Veterinary Parasitology 204 (2014) 311

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Veterinary Parasitology
journal homepage: www.elsevier.com/locate/vetpar

Anthelmintic resistance in cattle nematodes in the US

Louis C. Gasbarre
Gasbarre Consulting, United States

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 rst documented case of macrocyclic lactone resistance in gastrointestinal (GI) nematodes 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 subsequently animal productivity. Currently, there are no easy and quick means to detect
anthelmintic resistant GI nematodes. Denitive identication requires killing of cattle. The
most commonly used eld 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 dene the reasons for persistence of the egg counts. The appearance of
anthelmintic resistance is largely due to the development of very effective nematode control programs that have signicantly 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 different mode of action. Reduction of the selective pressure on the parasites can be attained
through a more targeted approach to drug treatments where the producers 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 programs, 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 sufcient to render sustainability unimportant.
2014 Published by Elsevier B.V.

1. History and current status of anthelmintic

resistance in US cattle nematodes

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.

Resistance to anthelmintic drugs by gastrointestinal

(GI) nematodes infecting ruminants has been demonstrated throughout the world. The rst examples were
seen in nematodes of small ruminants, and only later was

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

such resistance demonstrated in parasites infecting cattle. The rst 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 surviving parasite was Cooperia punctata. In addition, a small
number of Haemonchus placei remained after treatment
with macrocyclic lactones, and Haemonchus contortus resistant 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 addition, necropsy of treated animals indicated that treatment
with ivermectin was ineffective in reducing the number of developing or arrested Ostertagia ostertagi. Cattle
from this study were obtained from pastures in northern California prior to shipment to a dry lot operation.
These two denitive 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 Services 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 random 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 samples 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 subjected 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 situations 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 macrocyclic 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 denitively 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 parasite 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 demonstrated, the economic and health effects of pure Cooperia
or Haemonchus or mixed Cooperia-Haemonchus only infections 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. punctata 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 experimental infection of C. punctata at a level similar to that seen
under natural conditions resulted in a signicant reduction 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 correlated 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 parasites to reduce food intake in their host (Crompton, 1984).
It appears that the parasites surviving macrocyclic lactone
treatment have the potential to cause signicant health and
economic problems for the US cattle industry.
Another interesting aspect of current anthelmintic protocols is a seemingly large increase in the number of

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

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 numbers (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 rst is that drug resistance is increasing for
this parasite. This is difcult 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 explanation 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 following summer before hatching. As indicated earlier most
anthelmintic programs are focused on Ostertagia which is
a cool weather parasite, and as such most treatment programs 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 physiological or immunological changes in the gut remains to
be investigated.
At the present time it appears that in the US the following 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 benzimidazole class of drugs has only been conrmed for H. contortus,
and (5) the macrocyclic lactone resistant parasites have the
potential to signicantly impair cattle health and productivity. 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 denitive test for effectiveness of an anthelmintic
against any particular species of nematode parasite is treatment of the host with the drug followed by subsequent
killing of the host and recovery, enumeration, and speciation 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 sufcient number of animals must be included in both the treated and untreated
groups to render the differences statistically signicant.
This is especially true for nematode parasites given their
overdispersed distribution in their hosts. Nematode parasites 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 characterized 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 animals 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 overdispersion 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 signicant difference in worm numbers is less than that needed in a FECRT. To accurately assess
the proper numbers needed it is necessary to have an accurate estimate of the population variance which requires a
knowledge of parasite numbers and distributions. A number of 6 animals per group has been deemed sufcient by
the WAAVP to detect major differences between groups
(Powers et al., 1982).
While killing of a sufciently large group of cattle is necessary to denitively determine anthelmintic efcacy, such
a test is impractical if not impossible for eld 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 denitive
follow-up studies. As such, most eld 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 rst is an in vitro
measure of the effect of the drugs upon eld 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
rst 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 circumcinta 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 difcult 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 parasites. 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.

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

Studies to detect anthelmintic resistance in the eld

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 relatively 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 1014 days
after treatment. General guidelines have been developed
by the World Association for the Advancement of Veterinary 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 suggested 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 recommendations cause major problems in several areas. First,
because of the overdispersion of cattle fecal egg counts, it
is exceedingly difcult to nd sufcient numbers of cattle 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 existing parasite control programs that would allow such a level
of parasitism. Also, most US producers are aware of the negative effect on production that results from handling stress.
As such, many producers are adverse to the degree of handling 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 variance, (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 sampled) (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 values 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 Maryland 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 different calves and between samples taken on consecutive days
from the same calf respectively. In fact these two variables
accounted for 8085% 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 sampling, 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 previous 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 participating operations and thus reduce substantially our ability
to make broader implications from the nal data set. This
number is in agreement with a recent paper by Levecke
et al. (2012).
Other factors that need to be considered in dening a
sampling protocol are time between treatment and sampling, 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 second sampling, experience a freshly isolated eld 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 sample should ensure that the drug is given sufcient time to
act, but that also ensure that there is insufcient time for
reinfection and subsequent parasite patency. Ten to 14 days
seems to be optimal. Regarding the counting methodology,
it appears that a modied Wisconsin otation 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. Cattle fecal egg counts are much lower than those of small
ruminants for which the McMaster technique was developed. 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 guidelines 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 sensitivity of the modied Wisconsin technique the effect of

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

removing the low mean egg count cow-calf operations had

very little effect on the percentages of operations demonstrating 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 inuenced
by means of less than 10 eggs per gram. Finally, arithmetic
means should be used in all analyses based on the observation 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 raising 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 impossible 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 efcacious, safe drugs that have controlled the parasites and
have allowed producers to alter their management systems 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 production 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 rst and most important is that one cannot 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
efcacy. Such checks do need to be exhaustive measures,
but could be a simple screening using a simple test such as
a simplied FECRT to assess levels of efcacy. Presumptive
treatment failures would then need to be tested more rigorously 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 rst is
the requirement that all treated animals receive the calculated therapeutic dose. Administration of an under-dose
of a drug can signicantly 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 inaccurate estimation of the animals 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 denition 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 formulations 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 pourons 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 actually entering the animals is greatly inuenced 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 misapplication of the drugs and could result in signicantly
underdosing of animals. Failure to reach the desired drug
tissue levels is often considered to be a signicant 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 single drug until resistance appears followed by a change to
a second different class of drugs, or to rotations of different 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 eld
testing of this hypothesis has largely supported the theoretical assumptions (Leathwick et al., 2012; Geurden et al.,
2012). What is evident from both the models and eld
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 immediately. Because the use of pour-on macrocyclic lactones
has been so broadly embraced by the US cattle industry,

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

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
control

Probability of
selection for AR

Ability to
manage refugia

Dairy

Conventional

Low

High

Low

Easy

Grazing

Moderate

Moderate to high

Replacement
heifers
Replacement
heifers
Milking cows

Low to
moderate

Moderate

Cow-calf

Moderate to high

Moderate to high

Difcult

Stocker
Feedlot

Very high
High

Very high
Maximal

Moderate to
high
Very high
Very low

Beef

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 efcacy and to remove the macrocyclic lactone resistant species, a very effective program would be to
simultaneously administer an injectable macrocyclic lactone with either a benzimidazole or levamisole. Such a
program would protect the benzimidazole or levamisole
and obtain desired parasite control in areas where macrocyclic lactone resistance is high, and protect both drug
classes where macrocyclic resistance is not evident. If adoption 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 location 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 nematodes the total refugia would be expected to come from
two sources during the application of an anthelmintic to
the herd. The rst 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 programs 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 signicant 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

Calves
Yearlings
All
All

Very difcult
Not an issue

new high levels of the parasites by ingestion of infectious

forms from the pastures. This meant that really efcient
control programs would be those that reduced pasture larvae 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 during a prolonged dry period, (3) apply repeated treatments
over a short period of time at a critical period in transmission, 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 slowrelease 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 knowledge 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 applications applied over a given time period. In fact it is a much
more complex issue in that a single application at a critical 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 parasite transmission, and its 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
inuence effectiveness of the programs. Additionally,

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

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. Connement 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 exposure. 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 evident in young dairy stock, so care should be taken to look
for the effects of these parasites in early summer. Adult animals should not require routine deworming, but if they are
pastured during the dry period the producer should consider 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 systems for milk production need to have a program in place to
reduce parasite numbers in their milking animals. Management of replacement heifers and dry cows will be similar to
that described above for the connement dairies. The difference 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
difcult to assess worm burdens in adult dairy cattle as egg
output by the parasites is regulated by the cows 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 productivity 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 system (Gasbarre, 1997) making immunizations less effective.

All animals should be treated on arrival. Also the operators must assume that the animals coming into the facility
from such a wide variety of sources are harboring resistant 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 Oesophagostomum 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 sufcient 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 identication 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 signicant 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 programs. 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 exposure 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 signicantly 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 numbers to a manageable level. At weaning the calves should
be treated with an anthelmintic for the rst time. The producer may want to treat the cows a second time at the
end of the grazing season to remove an additional nutritional stress prior to a period of a lower nutritional plane
especially in the case of a Northern, spring calving operation. In years with very high moisture or in areas with a
prolonged grazing season (i.e. more than 6 months) additional treatments may be necessary. In almost all cases,
very aggressive suppressive anthelmintic programs such
a multiple early season treatments or slow-release formulations are unnecessary and can have the negative effect
of increased selection for anthelmintic resistance in cowcalf 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 treatments aimed at aiding animals through periods of stress.
In operations where the presence of anthelmintic resistant

10

L.C. Gasbarre / Veterinary Parasitology 204 (2014) 311

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 management 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 sufcient for mature, effective immune
responses especially in calves coming from cow-calf operations with high levels of parasite control. The maintenance
of refugia in this model is difcult to manage. Refugia maintained by not treating some animals will result in depressed
growth of the untreated animals and economic loss. Refugia
maintained as signicant numbers of parasites on pasture
will mean all cattle are continually exposed to reinfection. 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 important 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 effectiveness 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 inection 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. Beginning about 10 years ago we began to see the rst signs
that the effectiveness of the most widely accepted class of
drugs was beginning to decrease. Over the past 10 years this
erosion of efcacy has increased at an alarming rate. Experience 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 rst decision to be made
is how important is it for the parasite control programs to
be sustainable over time, or can the pharmaceutical industry develop new control agents at a rate sufcient to discard
the current control agents.

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