Drug Resistance in Equine Parasites: An Emerging Global Problem

REVIEW Drug Resistance in Equine Parasites: An Emerging Global Problem Heidi A. Brady, PhD, Dipl ACAP,a and Wade T. Nichols, PhD, PASb

ABSTRACT Effective parasite control is essential for the maintenance of optimal health and performance in the horse. The worldwide escalation of parasite resistance is a major cause of concern for the horse industry. Parasite resistance to every main class of equine anthelmintic has been documented. Furthermore, dual and cross resistance also have been widely reported, despite different climatic and management practices seen throughout the world. Studies documenting parasite resistance to major classes of equine anthelmintics are discussed. Disagreement among researchers exists regarding how to effectively control equine internal parasites. Current theories of factors leading to resistance and control programs are discussed. It is clear that parasite resistance and control in the horse is an area requiring continued intensive study. Keywords: Parasites; Anthelminitic; Resistance

INTRODUCTION Effective parasite control is an essential element in achieving a successful equine operation and maintaining healthy, productive horses. Controlling parasites allows the equine athlete to perform at individual maximum levels and contributes to efficient breeding herd performance. Parasites are dependent on and by definition adversely affect the host.1 These adverse effects have been widely documented in domestic farm animals.2-14 Many of these studies have correlated the interactions between nutritional efficiency and performance with parasitism.2-3,8-11 The utilization of nutrients is negatively affected by internal parasites, which induce protein deficiency, increase amino acid demand, and further depress appetite in affected animals.3,5-6,12,14 Effective parasite control is a key factor in feed efficiency, utilization of available nutrients, immune status, and intestinal health in all species.3,5-7,11-14 The From the Department of Animal and Food Sciences, Texas Tech University, Lubbock TXa; and Intervet/Schering Plough Animal Health, Roseland, NJb. Reprint requests: Heidi Brady, PhD, Box 42141, Department of Animal and Food Sciences, Texas Tech University, Lubbock, TX 79409. 0737-0806/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2009.04.186

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base of knowledge on the nutritional effects of parasitism is far greater in food animals than in the horse. In the horse, symptoms of parasitism include poor body condition, distension of the abdomen, slower rate of growth, weakness, and decreased digestion.15,16 Suboptimal performance15 and poor efficiency16 in the horse are also associated with parasite-burdened horses. Production inefficiency in the brood mare and low body score conditions have been well documented, with both lower conception rates and higher incidences of early embryonic losses.17,18 Internal parasites are one of the most common threats to equine health and well-being, especially in young and vulnerable foals and in geriatric horses. Recent concerns have emerged over increasing national and international studies documenting resistance to anthelmintics and over predicted resistance of equine parasites to additional classes of anthelmintics in the future. To date, resistance to every main class of equine anthelmintic has been documented. However, researchers disagree about the standardization of measurements of resistance and the determination of a threshold of fecal egg count (FEC) in horses requiring anthelmintic treatment. The existence of conflicting recommendations for anthelmintic regimens to be implemented in equine facilities to either decrease resistance from developing or to counteract a current resistance problem are problematic. The prevalence of parasite resistance continues to increase worldwide, and both cross resistance and side resistance are widely reported. To address this global problem, the Equine Parasite Drug Resistance Workshop was held in at the University of Copenhagen in Denmark (July 2008) to discuss the escalating problems of parasite resistance documented in horses throughout the world. The purpose of this symposium was to establish consensus recommendations for parasite control in the horse. It is clear that definitive research is needed in this important field. This review summarizes current studies on internal parasite control in the horse with respect to reported resistance and proposed regimens for parasite control.

EQUINE PARASITES WITH DEVELOPED RESISTANCE TO CURRENT ANTHELMINTICS Important equine parasites that have been reported to have developed resistance to at least one class of equine anthelmintics include ascarids, large strongyles, and small

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strongyles (cyathostomes). The clinical significance of these parasites has varied through time, changing with the introduction of new anthelmintics. Ascarids (Parascaris equorum) Although ascarids can infect the mature horse, they are much more problematic in the young animal. Ascarid loads present problems primarily in foals and yearlings, because older horses are thought to develop some level of immunity to these parasites. Because of the larger size of this roundworm, impaction colic requiring surgery is known to develop with high loads. Health problems associated with high ascarid levels include coughing, depression, anorexia, unthriftiness, poor weight gain, rough hair coat, pot belly appearance, and possible death caused by intestinal compaction and ileus or small intestine rupture.19 Emerging resistance to ascarids has been recently reported, possibly because of the increasing emphasis on cyathostome control in the horse. Large Strongyles Because of the harmful and often fatal effects of the migration of the large strongyles through the blood vessels of the horse, these parasites, including S. vulgaris, S. equinus, and S. edentatus, are considered of major importance in equine health. However, because of high efficacies of commonly used anthelmintics against large strongyles, most current studies in equine parasitology have focused on the more difficult and complex problem of cyathostome control and elimination. Controlling large strongyles in the horse, however, remains a very important aspect of total equine parasite control programs and needs to be considered in every anthelmintic program. Small Strongyles (Cyathostomes) The cyathostomes have emerged as the major equine parasite problem, presenting both clinical and subclinical effects. Most of the parasite loads in the adult horse include four species of cyathostomes. The rapid emergence of this threat to the equine and the pathogenicity of cyathostome infections in the horse have been reviewed.20-22 The understanding of cyathostome control is significantly complex and problematic because the efficacy of many equine anthelmintic regimens can be greatly reduced because of protected encysted mucosal stages of these parasites. Subclinical effects of cyathostomes include decreased digestive tract function and efficiency. Clinical symptoms include weight loss, rough hair coat, decreased performance, diarrhea, and possibly death. In the rare disease syndrome known as cyathostomosis or cyathostomiasis, submucosal larvae (mainly L4) emerge in synchrony or cohorts causing sudden onset of severe diarrhea, tissue damage, protein and fluid loss, low-grade colic, edema, rapid weight loss, and death in severe cases.21 The

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mechanisms governing the synchronous release of the submucosal larvae are unclear; however, it is thought to be caused by the removal of the inhibitory feedback associated with luminal and developing mucosal cyathostomes after treatment with anthelmintics.20,23

THE COMPLEXITIES OF RESISTANCE TO EQUINE ANTHELMINTICS Earliest reports of resistance of equine parasites to anthelmintics include studies from the United Kingdom24,25 examining the use of phenothiazine. In these early studies, reductions in fecal egg counts after treatment were examined systematically. This was followed by several studies from the state of Kentucky reporting resistance of cyathostomins to phenothiazine.26 Although these products are no longer in use, this review references many of the numerous reports from many countries that have subsequently documented resistance of equine parasites to commonly used anthelmintics. Definitions of Resistance It is very difficult to compare studies on resistance because of the lack of universal agreement in the literature regarding the definition of resistance of equine parasites to anthelmintics. Although there is recognized variation in FEC and actual parasite load of the horse, the use of FEC is the most common method used to evaluate parasite status of the horse. To determine whether resistance to an anthelmintic exists, fecal egg count reductions (FECR) can be calculated by comparing fecal samples taken immediately before anthelmintic treatment with posttreatment fecal samples taken 7 to 14 days posttreatment. There are several reported methods to determine resistance.27,28 The World Association for the Advancement of Veterinary Parasitology has defined resistance as FECR of less than 95% in tests 10 days apart using arithmetic means.27 Other thresholds27,29 for FECR have been suggested for defining resistance, including the 90% or 80% threshold. There is a difference between original lack of efficacy of an anthelmintic and the development of resistance to an anthelmintic. To address this difference, one standard of resistance of a population of parasites to a particular class of anthelmintic requires the documentation of preexisting efficacy of 90% or more against the population in question. Egg hatch assays and larval development assays are also used in the detection of resistance for various anthelmintics and parasites. Several methodologies currently used in the horse for parasite fecal egg quantification include the McMaster30 and the Modified Wisconsin Sugar Flotation31 methods. Quantitative analyses of eggs per gram of manure are commonly calculated for ascarids and strongyles. Differentiation between large and small strongyles, however, requires the use of larval cultures. An additional estimation

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of anthelmintic resistance is the determination of egg reappearance period (ERP) over time.32,33 One definition of ERP is the interval in which fecal egg count returns to 20% of pretreatment values.33 A shortening of ERP of an anthelmintic over time may be an early warning of the development of resistance, although there are inconsistent reports on ERPs for each anthelmintic class in use. Shortening of ERPs has been reported in equine anthelmintics.33-36 Comparisons of ERP studies, however, should be made with caution because of variables in pretreatment egg counts, stocking rates, pasture management, ages, and other variables between studies. This may be a very important area for future research in controlled studies over time. Factors Contributing to Resistance Factors contributing to the development of resistance have been reported to include high frequency of deworming and the continued use of only one class of anthelmintic. Studies in sheep have shown that the frequent use of an anthelmintic will directly affect the rate of selection of resistance.37 In addition, underdosing the animal is common in the equine industry, either by underestimation of the animal’s weight or by losing product during the administration of the anthelmintic. Also reported to accelerate the development of resistance is the decrease of refugia of parasites, either through anthelmintic action, season of treatment, or climatic conditions at time of treatment.38 Refugia is defined as the proportion of the parasite population that is not affected by the anthelmintic at the time of treatment, including parasites in untreated horses, encysted stages of parasites, and those on pasture not exposed to the anthelmintic. Parasites in refugia can function to dilute resistant population of parasites and thus decrease selection of resistance. Current studies have shown that resistance of parasites to anthelmintics is inherited, requiring the existence of resistant genes in the population of parasites. Resistance is influenced by selection pressure and many other factors.32 Dominant genes in the parasites are associated with a more rapid development of resistance than recessive genes.32 In summary, despite the differences outlined in defining resistance throughout the world and the multifactorial nature of contributing factors toward the development of resistance, most researchers agree that early detection of resistance is of great importance for control. Thus, many anthelmintic plans currently being proposed advocate herd testing by fecal samples at regular intervals.

CLASSES OF EQUINE ANTHELMINTICS Current anthelmintics that are in popular use in the equine industry can be classified into three main categories. Currently used benzimidazoles (BZM) include drugs such as fenbendazole (FBZ), oxfendazole, and oxibendazole

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(OBZ). Tetrahydropyrimidines are the pyrantel salts (PRT), which include pyrantel pamoate and pyrantel tartrate. Macrocyclic lactones (M/L) or avermectin/ milbemycins include ivermectin (IVM) and moxidectin (MOX). Within this category, MOX is classified as a milbemycin because it lacks the sugar groups of the avermectins. Other less common anthelmintic classes include simple heterocyclics, including piperazine, which is generally used as an additive to other classes of anthelmintics. Mechanisms of biologic action and efficacy of the currently used equine anthelmintics against specific parasites have been fully reviewed.39-41

RESISTANCE TO BENZIMADAZOLES In general, the mode of action for the BZM class is through interfering with the energy metabolism of the parasite by decreasing the absorption and digestion of glucose.42 Within this class, FBZ is labeled for the control of large strongyles, small strongyles, pinworms, and ascarids (Parascaris equorum). The larvicidal dose of FBZ, which is a 2 dose given for five consecutive days, is additionally effective for the control of all stages of mucosal cyathostome larvae, including encysted early third-stage hypobiotic larvae (eL3) and late third-stage and fourth-stage cyathostome larvae.43 The incidence of reported resistance to BZMs are detailed further. Ascarids No known studies in the horse have reported ascarids resistant to anthelmintics within the BZM class of anthelmintics. Large Strongyles The reason that resistance to BZMs is not commonly present in large strongyles in contrast to the higher incidence observed in cyathostomes is unclear; however, this may be related to the longer generation intervals of large strongyles. Small Strongyles (Cyathostomes) Equine studies documenting cyathostome resistance to BZMs are widespread and involve farms both in the United States and globally. Furthermore, cyathostome resistance to BZMs has been reported over several decades.44 Studies have shown that the ERP for BZMs has decreased from approximately 6 to 8 weeks 40 years ago34 to a 2001 estimations of 4 weeks.33 In many cases, this may be because of all the currently used equine anthelmintics, BZMs have been approved for the longest period. Reports of BZM resistance in cyathostomes by region are listed in the following sections.

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Reports of Cyathostomes Resistance in the United States Cyathostome resistance to BZMs has been reported in studies from across the United States, including Kentucky,45-52 Pennsylvania,53 Georgia,33,47 Louisiana,47,54 South Carolina,47 Florida,47,55 Tennessee,56 and Texas.57-59 The most common BZM used in these studies was FBZ. In many studies, cyathostome resistance to BZMs was seen after frequent use of BZMs or earlier versions of BZMs.46,50,52,54,58,59 Forty years documenting a BZM-resistant strain of cyathostomes (population B) in Kentucky was recently reviewed.52 Further investigations into BZM resistance in the western and northern areas of the United States need to be conducted to assess this problem under different management and climatic conditions. International Reports of Cyathostome Resistance Studies across the world have similarly documented strains resistant to BZMs, and in particular, to FBZ. In Canada, BZM-resistant cyathostomes has been reported.60 Researchers61,62 also documented resistance to the larvicidal dose of FBZ on farms in England and Scotland. In Denmark, cyathostome resistance to BZMs was reported in 13 of 16 farms (FECR ranging from 80% to -101%) after treatment regimens of an average of 7.1 and 5.3 times per year.63 Another study in Denmark determined that FBZ was ineffective in 33 of 44 farms in Denmark (79% resistance).28 Bauer and coworkers64 reported BZM-resistant small strongyles on German Thoroughbred studs. BZM resistance was documented in a study of five farms in the Czech Republic.65 On many of the Czech farms, underdosing of animals was frequent, as was the practice of administering the same class of anthelmintic for 5 or more years. Further reports of BZM resistance include Pomerania66 and Australia, among others.67

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rapidly from a high level of effectiveness in year 1, indicating the existence of cross-resistance.68 Cyathostome resistance to PRT (mean FECR of 66.5%) was also reported in a large farm in Louisiana.69 Cross-resistance was documented to FBZ and OBZ in this herd, although IVM was effective.69 Woods and coworkers55 found that PRT was ineffective (FECR less than 80%) in 4 of 12 horse farms in north central Florida.55 Other studies documenting resistance were reported in Georgia,33,47 North Carolina,45 South Carolina,47 and Kentucky.47 Many of the farms in these studies documented resistance to both PRT and BZMs. International Studies. In 1999, strongyle resistance to pyrantel was reported in English racehorses.70 In Denmark, resistance to pyrantel was documented on 3 of 15 farms, with BZM cross-resistance reported.28 Recently, PRT resistance was detected to cyathostomes in a large study in Denmark.71 Multiple drug resistance was documented in studies in southern and central Italy, showing cyathostome resistance to both PRT and BZM.72

RESISTANCE TO MACROCYCLIC LACTONES IVERMECTIN AND MOXIDECTIN

Cyathostomes

Within the M/L class of anthelmintics, IVM is approved for the control of stomach bots, adult large mouth stomach worms, threadworms, pinworms, adult roundworms (P. equorum), adult and fourth-stage larvae small strongyles, adult large strongyles, and adult hairworms. This class interferes with neurotransmission in the parasite and causes flaccid paralysis.39 The drug praziquantel controls tapeworms and has been approved for concomitant use with both IVM and MOX. The relatively recent approval MOX has been shown to control large strongyles, adult small strongyles, encysted cyathostomins, late L3/L4 mucosal cyathostome larvae, ascarids, pinworms, adult hairworms, adult large-mouth stomach worms, and bots. Variable results have been reported in effectiveness of MOX on encysted cyathostomes.73-76 Although both are macrocyclic lactones, MOX is theorized to have a higher efficacy against encysted larvae than IVM because of the lipophilic properties and longer residual effects associated with MOX.77,78 It has been suggested that a progressively shorter ERP with respect to IVM may precede significant resistance. The ERP of IVM 40 years ago was reported to be 9 to 10 weeks,34 in contrast to an estimated ERP of 6 weeks in a 2001 study.33 More recently, in 2007, the ERP of IVM was estimated to be less than 5 weeks on farms in Germany.36 Similar reductions in ERP with IVM have been reported.79-81

Reports in the United States. In 1996, PRT was reported to have weak activity (76%) against BZM-resistant cyathostomes from population S.50 This was again documented in this herd from 1992 to 1999, as efficacy of PRT declined

Ascarids Decreased efficacy and resistance of ascarids to M/Ls was first reported in 2002 by researchers from both Europe

RESISTANCE TO TETRAHYDROPYRIMIDINES The tetrahydropyrimidine class of anthelmintics includes PRT salts such as pyrantel pamoate and pyrantel tartrate. The mode of action for PRT is similar to that of acetylcholine, causing paralysis by massive contraction of the musculature system.20,21,24 This anthelmintic is approved for the removal of mature infections of large strongyles, small strongyles, pinworms, and large roundworms (P. equorum). The reason initial reports of resistance in this class are more recent than those showing BZM resistance is most likely because PRT is a newer drug class.

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and Canada.82 Ascarid resistance to IVM and MOX was reported in the Netherlands in a herd that had predominantly been treated with IVM for 10 years despite continued efficacy of these anthelmintics against strongyles.83 Two Canadian studies also showed IVM-resistant ascarids in foals.84,85 In Germany, anthelmintic treatment with IVM did not produce a significant reduction in FEC of ascarids.36 Dual and concurrent resistance has been reported in Kentucky isolates of P. equorum to both the M/L and the PRT.82 It was suggested that the development of resistance to IVM was in part attributable to the heavy and exclusive use of M/L in young foals and weanlings within the horse industry.82

non-BZM anthelmintics, were effective in herds exhibiting BZM resistance problem in Pennsylvania.53

Cyathostomes Many early investigators concluded that development of resistance of equine cyathostomes to M/Ls would be inevitable.32,41 Trawford et al86 reported resistance of cyathostomes to MOX in two herds from the Donkey Sanctuary in Great Britain. Recently, cyathostome FECR at 4 weeks in Thoroughbreds in Brazil was reported to be 5% and 65% with IVM and 16% with MOX.87 It was further stated that in Brazil, parasite control is a growing problem, indicated by increasing levels of colic-related deaths.87 Because of the shared mode of action in M/Ls, there is also potential for side resistance.32

GENERAL ANTHELMINTIC PROGRAMS

ANTHELMINTIC PLANS AFTER RESISTANCE Because of the tremendous variation in management practices and climatic conditions within equine production, it is difficult to extrapolate from diverse studies what methods may be effective on a premise once resistance has been detected. Several studies have demonstrated the effectiveness of IVM in elimination of cyathostomes in populations resistant to other classes of anthelmintics.44,50,55 Similarly, MOX was found to be 100% effective in the elimination of cyathostomes in an FBZ-resistant herd of nonpregnant mares.88 Administration of FBZ (10 mg/kg) was found to be effective in the elimination of ascarids in foals after apparent resistance to IVM was documented.84 In contrast, increasing the dosage of FBZ after resistance to this product was not effective in several studies.58,89,90 In addition, the administration of IVM at twice the recommended dose also failed to effectively reduce the numbers of ascarid egg counts on a farm where resistance to IVM and MOX was documented.83 Combination Although not commercially available, the administration of FBZ and piperazine (PPZ) (FBZ/PPZ) has been studied. This combined treatment was effective in several studies.50,91,92 The use of BZM/PPZ, as well that of as

Rotation Blanek et al58 examined the efficacy of fast (quarterly) rotation of PRT, IVM, and MOX followed by FBZ in a herd of Quarter Horses in Texas after known resistance to FBZ. Results showed that subsequent FECR were at high levels and that FBZ could be effectively implemented into this rotation after 9 months. This is in contrast to theories stating that an anthelmintic can never be effectively used again once resistance has been established.

The focus of current equine anthelmintic studies has shifted from the control of large strongyles to cyathostomes; however, it may be dangerous and contraindicated to develop anthelmintic regimens strictly on the basis of cyathostome control. Many researchers strongly believe that the selection of anthelmintics should be based on a total parasite control program involving multiple classes of anthelmintics. It is increasingly apparent that the parasite resistance to current equine anthelmintics is an area of great concern. In response, some European countries require that anthelmintics be obtained only by prescription from veterinarians. In 1999, legislation in Denmark required a prescription for the use of anthelmintics and prohibited anthelmintic treatment in a routine preventative regimen.71,93 Because of global concern of parasite resistance to all anthelmintics, responsible use of the existing anthelmintics and the development of effective control programs should be a priority for equine health worldwide. There is a great divergence of opinions in the literature on the development of effective anthelmintic usage regimens with the goal of decreasing or eliminating parasite resistance to anthelmintics. Rotation between the same class of anthelmintic, underdosing of any anthelmintic class, frequent usage of anthelmintics, and overstocking are all factors associated with selection for resistance to anthelmintics.38,41,94 Based on these potential risk issues, several anthelmintic programs have been suggested for the efficient control of parasites in the horse. Current equine parasite control regimens including interval dosing, targeted dosing, strategic dosing based on ERP, and slow and fast rotation between different classes of anthelmintics have been reviewed.41,58-59,95 Although all of these reviews have been conducted, there are not enough data on any one regimen to determine whether one practice is definitively more advantageous than another in reducing or eliminating parasite resistance. More clinical and field studies are needed to examine the efficacies of each of these

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proposed regimens for their effects on parasite control and resistance. Most scientists agree that careful monitoring of parasite loads should be performed in all equine management facilities. Nielsen94 stressed the need for sustainable programs of anthelmintic control, including maintenance of adequate refugia of parasites. It has been suggested, however, that because there are no long-term studies on selective parasite control, definitive studies are needed to both validate this approach as well as to determine the effect of this approach on other parasites such as Strongylus vulgaris.94 DiPietro and Todd40 have recommended that fecal egg counts and larval cultures be included in management plans at least three times annually in at least 20% of the herd. Additionally, regular FECR testing is highly recommended by many investigators both to monitor the status of the herd and to attempt to detect parasite resistance to any anthelmintic at an early period.58-59,63,96 One important gap in the following discussion of anthelmintic practices to control parasites and their subsequent effects on possible resistance is the lack of research in controlled studies examining these proposed equine anthelmintic regimens. Many of the recommendations (eg, fast vs slow rotation, selected anthelmintic treatment) are based on theory and have not been put to rigorous, repeatable field tests. Interval Dosing Interval dosing programs are designed to correlate the dose of specific anthelmintics with the egg reappearance period (ERP), although this can vary with the different classes of anthelmintics.62 These researchers stressed that because of the great variation in patterns of fecal egg output in individual horses, monitoring individual efficacies is highly recommended, and custom plans may be indicated for effective interval dosing regimens. Targeted and Selective Control Programs Several scientists recommend the targeted approach to decrease the frequencies and amounts of anthelmintics used by monitoring FECs and by using an anthelmintic only after FECs reach a certain level. There is disagreement in the literature, however, as to what threshold of FEC should be reached before treatment is recommended.96 Suggested critical levels of FEC for anthelmintic treatment include over 100 eggs per gram (EPG),97,98 200 EPG,44 or when 25% of animals exceed 200 EPG.99 Trials determining EPG threshold levels affecting health of the animal, production efficiency, or performance parameters do not exist. In a critical study, Nichols et al100 demonstrated improvements in body condition score and live weight gains based on treatment of horses with a herd EPG mean of 94 to 125. It is clear that research in this area is highly warranted if the industry is to adopt some level of

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clinical relevance as it pertains to EPG and the resulting effects on equine health, production, and performance. Little et al44 used targeted treatment of IVM after FEC reached more than 100 EPG in young horses and above 200 EPG in adult horses. This targeted use of IVM was shown to be effective in reducing FEC in a population of cyathostomes resistant to PRT and FBZ subsequent to 9 years of rapid rotation of FBZ, PRT, and IVM.

ROTATIONAL DEWORMING There is also disagreement between the types of rotational regimens in the horse. Although there are no definitive studies in the equine dealing with multiple resistance, the theory of increased multiple resistance attributable to frequent rotational plans is based on studies in sheep and goats.29,37,101,102 Some scientists have speculated that frequent alternation of anthelmintics in horses both increases and decreases the development of multiple resistance.40,95 A survey in Tennessee showed that most horse farms used the single class IVM in their control program, with the majority planning on the same program for the subsequent year.103 Herd97 recommended considering the problem of encysted parasites when evaluating an anthelmintic plan and cautioned against the trend of using IVM-based programs only. Hearn and Peregrine84 recommended a deworming program that is not uniquely based on the use of M/Ls. These researchers concluded that sole use of IVM will lead to IVM-resistant populations of ascarids, increased ascarid burdens in young foals, and increased associated colic and impaction risks. Slow rotation of different classes of anthelmintic was suggested.84 After 6 years of research investigating fast-rotation anthelmintic usage on a herd with known BMZ-resistant cyathostomes, Brady et al59 demonstrated that all classes of anthelmintics can be used effectively in a year-long fast rotation regimen. Therefore, when a known resistance population is encountered, a fast rotation of anthelmintics might be warranted. Slow Rotation Many recommendations include decreasing the frequency of anthelmintic use.39,97 One goal of lowering frequency of dosing is that the resistant parasites will be ‘‘diluted’’ with nonresistant parasites, thus decreasing the development of resistance.32,94 Some slow rotation plans involve the use of a single anthelmintic for a year, followed by another class in years 2 and 3. These regimens typically also include the targeted use of boticides (IVM/MOX) or drugs to control tapeworms at specific times of the year.33 Herd97 advocated this type of annual rotation to decrease development of resistance, suggesting that a move away from bimonthly anthelmintic treatments is necessary to prevent resistance. Recommendations included both a strategic use of anthelmintics based on

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epidemiologic analysis with annual anthelmintic rotation and pasture control (pasture vacuuming). Complete reliance and emphasis on chemical anthelmintics to control parasite problems may no longer be feasible because of the development of resistance, the shortening of ERP, and other warning signs.97 Rotation between classes of anthelmintic every other year has also been recommended.63 These investigators further recommended the discontinuation of any drug to which resistance has been documented.63 Woods et al55 suggested a slow rotation using one anthelmintic yearly, including small clinical tests yearly of anthelmintic efficacy. A suggested regimen included IVM (year 1), followed by PRT (year 2), followed by FBZ (year 3). Another slow rotation plan as recommended by Wescott39 involves the use of one anthelmintic for a portion of the year, followed by one from another class, thus ensuring that a generation of parasites is not under the exposure to multiple classes of anthelmintic in an effort to decrease resistance. Slow rotation was advocated, because, although no strong evidence has shown fast rotation of anthelmintics causes resistance, prolonged exposure of the parasites could in theory select for resistance.39 Also recommended in such programs was the combination of classes, such as the BZMs and PPZs.92 Fast Rotation The most commonly used anthelmintic program within the horse industry is known as ‘‘fast rotation.’’ This would include the use or rotation between anthelmintic classes at periods of three to six times per year. The theory behind fast rotation is to use different classes of anthelmintics throughout the year to minimize the parasite exposure to a particular class of anthelmintic. In this theory, if resistance does manifest itself to a particular class of anthelmintic, the next treatment with a different class of anthelmintic would eliminate or reduce that particular resistant parasite population. The type of anthelmintics used in a fast-rotation regimen depends greatly on parasite burdens within the animal, climatic conditions, season of year, and geography. Brady et al59 demonstrated that the use of FBZ can be reimplemented in a herd of horses known to have FBZ-resistant parasites after several rotations of different classes of anthelmintics and that a quarterly rotation can be very effective after resistance. This 6-year study is the only definitive study that has been conducted to date that examines the fast-rotation regimen and documents FECR over time. In implementing fast rotation, it is important to look at each farm individually, use frequent FECR testing to evaluate parasite load status, and plan use of anthelmintic products in consideration of climate and other factors such as grazing schedules.59 In contrast, other researchers stated that rotational use of anthelmintics selects for an anthelmintic-resistant population.95 Although no data exist

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in the horse detailing this phenomenon, these theories do warrant further consideration. Abbott and Baker104 stated that if resistance to a particular anthelmintic is documented, it should not be used during the grazing season (April to September); however, the product should not be eliminated in the rotational plan and should be used strategically for the unique action it possesses. Furthermore, it was theorized that rotation of only two classes would place a higher selection pressure for resistance to develop in contrast to three-way rotations. Chandler and Love62 recommended that in cases of known BZM resistance, this class should not be used except in cases in which there is an accumulation of inhibited encysted cyathostomes; in this case, the larvicidal treatment of fenbendazole was indicated. Uhlinger and Johnstone105 reported that there was no reversion to a susceptible state in populations of parasites on farms in which BZM resistance was documented despite a period of withdrawal (24–36 months) from this class of anthelmintic. In contrast, in Texas it was found that after BZM withdrawal and rotation between classes, FBZ could be effectively used in a rotational program for horses despite prior resistance to this class.58,59 Furthermore, in the follow-up studies in this herd, FBZ has continued to be effective at significantly reducing FEC in this rotation plan after 6 years.59 Nichols et al100 demonstrated that the use of a fast-rotation regimen, giving a different class of anthelmintic every 2 months, significantly reduced overall parasite burden as measured by FECR and actual enumeration of all lifephases of parasites within the animal, in comparison with nontreated horses. This research also indicated that pasture contamination of larvae by the end of the year-long study was essentially nonexistent in the pasture of treated horses. Other measured parameters such as body condition scores, live weight gain, and average daily gain also improved over time.100 Pasture Management Strategies for Equine Parasite Control As stated earlier, it is highly recommended that FECR be conducted frequently to determine parasite status of the herd. In addition, sound management practices, such as pasture rotation, pasture rotation between species of animals, reducing overcrowding, avoiding feeding horses on the ground, feces removal where feasible, composting of manure, and good quarantine practices of new horses before introduction on existing pastures, have been suggested by many researchers as important adjuncts to current therapies with the goal of decreasing the amount of anthelmintics used in the industry worldwide.59,104 Herd and Coles106 have recommended regimens combining pasture management and four or fewer yearly treatments of anthelmintics to reduce the selection pressure for

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resistance. Pasture management with precise use of current anthelmintic regimens has been suggested to be essential to preserve the efficacy of these equine anthelmintics.

gastrin-related responses in the calf. Vet Parasitol 2002;105:285– 301. 7. Urban JF Jr, Steenhard NR, Solano-Aguilar GI, Dawson HD, Iweala OI, Nagler CR, et al. Infection with parasitic nematodes confounds vaccination efficacy. Vet Parasitol 2007;148:14–20. 8. Myers GH, Pate FM, Warnick AC, Courtney CH, Machen RV,

SUMMARY In summary, many questions remain regarding parasite control in the horse. It is widely held that resistance in equine parasites will be an ever-increasing problem, and a greater understanding is needed to develop important recommendations to decrease risks of escalating the problem or hastening its speed. Many conflicting reports exist on which type of anthelmintic regimen should be recommended to achieve high levels of parasite control concurrent with the goal of preventing resistance. Researchers agree that monitoring of equine farms and ranches for FECR and ERP is essential in determining whether anthelmintic products are effectively controlling parasites. Furthermore, because of regional differences in both management practices and climate conditions, it is not likely that one ‘‘recipe’’ or rigid formula will work best for equine parasite control with anthelmintics. Recommendations for anthelmintic control of equine parasites on a premise must be based on known FECR values, ERP rates for the anthelmintics used, stocking rate, and pasture use. Timing of anthelmintic treatment at appropriate times should be based also on climatic conditions. The preservation of all classes of anthelmintics is important because there are no new classes on the horizon. Responsible use of anthelmintics in combination with sound management practices needs to be a priority in the horse industry. Sponsored by: Intervet Schering-Plough Animal Health, Millsboro, DE.

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