Chemotherapy of Rickettsial, Protozoal, and Chlamydial Diseases

0195-5616/88 $0.00

Clinical Pharmacology

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Chemotherapy of Rickettsial, Protozoal, and Chlamydial Diseases

Susan L. Longhofer, DVM*

Rickettsial and protozoal diseases are endemic in many areas of the United States. In nonendemic regions, these diseases are seen infrequently; however, the mobile nature of today's society has increased a veterinarian's chances of encountering animals with rickettsial or protozoal diseases. The purpose of this article is to discuss the therapeutic alternatives for these conditions (Tables 1 and 2). Not all of the drugs discussed are available to practitioners in the United States. It is hoped that drugs such as imidocarb dipropionate will become available as their therapeutic value in pet animal practice is recognized. Some antimicrobials mentioned in this section are discussed in greater detail in other articles in this issue. Many of these drugs do not have FDA approval for treatment of the particular diseases mentioned in this section. Currently recommended dosages and treatment protocols are found in Table 3. RICKETTSIAL DISEASES Rickettsial diseases are encountered in many geographic areas of the United States. The majority of the rickettsial organisms are sensitive to the tetracycline antibiotics; however, other chemotherapeutics may be utilized in resistant cases. Because results of serologic tests are usually not immediately available, response to tetracycline may be valuable as a diagnostic aid. Drugs With Efficacy Against Rickettsial Diseases

Tetracyclines. Tetracycline antibiotics disrupt bacterial protein synthesis. Newer generations of synthetic tetracyclines have increased the efficacy and diversity of this family of antibiotics. Tetracyclines used in veterinary *Resident, Small Animal Internal Medicine, Department of Medical Sciences, University of Wisconsin School of Veterinary Medicine, Madison, Wisconsin Veterinary Clinics of North Am£rica: SfiWll AnifiWl Practice-Vol. 18, No. 6, November 1988

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Table 1. Therapy of Choice for Specific Canine Diseases FIRST CHOICE

Ehrlichia spp Rickettsia rickettsia Neo rickettsia helminthoeca Coxiella burnetti Hemobartonella canis Chlamydiosis Giardia spp

Pentatrichomonas hominis Entamoeba spp Balantidium coli Acanthamoeba spp

lmidocarb dipropionate Tetracyclines Tetracyclines No information Tetracyclines Tetracyclines Metronidazole Metronidazole Metronidazole Metronidazole No information

SECOND CHOICE

Doxycycline Chloramphenicol Chloramphenicol Thiacetarsamide Quinacrine Tetracyclines

Coccidia

Toxoplasma spp Cystoisopora spp Hammondia spp Sarcocystis spp Cryptosporidium muris Leishmania donovani L tropica Babesia canis B gibsoni Encephalitozoon cuniculi Hepatozoon spp Trypanosoma cruzi Pneumocystis carinii

Clindamycin Sulfadimethoxine No information No information No effective treatment Sodium stibogluconate Ketoconazole lmidocarb dipropionate Diminazene aceturate No effective treatment No effective treatment Nifurtimox T rimethoprim/S ulfadiazine

Pyrimethamine/Sulfadiazine Trimethoprim/Sulfadiazine

Pentamidine Diminazene aceturate lmidocarb dipropionate Primaquine phosphate Pentamidine

medicine include chlortetracycline, oxytetracycline, tetracycline, and doxycycline. The tetracycline group has demonstrated efficacy against rickettsiae, chlamydiae, gram-negative and gram-positive bacteria, mycobacteria, and atypical mycobacteria. 6 Absorption of tetracyclines after oral administration is variable. Doxycycline is highly absorbed from the upper gastrointestinal tract, and reaches peak serum levels in 2 to 3 hours. 19 Other tetracyclines are less lipid soluble and therefore not as readily absorbed. Impaired absorption of tetracyclines can occur if administered with meals. Additionally, antacids, iron preparations, milk, and milk products decrease absorption of tetracyclines by chelation of the antibiotic within the gastrointestinal tract. 6 The absorption of doxycycline, however, is not affected by concurrent ingestion of food. Elimination of tetracycline, oxytetracycline, and chlortetracycline is primarily via renal excretion. Doxycycline is excreted by the small intestines, and unlike other members of the tetracycline group, the dosage of doxycycline need not be adjusted in patients with renal failure. Biliary excretion plays a role in the elimination of all forms of tetracyclines; biliary levels may exceed the plasma concentrations by 30-fold. 2 Disruption of normal gastrointestinal flora with resultant diarrhea is a common side effect of tetracycline administration. Pseudomembranous colitis caused by Clostridium difficile overgrowth has been reported in humans, 6 but has not been documented in animals. All members of the tetracycline group have an irritant effect on the gastrointestinal mucosa, which may result in nausea or emesis. Emesis can be minimized by dividing

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Table 2. Therapy of Choice for Specific Feline Diseases FIRST CHOICE

Coxiella burnetti Hemobartonella felis Chlamydiosis/Pneumonitis Giardia spp Pentatrichomonas hominis Entamoeba spp Coccidia Toxoplasma spp Cystoisopora spp Besnoitia spp Hammondia spp Sarcocystis spp Cryptosporidium muris Babesia felis Encephalitozoon cuniculi Hepatozoon felis Cytauxzoon felis Trypanosoma spp

No information Tetracyclines Tetracyclines Metronidazole Metronidazole Metronidazole Clindamycin Sulfadimethoxine No information No information No information No effective treatment Primaquine phosphate No effective treatment Primaquine phosphate/ Oxytetracycline No effective treatment No information

SECOND CHOICE

Chloramphenicol Chloramphenicol Furazolidone

Pyrimethamine/Sulfadiazine Trimethoprim/Sulfadiazine

Diminazene aceturate

Tetracyclines

the daily dose and adminiStering smaller amounts of the drug more frequently. Parenteral forms of oxytetracycline and doxycycline are available for animals that cannot be medicated orally; however, pain at the injection site is a major side effect of intramuscular administration, and phlebitis is a potential complication of intravenous injection. Additional side effects of tetracycline administration include the possibility of photosensitization or staining of deciduous teeth of puppies and kittens when administered to pregnant bitches and queens. Tetracyclines may also stain the permanent teeth of animals when administered early in life. A small percentage of cats may develop a drug-related fever during tetracycline administration. Characteristic signs are pyrexia (40 to 4l C), malaise, anorexia, and occasionally diarrhea; symptoms usually resolve within 48 hours of discontinuing the drug. Chloramphenicol. Although not used extensively in human medicine, chloramphenicol is a broad-spectrum antibiotic with antimicrobial activity against rickettsiae, chlamydiae, mycoplasmas, and gram-negative and grampositive bacteria. 2 Chloramphenicol'S mechanism of action against rickettsiae is by suppression of replication. Acquired resistance to chloramphenicol by rickettsial organisms has not been demonstrated. The primary side effects observed with chloramphenicol administration are anorexia, depression, emesis, diarrhea, weight loss, and reversible bone marrow suppression. 2 Cats seerri especially sensitive to the adverse effects of chloramphenicol. 22 Additional information on chloramphenicol may be found in other articles in this issue. lmidocarb Dipropionate. lmidocarb dipropionate is a carbanilide with antiprotozoal activity which is also effective against Ehrlichia canis. 1• 13• 15 The mechanism of action against E. canis is unknown. lmidocarb is administered intramuscularly or subcutaneously, and major side effects include pain at the injection site, panting, transient salivation, muscle 0

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Table 3. Recommended Dosages and Protocols

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DURATION FREQUENCY DRUG

Antibiotics Chloramphenicol

CANINE DOSAGE

50 mg/kg

FELINE DOSAGE

Clindamycin

3--13 mg/kg

50 mg/kg 3-13 mg/kg

Doxycycline

100 mg/kg 2.5 mg/kg

2.5 mg/kg

(hours)

ROUTE

(days unless otherwise indicated)

PO IV SQ PO IV SQ PO

8 12 8

7-14 7-10 7-21

IM PO IV

24 24

7-14

PO PO PO PO PO SQ

24 12 12 12 12

10-21 5 5-7 14 7-14 28

10 mg/kg 4 mg/kg 4 mg/kg 60 mg/kg 15 mg/kg

60 mg/kg 15 mg/kg

Sulfadimethoxine

25 mg/kg

25 mg/kg

PO IV IM

24

7-14

Tetracyclines Tylosin

20 mg/kg

20 mg/kg 25 mg

PO IV IM

8 24

14-28 3

5-10 mg/kg

PO

12

7-14

IM IV

24

10-12

Furazolidone Nitrofurazone Sulfadiazine Sulfadiazine/ Trimethoprim

Antiprotozoals Antimonials: Sodium stibogluconate Meglumine antimoniate

50-100 mg/kg (based on antimony)

4 mg/kg

PROTOCOL AND INDICATIONS

E H RS HU T Smaller dogs and cats should receive the higher dosage T E H R S U Use 5 mg/kg as a loading dose and follow with 2.5 mg/kg in 12 hours before starting the once-aday dosing E (Chronic ehrlichiosis)

c c

CSTU

csu

P T Monitor for signs of folic deficiency C S Use 50 mg/kg loading dose E H RS U U On introduction into a colony

u

L Repeat as needed Each drug is approximately 30% antimony by weight

Diminazene aceturate

3 mg/kg

Imidocarb dipropionate

5 mg/kg

Metronidazole Nifurtimox (Bayer 2502) Pentamidine isethionate

25---65 mg/kg 8-30 mg/kg 4 mg/kg 15 mg/kg

Primaquine phosphate Quinacrine hydrochloride Miscellaneous Amprolium

6.6 mg/kg

IM IM IM SQ

24 once once

3

PO PO SQ IM SQ POIM PO PO

24 24 24 24 12 24

5 3-5 months 14 twice once 5 5

PO

24

1()....14

0.5-1 mg/kg

PO PO

8-12 24

50 14-28

l.l mg/kg

IV IV

24 48

9 twice

3.5 mg/kg 10-25 mg/kg

0.5 mg/kg 11 mg/kg

10()....200 mg

Ketoconazole Pyrimethamine

10--20 mg/kg 1 mg/kg

Thiacetarsamide sodium

2.2 mg/kg

BG BC BF BC BG E May repeat in 14 days G A p BC BF G G C Larger puppies receive the larger dose L cutaneous form Administer folinic acid at 1 mg/kg/day H H

Key: C = Coccidia: Cystoisopora spp., T = Toxoplasma spp., L = Leishmania spp., A = Trypanosoma spp., E =Ehrlichia canis; S = Neorickettsia helminthoeca; U = Feline pneumonitis, canine chlamydiosis; G = Giardia spp., Pentatrichomonas hominis, Entamoeba spp., Balantidium coli; BC Babesia canis; BG = Babesia gibsoni; BF = Babesia felis; P = Pneumocystis carinii; R = Rickettsia rickettsia; H = Hemobartonella spp.

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tremors, emesis, and diarrhea. The adverse effects usually occur within 15 to 30 minutes of injection and can be alleviated with atropine. Due to the short duration of symptoms, administration of atropine is rarely necessary. The drug is not currently available in the United States. Thiacetarsamide Sodium. Thiacetarsamide sodium is an organic arsenical used primarily as an adulticide for Dirofilaria immitis. It has also been utilized in the treatment of Hemobartonella spp., but it does not have a strong action against Hemobartonella spp. The mechanism of action against the Hemobartonella organisms is unknown. The drug must be administered intravenously as perivascular injections lead to tissue necrosis. Acute hepatic and renal failure have been reported following administration of thiacetarsamide sodium. Treatment of Specific Rickettsial Diseases

Ehrlichia canis. Current protocols for treatment of E. canis utilize 2 to 4 weeks of oxytetracycline or tetracycline. 4 · 7 A clinical response characterized by increased appetite and decreased pyrexia may be apparent within 24 to 48 hours of initiation of therapy. Long-term, low-dose administration of tetracyclines, in conjunction with tick control, has been used to eradicate ehrlichiosis from kennels of dogs. 4 Doxycycline is more lipid soluble and has better tissue penetration than oxytetracycline. Dogs treated with doxycycline have fewer E. canis relapses than dogs treated with oxytetracycline, and doxycycline is more effective in eliminating the organism from chronically infected dogs. 21 Intravenous administration of doxycycline may be used in dogs with severe gastrointestinal symptoms. lmidocarb dipropionate has been utilized for treating canine ehrlichiosis. 1• 13· 15 lmidocarb is more effective than tetracycline in eliminating the organism, especially in cases with chronic bone marrow suppression. 15 Should it become available in the United States, imidocarb may be more economical than doxycycline and more convenient than oral dosing of tetracyclines three times a day. Rickettsia rickettsia. Tetracyclines and chloramphenicol are both effective for treating canine Rocky Mountain spotted fever. 7 Tetracyclines are preferred, but chloramphenicol may be administered to young dogs in which the risk of dental staining by tetracyclines is high. Both agents have a suppressive effect on rickettsial reproduction; full recovery depends on a competent host immune system. 7 Clinical response to tetracyclines may be seen within 24 to 48 hours of administration. If gastrointestinal signs are severe, parenteral forms of chloramphenicol or tetracycline may be administered. Neorickettsia helminthoeca. The rickettsial organism responsible for salmon poisoning is sensitive to several antibiotics, although tetracyclines are considered to be the drug of choice. 7 Chloramphenicol, penicillins, and sulfonamides have also been used in the treatment of salmon poisoning. Intravenous administration of these agents may be necessary due to the severe gastrointestinal signs inherent to the disease. Coxiella burnetti. Human infections with Q fever are treated with tetracyclines or chloramphenicol. Little information is available on the

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treatment of dogs and cats because Coxiella is usually an asymptomatic infection in these species. Hemobartonella spp. Tetracyclines, chloramphenicol, and thiacetarsamide sodium may be utilized to treat canine and feline hemobartonellosis. 7 · 9 While tetracyclines and chloramphenicol both have a suppressive action on reproduction of the Hemobartonella organisms, tetracyclines are the drug of choice for treating hemobartonellosis. A competent host immune system is required to eradicate the organism. Most cats treated for hemobartonellosis remain chronic carriers, and little information is available on carrier status in H. canis infections. No controlled studies have compared the efficacy of thiacetarsamide sodium to chloramphenicol or tetracyclines, but thiacetarsamide sodium may be associated with increased morbidity. Spiramycin has been used with chloramphenicol and metronidazole to treat H. felis infections with respiratory or neurologic signs. CHLAMYDIAL DISEASES Therapeutics for chlamydial diseases include tetracyclines and chloramphenicol, which have been discussed above. Alternative medications include sulfonamides and tylosin. Drugs with Efficacy Against Chlamydia} Diseases

Sulfonamides and Potentiated Sulfonamides. Sulfonamides and potentiated sulfonamides are discussed in greater detail in other articles in this issue. Frequently noted side effects of sulfonamide administration include nausea and emesis; anorexia is occasionally observed in cats receiving these medications. Less commonly observed adverse effects attributed to sulfonamide administration include thrombocytopenia, hemolytic anemia, keratoconjunctivitis sicca, polyarthritis, and allergic skin eruptions. 6 Tylosin. Tylosin is a macrolide-like antibiotic that inhibits replication of coccidia, chlamydiae, mycoplasmas, and some bacteria. Although tylosin is moderately well absorbed from the gastrointestinal tract, the powder is not very palatable and must be thoroughly mixed with food. Tylosin may also be administered by intramuscular injection. Pain and irritation at the site of injection are, however, common side effects of parenteral administration. Treatment of Specific Chlamydia} Diseases The clinical signs associated with feline chlamydiosis or pneumonitis are similar to those observed with viral upper respiratory pathogens. Differentiating the diseases is difficult, but response to antibiotics can help identifY chlamydia as the offending organism. Chemosis is a major symptom of feline chlamydiosis, and tetracycline ophthalmic ointments may be beneficial. In order to prevent ocular recurrences, the ointments should be applied for at least 2 weeks after clinical signs abate. If severe clinical signs necessitate the use of systemic antibiotics, tetracyclines are the drug of choice. To avoid staining of teeth in young kittens, chloramphenicol, sulfonamides, or tylosin may be used as alternative antibiotics. 7 In a cattery

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outbreak, long-term administration of low-dose tetracyclines may decrease recurrences. 7 Canine chlamydiosis is uncommon and is associated with exposure to psittacine birds with chlamydiosis. Respiratory symptoms are the most common clinical signs associated with canine chlamydia! infections. Like feline chlamydiosis, canine chlamydiosis is responsive to systemic tetracyclines. 5 PROTOZOAL DISEASES Few protozoal organisms have a wide distribution, but now that pets move all over the world with their owners, protozoal diseases previously diagnosed in only one area may be seen in any locale. Unless the presence of a protozoal organism is considered in the differential diagnosis list and appropriate diagnostic tests are performed, protozoal diseases can be easily overlooked. The armamentarium of drugs available for the treatment of protozoal diseases is extensive, and keeping a pharmacy stocked with all possible antiprotozoals is unrealistic. Drugs with Efficacy Against Enteric Protozoals

Metronidazole. Metronidazole is a nitroimidazole with activity against protozoa and anaerobic bacteria. 12 Metronidazole appears to work by reduction of its nitro group within the bacterial and protozoal cells, causing intracellular necrosis and disruption of DNA synthesis. The drug is well absorbed orally and reaches high concentrations in all tissues. 17 The penetrability of metronidazole allows it to be effective against both luminal and extraluminal amebiasis. Metronidazole is excreted primarily in the urine, and may discolor the urine dark red or reddish brown. Potential side effects of metronidazole include glossitis, stomatitis, nausea, and emesis; at higher doses neurologic signs may occur. 6 Because metronidazole is metabolized primarily in the liver, the dose should be decreased in animals with liver failure. Metronidazole has been shown to be carcinogenic and mutagenic in laboratory rodents, and although it has not been shown to be teratogenic, it should be administered cautiously during the first 3 weeks of pregnancy. Quinacrine Hydrochloride. Quinacrine hydrochloride is an acridine derivative originally used as an antimalarial agent. The mechanism of action against protozoal organisms is via inhibition of protein synthesis. Quinacrine is one of the alternate drugs for treatment of giardiasis in humans and animals. It is well absorbed after oral administration and slowly released from tissue stores. The drug may cause the skin and sclera to develop a yellowish discoloration. 6 Other side effects include anorexia, nausea, diarrhea, pruritus, skin rashes, and behavioral changes. Quinacrine should be avoided in pregnant animals. Furazolidone and Nitrofurazone. Furazolidone is a nitrofuran derivative that is efficacious against some protozoal organisms. 6 It is used for the treatment of Giardia in humans and is available in a liquid form which is convenient for dosing puppies and cats. Furazolidone is poorly absorbed

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by the gastrointestinal tract; however, some of the absorbed drug is excreted in the urine and may produce a brown discoloration of the urine. Additional side effects include hypotension, urticaria, emesis, diarrhea, fever, and arthralgias. Nitrofurazone is another nitrofuran derivative normally used topically for wounds and burns; however, it is coccidiostatic if administered orally. 2 Amprolium. Amprolium is a coccidiostat that acts by thiamine inhibition; however, symptoms of thiamine deficiency are rarely seen when administered at recommended dosages. The symptoms of thiamine deficiency include anorexia, emesis, diarrhea, depression, and neurologic signs; parenteral thiamine administration will rapidly reverse the symptoms. Amprolium is usually administered in the water source, though the powdered form may be added to food. Pyrimethamine. Pyrimethamine is a folic acid antagonist similar to trimethoprim. Bacterial and protozoal organisms do not have a folate transport mechanism and must utilize para-aminobenzoic acid for synthesis of folic acid. Pyrimethamine is used primarily as an adjunct to sulfonamides in treating toxoplasmosis. The use of pyrimethamine significantly reduces the dose of sulfonamides administered concomitantly. Pyrimethamine is well absorbed orally, but is not very palatable. Side effects of pyrimethamine administration are usually related to folic acid inhibition and may include anorexia, depression, and bone marrow suppression leading to anemia, leukopenia, or thrombocytopenia. Nausea and emesis may be seen. Although parenteral folinic acid administration is the preferred method of alleviating the toxicity created by folic acid antagonism, administration of oral folic acid may be attempted. Folic acid antagonists may be teratogenic and should not be administered to pregnant animals unless folinic acid is also administered. Clindamycin. Clindamycin (Antirobe, Upjohn, Kalamazoo, MI) is a lincosamide antibiotic that is bacteriostatic due to protein synthesis inhibition. The drug is effective against Toxoplasma gondii. 8 A combination of clindamycin and quinine is the treatment of choice for Babesia microti infections in humans. Clindamycin is well absorbed from the gastrointestinal tract and food does not interfere with its absorption. Emesis and nausea are occasionally reported side effects of oral administration. Clindamycin does .not penetrate the blood-brain barrier, even when meningeal inflammation is present. Enteric overgrowth with Clostridium difficile can lead to pseudomembranous colitis in humans administered clindamycin; this has not been observed in dogs. Clindamycin has a neuromuscular blocking action and should not be used with other neuromuscular blocking agents. Treatment of Specific Enteric Protozoal Diseases

Giardia spp. Metronidazole, quinacrine, and furazolidone are used for canine and feline giardiasis. Metronidazole is associated with both high efficacy and minimal side effects and is considered the drug of choice for dogs and cats. Quinacrine has greater efficacy in clearing Giardia organisms; however, administration of quinacrine is also associated with more side effects and should be reserved for resistant cases of giardiasis. 24 Because of the difficulty in demonstrating the Giardia trophozoites or oocysts, a

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therapeutic trial of metronidazole may be indicated in cases of persistent diarrhea, especially in endemic areas of the country. Trichomoniasis, Amebiasis, and Balantidiasis. Since the advent of metronidazole, a great reliance has been placed on this drug for treatment of human enteric protozoal infections. It is beyond the scope of this article to discuss all the antiprotozoals that have been historically utilized to treat enteric protozoa. Metronidazole should be used as a first line therapeutic for all ent.eric protozoa. Furazolidone or quinacrine may be used if metronidazole fails, and attempts should be made to identify and eliminate sources of reinfection. Coccidial Infections. Clinical signs related to Cystoisopora (Isopora), Besnoitia, Hamrruindia, and Sarcocystis spp. are unusual except in neonates or immunosuppressed animals. 7 Therapy for clinically affected animals includes sulfadiazine, sulfadimethoxine, nitrofurazone, or sulfadiazine/trimethoprim. Supportive care is probably more important than the coccidiostatic drugs. Whether or not to treat asymptomatic animals with evidence of coccidial infections is a controversial ·subject, and since there is no evidence that coccidiostatic drugs eliminate infection in asymptomatic carrier animals, therapy of these animals is not indicated. ·Prophylactic therapy in kennels with persistent coccidial infections include using amprolium in the bitches' drinking water prior to whelping and treatment of puppies prior to shipping with amprolium in their drinking water. Cryptosporidium muris is an enteric protozoal organism that is pathogenic in calves and immunosuppressed humans. Immunosuppressed dogs and cats may develop clinical signs referrable to the organisms. 7 No effective therapy exists for treating bovine cryptosporidiosis, although spiramycin or clindamycin and quinine are used in human infections. No published information is available on treating canine and feline infections. Toxoplasma gondii is a coccidia that may produce significant disease during its tissue phase in nondefinitive hosts. In utero, neonatal, and immunosuppressed animals are most at risk for development of clinical toxoplasmosis. Clindamycin is the current drug of choice in treating toxoplasmosis, especially in pregnant animals since it avoids the teratogenic effects of sulfonamides. 7· 8 Clindamycin has poor penetration into the central nervous system (CNS) and should not be used as the sole therapeutic agent in CNS toxoplasmosis. Clindamycin may be administered orally to cats to decrease, but not eliminate, the shedding of oocysts in feces. 7 The more traditional treatment for toxoplasmosis includes the use of a sulfonamide and a folic acid antagonist. Combination therapy with pyrimethamine and sulfadiazine is most commonly used, but trimethoprim and sulfadiazine may also be effective. 9 Folic acid supplementation or parenteral folinic acid should be used to prevent bone marrow suppression if the therapy with pyrimethamine exceeds 2 weeks. Alternatively, tetracyclines and chloramphenicol may have limited action against Toxoplasma organisms.7 Drugs with Efficacy Against Nonenteric Protozoa Antimonials. Sodium stibogluconate and meglumine antimoniate are pentavalent antimonial compounds used for therapy of Leishmania infec-

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tions. Because antimonials are poorly absorbed orally and cause extreme gastrointestinal irritation, they are administered parenterally. The mechanism of action of antimonials is unknown. Side effects of antimonial administration include gastrointestinal disturbances, hepatic failure, skin rashes, and electrocardiographic changes. 6 • 23 Excretion of antimonials is via the kidneys, and the drug should not be used in animals with renal failure. Sodium stibogluconate is available in the United States only through the Centers for Disease Control in Atlanta, Georgia. Aromatic Diamidines and Carbanilides. Diminazene aceturate is an aromatic diamidine which interferes with protozoal DNA synthesis. 2 The drug is effective against Babesia canis and B. gibsoni. Diminazene must be administered parenterally, and pain at the injection site is a frequent side effect. Microhemorrhages in the CNS are a potential adverse effect; the hemorrhages are usually dose related, and the risk may be minimized by dividing the dose over a 72-hour period. 10 A hemorrhagic gastroenteritis has also been reported. Diminazene aceturate is not currently available in the United States. · Pentamidine isethionate is an aromatic diamidine that may be used for treating B. canis, Leishmania spp., and Pneumocystis carinii. 7• 23 More effective drugs are available for these conditions, and pentamidine is reserved for therapy in cases where side effects of the recommended drugs prevent their use. Its mechanism of action against protozoans is unknown, although interference of aerobic glycolysis may play a significant role. 6 Side effects include anaphylaxis, hypotension, pain during injection, diarrhea, and emesis; hypoglycemia and hyperglycemia have both been reported. Hemorrhage and malacia of the CNS may occur. 11 Imidocarb dipropionate is a carbanilide with a direct antiprotozoal action; it is used for treatment of B. canis. infections and is especially effective in those cases with concurrent ehrlichiosis. 1 Side effects of imidocarb administration, in addition to the expected pain during injection, may include a cholinesterase effect with ptyalism, lacrimation, tremors, emesis, and diarrhea. The adverse effects usually occur within 15 to 30 minutes of injection and can be alleviated with atropine if necessary. This drug is not currently available in the United States. Quinuronium Derivatives. Quinuronium sulfate is an older antiprotozoal drug that has minimal efficacy against B. canis. Side effects, characterized by anti-cholinesterase action and histamine release, have limited the use of this drug. 2 Quinuronium sulfate is not available in the United States. Other quinuronium derivatives currently in use include nifurtimox, diiodohydroxyquin and iodochlorhydroxyquin. The latter two drugs are used as amebicides, and for the most part, they have been replaced by metronidazole. Nifurtimox (Bayer 2502) is used in the treatment of South American trypanosomiasis caused by Trypanosoma cruzi. The drug is well absorbed orally and is rapidly biotransformed in the body. Nifurtimox will clear blood infections of T. cruzi, but will not destroy the tissue forms. 6 • 23 Side effects of nifurtimox include convulsions, which can be controlled by anticonvulsants, and gastrointestinal irritation, which can be minimized by concomitant administration of aluminum hydroxide preparations. 6 Weight loss, skin

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rashes, and anorexia have also been reported. 23 Nifurtimox is available in the United States only through the Centers for Disease Control. Miscellaneous. Fumagillin is an antibiotic that is used to control Nosema apis in honey bees. 18 It has been used in vitro to inhibit replication of Encephalitozoon cuniculi. The drug is effective against Entamoeba histolytica in rabbits and rats, and human trials have shown fumagillin to be effective in temporarily preventing fecal shedding of Giardia lamblia, Pentatrichomonas homis, and E. histolytica. In experimentally infected mice, fumagillin has a cidal effect against Toxoplasma gondii. The exact mechanism of action is unknown, but fumagillin is thought to disrupt nucleic acid synthesis and to alter the fatty acid metabolism of the organisms. 18 Spiramycin is a macrolide antibiotic available in the United States as an orphan drug for the treatment for human infections with Cryptosporidium muris. Used as an animal feed additive in Europe because of its coccidiostatic action, spiramycin may be used as an adjunctive therapy to sulfonamides and pyrimethamine in the treatment of Toxoplasma gondii infections. Spiramycin has been used as a treatment for Hemobartonella felis, and the drug is also effective against mycoplasmas. Primaquine phosphate is an 8-aminoquinoline antimalarial drug that disrupts mitochondrial function in protozoal organisms. 6 It is used in veterinary medicine for treating Babesia felis infections. 14 The drug is well absorbed orally, but may cause significant gastrointestinal irritation and vomiting, especially in anorexic cats. Parenteral administration is effective, but no parenteral form is commercially available. The oral form may be rehydrated with sterile saline for intramuscular injection. 14 Chloraquine phosphate is a 4-aminoquinoline antimalarial that has an in vitro activity against Encephalitozoon cuniculi. The drug is well absorbed orally. Side effects associated with chloraquine administration include gastrointestinal irritation and pruritus. Treatment of Nonenteric Protozoal Diseases

Leishmania spp. Leishmaniasis is difficult to treat, and there have been few sucesses in canine patients. Public health safety should be a consideration when deciding to treat infected dogs. Pentavalent antimonials (for example, sodium stibogluconate and meglumine antimoniate) offer the best therapeutic choice for visceral leishmaniasis and they are less toxic than other antiprotozoal drugs with activity against Leishmania spp. 7 Current protocols require long-term parenteral administration, and emphasis should be placed on supportive care and adequate nutrition. 7 Pentamidine may be used as a second choice drug if adverse side effects are encountered with the antimonials. Ketoconazole has been effective in the treatment of cutaneous leishmaniasis in human and canine patients. 16· 20 Babesia spp. Differences exist in the susceptibility of large and small Babesia organisms to therapy; the small organisms are generally more resistant. 2 B. felis and B. gibsoni are classified as small Babesia organisms, while B. canis is considered a large organism. The presence of multiple strains of B. canis leads to a variety of clinical signs associated with the organism. Some B. canis infections are fairly avirulent and may be clinically

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apparent only in debilitated puppies. B. canis is responsive to therapy with imidocarb dipropionate, diminazene aceturate, or pentamidine isethionate.1· 7 B. gibsoni is difficult to treat because it is resistant to most of the antiprotozoal drugs. Infections with B. gibsoni respond best to therapy with diminazene, although imidocarb may be used in dogs who have minimal clinical signs. 10 B. felis is treated with primaquine phosphate administered orally or parenterally, but recrudescence is common. 14 Diminazene is the second drug of choice for feline babesiosis. In all forms of babesiosis, complete elimination of the organisms is rarely achieved and a carrier state usually persists. Clindamycin and quinine are the drugs of choice in B. microti infections in humans, but no veterinary information has been published on the efficacy of the combination. MisceUaneous Protozoal Diseases. Little published information is available on successful therapy of canine trypanosomiasis. Nifurtimox has been reported to be effective in treating experimental and natural canine Trypanosoma cruzi infections. 7 The public health implications ofT cruzi must be considered before deciding to treat an infected dog. Canine infections with Pneumocystis carinii are rare and have been reported primarily in young Dachshunds. A trimethoprim-sulfonamide combination is most effective in treating human and canine P. carinii infections. 6· 7 Intravenously administered potentiated sulfonamides are used to treat human patients to insure adequate tissue levels, but oral forms of the drug have been effective. Pentamidine is the second drug of choice, but is associated with more adverse side effects. No consistently effective treatment exists for Hepatozoon canis infection, though one case reportedly responded to a trimethoprim-sulfonamide combination. 3 Variable results were achieved using imidocarb dipropionate in clinical and experimental infections. 13 Primaquine phosphate is currently under investigation because of its in vitro activity against the organism and may offer the best therapeutic option. 7 A case of hepatozoonosis in a cat was treated sucessfully with oxytetracycline and primaquine phosphate. 7 No effective therapy exists for treating Cytauxzoon felis or Encephalitozoon cuniculi infections. Tetracyclines may prolong the clinical course in Cytauxzoon felis infections, but they do not change the eventual outcome. 7 Chloraquine phosphate and fumagillin both have in vitro activity against the Encephalitozoon cuniculi organisms, but no in vivo trials have been completed. 11 • 18

REFERENCES 1. Adeyanju BJ, Aliu YO: Chemotherapy of canine ehrlichiosis and babesiosis with imidocarb dipropionate. JAm Anim Hasp Assoc 18:827, 1982 2. Booth NH, McDonald LE: Veterinary Pharmacology and Therapeutics, ed 5. Ames, Iowa State University Press, 1982 3. Craig TM, Smallwood JE, Knauer KW, et al: Hepatozoon canis infection in dogs: Clinical, radiographic and hematologic findings. JAm Vet Med Assoc 173:967, 1978 4. Davidson DE, Dill GS, Tingpalapong M, et al: Prophylactic and therapeutic use of tetracycline during an epizootic of ehrlichiosis among military dogs. J Am Vet Med Assoc 172:697, 1978

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5. Fraser G, Norval J, Withers AR, et al: A case history of psittacosis in the dog. Vet Rec 85:54, 1969 6. Gilman AG, Goodman LS, Rall TW, et al: The Pharmacologic Basis of Therapeutics, ed 7. New York, Macmillan, 1985 7. Green CE: Clinical Microbiology and Infectious Diseases of the Dog and Cat. Philadelphia, WB Saunders, 1984 8. Green CE, Cook JR, Mahaffey EA: Clindamycin for treatment of Toxoplasma polymyositis in a dog. J Am Vet Med Assoc 187:631, 1985 9. Holzworth J: Diseases of the Cat, Medicine and Surgery. Philadelphia, WB Saunders, 1987 10. Longhofer SL: Unpublished data, 1986 11. Morgan RV: Handbook of Small Animal Practice. New York, Churchill Livingstone, 1988 12. Neff-Davis CA, Davis LE, Gillette EL: Metronidazole: A method for its determination in biological fluids and its disposition kinetics in the dog. J Vet Pharmacol Ther 4:121, 1981 13. Ogunkoya AB, Adeyanju JB, Aliu YO: Experiences with the use of Imizol in treating canine blood parasites in Nigeria. J Small Anim Pract 22:775, 1981 14. Potgieter FT: Chemotherapy of Babesia felis infection: Efficacy of certain drugs. J S Afr Vet Assoc 52:289, 1981 15. Price JE, Dolan TI: A comparison of the efficacy of imidocarb dipropionate and tetracycline hydrochloride in the treatment of canine ehrlichiosis. Vet Rec 107:275, 1980 16. Reinke SI: Canine leishmaniasis. Proceedings of the American College of Veterinary Dermatology, New Orleans, 1986 17. Rosenblatt JE, Edson RS: Metronidazole. Mayo Clin Proc 62:1013, 1987 18. Shadduck JA: Effect of fumagillin on in vitro multiplication of Encephalitozoon cuniculi. J Protozool 27:202, 1980 19. Shaw DH, Rubin SI: Pharmacologic activity of doxycycline. JAm Vet Med Assoc 189:808, 1986 20. Urcuyo FG, Zaias N: Oral ketoconazole in the treatment of leishmaniasis. Int J Dermatol 23:414, 1982 21. Van Heerden J, Immelman A: The use of doxycycline in the treatment of canine ehrlichiosis. J S Afr Vet Assoc 50:241, 1979 22. Watson ADJ, Middleton DJ: Chloramphenicol toxicosis in cats. Am J Vet Res 39:1199, 1978 23. Wolfe MS: Antiparasitic agents. In Mandell GL, Douglas RG, Bennett JE (eds): Principals and Practice of Infectious Diseases. New York, John Wiley & Sons, 1979 24. Zimmer JF, Burrington DB: Comparison of four protocols for the treatment of canine giardiasis. J Am Anim Hosp Assoc 22:168, 1986 Department of Medical Sciences School of Veterinary Medicine University of Wisconsin 2015 Linden Drive West Madison, WI 53706