Drug resistance in parasites, like the worms themselves, can progress unnoticed, until the damage is done. Today, with resistance becoming more common, veterinarians and parasitologists are sounding the alarm, saying we’re reaching a tipping point, where changing practices can preserve the efficacy of existing products, but inaction could allow multi-drug resistance to become the norm.
Even the most effective treatments do not kill every worm, because some worms carry a genetic makeup that allows them to survive treatment. Even if the number of survivors is small, they pass the resistance trait on to their offspring. Within a few generations, resistant parasites dominate the population and treatment with that drug, or class of drug, becomes ineffective.
As concerns over drug resistance grows, producers need to move away from simple “cookbook” formulas for deworming cattle, says Louisiana State University Extension Veterinarian Christine Navarre, DVM, MS. Navarre recently outlined current thinking on parasite control at the Academy of Veterinary Consultants Summer Conference in Denver.
The “ideal” parasite-control program for any operation depends on a range of factors, including geography, cattle type, production schedule, pasture management, types of endemic parasites and, importantly, levels of resistance already established in local parasite populations. Producers, Navarre says, need to work with their veterinarians to customize and implement control programs that include components such as refugia, surveillance and possibly treatments with combinations of drugs, along with other best practices, for sustainable management of internal parasites.
University of Georgia veterinarian Ray Kaplan, DVM, PhD, studies parasite-resistance trends and options for addressing the emerging problem. Drug resistance among nematode worms infecting livestock is not a new phenomenon, Kaplan says. Globally, producers of goats, sheep and other small ruminants have battled resistant worms for decades. In some locations, multi-drug resistance has left small-ruminant producers with no effective treatments.
The emergence of resistance among worms affecting cattle has, fortunately, been slower, but it is happening. While data is limited, evidence suggests resistance to macrocyclic lactones emerging in Cooperia, Haemonchus and Ostertagia. The risk of having no effective anthelmintics is very real, Kaplan says, adding that the best time to address drug resistance is before it reaches significant levels.
Most producers probably are not aware of the emergence of resistant populations of worms, but when researchers look for resistance, they find it. Kaplan and his team currently are collecting data from a cross-section of cattle operations in Georgia, and he shares some early results. Of the first seven farms tested, researchers found worms resistant to macrocyclic lactones on six. All six of those farms had Cooperia species with resistance. On one farm, they found Haemonchus and Ostertagia, also with resistance to macrocyclic lactones.
Based on current research and trends, Kaplan believes the prevalence of Cooperia with resistance to macrocyclic lactones has reached at least 75% and possibly as high as 90% of cattle herds. Kaplan also notes that cattle movement in the United States facilitates the spread of parasites. “If resistance develops anywhere, it will spread everywhere,” he says.
Limited drug options
Kaplan points out the drugs currently in use for controlling worms in U.S. cattle fall into three chemical classes: benzimidazoles, imidazothiazoles, and macrocyclic lactones. Resistance to one drug can result in resistance across that class, and in some locations, nematode parasites have developed multi-drug resistance resulting in “total anthelmintic failure.”
In New Zealand, researchers conducted a prevalence study in 2006 and found multi-drug resistant worms, primarily Cooperia species, on 74% of the operations surveyed. Cooperia, Kaplan points out, cause production losses in U.S. cattle herds, but generally do not cause clinical disease.
However, Kaplan says macrocyclic lactone resistance appears to be emerging in Ostertagia ostertagi, also known as the brown stomach worm, which is a more damaging nematode parasite in cattle. In a recent Australian study, three of 20 farms were found to harbor O. ostertagi populations with resistance to all three classes of anthelmintics. “Widespread resistance in O. ostertagi would be a big game changer,” Kaplan says.
Resistance is likely to outpace introduction of new products, Kaplan says. So the best strategy for long-term parasite control is to preserve the efficacy of existing products through management.
Killing every worm is an unrealistic and potentially counterproductive goal. Navarre challenges producers to think in terms of “good worms” and “bad worms,” with the bad worms being resistant to one or more drugs and the good worms remaining susceptible. Refugia is the means by which producers maintain a population of susceptible parasites on the ranch, improving sustainability of their control programs. Refugia typically means leaving some animals untreated, but also can involve grazing decisions – leaving some pastures as refuges for susceptible worms rather than trying to keep every pasture “clean.”
Kaplan points out that if you treat all the animals in a herd, the only parasites left are those with resistance to the treatment. With a refugia system in place, the majority of worms within the herd or pasture remain susceptible to treatment.
Research results in small ruminants and cattle demonstrate that ranchers can implement refugia with no significant loss of productivity, while dramatically slowing the development of resistance. Selective treatments greatly reduce the overall parasite burden within the herd or on a pasture, and producers can select some of the healthiest cattle – those least affected by parasites – for the non-treatment group.
In April 2013, FDA released a paper with recommendations for detecting and preventing drug-resistant parasites, with a focus on refugia. The authors list practices they believe contribute to anti-parasitic resistance, including treating every animal in the herd and general overuse of antiparasitic drugs. The brochure, titled “Antiparasitic Resistance in Cattle and Small Ruminants in the United States: How to Detect It and What to Do about It,” is available online.
Develop drug combinations
Refugia works hand-in-hand with drug efficacy, Kaplan says. Refugia protects efficacy by preserving a drug-susceptible population of parasites. A high level of efficacy, generally achieved only with a combination treatment, is necessary to keep the portion of a herd that is left untreated to a minimum. Combination treatments involve using two or more dewormers, from different drug classes, simultaneously.
Mathematically, at lower levels of drug efficacy, the percentage of cattle left untreated needs to increase just to maintain that level of efficacy. For a sustainable system, drug efficacy needs to be better than 98% and ideally better than 99%, Kaplan says.
Kaplan describes the concept behind combination therapy. Even with 99% efficacy for a single drug, the resistance rate increases dramatically within just a few generations of worms. However, using a combination of drugs can have a big impact on survival rates. Say, for example, you have two drugs, each of which will kill 98% of worms when used alone, meaning a 2% survival rate. Drug A kills 98% of the worms in an animal, and Drug B kills 98% of the survivors of Drug A. Using both drugs in combination increases treatment efficacy to 99.96 percent, or a survival rate of 0.04% – a 50-fold decrease in survival. If fewer resistant worms survive then you need less susceptible worms left behind to dilute them out.
Kaplan says with 99% efficacy, you can leave 10% of the herd untreated for a sustainable refugia system. If efficacy drops to 95%, the refugia requirement jumps to 30%.
There currently are no approved combination dewormers available in the United States, and due to chemical incompatibilities, existing dewormers cannot be mixed and delivered in a single dose. Until combinations become available, producers, with veterinarian oversight, must administer a separate, full dose of each drug for combination therapy.
In the ongoing Georgia study, Kaplan’s team has treated cattle with a combination of macrocyclic lactones and fenbendazole, achieving an average of 99% efficacy. Many farms, he says, have used macrocyclic lactones exclusively for decades, while fenbendazole use has declined. Combining the two achieves significantly higher efficacy compared with either drug on its own.
An Australian study, recently reported in the International Journal for Parasitology demonstrated that combination therapy can stop or possibly even reverse the emergence of drug-resistant parasites. The five-year study evaluated the efficacy of combined albendazole, ivermectin and levamisole against Teladorsagia circumcincta in sheep. Overall, there was a significant improvement in the effectiveness of both levamisole and ivermectin against T. circumcincta, and a positive but non-significant trend in efficacy of albendazole. The researchers say the almost exclusive use of combination anthelmintics, integrated with other resistance management strategies, did not result in further resistance development despite all farms exhibiting resistance to multiple drugs prior to the study. They conclude that “measured increases in anthelmintic efficacy suggests that adoption of best practice management strategies may extend the useful life of anthelmintics even after resistance has been diagnosed.”
Rotating between classes of anthelmintics does little or nothing to slow the development of resistance, Kaplan explains. Each individual treatment leaves enough survivors to establish a resistant population over time. Kaplan acknowledges that combination therapy increases treatment costs, but he believes the long-term benefits will easily pay off.
As for timing, Kaplan says the “best” parasite-control schedule varies depending on geography and overall management systems on a ranch. However, the optimal times to treat with a single drug on your operation also are the optimal times to use combination therapy.
Navarre acknowledges the extra cost could deter producers from considering combination treatments, but says they might need to accept some higher costs as investments in the long-term protection of animal health and performance.
Monitor for resistance
Diagnostic testing is required to determine the existence and extent of parasite problems and anthelmintic resistance on each ranch, Navarre says. Quantitative fecal egg counts can determine the magnitude of parasite problems, and the fecal egg count reduction test (FECRT) can be used to estimate anthelmintic resistance. Navarre notes that the FECRT has limitations, with consistently accurate and representative before-and-after counts challenging to achieve. Efficacy below a 95% reduction, and probably below 98%, indicates resistance, with the trend being especially important.
Kaplan suggests running the FECRT in a cow-calf herd about every two years. If the reduction in post-treatment egg counts is less than 95%, or if the reduction is declining over time, resistance is likely emerging.
Accuracy of the FECRT depends on using proper sampling procedures and diagnostic testing. Kaplan and his team recently completed a study comparing several FEC methods, and results show the Mini-FLOTAC test provides significantly better accuracy compared with the more common McMaster and Modified Wisconsin Floatation methods. Several university parasitology laboratories have switch over to the relatively new Mini-FLOTAC method, and Dr. Kaplan’s lab now uses this method routinely for performing FECRT.
Navarre notes that a treatment failure does not necessarily equal resistance. Mistakes in estimating cattle weights, calculating dosage, mixing or administering products can easily result in improper or inconsistent doses. Ensuring an efficacious dose for every animal treated is critical for short-term success and for minimizing development of resistance over time.
Using pooled samples can help to reduce the cost of FECRT. Kaplan and his team recently conducted a study comparing the use of pooled samples with individual samples, and published their results in the journal Veterinary Parasitology in a report titled “Utilization of composite fecal samples for detection of anthelmintic resistance in gastrointestinal nematodes of cattle.”
Typically, Kaplan says, sampling has involved 15 to 20 animals, with the same animals tested before and after treatment. For pooled samples, workers still need to collect samples from the same animals before and after treatment, but can combine portions of those samples for a single test, significantly reducing the time and cost of testing. In their research, the Georgia team found greater than 95% agreement in drug efficacy between individual and composite sampling methods, demonstrating composite sampling is appropriate to evaluate drug efficacy. For all groups tested the efficacy calculated by composite sampling was within the 95% confidence interval for efficacy calculated using individual sampling. The use of composite samples was shown to reduce the number of fecal egg counts required by 79%. “These data demonstrate that pooling fecal samples from a group of cattle and then performing repeated FEC on that composite sample yields results very similar to performing individual FEC on those same animals, while substantially reducing the cost of performing a FECRT as compared to individual fecal samples,” they conclude.
Pasture rotations and grazing management can reduce worm populations. Kaplan also suggests culling the most heavily infected cattle, as susceptibility to worms is a heritable trait. The authors of the FDA paper on drug resistance recommend additional management steps, including isolating new livestock and reducing stocking densities.
Navarre provides this summary list of steps veterinarians can take with clients in designing effective, sustainable parasite-control programs.
· Minimize other stressors.
· Maximize nutrition.
· Understand parasites in your locale.
· Use best statistical analysis for FECRTs.
· Think about refugia.
· Think about pasture management.
· Don’t buy resistant worms.
· Proper product selection and use.
· Cull poor-doers.
“We need to think of effective anthelmintics as valuable, irreplaceable resources,” Kaplan says. “We need to preserve their efficacy as long as possible.”