Drugs for the Treatment of Protozoal Infections

Chapter 12 Drugs for the Treatment of Protozoal Infections




Protozoal infections can provide diagnostic as well as therapeutic challenges for the small animal clinician. The situations can range from the simple treatment of a young kitten with coccidiosis to the more robust challenges of chronic giardiasis in a breeding kennel. Although several of the protozoa are well characterized and relatively easy to treat, others are poorly understood and have no specific agents available for therapy. Three types of infections caused by major pathogens are presented here: common enteric coccidia, toxoplasmosis, and giardia. The pathogens are known to affect dogs and cats, and two are significant zoonotic agents.


This chapter does not include the protozoa that appear only sporadically in the veterinary literature (Balantidium, Pentatrichomonas, Entamoeba, Hammondia, Besnoitia, and Sarcocystis spp.). These organisms are not adequately documented as pathogens of dogs and cats and thus require no therapy. Also excluded are selected protozoal pathogens that are partially characterized but have no effective treatment available. Textbooks of parasitology or infectious disease should be consulted for a complete discussion of these sporadic, spurious, or untreatable pathogens.1,2


Therapy of protozoal infections, which are often zoonotic, must include use of therapeutic agents along with supportive therapy and proper hygiene and husbandry to clean up the environment and prevent spread to other animals and people. No therapeutic agent, no matter how safe or effective, can be expected to treat these diseases without supportive therapy and hygiene. Table 12-1 lists the therapeutic agents discussed in the text. These drugs are discussed below as well as in specific chapters.




Common Enteric Coccidiosis



Biology


The most common protozoa in small animal veterinary medicine are the coccidians, which cause a condition termed coccidiosis. Coccidia are very host specific. Dogs and cats are infected with several species in the genus Isospora. Diagnosis is readily made by conventional fecal floatation techniques using concentrated sugar or salt solutions. Careful identification of coccidia oocysts may reveal the presence of spurious coccidia from other genera, especially Eimeria spp., which commonly parasitize food animals, thus indicating coprophagy. Nevertheless, coccidia are ubiquitous in young dogs and cats and commonly cause disease, especially in those with suboptimal nutrition, immune status, or stress.


Coccidia are obligate intracellular parasites that depend on dispersion of fecal oocysts for transmission. This fact alone illustrates the importance of hygiene. There are four species that infect dogs (Isospora canis, Isospora ohioensis, Isospora burrowsi, and Isospora neorivolta) and two that infect cats (Isospora felis and Isospora rivolta). Although direct ingestion of the oocyst is the primary means of infection, rodents can serve as paratenic hosts if they ingest the oocyst and then are eaten by the definitive host.


Coccidia have life cycles that are more complex than other infectious agents (Figure 12-1). Each life cycle includes both sexual and asexual phases. This is important to remember because the therapeutic agents used to treat and control coccidia are primarily effective against the asexual stage of the life cycle.





The oocyst is passed in the feces, and, after suitable exposure to air, heat, and moisture, the oocyst sporulates. This process may take only a few hours or a few days, depending on the species of coccidia and on the environmental conditions. During sporulation each oocyst develops into two sporocysts that contain four sporozoites each; thus each oocyst contains a total of eight infective sporozoites.


After ingestion the sporozoites are liberated from the oocyst and invade the enterocytes that line the small intestine. Once inside the enterocytes, the sporozoites turn into trophozoites, which undergo asexual fission (properly termed schizogony or merogony) to produce many daughter schizonts. After 4 days the enterocyte ruptures and releases the multiple schizonts (or meronts). This schizont stage is the place in the life cycle where therapeutic agents have a chance to break the life cycle. Because the schizonts are released from the cell only every 4 days, the therapeutic agent should be present in the gut for several multiples of this period, usually 14 to 21 days. The daughter schizonts are capable of infecting new enterocytes and repeating the cycle of fission into many daughters and rupture of the subsequent enterocytes. The number of asexual cycles has been determined for each species of coccidia; the small animal pathogens typically have two or three asexual cycles before entering the sexual stage of the life cycle.


The schizont, produced by the last cycle of asexual fission, enters another enterocyte and develops into either a male or a female gametocyte. The female gametocyte enlarges and forms a singular large cellular structure within the enterocyte. The male gametocyte undergoes fission to produce many small biflagellate male sex cells. The enterocytes rupture, and the motile male sex cells fertilize the female gametocytes, which mature to a zygote and then pass out in the feces in the form of an oocyst. The fresh oocysts are exposed to the external environment, where they sporulate and infect new hosts.


The repeated intracellular invasion of enterocytes and subsequent rupture can produce substantial pathology to the gut, especially if the infected host is young, weak, malnourished, or stressed. Normal animals, in otherwise good health, usually experience coccidial infection followed by an effective immune response that limits and eliminates the infection without therapeutic intervention. Most clinicians prefer to intervene when coccidia are identified in a fecal floatation. Therapy is usually successful in eliminating the coccidial oocysts, although it is not known how many of these animals would have spontaneously cleared the infection without intervention.



Treatment



Sulfas and Potentiated Sulfas


Use of sulfonamides is the treatment of choice for small animal coccidia as well as a number of other protozoal organisms. Unfortunately there is a paucity of research information to support their efficacy. Two pivotal studies on sulfamethoxine and sulfaguanidine against coccidia support their utility; however, these two agents are no longer available in the United States.3,4 Clinicians have empirically substituted more readily available sulfonamides and enjoyed apparent clinical success.5 Currently there is one simple sulfa and three potentiated sulfas that are commonly used in the United States: sulfadimethoxine (Albon), sulfadimethoxine with ormetoprim (Primor), sulfadiazine with trimethoprim (Di-Trim, Tribrissen), and sulfamethoxazole with trimethoprim (Bactrim, Septra).




Sulfonamide Chemistry and Mechanism of Action


The sulfonamides are discussed in more depth in Chapter 7. Each is a structural analog of para-aminobenzoic acid that competitively inhibits the dihydropterate synthetase step in the synthesis of folic acid, which is required for synthesis of RNA and DNA. Inhibition by sulfas impairs protein synthesis, metabolism, and growth of the pathogen. A vast array of sulfa agents have been created and described; all but a few have been lost in the sands of time. The important differences among these agents involve their solubility, duration of action, and activity against key pathogens. Fortunately, the three sulfas included in this discussion demonstrate acceptable performance in all three categories; solubility is adequate, they are given once or twice daily, and they have a reasonably broad spectrum of action. The sulfa drugs are primarily effective against the schizont stages of coccidian; thus prolonged treatment may be required for the drug to effectively block the life cycle.









Sulfadiazine or Sulfamethoxazole with Trimethoprim


Sulfadiazine with trimethoprim is the potentiated sulfa with the most years of actual use in veterinary medicine. For many years it was the only potentiated sulfa approved for use in animals. Trimethoprim is a diaminopyrimidine potentiator with very low mammalian toxicity. The available tablets contain 25/5, 100/20, 400/80, or 800/160 mg sulfadiazine/mg trimethoprim, respectively (Tribrissen, Di-Trim). The tablets are designated by the total weight of active ingredient in each tablet; thus Tribrissen 30 contains 25 mg sulfadiazine and 5 mg trimethoprim. The approved dose is 30 mg/kg orally or 26.4 mg/kg by subcutaneous injection daily for up to 14 days. The preferred dose for bacterial infections in dogs and cats is 30 mg/kg once or twice daily and may be indicated for severe coccidial infections. The manufacturer recommends that animals with marked hepatic parenchymal damage, blood dyscrasias, or previous sulfonamide sensitivity should not be given this product.8,10


Sulfamethoxazole with trimethoprim is a readily available product approved for use in people (Bactrim, Septra); it is not currently approved for use in animals. Because of its similarity to veterinary potentiated sulfonamides and because low-cost generics are available, it is widely used in veterinary medicine. There is some controversy regarding the appropriate dosing regimen for this human-labeled product in animals, but many clinicians gain acceptable clinical results using the same dose as sulfadiazine.


Sulfamethoxazole with trimethoprim is available in a fixed combination of 5:1 sulfamethoxazole to trimethoprim as tablets and pediatric suspension. The available single-strength tablets contain 400/80 mg and double-strength tablets contain 800/160 mg trimethoprim, respectively (Bactrim, Septra). The pediatric oral suspension contains 40 mg sulfamethoxazole and 8 mg trimethoprim per milliliter. The dose for bacterial infections and coccidiosis in dogs and cats is 30 mg/kg once daily for 10 days10 and may be indicated in severe coccidial infections.



Amprolium


Amprolium (Amprol, Corid) is an antiprotozoal drug that is a structural analog of thiamine. It is freely soluble in water, methanol, and ethanol. The close structural similarity between amprolium and thiamine allows amprolium to compete with thiamine for absorption into the parasite. It is most effective against the first-generation schizont stage and thus is more effective for prevention than treatment.


At very high doses, amprolium may produce thiamine deficiency in the host. Thiamine deficiency can be treated by adding thiamine to the diet, although excessive thiamine supplementation may decrease the efficacy against the pathogen. In dogs adverse reactions are apparently rare and may consist of neurologic abnormalities, depression, anorexia, and diarrhea.10


Amprolium is approved for use in the drinking water or feed of poultry and cattle for the prevention and treatment of coccidia. Treatment for dogs and cats requires adapting the approved formulations to small animal use. The target dose for treatment of dogs is 100 to 200 mg/kg by mouth daily in food or water.10 Dogs may be treated by mixing 30 mL (2 Tbs) of 9.6% amprolium solution to 1 U.S. gallon (3.8 L) of drinking water and offering it as the sole source of drinking water.11 Alternatively, 1.25 g of 20% amprolium powder can be mixed with daily ration sufficient for four puppies.12 Amprolium should be provided in either the food or the water but not in both for a period of 7 days. It may be given as a treatment for coccidia or as a preventive measure for 7 days before puppies are shipped or to bitches just before whelping.


Cats may be treated at a dose of 60 to 100 mg/kg by mouth once daily for 7 days, which may be accomplished by direct oral administration.13 Placement of medication in food or water may be more unreliable for cats than for dogs owing to the finicky eating habits of many cats.



Furazolidone


Although the nitrofurans (nitrofurazone and furazolidone) have been reported in the literature as being effective in the treatment of coccidiosis and were once widely available for oral treatment of food animals, they have been systematically eliminated from the veterinary marketplace in the United States because of concerns regarding carcinogenicity. Furazolidone apparently inhibits numerous microbial enzyme systems, especially those related to carbohydrate metabolism, but the actual mechanism of action remains to be determined.14 Furazolidone is still available in a dosage form that is approved for human use (Furoxone). Potential toxicity includes gastrointestinal disturbance, peripheral neuritis, decreased spermatogenesis, and weight gain.15 Dogs and cats can be treated with 8 to 20 mg/kg orally, 1 to 2 times daily, for 5 days.10,13 The product is available in 2 formulations approved for use in people (Furoxone): 100-mg tablets and an oral liquid containing 3.34 mg/mL.




Toxoplasmosis




Enteroepithelial Life Cycle


The enteroepithelial life cycle of T. gondii in cats is similar to the life cycle of the common enteric coccidia (Figure 12-2). Toxoplasma oocysts are ingested from the environment; alternatively, tissue cysts may be ingested by carnivorism. Once ingested, bradyzooites are released that penetrate the epithelial cells and begin a cycle of asexual reproduction. The sexual stage of the cycle proceeds when the zooites differentiate into microgametes and macrogametes. The macrogametes are fertilized by the microgamete, and the resulting union produces an oocyst that is shed in the feces to begin the cycle again. It is believed that the enteroepithelial life cycle and the resulting oocysts occur only in cats; therefore only cats shed infective oocysts.









Clindamycin


Clindamycin is currently considered the drug of choice for treating toxoplasmosis. Structurally, clindamycin is a congener of lincomycin. Clindamycin is well absorbed (90%) after oral administration and is widely distributed in most tissues, except the central nervous system. It readily crosses the placenta and is extensively bound to plasma proteins. The drug is metabolized in the liver and excreted primarily in the urine and bile.18 Gastrointestinal upset is sometimes reported in animals receiving clindamycin. Severe, even fatal, pseudomembranous enterocolitis has been reported in people, caused by overgrowth of Clostridium difficile.



Treatment of systemic Toxoplasma infection in dogs can be accomplished with oral or intramuscular clindamycin at 10 to 20 mg/kg twice daily for 2 weeks.17,19 Cats can be treated for systemic infections with oral or parenteral clindamycin at 10 to 12.5 mg/kg twice daily for 2 to 4 weeks; this antimicrobial is also useful to control shedding of oocysts.20 The drug should be given with caution to cats with pulmonic toxoplasmosis; parenteral administration to experimentally infected cats resulted in several deaths.10


Clindamycin is available in two veterinary formulations (Antirobe): capsules containing 25, 75, or 150 mg and an oral solution containing 25 mg/mL. Similar clindamycin formulations are available for use in humans (Cleocin): 75- and 150-mg oral capsules, an oral pediatric suspension (15 mg/mL), and an injectable solution containing 150 mg/mL.



Sulfa Plus Pyrimethamine


The more time-tested therapeutic regimen for toxoplasmosis is a combination of sulfonamide and pyrimethamine. The sulfonamides were discussed previously. Pyrimethamine is structurally and pharmacologically similar to the folic acid antagonist trimethoprim. Pyrimethamine is primarily used in veterinary medicine to treat toxoplasmosis and equine protozoal myelitis, or “equine toxoplasmosis.” Little pharmacokinetic data are available for pyrimethamine use in dogs and cats, but in humans it is well absorbed after oral administration. It is well distributed to the kidneys, liver, spleen, and lungs. The metabolic pathway is unclear, but pyrimethamine metabolites may be found in the urine.


Pyrimethamine can cause anorexia, malaise, vomiting, depression, and myelosuppression. Concomitant oral administration of folinic acid or brewer’s yeast may help alleviate some of these clinical signs. Because toxicity may develop rapidly in cats, they should have frequent hematologic monitoring. It is a teratogen in rats but is sometimes used by pregnant women.10


Dogs and cats are treated for systemic Toxoplasma infections at a dose of 30 mg/kg sulfa and 0.25 to 0.5 mg/kg pyrimethamine orally twice daily for 2 weeks. Cats may be treated to control shedding of oocysts at a dose of 100 mg/kg sulfa and 2 mg/kg pyrimethamine orally once daily for 1 to 2 weeks.17


Pyrimethamine alone is available in 25-mg tablets (Daraprim) and in combination tablets containing 25 mg pyrimethamine and 500 mg sulfadoxine (Fansidar). These dosage forms are likely to be difficult for most cat owners to administer.

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Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Drugs for the Treatment of Protozoal Infections

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