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.

Figure 12-1 Life cycle of Isospora felis, which is typical of the Isospora spp. The mode of transmission may be direct, via ingestion of sporulated oocysts from the environment, or indirect, via ingestion of cysts in prey animals. Sexual and asexual reproduction of the parasite occurs in the intestines of the definitive host (in this case, a cat), and unsporulated oocysts are shed in the feces of definitive hosts.

(From Dubey JP, Greene CE: Enteric coccidiosis. In Greene CE, editor: Infectious diseases of the dog and cat, ed 2, Philadelphia, 1998, Saunders, p. 511.)

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

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.

Quinacrine

Quinacrine has demonstrated useful activity in the treatment of coccidiosis. Efficacy is variable, as is the relationship between plasma and tissue concentrations. Commercial production in the United States. (Atabrine) was discontinued in 1993.

Biology

Toxoplasmosis is caused by Toxoplasma gondii, an obligate intracellular coccidian parasite. The parasite and the disease occur worldwide and have serious zoonotic impact. The domestic cat and other cats serve as the definitive hosts of this parasite. All other warm-blooded animals serve as intermediate hosts. In the United States, infection rates range from 0% to 100% in cats, 30% in dogs, and 30% to 60% in people. Although infection and seroconversion are common, clinical disease and diagnosis are rare.¹⁶

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.

Figure 12-2 Life cycle of Toxoplasma gondii.

(From Dubey JP, Lappin MR: Toxoplasmosis and neosporosis. In Greene CE, editor: Infectious diseases of the dog and cat, ed 2, Philadelphia, 1998, Saunders, p. 494.)

Extraintestinal Life Cycle

The extraintestinal life cycle occurs in all warm-blooded animals, including cats. This cycle begins when oocysts or infected tissues are ingested. The bradyzoites or sporozoites penetrate intestinal cells and undergo asexual reproduction and then break out of the gastrointestinal tract to infect virtually all other tissues, including the brain, striated muscle, and liver. After entering these extraintestinal tissues, they penetrate the cell and multiply until the cell is destroyed. The tachyzoites are released to infect other cells, and the cycle repeats. Eventually, the tachyzoites form tissue cysts that remain viable and infective for the life of the animal. These tissue cysts are infective to all warm-blooded animals and infect all animals who ingest the infected tissues. It is the ubiquitous tissue migration and replication across innumerable species that makes the pathogen so insidious and dangerous.

Congenital Transmission

If the host is infected during pregnancy, then the tachyzoites move across the placenta to infect the developing fetus. Infection during the first half of the pregnancy leads to more severe disease in the fetus. Women infected during pregnancy risk congenital malformation, mental retardation, and death of the unborn fetus. Women should be cautioned to avoid exposure to cat feces and to refrain from consuming undercooked meat during pregnancy.

Clinical Signs

Clinical signs in cats are most severe in prenatally infected kittens. Such kittens may be stillborn or die before weaning. Clinical signs relate to pathology in the liver, lungs, and central nervous system. Adult cats typically demonstrate anorexia, lethargy, dyspnea, weight loss, icterus, vomiting, diarrhea, stiff gait, shifting leg lameness, or neurologic deficits. Ocular lesions may include uveitis in the anterior and posterior chambers, iritis, iridocyclitis, and detached retina. In severe cases respiratory or central nervous system involvement may cause death.¹⁷

Infected dogs may show clinical signs related to respiratory, neuromuscular, or gastrointestinal pathology. Generalized toxoplasmosis is characterized by fever, tonsillitis, dyspnea, diarrhea, and vomiting.¹⁷ More devastating clinical signs may be seen in dogs with neurologic or muscular involvement. Seizures, neurologic deficits, tremors, ataxia, paresis, or paralysis may be seen in these animals. Ocular lesions in dogs are infrequently reported.¹⁷

Diagnosis

Antemortem diagnosis of toxoplasmosis is a significant diagnostic challenge primarily because of the usual lack of clinical signs in infected animals. Fecal floatation for infected cats may reveal small oocysts that are indistinguishable from other coccidia. It is also important to realize that infected cats shed oocysts for only 1 to 2 weeks after their first exposure, thereafter forming a protective immunity that prevents further shedding of oocysts. Many other tools have been applied to the diagnosis of toxoplasmosis, including clinical chemistry, which may reveal elevated liver enzymes; cytology, which may detect tachyzoites; radiology, which could suggest inflammation of target organs; serology, which would reveal a past infection; and parasite isolation. Unfortunately, no simple, specific, and timely diagnostic tool is available to detect an active case of toxoplasmosis.

Treatment

Treatment of toxoplasmosis may have several goals: to prevent shedding of oocysts from infected cats, to prevent transmission of toxoplasmosis by ingestion of infected tissues, to prevent tachyzoite replication in nonfeline host tissues, and to prevent prenatal infections. In some cases the goal may be to alleviate clinical signs of an active infection.

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.