In veterinary school there we many sayings, but one that stood out was “Treat for the treatable.” As a student, one of my patients was a polar bear, trucked in from the Jacksonville zoo. The differential list of diseases that brought him to UF was long. Some diseases were difficult to diagnose and rule out. And some things on the list were not treatable. He could have a tumor, pancreatitis, or dying-polar-bear disease, among other possibilities. He could have a bacterial infection, some brave soul had procured a blood sample and his white blood cell count was high. A bacterial infection was treatable. We went with that.
There is another saying, appropriate in many instances and that is “If it isn’t broken, don’t fix it!” That works in veterinary medicine as well. Treating conditions that don’t need treating is a poor idea. Especially using antimicrobials in horses.
Antibody against S. neurona in horses
Antibodies against Sarcocystis are found in almost all horses in the United States. You probably remember that there are two species of Sarcocystis, S. fayeri and S. neurona, that infect horses and infected horses produce antibodies. The infected horses resolve the infection in cases of S. neurona or the parasite formed muscle cysts, in cases of S. fayeri. A seropositive status doesn’t mean horses are diseased. Only a small fraction of S. neurona infected horses are diseased. Antibodies don’t mean disease, rule out some diseases and remember to treat for the treatable.
Antibodies are protective! When a horse is exposed to the parasite, antibodies are boosted and the parasites are eliminated. The protection is serotype specific, if the antibody is against SAG 1 strains, the SAG 1 strains are eliminated. Ditto for the other serotypes. Inflammation can accompany the immune responses to the gut infections and occasionally, there are signs associated with the inflammatory response, but antiprotozoal drugs are contra-indicated to treat inflammation.
It was shown by experiment that Sarcocystis attempts to evade the immune system by changing the surface proteins it displays after the parasites reach the blood stream. Chronic anti-protozoal therapy in horses decreases natural immune responses to organisms and this leaves the horses with decreased defenses against repeat infections. It was also shown by experiment that giving anti-protozoals for up to 100 days before challenge, the prophylactically treated horses had a more severe inflammatory response.
Antibodies against S. neurona and EPM
The clinical criteria for EPM is a horse with clinical signs and antibodies. However, the accepted criteria for eliminating EPM from the differential diagnosis is no antibodies against S. neurona. A horse that is seronegative is unlikely to have EPM. Again, if it isn’t broken, don’t fix it! It is possible that chronic administration of anti-protozoals induces a refractory inflammatory response. In fact, that is part of our algorithm to identify horses with PNE.
The main reasons that overuse of antimicrobials are a worldwide concern is increased drug resistance, emerging cross resistance, and lack of new drugs that have a novel mechanism of action. These issues reduce the effectiveness of anti-protozoal therapies in humans and animals. Protozoa can acquire resistance because they have mutations in genes enabling the parasite to resist the killing effects of antimicrobial agents and drug use selects for resistant strains.
Leishmaniasis is a disease caused by protozoa parasites in the genus Leishmania. The sand fly is a vector for the infective stage of Leishmania, the parasite infects and lives in the macrophage of the mammalian host. There is a visceral (gut) form of this disease and a cutaneous form. Treatment fails for economic, toxic, and resistance issues. It took close to 100 years for the organism to become resistant to the standard treatment! It is possible that it took that long because the parasite needed to develop multiple resistant factors. Resistance factors can be a loss or a gain of function that allows the parasite to live in the presence of the antimicrobial.
Resistant strains for drug discovery
It usually takes years for a parasite to become resistant to a drug. Bacteria are easily selected for resistance in the laboratory because they multiply quickly. Bacteria are useful to develop protocols for selecting resistant organisms, the effective protocol uses sub-lethal doses of drug, given over long periods.
For example, the bacteria are plated onto medium containing a small amount of drug. Surviving colonies are transferred to media with ever increasing doses of the drug until a population is selected that has resistance. It will be the only colony on the plate. The hospital was a good example of selecting resistant organisms infecting people because in the hospital environment many antibiotics are given. Hospital patients are at risk for MRSA, methicillin-resistant Staphylococcus aureus. There is a declining population of people that get MRSA in the hospital recently due to vigilance of health care workers. There is an increasing population of community MRSA infections because people overuse, or inappropriately use, antibiotics.
It is easy to find parasites that have resistance to anti-parasitic drugs. Parasites are isolated from fecal samples, either from animals that have received the drug or housed in an environment with animals receiving chronic drug administration. This is an issue for food producing farm animals. Overuse of drugs results in environmental exposure, and that leads to resistance. We are currently using a drug resistant strain of C. elegans for drug selection.
EPM researchers developed a strain of S. neurona that was resistant to ponazuril and pyrithiamine. The laboratory strain was useful for drug discovery but the ability to create such a strain indicates that resistance will eventually be an issue in field cases of EPM. This is most likely already an issue in some environments.
The horse is a dead end host for S. neurona and horses are not a factor in selecting resistant strains of S. neurona. When the drug is inadvertently given to the definitive host the selective processes begins. The definitive host is dosed when multiple animals are given anti-protozoal drugs resulting in increased exposure in the environment. Unmetabolized drug is excreted into the environment in the feces of the treated horse.
The take home message
It is important to only treat animals that require treatment. Horses that need treatment are identified by a good neurological workup of their clinical signs and lab testing for antibodies related to the infection. It is important to use the correct dose and duration of an intended therapy. Intermittent, under dosing is a recipe for resistance. Treating inappropriately results in environmental exposure and increasing exposure to definitive hosts.