USING EPM MEDICATIONS TO PREVENT EPM INFECTIONS

This entry is part 2 of 2 in the series 2024 Series on EPM

Should equine protozoal myeloencephalitis (EPM) medications be given long term to horses who do not currently have EPM in order to prevent infection?  The current typical protocols are to give a low dose daily or twice weekly.  This practice was rare a few years ago but is now becoming more common, particularly in areas of the country in which EPM exposure is likely.

I advise clients NOT to use these protocols because the existing evidence indicates limited or unclear efficacy to prevent infection, there are no studies that focus on toxicity with long term administration, and there is the possibility that chronic use (overuse) of these medications will lead to resistant protozoa – an equine health emergency.

But let’s back up. In order to know if these protocols should be used, we need the answers to these key questions:

(1) Does long term dosing prevent infection? 

Short answer:

  • Diclazuril: unclear because of the absence of measures of infection in the available studies
  • Ponazuril: infection may be prevented in some horses when the treatment dose is used daily or when a higher dose is used weekly

(2) Is long term dosing safe?

Short answer: unknown; no study has measured toxicity

Clinical experience with horses on these protocols suggests that a proportion will begin to show evidence of systemic toxicity after several months of chronic dosing. Signs of toxicity usually take the form of skin lesions and associated hair loss or sores in and around the mouth.

(3) Does long term dosing create the potential for resistant protozoa?

Short answer: Unclear but possible. No studies raise this as a concern, however, this is a critical issue, particularly given the funding of the diclazuril studies by the manufacturer of Protazil. Resistance to wormers, antibiotics, and anti-protozoals are major public and equine health threats.

Here are the detailed answers.

AVAILABLE STUDIES: Four studies have evaluated the use of anti-protozoals to prevent infection rather than to treat infection.

Two studies examined the ability of diclazuril (brand name Protazil) to prevent infection with S. neurona (the more prevalent protozoa that causes EPM) when horses were in environments with naturally high rates of EPM exposure (i.e., horses were not purposefully infected). Part of the interest in using diclazuril for prevention is its availability as an easily fed top dress (as Protazil) and recent work indicating that dosing at half the treatment dose either daily or twice weekly maintains adequate drug concentrations in the spinal cord to inhibit S. neurona (Hunyadi, et al., 2015; Hunyadi et al., 2018), suggesting that lower dosing or less frequent dosing may be effective.

Two studies examined the ability of ponazuril (brand name Marquis) to prevent infection when horses were purposefully infected with S. neurona; in one study the horses also were then stressed by a long-distance haul (note that the difference in outcomes between the two ponazuril studies is accounted for by the use of a hauling stressor in the 2006 study; hauling stress can precipitate a break-through infection and associated symptoms).

ANSWERS TO KEY QUESTIONS:

(1) Does chronic dosing with an anti-protozoal prevent S. neurona infection? 

Diclazuril studies: Unclear. The only way to know if infection has occurred is to check a CSF titer or to assess for neurological behaviors or to check a blood titer and assess for neurological behaviors. In the absence of these measures, it is not possible to determine that infection has occurred. The diclazuril studies did not include these measures; this omission means that neither study proves that chronic, low dosing can prevent infection. All that we know from these studies is that chronic, low-dose use of diclazuril may reduce the likelihood of a positive blood titer among horses up to age one year or that it may reduce the magnitude (but not the number) of positive titers among adult horses. Blood titers in isolation are not valid proxies for infection (for a detailed discussion of titers, how to interpret them, and why they cannot be used as sole evidence of infection, see https://4oaksequine.com/equine-protozoal-myeloencephalitis-epm/; for a recorded webinar that covers similar information, see here https://4oaksequine.com/product/webinar-epm-2024-02-05/).

We know nothing about infections based on findings from these studies.

Ponazuril studies: No. The two ponazuril studies measured CSF titers and neurological behaviors in addition to blood titers, making it possible to draw conclusions about infections. These studies indicate that when horses are deliberately infected with S. neurona and then subjected to a hauling stressor, the administration of daily ponazuril does not reliably prevent infection as indexed by positive CSF titers and neurological symptoms. When horses are deliberately infected, but not subjected to a hauling stressor, the administration of ponazuril weekly or every two weeks does not prevent infection as indicated by positive CSF titers.

STUDY DETAILS.

Diclazuril Study 1 (Pusterla et al., 2015): In this study 33 foals on a farm with high S. neurona exposure were either not treated (17 foals) or were treated daily with 0.5 mg/kg of diclazuril (one-half the treatment dose for infection) from age 1 month to 12 months (16 foals). Monthly blood titers were drawn.

This study was potentially confounded from the beginning. Although all of the mares had positive S. neurona titers, the mares who gave birth to the untreated foals had significantly higher titers (median 640) than did the mares who gave birth to the treated foals (median 320). This immunity is passed to the foals when they ingest their mothers’ colostrum. Not surprisingly, 24 hours after colostrum ingestion (weeks before drug administration), 96% of the foals who would become the untreated group but only 69% of the foals who would become the treated group had positive blood titers. This discrepancy reflects the differences between the mothers’ immune status and it means that the foals that would become the untreated group started life with higher titers than did the foals that would become the treated group.

At age 4 months, the two groups of foals (having been either not treated or treated for four months) exhibited similar proportions of positive titers (ranging from 20-35%). For the next 8 months, the foals in the untreated group exhibited higher proportions with positive titers (from 53 to 88%) compared to the foals in the treated group (from 6 to 29%).

Does this study indicate that daily treatment with low-dose diclazuril prevents EPM infection in foals up to 12 months of age? It does not. No indices of infection – CSF titers or neurological symptoms – were measured. Blood titers alone are only loosely predictive of infection. Horses may have high titers without being symptomatic (meaning that the protozoa have not entered the nervous system because the horse’s immune system is effective in controlling the infection) and they may have low titers with extreme symptoms indicating infection. This second scenario is common in horses who are immunocompromised, such as insulin resistant horses.

In addition, the discrepancy in the mares’ immune status at the beginning of the study raises potential questions about the results. The implications of the higher titers in the mares whose foals became the untreated group are not known. One interpretation of high titers (in the absence of symptoms) is that that the horse’s immune system is strong. Without verification that the untreated foals’ greater proportion of positive blood titers reflects infection, it is equally possibly that this group simply had a more active immune system and potentially had a similar number or even fewer infections than did the treatment group. Without measures of infection, it is impossible to know.

Diclazuril Study 2 (Pusterla et al., 2021): In this study 20 horses were moved from a low-EPM risk environment to a high-risk EPM environment. Ten horses were assigned to serve as untreated controls and ten horses were assigned to the treatment group. Treatment consisted of 0.5 mg/kg diclazuril (one-half the daily treatment dose) given twice a week for one year. At the beginning of the study, 7 of 10 horses in the control group and 8 of 10 horses in the treatment group had positive blood titers. Blood titers were measured monthly. At three months and throughout the remainder of the study, all of the horses in both groups (untreated controls and treated) had positive blood titers. The only difference between groups was that the treated horses had lower positive titers than did the untreated horses. The authors note that “the horses were monitored daily through visual assessment and evaluated for attitude and appetite” and that “none of the horses developed neurological deficits.” However, it does not appear that neurological exams were carried out. The detection of neurological symptoms by casual observation is almost impossible, especially if symptoms are subtle and early-stage. Therefore, this assertion is not compelling evidence of the absence of symptoms — or the absence of infection.

Does this study indicate that daily treatment with low-dose diclazuril prevents EPM infection in horses over 12 months? It does not. No indices of infection – CSF titers or neurological symptoms – were measured. Blood titers alone do not reliably predict infections.

Ponazuril Study 1 (Furr et al., 2006). A group of 18 horses (6 in each group) were administered 1 million S. neurona sporocysts and given no treatment, 2.5 mg/kg ponazuril, or 5 mg/kg ponazuril (this is the current treatment dose for active EPM infection) once daily beginning seven days before infection and continuing for 28 days post-infection. On the day of infection horses were stressed by a long-distance haul. Blood titers, cerebrospinal fluid (CSF) titers, and neurological behaviors were measured periodically throughout the study.

During the study, 100% of the control horses (who were not administered ponazuril), 71% of the horses in the 2.5 mg/kg group, and 40% of the horses in the 5 mg/kg group developed neurological signs, consistent with infection (the protozoa had reached the spinal cord).

Conclusion. When horses were infected with S. neurona and subjected to a hauling stressor, administration of low-dose (2.5 mg/kg) did not prevent infection. Administration of a treatment dose of ponazuril (5 mg/kg) reduced infection rates but did not prevent infection in all horses.

Ponazuril Study 2 (Mackay et al., 2008). A group of 15 horses (5 in each group) were infected with 612,500 S. neurona sporocysts and given no treatment, 20 mg/kg ponazuril once every 7 days, or 20 mg/kg once every 14 days for twelve weeks. This is a much higher dose than used for daily treatment with the goal of maintaining an adequate concentration in the spinal cord for a long period. An additional group of 5 horses served as controls; these horses were not infected and were not treated. Blood titers, CSF titers, and neurological behaviors were measured periodically throughout the study. These horses were not subjected to a hauling stressor.

During the study, 3 of the 20 horses developed neurological signs. One horse was in the group that was neither infected nor treated; presumably this horse developed an infection from environmental exposure. The other horses were in the every 7-days treatment group and every 14-days treatment group, respectively. Note that these results are in contrast to the 2006 study above in which horses were exposed to a hauling stressor and many more horses developed neurological signs.

By week 12, all of the horses who had been infected had positive blood titers regardless of ponazuril treatment (none, every 7 days or every 14 days). With regard to CSF titers, 100% of the horses who were infected but not treated and 100% of the horses who were infected and treated every 14 days had positive CSF titers. Among the horses who were infected and treated every 7 days, 40% had positive CSF titers. None of the uninfected horses had positive CSF titers.

Conclusion. Administration of high doses of ponazuril weekly or every 14 days did not prevent the development of positive blood and CSF titers to EPM in horses purposefully infected. It does not appear that it prevented the development of neurological symptoms either but given that only a few horses developed symptoms, this issue remains unclear. Administration of high dose ponazuril weekly reduced the proportion of horses who had infections as indicated by positive CSF titers

(2) Is long term dosing safe?

The safety of long term dosing with anti-protozoals is unknown. None of the studies above measured liver or kidney function or conducted regular physical exams to detect signs and symptoms that may have indicated toxicity.

Four Oaks Equine’s clinical experience with several hundred EPM horses every year suggests that a proportion of horses begin to exhibit skin lesions and hair loss or lesions of the lips and mouth mucosa after 6 to 9 months on chronic dosing regimens. In all cases the symptoms resolved with discontinuation of the medication.

(3) Does long term dosing create the potential for resistant protozoa?

This is a complex question. In any circumstance in which medications are used in the absence of the condition the medication is intended to treat, the potential for the development of resistance exists. With regard to S. neurona, because as far as anyone knows the protozoa do not pass out of the horse’s body, the development of resistance would be confined to that particular horse. However, this possibility means that within that horse the protozoa most resistant to the effects of the anti-protozoals could survive and eventually become the dominant population within that horse. At that point, the anti-protozoals would no longer be effective for this animal. This is within-animal resistance.

In addition, very little is known about the life cycle of N. Hughesi, the other organism known to cause EPM. The impact of chronic anti-protozoal use on this organism, therefore, is unknown.

Of the three key questions, the answer to this question is by far the most important. Once resistance has developed, IT CANNOT BE FIXED. This issue is not addressed by any of the published studies but it is of paramount and pressing concern. It is of particular concern given the funding of the diclazuril studies by Merck, the company that manufactures Protazil.

The development of resistance when medications are used in the absence of infection is well-documented in other areas that negatively affect equine and human health. For example, widespread resistance to widely-used chemical wormers is a direct consequence of the decades-long practice of worming on a schedule, without fecals, with the result that many horses are wormed who did not need treatment. This practice has resulted in an estimated efficacy of fenbendazole (Panacur) of only 25% against current parasite populations (see https://avmajournals.avma.org/downloadpdf/view/journals/javma/225/6/javma.2004.225.903.pdf
). Antibiotic resistant infections are another area that has profound negative consequences for equine and human health; it is estimated that millions of people die every year from these infections (https://www.cdc.gov/drugresistance/national-estimates.html). Estimates for horses are less clear but Four Oaks Equine regularly deals with horses who are sick or dying from an antibiotic-resistant infection. Protozoa resistance to medications is also a widespread public and animal health problem (see here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888673/).

Regardless of the efficacy of the anti-protozoals to prevent EPM, the possibility that their chronic use (overuse) could lead to resistant protozoa should be central to the decision to use these medications in this way. If S. Neurona becomes resistant (within the same horse) or N. Hughesi develops some form of resistance, then the treatment options are limited, leading to the possibility of untreatable EPM infections with consequent devastating disability.

There are other methods to prevent EPM infection that do not foster resistance. These include tactics to buffer stress, boost gut health, improve immune strength and vigilance, and foster nervous system resilience. These also include non-medicinal tactics to deter the protozoa.

Need help with an EPM prevention strategy, a complicated EPM horse or other complicated horse? Please go to https://4oaksequine.com.

REFERENCES:

Furr, M., et al., Prophylactic administration of ponazuril reduces clinical signs and delays seroconversion in horses challenged with Sarcocystis neurona. Journal of Parasitology, Vol 92(3); 2006; 637-643.

Hunyadi, L., et al. Pharmacokinetics of a low dose and FDA-labeled dose of diclazuril administered orally as a pelleted top dressing in adult horses. Journal of Veterinary Pharmacol Thera; 38; 2015; 243-248.

Hunyadi, L., et al. Diclazuril nonlinear mixed-effects pharmacokinetics modeling of plasma concentrations after oral administration to adult horses every 3-4 days. Vet J, 242; 2018; 74-76.

MacKay, R.J., et al. Effect of intermittent oral administration of ponazuril on experimental Sarcocystis neurona infection of horses. AJVR, Vol 69(3), March 2008; 396-402

Pusterla, N., et al. Daily feeding of diclazuril top dress pellets in foals reduces seroconversion to Sarcocystis neurona. The Veterinary Journal, Vol 206; 2015; 236-238.

Pusterla, N., et al. Investigation of the bi-weekly administration of diclazuril on the antibody kinetics to Sarcocystis neurona in healthy horses. Journal of Equine Veterinary Science, Vol 104; 2021; 103713.

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