Cyathostomin Resistance to Moxidectin - The risks and reality

Cyathostomin Resistance to Moxidectin - The risks and reality

By Dr Emma Alsop BVSc Cert EM(IntMed) MRCVS

cyatho photo 1

Introduction

Small strongyles (cyathostominea) are now the main parasitic pathogen in equines. The successful anthelmintic strategies used for the control of large strongyles have inadvertently led to the selection of drug resistant cyathostomes. There is a worldwide increase in the reported levels of anthelmintic resistance, and of most concern is the resistance of the cyathostominea to the macrocyclic lactones. There is documented evidence of cyathostomin resistance to the benzimidazoles and pyrantel salts. The growing evidence for resistance to both ivermectin and moxidectin must now be considered when designing worming programs. Strategies to slow down the selection for resistance, thereby extending the lifetime of currently effective anthelmintics must be implemented whenever possible.

Cyathostominae life cycle and pathogenicity

There are over 50 species of cyathostominea, with around 10 – 12 making up the bulk of equine infestations.¹ Many horses harbour burdens of thousands of cyathostomes without detectable illness but the parasite has the potential to cause severe disease.

The cyathostome lifecycle

The cyathostomes have a direct, non-migratory life cycle. Only the L3 phase of the cyathostominaeare is infective. These are ingested from pasture, with faecal egg shedding by the female adults, shown to be highest at dawn and dusk. Stabled horses are at a lower risk, as the ammonia and moisture levels are detrimental to L3 survival. The ingested L3’s penetrate the wall of the caecum and colon, where they either develop into L4’s and on to female adult egg producing L5’s or they undergo a state of arrested development, known as HYPOBIOSIS, encysting within the walls of the large intestine, to re-emerge when environmental conditions are more conducive to larval survival. The infective L3 larvae cannot ingest nutrients therefore their survival time is temperature dependent. In hot conditions, catabolism is rapid so the larvae are short lived, in colder conditions the larvae survive on pasture for much longer periods of time.

Weight loss, poor coat quality, poor performance and decreased food utilisation are less severe clinical signs of infection. More severe cases will show anaemia, pyrexia, severe weight-loss and varying degrees of a protein losing enteropathy, leading to hypo-proteinaemia and ventral oedema. Simultaneous emergence of the encysted cyathostomes can cause the clinical syndrome LARVAL CYATHOSTOMIASIS, with a reported mortality of up to 50%.²,,3 In the author’s experience, this is seen more commonly in younger horses and in areas of more extreme climate changes between seasons.

Factors stimulating the formation of and re-emergence of the hypo biotic larvae are complex and not fully understood. Factors influencing hypobiosis may include cold conditioning of the L3 larvae just prior to ingestion, the population density of adult parasites within the intestinal wall and lumen and host immunity factors.² Anthelmintic treatment that targets the luminal stages may stimulate re emergence as this will cause a decrease in the luminal nematode population.

The inhibited larvae can remain encysted for months to years.⁴ A consequence of this is that horses can have infestations of millions of NON EGG PRODUCING juvenile stages of cyathostominae and therefore have a negative or low faecal egg count (FEC).⁵

Host Immunity and recognition of Shedders

Horses show a huge variation in their susceptibility to cyathostomes and no life long immunity develops. Therefore there is constant and life long exposure within grazing horses/ horses with access to pasture. 6 Most horses will regulate their infection levels and consistently have low levels of infection. Fewer animals will have higher nematode infestations (> 500egg per gram (epg)). The majority of the parasites will be within the minority of the population. It is these individuals that require identifying and addressing, as these are the animals contributing to the bulk of pasture contamination. The aim of targeted worming control is to prevent contamination of the environment with the eggs of the target parasite, therefore decreasing the number of female adult worms before they can reproduce.

The only way to identify the shedders and gain a grip on the overall levels of infestation and presence or absence of anthelmintic resistance is by the use of FEC’S and FECRT’s (faecal egg count reduction tests).

Anthelmintic Resistance

Owner concern, and easily available safe, effective and inexpensive anthelmintics have lead to the dramatic over-use of and the development of resistance. To the authors knowledge there are no new anti-parasitic chemicals being developed, or even in the pipeline. What is available now is all we have got. Using the interval dosing system successfully treated Strongylus vulgaris. By the early 1980’s S. vulgaris was becoming uncommon and cyathostomes were starting to account for 100% of strongyles eggs seen in FEC’s. In 1983, the release of the first macro cyclic lactone, ivermectin, further reduced the prevalence of S. vulgaris.

Unfortunately, worming programs have become more and more haphazard, with poor client education and easily available anthelmintics, often being sold from non-veterinary outlets. The increasing practice of the use of ‘off label’ anthelmintic is also contributing to resistance development. The nematodes are being exposed to sub-therapeutic doses of the anthelmintic, thus providing ideal conditions for resistance development (authors own experience). Of great concern is that reversion to drug susceptibility does not seem to occur in parasitic nematodes even when not exposed to that drug class for years.⁸

How does resistance develop?

Resistance is described as “a measurable decrease in the efficacy of a compound against a population of worms that were previously susceptible”.

Anthelmintic resistance in nematodes is an inherited characteristic that is passed on from one generation to the next via the genome. The cyathostomes have extremely high levels of genetic diversity.⁷ Resistance can develop upon first exposure to a drug or relatively quickly thereafter due to this genetic diversity combined with a huge population size and the fact that the steps required for a genotype to change from susceptible to resistant are relatively simple. Resistance to macro cyclic lactones is thought to involve several DNA mutations before the nematode acquires the full resistant genotype. The resistant genotype will then proportionally increase in the population. The rapid and widespread movement of horses allows quick and efficient distribution of these resistant worms to new farms and herds.

Moxidectin Resistance

Ivermectin is not effective against against encysted larvae, the most pathogenic life stage that can potentially cause fatal colitis. Controlling this life-stage is vital to reducing cyathostomin-induced disease. The lack of anthelmintic efficacy against the encysted stages may also have contributed to the relatively slow development of resistance to ivermectin. These ‘untouched’ encysted L3’s increase the amount of untreated, susceptible worms, the ‘in refugia’ population, which is vital in diluting resistant genotypes, slowing down the onset of resistance.

One of the early signs of resistance is a reduction in the egg reappearance period (EPG). The EPG is the duration post deworming when he egg count remains negligible The EPG varies according to the anthelmintic used: Benzimidazoles at 6- 8 weeks, pyrantel at 6 weeks, ivermectin 8-10 weeks and moxidectin > 13 weeks.⁹

A decreased ERP for ivermectin has been reported in Europe, Brazil and the U.S.A.¹⁰-¹¹ Of much greater concern is the reported evidence of reduced efficacy of moxidectin¹²-¹³ . In the authors own personal experience there have recently been cases of reduced EPG and failure of a reduction in FEC’s of >80%. In fact the author has personal experience of cases of no reduction, but an increase in FEC’S when taken prior to and 7 days post moxidectin treatment in two equines from the same farm. Moxidectin resistant cyathostomins have also been reported in the UK.¹⁴

How do we address this emerging situation?

If the random, blanket use of anthelmintic continues then widespread moxidectin resistance is inevitable. Action needs to be taken now by veterinary professionals to change current worming regimes and become proactive in devising strategies that provide nematode control whilst preventing resistance. No single protocol can be applied uniformly due to varying environmental influences, pasture management principles and herd dynamics.

Veterinarian need to enhance their r understanding of the principle aims of control, the target parasites and the diagnostic tests available (along with their limitations) and arm themselves with the knowledge of the parasite populations sensitivity and resistance, then a best practice control program can be established for each individual setting. Interval dosing is the traditional method of worming and this was highly effective in reducing the incidence of S vulgaris. This is the administration of a specific drug at regular time intervals throughout the high-risk periods. This method has several negative aspects (1)t owners are worming horses that don’t necessarily require treating, thus decreasing the ‘in refugia’ population thus speeding up the development of resistance (2) unnecessary costs incurred (3) many owners are also dosing as the wrong intervals due to a lack of information on ERP’s thus often exposing worms to constant sub-therapeutic levels of drug. This is thought to be one of the main reasons for widespread Parascaris equorum resistance to ivermectin.¹⁶

Strategic dosing employs the use of an anthelmintic at specific times to disrupt the seasonal cycle of transmission. This can become ineffective in periods of abnormal weather patterns and with the introduction of horses with high levels of infestation.

In the author’s opinion, targeted dosing is the most logical approach to providing good anthelmintic cover in adult horses and slowing anthelmintic resistance. This will also get the veterinarian re- involved in deworming strategies. For each individual yard/ herd/pasture, individual levels of infestation and the presence of resistance to each anthelmintic, needs to be established. Although faecal monitoring will increase the costs of administering control programs, the alternative, i.e., expanding resistance is unacceptable.

The gold standard practical technique is the FEC (faecal egg count) and FECRT (faecal egg count reduction test).¹⁷ (Fig 1). The main limitations of these tests are the assumption that all strongyles eggs seen are small strongyles and that the FEC gives you no indication of the mucosal larval parasite levels. They will however give you an indication of that animal’s potential to contaminate the pasture. These mucosal levels must not be allowed to build up to high levels in young horses due to the risk of larval cyathostomiasis, therefore the use of a larvicidal treatment needs to be incorporated into the regime of deworming young horses. Foals and weanlings should be considered separately from the adult population.

If a dewormer has just been administered start monitoring by taking FEC’s after the ERP of the administered anthelmintic has elapsed. Individuals with FEC above the designated threshold should then be treated. Repeat FEC’s should be performed at 10-14 days post treatment to establish the presence of resistance. FEC’s can then be performed at 2-3 monthly intervals dependent upon the ERP of the product used. As the egg excretion dynamics of the population become apparent, FEC frequency can be reduced as the ‘high shedders’ become identified and controlled. A larvicidal dose of anthelmintic must be administered when appropriate, independent of FEC data especially in youngsters (moxidectin 0.4mg/kg or 5 days fenbendazole 10mg/kg).

The suggested criteria used to define anthelmintic resistance are that FEC’s should be reduced by 95% after the administration of a macro cyclic lactone or Benz imidazole, and 90% after administration of pyrantel, at 10-14 days post treatment.¹⁸ Horses with high FEC results can then be targeted and wormed appropriately, with follow up FEC’s giving information on the presence of resistance. The ‘cut-off’ value for when to treat is a contentious issue and in the authors experience the value used needs to be tailored to each individual setting/yard/ herd. The most frequently cited FEC cut off value for determining treatment is 200-500 epg. Suggestions for repeat the treatment have been reviewed ²⁰ (and include when faecal egg counts rise to 10 per cent of the counts recorded before treatment²¹; when 50 percent of horses have a mean epg above 200 ²² and when the mean epg of all the horses is more than 100. ²³ Shedders should be treated to their FEC’s. New arrivals to the population should have FEC’s performed and treated accordingly, prior to release onto common pasture. Clearly, as well as anthelmintic control, good pasture hygiene should be maintained with frequent removal of faeces from the pasture.

Scheduling of Anthelmintics – yes or no?

One way to gain further control over anthelmintic use and abuse is to reschedule the anthelmintic, or consider scheduling moxidectin-based products. Denmark introduced prescription only restrictions of anthelmintic drugs in 1999 and other European countries have implemented similar legislations over recent years (Germany and Austria). In Denmark, the frequency of treatment decreased over time. It has to be noted however, that with the reduction in anthelmintic treatment frequency and the use of targeted dosing, the potential for an increase in prevalence of other types of parasite (of most concern Strongylus spp, also Oxyuris equi and Gasterophilus spp) could occur. Denmark compared their incidence of Strongylus spp over a 10 year period to that of neighbouring Sweden who had not instituted selective targeted dosing regimes to such a level and found that the prevalence of Strongylus was similar between the two countries.²⁴ Further development h further development of FEC analysis techniques and larval burden detection techniques is also required.

For more info go to:
AAEP Parasite Control Guidelines. Lexington, Ky: American Association of Equine Practitioners, 2013. Available at: http://www.aaep.org/info/parasite-control-guidelines.

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