealand, No 196, Molento MD, Antunes J, Bentes RN, Coles GC. Anthelmintic-resistant nematodes in Brazilian horses. Veterinary Record 162: , 2008.

5 18. Kaplan RM. These ain t your father s parasites: an evidence-based medical approach to equine parasite control. The Practitioner October, Swiderski C, French DD. Paradigms for parasite control in adult horse populations: a review. Proceedings, 54 th Annual Meeting, American Association of Equine Practitioners, San Diego, California, , Lyons ET, Tolliver SC, Drudge JH. Historical perspective of cyathostomes: prevalence, treatment and control programs. Veterinary Parasitology 85:97-112, Chapman MR, French DD, Taylor HW, Klei TR. One season of pasture exposure fails to induce a protective resistance to cyathostomes but increases numbers of hypobiotic third-stage larvae. Journal Parasitology 88: , Love S, Murphy D, Mellor D. Pathogenicity of cyathostome infection. Veterinary Parasitology 85: , Lichtenfels JR, Gibbons LM, Krecek RC. Recommended terminology and advances in the systematics of the Cyathostominea (Nematoda: Stongyloidea) of horses. Veterinary Parasitology 107: , Ogbourne CP. The prevalence, relative abundance and site distribution of nematodes of the subfamily Cyathostominae in horses killed in Britain. Journal Helminthology 50: , Matthews JB. An update on cyathostomins: anthelmintic resistance and worm control. Equine Veterinary Education 20: , Rupashinge D, Ogbourne CP. Laboratory studies on the effect of temperature on the development of the free-living stages of some strongylid nematodes of the horse. Zeitschrift Parasitenkune 55: , Lucker JT. Survival and development at low temperatures of eggs and preinfective larvae of horse strongyles. Journal Agricultural Research 63: , Reinemeyer CR. Controlling strongyle parasites of horses: a mandate for change. Proceedings, 55 th Annual Meeting, American Association Equine Practitioners, Las Vegas, Nevada, pp , Murphy D, Love S. The pathogenic effects of experimental cyathostome infections in ponies. Veterinary Parasitology 70:99-110, Dowdall SM, Matthews JB, Mair T, Murphy D, Love S, Proudman CJ. Antigen-specific IgG(T) responses in natural and experimental cyathostominae infection in horses. Veterinary Parasitology 106: , Prichard RK, Hall CA, Kelly JD, Martin IC, Donald AD. The problem of anthelmintic resistance in nematodes. Australian Veterinary Journal. 56: , Lyons ET, Tolliver SC, Collins SS. Probable reason why small strongyle EPG counts are returning early after ivermectin treatment of horses on a farm in central Kentucky. Parasitology Research 104: , McFarlane D, Hale GM, Johnson EM, Maxwell LK. Fecal egg counts after anthelmintic administration to aged horses and horses with pituitary pars intermedia dysfunction. Journal American Veterinary Medical Association 236: Nielsen MK, Haaning N, Olsen SN. Strongyle egg shedding consistency in horses on farms using selective therapy in Denmark. Veterinary Parasitology 135; , Nielsen MK. Equine Strongyle Parasites: Control strategies, epidemiology and improved methods for diagnosis of Strongylus vulgaris [PhD Thesis]. University of Copenhagen, Wolstenholme AJ, Fairweather I, Prichard R, von Samson-Himmelstjerna G, Sangster NC. Drug resistance in veterinary helminthes. TRENDS Parasitology 20: , Van Wyk JA. Refugia overlooked as perhaps the most potent factor concerning the development of anthelmintic resistance. Onderstepoort Journal Veterinary Research 68:55-67, Pomroy WE. Anthelmintic resistance in New Zealand: A perspective on recent findings and options for the future. New Zealand Veterinary Journal 54: , Nielsen MK, Kaplan RM, Thamsborg SM, Monrad J, Olsen SN. Climatic influences on development and survival of free-living stages of equine strongyles: implications for worm control strategies and managing anthelmintic resistance 174: Eysker M, Bakker J, van den Berg M, van Doorn DC, Ploeger HW. The use of age-clustered pooled faecal samples for monitoring worm control in horses. Veterinary Parasitology 151: , Gomez HH, Georgi JR. Equine helminth infections: control by selective chemotherapy. Equine Veterinary Journal 23: , 1991.