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Veterinary Parasitology 204 (2014) 3–11

Veterinary Parasitology 204 (2014) 3–11 Contents lists available at ScienceDirect Veterinary Parasitology jo urnal

Contents lists available at ScienceDirect

Veterinary Parasitology

jo urnal homepage: www.elsevier.com/locate/vetpar

jo urnal homepage: www.elsevier.com/locate/vetpar Anthelmintic resistance in cattle nematodes in the US Louis

Anthelmintic resistance in cattle nematodes in the US

Louis C. Gasbarre

Gasbarre Consulting, United States

US Louis C. Gasbarre ∗ Gasbarre Consulting, United States a r t i c l e

a r t i c

l e

i n f o

Keywords:

Anthelmintic resistance Gastrointestinal nematodes Cattle Cows Bovine Drug

a b s t r a c t

The first documented case of macrocyclic lactone resistance in gastrointestinal (GI) nema-

todes of cattle was seen in the US approximately 10 years ago. Since that time the increase incidence of anthelmintic resistance has continued at an alarming rate. Currently parasites

of the genera Cooperia and/or Haemonchus resistant to generic or brand-name macrocyclic

lactones have be demonstrated in more than half of all operations examined. Both of these parasite genera are capable of causing economic losses by decreasing food intake and sub- sequently animal productivity. Currently, there are no easy and quick means to detect anthelmintic resistant GI nematodes. Definitive identification requires killing of cattle. The most commonly used field detection method is the fecal egg count reduction test (FECRT). This method can be adapted for use as a screening agent for Veterinarians and producers to identify less than desired clearance of the parasites after anthelmintic treatment. Further studies can then define the reasons for persistence of the egg counts. The appearance of anthelmintic resistance is largely due to the development of very effective nematode con- trol programs that have significantly improved the productivity of the US cattle industry, but at the same time has placed a high level of selective pressure on the parasite genome. The challenges ahead include the development of programs that control the anthelmintic resistant nematodes but at the same time result in more sustainable parasite control. The goal is to maintain high levels of productivity but to exert less selective pressures on the parasites. One of the most effective means to slow the development of drug resistance is through the simultaneous use of multiple classes of anthelmintics, each of which has a dif- ferent mode of action. Reduction of the selective pressure on the parasites can be attained through a more targeted approach to drug treatments where the producer’s needs are met

by selective treatment of different classes of animals and not by blanket treatment at a location. The implementation of such programs will vary by the sector of the industry and the individual site. In general, the feedlot will be the easiest sector for developing of pro- grams, while stocker/backgrounder operations will provide the most challenging problems.

A major question that must be addressed is whether it is important that parasite control

programs to be sustainable over time, or if the pharmaceutical industry develop new control agents at a rate sufficient to render sustainability unimportant.

© 2014 Published by Elsevier B.V.

Corresponding author at: 190 Little Crazy Woman Road, Buffalo, WY 82834, United States. Tel.: +1 307 684 5292. E-mail address: Lcg190@hughes.net

http://dx.doi.org/10.1016/j.vetpar.2014.03.017

0304-4017/© 2014 Published by Elsevier B.V.

1. History and current status of anthelmintic

resistance in US cattle nematodes

Resistance to anthelmintic drugs by gastrointestinal (GI) nematodes infecting ruminants has been demon- strated throughout the world. The first examples were seen in nematodes of small ruminants, and only later was

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L.C. Gasbarre / Veterinary Parasitology 204 (2014) 3–11

such resistance demonstrated in parasites infecting cat- tle. The first documented case of such resistance in GI nematodes of cattle in the US was seen approximately 10 years ago in an intensively grazed stocker operation (Gasbarre et al., 2009a, 2009b). In that study less than desired reductions in both fecal egg counts and worm numbers after anthelmintic treatment were seen mainly against the macrocyclic lactones, and the predominate sur- viving parasite was Cooperia punctata. In addition, a small number of Haemonchus placei remained after treatment with macrocyclic lactones, and Haemonchus contortus resis-

tant to both the macrocyclic lactones and benzimidizoles were also isolated. The cattle in this study were initially acquired from the southeastern US and then shipped to

a stocker operation in the north central US. Soon after

this report was published, a second report demonstrated that adult Cooperia sp were not reduced in number after treatment with ivermectin (Edmonds et al., 2010). In addi- tion, necropsy of treated animals indicated that treatment

with ivermectin was ineffective in reducing the num- ber of developing or arrested Ostertagia ostertagi. Cattle from this study were obtained from pastures in north- ern California prior to shipment to a dry lot operation. These two definitive studies indicated that macrocyclic lactones were not effectively removing members of the genus Cooperia at levels consistent with label claims. In both studies, necropsy of the cattle were done at 14 days

post anthelmintic treatment to demonstrate the continued presence of the parasites. Additionally, the results showed that such anthelmintic resistance was demonstrable in widely separated geographical regions of the US, i.e. the Southeast and Northwest. In a preliminary attempt to assess the magnitude of the problem posed by the potential selection for GI nematodes resistant to the most commonly used agents for control

of nematode parasites in the US, a study was initiated as a

part of the United States Department of Agriculture, Animal

and Plant Health inspection Service’s periodic survey of the American cow-calf industry (USDA, 2010). These surveys are performed at irregular intervals to assess health issues of the industry. For this survey, producers in 24 States covering about 88% of US cattle in cow-calf operations were given the opportunity to participate (Ballweber et al. submitted for publication). Producers were asked to follow their usual management protocols with the exception of collecting 20 random samples at the time of their next scheduled anthelmintic treatment. Samples were taken from the rectum or taken from an observed defecation. The producers were asked to take a second sample 14 days after the anthelmintic treatment, Samples were again to be ran- dom from the rectum or an observed defecation. Animals sampled were from 6 to 18 months of age, pastured for at least 4 weeks, and not treated with any anthelmintic for at least 45 days (Stromberg et al. submitted for publication).

A total of 61 producers from 17 States submitted sam-

ples that met all the study criteria. The results of the fecal egg count reduction test (FECRT) showed that more than one-third of all participating operations did not reach the recommended reduction of at least 90% (Coles et al., 1992, 2006). All operations with less than a 90% reduction in the FECRT had used either an injectable or a pour-on

formulation of either a brand name or a generic macrocyclic lactone (Gasbarre et al. submitted for publication). Parasite eggs recovered from feces of treated animals were sub- jected to PCR analyses (Zarlenga et al., 2001). In most cases, remaining parasites were members of the genera Cooperia. To date studies in the US seem to mimic the situa- tions reported from the major cattle raising regions of the world (Sunderland and Leathwick, 2011). The initial and most widespread resistance seems to be in Cooperia spp. against the macrocyclic lactones. This has been the case in Europe (Stafford and Coles, 1999; El-Abdelllati et al., 2010), New Zealand (Vermunt et al., 1995; Hosking et al., 1996; Waghorn et al., 2006), and South America (Suarez and Cristel, 2007). Additionally, in areas where Haemonchus is prevalent, there have also been reports of resistance by Haemonchus sp. against the macrocyclic lactones (Soutello et al., 2007; Costa Mdo et al., 2011). Finally, there appears to be a delayed and less widespread resistance to the macro- cyclic lactones by O. ostertagi. There have been suspected instances of such resistance in New Zealand (Mason and McKay, 2006) and here in the US (Edmonds et al., 2010), but more work needs to be done to definitively identify such resistance. A major question remains regarding the importance for the cattle industry of the current level of anthelmintic resistance in US cattle parasites. Historically, O. ostertagi has been considered the most important nematode para- site for American cattle. The timing of most anthelmintic programs have been designed to control this pathogen (Williams et al., 1986; Rew and Vercruysse, 2002). Because resistance in Ostertagia has not yet been widely demon- strated, the economic and health effects of pure Cooperia or Haemonchus or mixed Cooperia-Haemonchus only infec- tions have yet to be determined. Most studies of pure Cooperia infections have usually involved C. oncophora, and these studies have indicated that the pathogenic effects of this parasite are relatively mild (Borgsteede and Hendriks, 1979; Satrija and Nansen, 1992). In contrast infections with other Cooperia sp. such as C. pectinata or C. punc- tata have been demonstrated to be much more severe (Herlich, 1965; Keith, 1967). A recent study using a strain of macrocylic lactone resistant C. punctata isolated directly from a stocker operation found that a pure experimen- tal infection of C. punctata at a level similar to that seen under natural conditions resulted in a significant reduc- tion in both feed intake and weight gain in animals under feedlot conditions (Stromberg et al., 2012). Additionally, a study using macrocyclic lactone treatment of cattle in an area where macrocyclic lactone-resistant parasites were present, showed decreased body weights that were cor- related with the effectiveness of the treatment, i.e. animals with higher fecal egg counts had lower body weights. In this study, the negative effects on body weight were ascribed mainly to drug resistant Haemonchus (Borges et al., 2013). These affects are likely due to the propensity of the para- sites to reduce food intake in their host (Crompton, 1984). It appears that the parasites surviving macrocyclic lactone treatment have the potential to cause significant health and economic problems for the US cattle industry. Another interesting aspect of current anthelmintic pro- tocols is a seemingly large increase in the number of

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Nematodirus helvetianus found in US cattle. N. helvetianus is an intestinal parasite usually seen in relatively low numbers in predominately young animals. In young cattle it can be a severe pathogen if acquired in high num- bers (Herlich and Porter, 1953), but older cattle appear to develop a strong immunity over time. The appearance in cattle in high numbers in recent studies suggests that current anthelmintic protocols are altering conditions to favor N. helvetianus transmission (Gasbarre, unpublished observations). There are several factors that could be involved. The first is that drug resistance is increasing for

this parasite. This is difficult to assess because N. helvetianus

is a very poor egg producer and the standard FECRT is not

suitable for use regarding this species. A second explana- tion is that the timing of current anthelmintic programs misses N. helvetianus. This parasite differs from most GI nematodes in that the eggs deposited on pasture can lie

unhatched for an extended period of time. The eggs of the parasite overwinter on pastures in the northern US, but

only hatch after a warm period (Herlich, 1954). This means that eggs passed in the fall will lie on pasture until the fol- lowing summer before hatching. As indicated earlier most anthelmintic programs are focused on Ostertagia which is

a cool weather parasite, and as such most treatment pro- grams call for spring or fall treatments thus missing the peak transmission of Nematodirus. A third factor that may explain the high number of Nematodirus, are observations in sheep that indicate the presence of abomasal parasites lowers the rate of establishment of Nematodirus infections (Mapes and Coop, 1970, 1971). Whether this is due to phys- iological or immunological changes in the gut remains to be investigated. At the present time it appears that in the US the fol- lowing is the state of resistance in cattle nematodes: (1) there is widespread and rapidly increasing resistance by Cooperia spp. to the macrocyclic lactones, (2) resistance by Haemonchus sp. to macrocyclic lactone use is becoming more common, (3) there has only been one documented instance of resistance against the macrocyclic lactones by O. ostertagi, (4) resistance against drugs in the benzimida- zole class of drugs has only been confirmed for H. contortus, and (5) the macrocyclic lactone resistant parasites have the potential to significantly impair cattle health and produc- tivity. A somewhat related issue is the seeming increase in Nematodirus helvetianus numbers in US cattle. Whether this could be due to increasing anthelmintic resistance in this parasite, improper timing of treatment, or selective removal of other parasites by drug treatment remains to be determined. In any case this increase could pose severe health problems in young cattle in the US.

2. Methods to detect anthelmintic resistance in

cattle parasite

The definitive test for effectiveness of an anthelmintic against any particular species of nematode parasite is treat- ment of the host with the drug followed by subsequent killing of the host and recovery, enumeration, and speci- ation of the nematodes surviving treatment (Wood et al., 1995). Comparison of the numbers of worms recovered to recoveries from untreated animals of the same group will

allow direct measure of the effectiveness of the drug when administered according to an approved protocol. Such data are required for the licensing of a pioneer anthelmintic. One caveat to this test is that a sufficient number of ani- mals must be included in both the treated and untreated groups to render the differences statistically significant. This is especially true for nematode parasites given their overdispersed distribution in their hosts. Nematode para- sites are not usually distributed in a host population in the “normal” bell-shaped curve but rather they are arranged in what is referred to as a “negative binomial” distribution (Crofton, 1971a, 1971b). Such a distribution is character- ized by the standard deviation exceeding the mean of the group. This means that the majority of the animals will have relatively low numbers of the parasites while a few ani- mals will harbor the bulk of the parasites. As such the size of the group will need to be large enough to include some of the “high parasite” animals. Fortunately, the overdisper- sion is usually greater in the fecal egg counts than it is in nematode numbers, so that the number of animals needed for demonstration of a significant difference in worm num- bers is less than that needed in a FECRT. To accurately assess the proper numbers needed it is necessary to have an accu- rate estimate of the population variance which requires a knowledge of parasite numbers and distributions. A num- ber of 6 animals per group has been deemed sufficient by the WAAVP to detect major differences between groups (Powers et al., 1982). While killing of a sufficiently large group of cattle is nec- essary to definitively determine anthelmintic efficacy, such

a test is impractical if not impossible for field studies meant to detect or survey anthelmintic resistance. The labor, cost, and loss of valuable animals precludes the utilization of such methodology in all but very focused and definitive follow-up studies. As such, most field studies must rely upon less precise measures to determine the sensitivity of the parasites to the anthelmintic agents. These tests have usually fallen into two categories. The first is an in vitro measure of the effect of the drugs upon field populations after exposure to the pertinent anthelmintic. The second is

a measure of the effect upon egg output of an anthelmintic treatment. In vitro tests for anthelmintic resistance were first developed for use in small ruminant populations and have been used with good success in this area. In most small ruminant systems the target nematode for control is the baberpole worm, H. contortus. In some temperate regions such as northern Europe and New Zealand, Telodorsagia cir- cumcinta may be the main concern. As such the in vitro systems have a limited range of targets. In cattle in the US there may be up to 25 different species of nematodes infecting the cattle, with at least 10 different species being of economic importance (Ciordia, 1973). In addition, some of the parasites, especially O. ostertagi are very fastidious and difficult to maintain in vitro for even short periods of time. This has resulted in very limited use of in vitro anthelmintic resistance testing methods for cattle para- sites. There have been recent advances in Europe where the important parasites are Ostertagia and C. oncophora in the adaptation of in vitro detection methods (Demeler et al., 2010, 2012), but as of date very few laboratories offer such testing.

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Studies to detect anthelmintic resistance in the field have in most cases focused on the use of the fecal egg count reduction test (FERCT). Historically fecal egg counts have been used as the method of choice because of both the relative ease in acquiring the sample, and the rela- tively non-invasive nature of the sample collection. This test requires a sampling of a group of animals at the time of treatment followed by a second sampling 10–14 days after treatment. General guidelines have been developed by the World Association for the Advancement of Veteri- nary Parasitology (WAAVP). The methodology has been most thoroughly documented for small ruminants where standard procedures have been developed (Coles et al., 1992). In cattle, the guidelines are less clear but the sug- gested group size is 10 animals. An important requirement has been the necessity to sample the same animals before and after treatment to reduce variance in the assay (Coles et al., 1992). The guidelines also suggest that animals with egg counts below 150 be excluded from the test. In planning extensive surveys of US cattle producers these recom- mendations cause major problems in several areas. First, because of the overdispersion of cattle fecal egg counts, it is exceedingly difficult to find sufficient numbers of cat- tle with egg counts over 150 eggs per gram. At this level clinical parasitism would usually been seen in the herd. Young calves will sometimes reach these levels, but most US producers are strongly aware of the negative impact of parasites and very few producers do not have in place exist- ing parasite control programs that would allow such a level of parasitism. Also, most US producers are aware of the neg- ative effect on production that results from handling stress. As such, many producers are adverse to the degree of hand- ling necessary to sort the cattle to insure that the same animals are collected at an approximate 2 week interval. The opportunity to participate in the NAHMS cow-calf study provided an impetus to re-evaluate the standards for the FECRT in American cattle. In planning this study it became evident that the requirement to sample the same animals before and after treatment would greatly reduce the voluntary producer participation that is a hallmark of NAHMS surveys. To determine if alternate sampling techniques could be utilized we decided to look at the major sources of variation within the fecal egg count methodology. A previous report provides some analyses of the precision of this methodology (Gasbarre et al., 1996). Important information gleaned from this study included:

(1) the repeatability of the procedure is approximately 0.7 and that repeated sampling of the animals reduces the vari- ance, (2) these reductions in variance are small and that after 3 samplings the variance reduction is minimal, and (3) the overdispersed nature of fecal egg counts within a group of animals requires a within group size of at least 17 to account for all intervals in the distribution (if the group contained less than 17 animals then all animals are sam- pled) (Gasbarre et al., 1996). Using data from that study to gain additional information about the variances associated with fecal egg counts, we parsed the variances associated with the counting procedure. Using a large data set of val- ues collected over a four year period, the variances were attributed into four categories: between years, between days, among animals, and within the same animal. In this

data set calves from the same cow/calf operation in Mary- land were sampled for 3 consecutive days at the same time of year over a 4 year span. This resulted in just under 4000 samples. All samples were processed and read by the same two individuals. Analysis of these data showed that both the year of sampling and the day of sampling were very minor components of the total variance. In other words, the grand mean of the 3 days each year, and the mean on each of the 3 days were very close. In contrast the two largest sources of variation were between the differ- ent calves and between samples taken on consecutive days from the same calf respectively. In fact these two variables accounted for 80–85% of the total variance over the 4 year period. From this we concluded that fecal egg counts are a reliable measure of the group, but without repeated samp- ling, are less reliable when assessing an individual animal (Gasbarre et al., submitted for publication). Based on these analyses, the FECRT was used as a measure of change in a group and not to measure the change within an individual animal. Based on the previ- ous estimate that the minimum number required was 17, collection of feces from 20 different individuals, should provide an accurate measure of the change in the group mean 14 days after drug treatment. While sampling of the same animals each time might further reduce variance, this likely would have reduced the total number of participat- ing operations and thus reduce substantially our ability to make broader implications from the final data set. This number is in agreement with a recent paper by Levecke et al. (2012). Other factors that need to be considered in defining a sampling protocol are time between treatment and samp- ling, the counting technique to use, and whether there should there be a threshold egg count value for inclusion in the study. In terms of time between treatment and sec- ond sampling, experience a freshly isolated field stain of C. punctata indicates that these parasites have a shorter prepatent period than expected (Stromberg et al., 2012). The time interval between treatment and follow-up sam- ple should ensure that the drug is given sufficient time to act, but that also ensure that there is insufficient time for reinfection and subsequent parasite patency. Ten to 14 days seems to be optimal. Regarding the counting methodology, it appears that a modified Wisconsin flotation method is the best suited procedure (Cox and Todd, 1962; Bliss and Kvasnicka, 1997). As practiced in most laboratories, this methodology had a sensitivity of from 0.5 to 3 eggs per gram of feces. In contrast the minimal detectable limit of the McMaster technique is 25, 50 or 100 eggs per gram of feces depending upon the exact methodology used. Cat- tle fecal egg counts are much lower than those of small ruminants for which the McMaster technique was devel- oped. The use of this methodology on cattle samples that are expected to have means less than 100 eggs per gram of feces is likely inappropriate. Finally, the WAAVP guide- lines which suggest the McMaster technique, also indicate that fecal egg counts cannot be used on samples where the egg counts are less than 150 eggs per gram (Coles et al., 2006). Data analyses performed on data derived from the NAHMS study indicated that the using the greater sensi- tivity of the modified Wisconsin technique the effect of

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removing the low mean egg count cow-calf operations had very little effect on the percentages of operations demon- strating less than 90% FECRT values. A determination of an absolute threshold egg per gram value will require more analysis, but it is plain that such a threshold will depend upon the sensitivity of the detection methods used. In the NAHMS study, the results were not substantially influenced by means of less than 10 eggs per gram. Finally, arithmetic means should be used in all analyses based on the obser- vation of Dobson et al. (2009).

3. Options for management guidelines for

anthelmintic resistance in us cattle operations

When developing sustainable parasite control programs for the US cattle industry it is important to realize that rais- ing cattle in the US is not a single production system but is instead a collection of at least 5 major types of operations each of which differs depending on geographic location, available resources and traditional practices. It is impos- sible to devise a single set of management guideline for each operational type let alone for all cattle operations. Table 1 outlines the 5 major types of operations and gives

a very brief listing of concerns regarding the likelihood of development of anthelmintic resistance and our ability to manage the most important factor in the development of anthelmintic resistance, which is the magnitude of the selective pressure for anthelmintic resistance that we place on the parasite genome. For the last 30 years the industry has had the luxury of having a toolbox of highly effica- cious, safe drugs that have controlled the parasites and have allowed producers to alter their management sys- tems so that productivity is maximized. New systems have been devised such that the goal of treatment have become pounds of gain rather than treatment of sick animals. We are now reaching a point where the current systems are no longer giving accustomed results. It will be important to develop systems that try to balance maximum produc- tion while at the same time reducing selective pressure for the development of resistance by the parasites. In many cases this will involve some trial and error for individual operations. There are several important points that must be kept in mind throughout the development of new treatment paradigms. The first and most important is that one can-

not assume that treatment with any agent has successfully cleared the infecting parasites. It is critically important that producers and veterinarians check at regular intervals to determine if treatments have achieved the desired level of efficacy. Such checks do need to be exhaustive measures, but could be a simple screening using a simple test such as

a simplified FECRT to assess levels of efficacy. Presumptive treatment failures would then need to be tested more rigor- ously before progressing or modifying either the treatment protocols or drug agents used. A second issue is to use anthelmintics in such a way as to minimize selection for resistance. At this time there are two major issues regarding this concern. The first is the requirement that all treated animals receive the calcu- lated therapeutic dose. Administration of an “under-dose” of a drug can significantly promote the development of

resistance to the drug by nematode parasites (Smith et al., 1999). Many operators apply anthelmintics in such a way that a portion of animals receive less than the label dose of the drug. Under-dosing commonly results from inac- curate estimation of the animal’s weight because animals are not weighed, or aids in weight estimation such as girth tapes, are not used. Another aspect is that the drugs will be administered as a dose for the average animal weight, which by definition means that at portion of the animals will be under-dosed. A second potent source of under-dosing is the widespread use of pour-on formula- tions of the drugs. Pour-on formulations have been eagerly accepted by cattlemen and Veterinarians because of their

ease of use and perceived diminished stress for the cattle. The pour-ons allow the drugs to be administered without catching the cattle in head gates or squeeze chutes. As such, the animals are likely less-stressed, the time required to administer the drugs is decreased, and there is less danger

of injury to the animal handlers. This has resulted in pour-

ons being the method of choice of US cattle operations, with very few operations using any other drug delivery system (Ballweber and Baeten, 2012). The problem is that even if the drug is applied according to precise label guidelines, there is great variation in the amount of drug that enters the treated animal, and how it is distributed in individual animals (Sallovitz et al., 2002, 2003; Laffont et al., 2003; Leathwick and Miller, 2013). A number of studies have shown the amount of topically administered drugs actu- ally entering the animals is greatly influenced by grooming behavior of the animals (Bousquet-Melou et al., 2004; Sallovitz et al., 2005; Imperiale et al., 2009). Obviously, such a delivery system offers a great opportunity for mis- application of the drugs and could result in significantly underdosing of animals. Failure to reach the desired drug

tissue levels is often considered to be a significant factor in the selection for drug resistance. Another important factor in slowing the appearance of anthelmintic resistance is the concept of simultaneously applying different classes of drugs each with a different mode of action. Mathematical models have indicated that the use of such “combinations” will slow the development of resistance when compared to either the use of a sin- gle drug until resistance appears followed by a change to

a second different class of drugs, or to rotations of dif- ferent classes of drugs (Smith, 1990; Dobson et al., 2011; Leathwick, 2013). This treatment option is currently being utilized in Australia and New Zealand to extend the life of a recently released new class of drug for use in sheep where all current classes of drugs have resistance issues (Leathwick et al., 2009; Dobson et al., 2012). Limited field testing of this hypothesis has largely supported the theo- retical assumptions (Leathwick et al., 2012; Geurden et al., 2012). What is evident from both the models and field tests is that the combinations only delay resistance when the frequency of resistant types is low, i.e. a new drug class or with an existing drug class where resistant has not been demonstrated or is in very low prevalence. With this in mind, it is very important that the adoption of the “combination” treatment in US cattle be initiated imme- diately. Because the use of pour-on macrocyclic lactones has been so broadly embraced by the US cattle industry,

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Table 1 Characteristics of cattle production systems in the US and the danger of developing anthelmintic resistance and management of refugia.

Production type

Operation type

Parasite impact

Production needs

Target for

Probability of selection for AR

Ability to

 

control

manage refugia

Dairy

Conventional

Low

High

Replacement

Low

Easy

 

heifers

 

Grazing

Moderate

Moderate to high

Replacement

Low to

Moderate

 

heifers

moderate

Milking cows

Beef

Cow-calf

Moderate to high

Moderate to high

Calves

Moderate to

Difficult

 

Yearlings

high

 

Stocker

Very high

Very high

All

Very high

Very difficult Not an issue

Feedlot

High

Maximal

All

Very low

use of other drug classes such as the benzimidazoles and levamisole has been very low. As a result there has been very little selective pressure exerted by these compounds and resistance to these drugs is of very low frequency. To protect their efficacy and to remove the macrocyclic lac- tone resistant species, a very effective program would be to simultaneously administer an injectable macrocyclic lac- tone with either a benzimidazole or levamisole. Such a program would protect the benzimidazole or levamisole and obtain desired parasite control in areas where macro- cyclic lactone resistance is high, and protect both drug classes where macrocyclic resistance is not evident. If adop- tion of such combinations is delayed until resistance to both classes of drugs is evident, the protective delaying action of the combination will be lost (Leathwick et al., 2012). The most important factor in the development of anthelmintic resistance is the level of selective pressure being applied against the parasite genome. One method of reducing this pressure is by management of what is known as a “refugia” (Van Wyk, 2001). Refugia refers to the portion of the total nematode population at a given loca- tion which is on the pasture at the time of anthelmintic treatment and do not develop to the infective stage and are not ingested prior to clearance of the anthelmintic from the treated host. As such these parasites are not exposed to the drug when it is applied. In the case of GI nema- todes the total refugia would be expected to come from two sources during the application of an anthelmintic to the herd. The first of these would be the parasites that are on the pastures themselves at the time of drug application. The pasture forms would be a mixture of the free-living stages of the parasite, and the ensheathed infective forms which have not been ingested. The second component of the refugia would be the parasitic forms of the parasite that are within animals that do not receive the anthelmintic treatment. In the 1980s an important change took place in anthelmintic treatments in the US that has resulted in

a conscious attempt to reduce both of these sources of refugia. This change was the adoption of what are known as “strategic deworming programs”. The goal of such pro-

grams was the reduction of both the numbers of parasites

in the host and a reduction in the number on the pastures

(Williams et al., 1986). The rational was such: treatment once parasites reached a significant level in the host results in clearing parasites from the host, but because this has also allowed time for large numbers of parasites to build-up on the pastures the treated host will very rapidly build-up

new high levels of the parasites by ingestion of infectious forms from the pastures. This meant that really efficient control programs would be those that reduced pasture lar- vae at the same time they reduced parasitic forms in the host. Some of the keys to a good strategic program were:

(1) treat all animals in the herd to eliminate eggs being shed to the pastures, (2) treat at such a time when most parasites were in the host, i.e. early in the spring of dur- ing a prolonged dry period, (3) apply repeated treatments over a short period of time at a critical period in transmis- sion, and (4) use a drug with a long active persistence in the host. Such suppressive programs are extraordinarily effective (Williams et al., 1988, 1990). But even early in the use of these programs some were warning of the dangers of selection for anthelmintic resistance (Williams, 1997). The problem has been that because these programs are extraordinarily effective economically, they have become the norm in US cattle production. Additionally, there are some who feel that suppressive chemotherapy with slow- release of the anthelmintic over a prolonged period of time is a method to maintain optimal productivity. While such programs may increase to some degree productivity they will exert an even greater selective pressure on the parasite genome and will shorten the effective life of the anthelmintic agent. Some are now counseling to expand the size of the refugia by leaving a percentage of animals untreated as has been done with sheep in New Zealand (Leathwick et al., 2009, 2012). The ability to put this into practice in cattle remains unclear and will require much more knowl- edge than is currently available (Charlier et al., 2012). For instance, a commonly held belief has been that one of the most important factors for the selection for anthelmintic resistance in cattle was simply the number of drug appli- cations applied over a given time period. In fact it is a much more complex issue in that a single application at a criti- cal period, i.e. a period of prolonged drought, can have a much greater effect than several applications at periods of high survival of parasites on the pastures. These factors are further compounded by the asymmetrical nature of para- site transmission, and it’s affect in selection for rare genetic variations (Cornell et al., 2003). In this last section I will try to distil some general recommendations for the various facets of the US cattle industry. We must keep in mind that these are general in nature only, each location will have their own peculiarities and objectives with could greatly influence effectiveness of the programs. Additionally,

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timing of treatments will vary greatly over the geographic regions of the US. Central to all recommendations is the need to check at periodic intervals for the effectiveness of the control program instituted.

4. Confinement dairy

This is a sector of the US cattle industry that requires the least intensive parasite control and hence has the least chance of selection for anthelminic resistance. Parasite control is needed only in the replacement heifers if they are raised on pasture and for cows just prior to entering the milking cycle if the dry cows received pasture expo- sure. Parasite control in the replacement heifers should be geared toward allowing adequate parasite exposure to insure build-up of immunity to the parasites, coupled with an adequate growth of the replacement stock. One note of caution is that the effects of Nematodirus are especially evi- dent in young dairy stock, so care should be taken to look for the effects of these parasites in early summer. Adult ani- mals should not require routine deworming, but if they are pastured during the dry period the producer should con- sider anthelmintic treatment shortly before the cows enter the milking cycle because the added stress of GI nematodes can have a detrimental effect on cows given the normal high stress associated with milk production.

5. Grazing dairy

Treatment of milk cows that have routine exposure to pasture has been shown to increase milk output (Thomas et al., 1984; Gross et al., 1999). As such dairy producers who have moved toward intensive rotational grazing sys- tems for milk production need to have a program in place to reduce parasite numbers in their milking animals. Manage- ment of replacement heifers and dry cows will be similar to that described above for the confinement dairies. The dif- ference will be in management of the milking cows. Even low parasite numbers can reduce milk production in cows already stressed by milk production. At the same time it is difficult to assess worm burdens in adult dairy cattle as egg output by the parasites is regulated by the cow’s immune system. Even extremely low egg counts in cows does not indicate an absence of GI nematodes. Given the importance of having the adult cows with nematode counts as low as possible these systems should consider using combinations of drugs approved for use in lactating animals on a regular basis. An adequate refugia can be maintained on the farm in the dry cows and replacement heifers as described above.

6. Beef feedlot

This is the sector of the cattle industry where decisions regarding anthelmintic treatment are the clearest. Because all animals are a dead end once they reach the feedlot, there is no danger of spreading anthelmintic resistance to other locations. It addition the lots require maximum produc- tivity from the animals. Even a relatively small number of parasites can affect animal growth by decreasing feed intake and larger numbers may disrupt the immune sys- tem (Gasbarre, 1997) making immunizations less effective.

All animals should be treated on arrival. Also the opera- tors must assume that the animals coming into the facility from such a wide variety of sources are harboring resis- tant parasites. As such, this is the ideal location for the use of anthelmintic combinations on all animals. Once treated at the therapeutic dosage on arrival most parasite issues should be over. Occasionally outbreaks of Oesophagosto- mum radiatium are seen in feedlots during the winter (Gasbarre, unpublished observation). This is likely the result of parasites that survived treatments on arrival at the feedlot, with subsequent egg shedding of a parasite that can be a skin-penetrator if given sufficient exposure time. This problem is seen in the form of condemned intestinal tracts at the slaughter plant. Usually by the time such outbreaks are detected by the identification of colonic nodules at the slaughter facility it is too late for meaningful action, and the problem usually resolves within a short time period.

7. Beef cow-calf

Based upon the NAHMS survey, there is a very sig- nificant level of macrocyclic lactone resistance in major cow-calf areas of the US. In spite of this, there are ways to maintain a refugia in most operations and the high levels of resistance are likely a result of non-sustainable control pro- grams. In most cases, maximal growth of the pre-weaned calves is not absolutely necessary, and unweaned calves can maintain what for cattle are relatively high egg counts without serious weight loss. Additionally, this early expo- sure to parasites is important for the generation of immune responses that will protect the animals throughout life. In most cases it is not necessary to treat the unweaned calves until the time of weaning. Treatment at this time will be important both for animals being marketed and for the replacement stock. Similarly, the dams do not need to be parasite free as milk production will not usually be signifi- cantly impacted by low parasite numbers. As a result, it is very possible to attain adequate levels of parasite control without placing undue selective pressure on the parasite genome. Generally, a treatment of the cows about one month into the grazing season will lower parasite num- bers to a manageable level. At weaning the calves should be treated with an anthelmintic for the first time. The pro- ducer may want to treat the cows a second time at the end of the grazing season to remove an additional nutri- tional stress prior to a period of a lower nutritional plane especially in the case of a Northern, spring calving oper- ation. In years with very high moisture or in areas with a prolonged grazing season (i.e. more than 6 months) addi- tional treatments may be necessary. In almost all cases, very aggressive suppressive anthelmintic programs such a multiple early season treatments or slow-release formu- lations are unnecessary and can have the negative effect of increased selection for anthelmintic resistance in cow- calf operations. If used on the calves they may impede the development of immune responses in the calves, and the economic gain of treatment in the cows would be highly variable. In general the focus should be on keeping a low level of parasite transmission on the pastures with treat- ments aimed at aiding animals through periods of stress. In operations where the presence of anthelmintic resistant

10

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parasites has been demonstrated the use of simultaneous administration of combinations of classes of drugs with different modes of action should be encouraged.

8. Beef stocker/backgrounder

This sector of the industry poses the greatest challenge for sustainable parasite control. The operations are very diverse and individual operations may have unique man-

agement options. Producers require maximal growth of their animals and those using intensive grazing programs are potentially exposing the animals to maximal parasite transmission. In addition, the age and previous exposure to parasites are not sufficient for mature, effective immune responses especially in calves coming from cow-calf opera- tions with high levels of parasite control. The maintenance

of refugia in this model is difficult to manage. Refugia main-

tained by not treating some animals will result in depressed

growth of the untreated animals and economic loss. Refugia

maintained as significant numbers of parasites on pasture will mean all cattle are continually exposed to reinfec- tion. As such, this segment of the industry has the greatest potential for selection of resistant parasites. Treatments in this sector should be with drug combinations to reduce the rate of development of resistance. It is also impor- tant that the producer practice good pasture management and not permit overgrazing of the pastures, and should also implement procedures that are detrimental to parasite development. Examples of such procedures would include disruption of fecal pats during dry periods, maintenance of the pasture grass height of at least 4 inches, grazing of crop residues when possible, etc. Because of the effec- tiveness of the anthelmintic agents in the past, producers have often by-passed these management tools because it has been easier to add another drug treatment rather than invest more time or manpower into pasture management. In general, the producer should treat all animals coming into their operation with a combination of two classes of anthelmintic. They should then monitor fecal egg counts on

a regular schedule and administer appropriate treatment when counts reach a pre-set level. This adds expense to the operation in the form of the cost of the egg counts, but

it would minimize unnecessary treatments thus reducing

cost and at the same time reducing selective pressures. In conclusion, the US cattle industry has reached an important inflection point. The industry was given an important set of tools by which to increase productivity and consequently economic gain with the advent of the modern anthelmintic classes about 30 years ago. Begin- ning about 10 years ago we began to see the first signs

that the effectiveness of the most widely accepted class of drugs was beginning to decrease. Over the past 10 years this erosion of efficacy has increased at an alarming rate. Expe- rience in other parts of the world has shown that action must be taken early, or it will be too late to affect the outcome. It is now time to change some perceptions and treatment paradigms. Perhaps the first decision to be made

is how important is it for the parasite control programs to

be sustainable over time, or can the pharmaceutical indus- try develop new control agents at a rate sufficient to discard the current control agents.

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