Canine and Feline Infectious Diseases || Antiprotozoal Drugs

97 Antiprotozoal Drugs Used Primarily for Gastrointestinal Infections Amprolium Amprolium is a thiamine analogue that is used to prevent and treat intestinal coccidiosis (Table 10-1). It is available as a feed additive for livestock and is sometimes administered in food or drinking water to puppies and kittens. Adverse effects of anorexia or diarrhea are rare and primarily occur at high doses and with prolonged use. Central nervous system (CNS) signs parasitic infections in human patients, it been associated with anorexia and reversible bone marrow suppression in dogs and cats especially when high doses are administered for more than 5 days.5 As a result, fenbendazole is used more commonly in small animals. Nitroimidazoles Protozoa reduce nitroimidazoles to nitro anion free radicals, which cause damage to parasite DNA. Some nitroimidazoles are mutagens and carcinogens, but carcinogenesis has not been dem- onstrated in dogs and cats with long-term use. Metronidazole, CHAPTER 10 Antiprotozoal Drugs Jane E. Sykes and Mark G. Papich w KEY POINTS • Antiprotozoal drugs often have a restricted spectrum of activ- ity, although some are also active against bacteria and fungi. Many interfere with enzyme pathways specific to certain proto- zoal species. • Treatment with antiprotozoal drugs may not consistently clear an infection. INTRODUCT ION The use of antiprotozoal drugs in dogs and cats is frequently extrapolated from their use in human patients or food animal spe- cies. Almost all antiprotozoal drugs are not specifically approved for treatment of protozoal infections in dogs and cats. Some antibacterial and antifungal drugs also have antiprotozoal activ- ity (see Chapters 8 and 9 for the use and adverse effects of these drugs). In vitro activity of antiprotozoal drugs, and monitoring of resistance, is more difficult for antiprotozoal drugs because stan- dardized susceptibility testing is not routinely performed for these pathogens. In addition, many antiprotozoal drugs are designed to be active in the lumen of the intestine for treatment of intestinal protozoal infections and the concentration of active drug in the intestinal lumen after oral administration is difficult to measure. Therefore, the concentration of drug to which these pathogens are exposed is often not known. The activity and dosage regimens of antiprotozoal drugs are often based on the results of clinical trials, rather than concentration-exposure relationships between anti- protozoal drugs and the organism of interest. Many antiprotozoal drugs are active only against a restricted range of protozoal species. To reflect this, drugs in this chapter are organized into antiprotozoal drugs primarily used for gastroin- testinal infections; those with a broad spectrum of activity; those used to treat systemic protozoal infections (such as hepatozoono- sis, toxoplasmosis, neosporosis, and sarcocystosis); antiprotozoal drugs used to treat leishmaniosis; and those used to treat Chagas’ disease. For many infections, treatment does not consistently result in parasitologic cure. • Resistance to antiprotozoal drugs is a growing problem among protozoal pathogens. • Some antiprotozoal drugs have minimal to no adverse effects, whereas for others, adverse effects severely limit use. • The availability of antiprotozoal drugs is restricted in some countries. can result from thiamine deficiency, which is reversible on addi- tion of thiamine to the diet. However, thiamine supplementa- tion may interfere with the drug’s efficacy. Benzimidazoles Fenbendazole and Albendazole Benzimidazoles bind to β-tubulin within a variety of helminths and protozoa. This leads to inhibition of tubulin polymerization and the formation of microtubules, with impaired cell division. Glucose uptake by parasites is also impaired. Resistance can result from production of altered β-tubulin by parasites, which reduces binding of benzimidazole drugs. Fenbendazole is widely used to treat giardiasis in dogs and cats. It is safer than metronidazole, can be administered to young animals, and has higher efficacy, although treatment failure can still occur. A second course of treatment or administration of fenbendazole in combination with metronidazole can be effec- tive in refractory cases. Administration with food may improve absorption, but the fat content of the food does not influence absorption.1 Adverse effects of fenbendazole are very rare but can include decreased appetite, vomiting, diarrhea, and rarely reversible pancytopenia.2 At high doses used to treat Mesoces- toides spp. peritonitis (100 mg/kg q12h), neurologic signs have been observed.3 Febantel is metabolized to a benzimidazole compound and has been used in combination with praziquantel and pyrantel (Drontal Plus) to treat Giardia spp. infection in dogs, although efficacy at label dosages has been variable and some dogs can re-shed low numbers of cysts when treatment is discontinued.4 Albendazole has an affinity for rapidly divid- ing cells, and although it is used extensively for treatment of Sulfadimethoxine 55 on day 1, 27 thereafter 24 D, C PO 3-23 or for 48 hr after signs resolve Isosporiasis with or without a dihydro- folate reductase inhibitor. C, Cats; D, dogs. ronidazole, and tinidazole have primarily been used to treat enteric protozoal infections. Benznidazole is specifically used to treat infections with Trypanosoma cruzi. Metronidazole Metronidazole is used to treat giardiasis in dogs and cats, although efficacy may be as low as 50%. It also has activity against amoebic infections. The clinical use and adverse effects of metronidazole are described in Chapter 8. Doses of metro- nidazole used for treatment of giardiasis have the potential to be associated with neurotoxicity, so fenbendazole is preferred because of greater safety and efficacy. Metronidazole can be combined with fenbendazole for refractory giardiasis. Tinidazole Tinidazole is a 5-nitroimidazole that has amoebicidal, giardicidal, trichomonicidal, and anaerobic bactericidal activity. It is some- times used as a single-dose treatment for giardiasis in human patients. The efficacy of tinidazole for treatment for giardiasis in dogs and cats has not been evaluated, and the half-life in dogs (4.4 hours) and cats (8.4 hours) is shorter than that in human patients (>12 hours).6,7 Tinidazole is very well absorbed in dogs and cats, with a bioavailability of 100%. Adverse effects are similar to those of metronidazole. Like metronidazole, tinidazole has a bitter taste. Ronidazole Ronidazole is the drug of choice for treatment of Tritrichomonas foetus infections, which are less responsive to metronidazole and tinidazole.8-10 Resistance to ronidazole has been identified in some isolates of T. foetus and is associated with treatment failure in infected cats.11 Resistance is thought to result from increased oxygen-scavenging capacity by the parasite, whereby oxygen competes effectively with ronidazole and other nitro- imidazoles for ferredoxin-bound electrons. Ronidazole is absorbed rapidly and completely after oral administration to cats. Some compounded formulations may have decreased efficacy as a result of low ronidazole content or differences in drug release at the site of action (the large bowel). A modified-release formulation that is delivered to the colon may have improved efficacy.12 Decreased appetite, vomiting, and neurologic signs can occur in dogs and cats, especially at doses above 30 mg/kg q12h in cats and at doses as low as 10 mg/ kg/d in dogs.13 Once daily dosing is probably sufficient because of the long half-life of the drug in cats.12 Doses of 20 mg/kg or less may not effectively clear infection with T. foetus. Neuro- logic signs result from γ-aminobutyric acid (GABA) antagonism in the CNS and include ataxia, decreased mentation, agitation, tremors, and hyperesthesia, which occur up to 9 days after the start of treatment and resolve when the drug is discontinued.13 Nitozoxanide Nitazoxanide is a nitrothiazolyl-salicylamide derivative that has activity against Giardia spp., Cryptosporidium spp., Sarcocystis neurona, some anaerobic bacteria, Helicobacter spp., and Cam- pylobacter jejuni. It inhibits the pyruvate-ferredoxin/flavodoxin oxidoreductase enzyme-dependent electron transfer reaction 98 SECTION 2 Antiinfective Therapy TABLE 10-1 Suggested Doses of Drugs That Are Primarily Used to Treat Protozoa Drug Dose (mg/kg) Interval (hours) Species Route Fenbendazole 50 24 C, D PO Albendazole 25 12 C, D PO Metronidazole 15 12 C, D PO Tinidazole 15 12 24 D C PO Ronidazole 30 24 C PO Paromomycin 10 8 D PO Nitazoxanide 100 mg/animal 12 D, C PO Amprolium 1.25 g of 20% powder or 30 mL of 9.6% solution to 3.8 L of water 24 D, C PO l Infections of the Gastrointestinal Tract in Small Animals Duration (days) Comments 5 Giardiasis. May be administered with food. Safe in pregnancy. 3 Giardiasis. May cause bone marrow sup- pression. Do not use in pregnancy. 8 Giardiasis. Use caution with hepatic insufficiency. Dose for metronidazole benzoate is 25 mg/kg. 5 Giardiasis. Administer with food or in capsules to reduce bitterness. 14 Tritrichomoniasis. Avoid doses ≥60 mg/ kg/day. Compounded from powder. 5-10 Cryptosporidiosis. Caution in animals with diarrhea due to possible systemic absorption. Avoid in cats. 3 Cryptosporidiosis. Efficacy and safety unclear. Vomiting common in cats. 7 Isosporiasis. Add to food. Do not ad- minister for prolonged periods. that is essential for anaerobic metabolism in these organisms. Resistance has been documented in Giardia spp.14 Reports of nitazoxanide use in dogs and cats have been rare, and its efficacy in dogs and cats is largely unknown. An equine formulation (Navigator) that was used to treat equine proto- zoal meningoencephalitis caused by Sarcocystis neurona has been removed from the market. Doses have been extrapolated from those used for human patients. Nitazoxanide treatment of cats co-infected with Cryptosporidium spp. and T. foetus led to cessation of shedding during treatment, but infection was not eliminated.15 Vomiting occurred frequently, especially at higher doses (75 mg/kg PO q12h). In humans, nitazoxanide is rapidly absorbed from the gastrointestinal tract and metabolized to the active metabolite tizoxanide, which is highly protein bound. After hepatic glucuronidation, it is excreted in urine and bile. Antibacterial Drugs with Broad-Spectrum Antiprotozoal Activity Folic Acid Antagonists Trimethoprim, pyrimethamine, ormetoprim, and sulfadiazine inhibit parasite replication through folate antagonism. Synergis- tic combinations of sulfadiazine with trimethoprim or pyrimeth- amine are primarily used to treat toxoplasmosis, neosporosis, and intestinal coccidiosis (Isospora spp. infections) in dogs and cats. A combination of pyrimethamine, trimethoprim-sulfadia- zine, and clindamycin has also been used to treat Hepatozoon americanum infections.16 The mechanisms of action, use, and adverse effects of trimethoprim and sulfonamides are discussed in Chapter 8. Pyrimethamine Like trimethoprim, pyrimethamine inhibits dihydrofolate reduc- tase, which is necessary for synthesis of thymidine. However, in contrast to trimethoprim, it has a greater affinity for the pro- tozoal enzyme than the bacterial enzyme. Resistance to pyri- methamine can occur when parasites synthesize dihydrofolate reductase enzymes with an altered drug target site. Pyrimeth- amine is well absorbed after oral administration and penetrates a variety of tissues including the CNS. Hepatic metabolism and some renal excretion occur. Although clearance of pyrimeth- amine is not affected by renal disease, the use of caution with hepatic or renal insufficiency has been recommended in human patients. Pyrimethamine is well tolerated. Gastrointestinal signs such as vomiting, diarrhea, and decreased appetite occur in some treated animals. Bone marrow suppression can occur with pro- longed treatment at higher doses as a result of folic acid defi- ciency. In human patients, concurrent administration of folinic acid is recommended when high doses are used for treatment of toxoplasmosis. Folinic acid, but not folic acid supplemen- tation also reverses marrow suppression in dogs treated with pyrimethamine.17 The CBC should be monitored weekly during treatment, and supplementation should be provided if leukope- nia develops and continued treatment is necessary. Stomatitis, ulcerative glossitis, and exfoliative dermatitis have also been described in human patients as a result of folic acid deficiency.18 Other adverse effects of pyrimethamine-sulfadiazine combina- tions result from the sulfadiazine component (see Chapter 8). Unlike trimethoprim-sulfadiazine, there are no approved formulations of pyrimethamine-sulfonamides for dogs and 99CHAPTER 10 Antiprotozoal Drugs cats. Pyrimethamine is available as a single agent in tablets but should be administered with a sulfonamide for the best efficacy. Another alternative is the combination of pyrimethamine-sulfa- diazine, which is available in an oral liquid suspension for horses (ReBalance). Although off-label, it is a convenient formulation for small animal veterinarians. This formulation can be admin- istered at a dose of 1 mg/kg pyrimethamine + 20 mg/kg sulfa- diazine PO q24h. This is equivalent to 0.33 mL of the equine formulation per 4 kg of body weight for dogs and cats. Macrolides and Lincosamides Clindamycin, azithromycin, and clarithromycin have antipro- tozoal activity. The use of these macrolides and lincosamides in dogs and cats and their adverse effects are discussed in Chap- ter 8. Clindamycin is the most widely used antiprotozoal for treatment of toxoplasmosis and neosporosis in dogs and cats. Although clindamycin inhibits shedding of Toxoplasma gondii oocysts by cats,19 clinical efficacy of clindamycin for treating toxoplasmosis in dogs and cats has been questioned by experts and in published studies. Trimethoprim-sulfonamides are a suit- able alternative, or if clindamycin is used, pyrimethamine may be used in combination. In human patients, pyrimethamine and clindamycin are used as a substitute for pyrimethamine and sulfadiazine for treatment of toxoplasmosis in sulfadiazine- sensitive individuals. Azithromycin is used in combination with atovaquone for treatment of babesiosis and cytauxzoonosis. Paromomycin Paromomycin is the only aminoglycoside antibiotic that has efficacy against protozoa. It is poorly absorbed from the gas- trointestinal tract and so has been used to treat enteric proto- zoal infections, particularly cryptosporidiosis. It is ineffective for treatment of tritrichomoniasis in cats.10 Furthermore, when used to treat intestinal protozoal infections in cats, paromomy- cin has been absorbed systemically because of intestinal muco- sal compromise, with resultant acute renal failure, deafness, and cataract formation.20 As a result, its use has been limited. In human patients, paromomycin has been used topically to treat cutaneous leishmaniasis and parenterally to treat visceral leishmaniasis.21 Tetracyclines and Ciprofloxacin Doxycycline has primarily been used for malaria prophylaxis in humans. Ciprofloxacin is thought to inhibit DNA gyrase within a chloroplast organelle (the apicoplast) of apicomplexan para- sites (see the triazines, later). It is an alternative to sulfadiazine for treatment of isosporiasis in human patients.18 Tetracyclines and ciprofloxacin have not been widely used for prevention or treatment of protozoal infections in dogs and cats with the pos- sible exception of doxycycline as part of combination treatment for babesiosis (see Chapter 75). Antiprotozoal Drugs Used for Systemic Protozoal Infections Quinolone Derivatives Atovaquone Atovaquone is a hydroxynaphthoquinone that inhibits electron transport in protozoa by targeting the cytochrome bc1 com- plex (Table 10-2). It has been used in combination with other antiprotozoal drugs as an alternative treatment for malaria, Diminazene 3-5 Once D Deep IM N/A Babesiosis and African trypanosomiasis. Narrow aceturate therapeutic range. Ponazuril 20-50 12-24 D PO 3-28 Toxoplasmosis, neosporosis, isosporiasis. Optimal dose, duration, efficacy, and adverse effects unknown. Toltrazuril 5-10 18 12-24 D C PO 1-14 Hepatozoonosis, isosporiasis. One dose may be effec- tive for isosporiasis. Optimal dose and duration for hepatozoonosis unknown. C, Cats; D, dogs; N/A, not applicable. toxoplasmosis, and pneumocystosis in human patients.18 In veterinary medicine, atovaquone is used in combination with azithromycin for treatment of Babesia gibsoni and Babesia conradae infections and cytauxzoonosis (see Chapters 75 and 76), but is expensive. Resistance has been reported in Plas- modium spp., T. gondii, Pneumocystis jirovecii, and canine B. gibsoni strains as a result of mutations in the cytochrome bc1 complex. Atovaquone is highly lipophilic and extensively protein bound. Little is known about atovaquone metabolism in dogs and cats. Its oral bioavailability increases significantly when food is administered concurrently. Atovaquone is available alone or in a formulation with proguanil for treatment and prevention of malaria in human patients. The combination formulation may cause vomiting and diarrhea in dogs, but otherwise atovaquone appears well tolerated by both dogs and cats.22-24 In human patients, adverse effects have included gastrointestinal signs, headache, fever, and increased liver enzyme activities. Coadmin- istration with metoclopramide, tetracycline, or rifampin signifi- cantly decreases plasma drug concentrations in humans. Decoquinate Decoquinate is a 4-hydroxyquinolone coccidiostat that inhib- its electron transport in protozoal mitochondria and interferes with sporozoite development. It likely has a similar mechanism of action to atovaquone, because resistance to atovaquone can result in cross-resistance to decoquinate.25 Although developed as a food additive for use in production animals, decoquinate can be used successfully and without adverse effects to prevent relapses in dogs that are chronically infected with Hepatozoon americanum.16 Decoquinate also appeared to be effective for treatment of Sarcocystis spp. myositis in a dog.26 Its distribution and metabolism in dogs and cats have not been described. Aromatic Diamines The aromatic diamines include imidocarb dipropionate, dim- inazene aceturate, pentamidine isethionate, and phenamidine isethionate. These drugs inhibit DNA synthesis in protozoa. In dogs, imidocarb and diminazene have been used most widely, primarily for treatment of Babesia spp. and Hepatozoon canis infections. In general, the use of imidocarb has been preferred over diminazene because of diminazene’s narrow therapeu- tic index. Pentamidine and phenamidine have also been used in dogs. Pentamidine isethionate is a second-line treatment for leishmaniasis in human patients and is used as an alternative to diminazene for treatment of African trypanosomiasis (see Chapter 78). Treatment of protozoal infections using the aro- matic diamines may not result in complete parasite elimination. Imidocarb Dipropionate Imidocarb dipropionate is primarily used to treat large Babesia spp. and Hepatozoon canis infections in dogs. More effective 100 SECTION 2 Antiinfective Therapy TABLE 10-2 Suggested Doses of Drugs Primarily Used to Treat Systemic Protozoa in Small Animals Drug Dose (mg/kg) Interval (hours) Species Route Du (d Pyrimethamine 1 0.5-1 24 D C PO 14 Clindamycin 22 12 D, C PO Azithromycin 10 24 D, C PO 10 Atovaquone 13.3 15 8 D C PO 10 Decoquinate 10-20 12 D PO ≥3 Imidocarb dipropionate 6.6 5 Once, repeat in 14 days D C Deep IM N/ l Diseases Excluding Leishmaniosis and Trypanosomiasis ration ays) Comments -28 Primarily neosporosis, toxoplasmosis, and American hep- atozoonosis. Use with a sulfonamide. Use caution with hepatic and renal insufficiency. Monitor CBC. Folinic acid supplementation (5 mg/day) may be required. Toxoplasmosis, neosporosis, sarcocystosis, and Americ an hepatozoonosis. Babesiosis and cytauxzoonosis. Used with atovaquone. Babesiosis and cytauxzoonosis with azithromycin. Administer with food. 65 American hepatozoonosis and sarcocystosis. Powder (6% decoquinate; 60 mg active ingredient per gram) is mixed with food. This equates to 0.5 to 1 table- spoon/10 kg body weight q12h. A Large Babesia spp. infections. Caution with hepatic or renal insufficiency. Avoid use with other cholinesteras e inhibitors. compound inhibits protozoal enzymes and damages protozoal agents have replaced imidocarb for treatment of canine mono- cytic ehrlichiosis and feline cytauxzoonosis. Imidocarb is given by intramuscular injection, twice, 2 weeks apart. It is generally well tolerated, although it can cause tran- sient pain at the site of injection. It appears to be eliminated in urine and feces.27 Acute adverse effects result from its anti- cholinergic activity and include vomiting, shivering, hypersali- vation, lacrimation, diarrhea, agitation, lethargy, pyrexia, and periorbital swelling. These generally resolve within a few hours. A possible association between imidocarb treatment and acute renal tubular necrosis has been reported in dogs.28 Massive hepatic necrosis was described after overdosage of dogs with 10 times the recommended dose.29 Diminazene Aceturate Diminazene aceturate is administered parenterally, primarily to dogs, for treatment of babesiosis, African trypanosomiasis, and, most recently, infections with Rangelia vitalii, a novel protozoal pathogen of dogs from Brazil.30 Diminazene aceturate is not readily available in the United States. Resistance to diminazene has been described in Babesia gibsoni.31 Although formulations for small animals are not available, a powdered commercial drug formulation (Veriben) has been reconstituted with sterile water to a concentration of 7 mg/mL and administered intramuscularly at a dose of 3 mg/kg dim- inazene diaceturate for a pharmacokinetic study in cats.32 The dose was well tolerated, and diminazene was eliminated with a half-life of only 1.7 hours and a peak concentration of only 0.5 µg/mL. Development of clinically effective doses from these data requires further studies. Diminazene was administered to seven cats experimentally infected with Trypanosoma evansi at a dose of 3.5 mg/kg intramuscularly on five consecutive days.33 The treatment was 85.7% efficacious for elimination of the par- asite, and no adverse effects were observed. Effective doses of diminazene approach doses that are toxic, so it should be used with caution.34 Adverse effects include tachycardia and CNS signs such as ataxia, nystagmus, and opis- thotonos. A single treatment can be given, or the dose can be repeated 72 to 96 hours after drug administration. In some pro- tocols for B. gibsoni infections, diminazene administration has been followed a day later by treatment with imidocarb. Triazine Antiprotozoals (Toltrazuril and Ponazuril) Toltrazuril and its major metabolite ponazuril (toltrazuril sul- fone, Marquis) are triazine-based antiprotozoal drugs that have specific activity against apicomplexan coccidial infections. Tol- trazuril is not available within the United States. Ponazuril and toltrazuril appear to act on a plastid-like chloroplast organelle (the apicoplast) in apicomplexan protozoa, which may have originally been acquired from a green alga.35 This organelle contains a small circular genome and operates key biochemi- cal pathways. Although their mechanism of action is unclear, triazines may inhibit metabolic enzymes or decrease pyrimi- dine synthesis within the apicoplast. Ponazuril and toltrazuril have been used in animals to treat isosporiasis, toxoplasmosis, neosporosis, and equine protozoal meningoencephalitis. Tri- azine resistance has been described in coccidia from production animals.36 In dogs and cats, toltrazuril has been used to treat isospo- riasis and hepatozoonosis, although infection may persist in some animals.16,37-42 In Europe it is available in combination with the anthelmintic emodepside (Procox Oral Suspension for 101CHAPTER 10 Antiprotozoal Drugs Dogs, Bayer Animal Health) for treatment of isosporiasis and roundworm infections in puppies over 2 weeks of age. The sus- pension contains 18 mg/mL of toltrazuril, and a single 9-mg/kg dose is recommended. Toltrazuril appeared to be as effective as trimethoprim-sulfadiazine-clindamycin-pyrimethamine for treatment of canine American hepatozoonosis.16 One dog with Hepatozoon canis infection recovered after treatment with tol- trazuril and trimethoprim-sulfamethoxazole,42 but a toltrazuril and imidocarb combination did not offer benefit over treat- ment of H. canis infection with imidocarb alone.43 Dogs with H. canis infection respond clinically within 72 hours of starting treatment with toltrazuril. Anecdotal reports exist of the use of ponazuril to treat Isospora spp. infections in dogs and cats, but its efficacy is unclear. Doses of ponazuril used have ranged from 20 to 50 mg/kg for 2 to 5 days. In one dog, ocular toxoplasmo- sis that was refractory to clindamycin resolved after treatment with ponazuril for 28 days.44 The pharmacokinetics of the triazines in dogs has not been reported. In horses, ponazuril crosses the blood-brain barrier to some extent and achieves concentrations in the cerebrospinal fluid sufficient to inhibit protozoa. It has long half-life in horses (>4 days) and in cattle (2 to 3 days). Because of its specific activ- ity against apicomplexan parasites, significant toxicity in mam- malian species has not been reported. Antileishmanial Antiprotozoal Drugs Antifungal Agents Amphotericin B Amphotericin B is a treatment of choice for human visceral leish- maniasis.18 It is thought to bind to ergosterol in the protozoal membrane, and blocks the ability of Leishmania spp. to bind to and enter macrophages.45 Lipid amphotericin B formulations have been used to treat visceral leishmaniosis in dogs, although organ- ism persistence and relapse have been reported in some dogs after twice-weekly treatment for up to 10 administrations (0.8 to 3.3 mg/ kg intravenously).46,47 In an effort to reduce selection for resistant parasites, the World Health Organization recommends against the use of amphotericin B for treatment of canine leishmaniosis.48 A full discussion of amphotericin B is provided in Chapter 9. Azole Antifungals Azole antifungals such as fluconazole have been used to treat cutaneous leishmaniasis in human patients. More effective antiprotozoal drugs are substituted for visceral leishmaniasis. Posaconazole and ravuconazole also have activity against Try- panosoma cruzi (see Chapter 78), and fluconazole may have activity against Toxoplasma (see Chapter 72). Antimony Compounds Sodium stibogluconate (Pentostam) and N-methylglucamine antimoniate (meglumine antimoniate, Glucantime) are derived from the heavy metal antimony (Sb). They are called pentava- lent antimony compounds (symbol Sbv) because they contain Sb atoms that have five electrons in their outer shell. Pentava- lent antimonials have been recommended as the first choice for treatment of Leishmania infections in humans and in dogs.49 Their mechanism of action is still not completely clear, but it is thought that pentavalent antimony undergoes reduction to the more toxic trivalent version, possibly within macrophage phagolysosomes or within the parasite itself.50 The trivalent Allopurinol Allopurinol is a purine analogue. In parasites, allopurinol is metab- olized to derivatives that are incorporated into RNA, which leads to impaired protein synthesis. Resistance can occur and appears to result from reduced activity of purine transporters and a reduced ability to accumulate purine.55 Although it has been used alone for treatment of canine leishmaniosis, allopurinol is most commonly used in combination with meglumine or miltefosine. Allopurinol is rapidly absorbed from the gastrointestinal tracts of dogs. Peak drug concentrations occur 1 to 3 hours after adminis- tration.56 Allopurinol is not bound to plasma proteins. Allopurinol rarely causes adverse effects in dogs. It inhibits mammalian xan- thine oxidase, which results in decreased uric acid production from xanthine. As a result, long-term use can result in xanthine urolithi- asis.57 In human patients, allopurinol most commonly causes skin rashes. Gastrointestinal signs can also occur. Rarely administra- tion of allopurinol to humans results in aplastic anemia or a hyper- sensitivity syndrome characterized by toxic epidermal necrolysis with hepatic and renal failure.58,59 Serious adverse reactions are steady-state plasma concentration is reached after 3 to 4 weeks of treatment. Clearance is believed to result from slow hepatic metabolism and excretion in bile. In dogs, adverse effects of treat- ment are mild and transient and consist of occasional vomiting and diarrhea.65 In contrast to meglumine antimoniate, miltefos- ine does not appear to contribute to renal pathology in dogs.54,66 Antiprotozoal Drugs for Treatment of Chagas’ Disease Benznidazole Benznidazole is a nitroimidazole that is used to treat acute Cha- gas’ disease (see Chapter 78). Benznidazole is activated by a parasite-specific nitroreductase to produce toxic metabolites.67 Resistance can result from reduction in the level of activity of the nitroreductase and confers cross-resistance to nifurtimox. Benznidazole is lipophilic, is readily absorbed from the gas- trointestinal tract, and undergoes hepatic metabolism. In the United States, it is available from the Centers for Disease Con- trol and Prevention (CDC). The main adverse effect of treat- ment in dogs is vomiting. In human patients, it can cause skin 102 SECTION 2 Antiinfective Therapy DNA.51 Resistance to antimonials is an emerging problem in human Leishmania spp. isolates. This has led to the use of higher drug dosages, with an associated rise in the rate of drug toxicity. The availability of antimonial drugs is limited in the United States. Both sodium stibogluconate and meglumine antimoniate are administered subcutaneously (Table 10-3). The treatment of choice for canine leishmaniosis is a combination of meglumine antimoniate and allopurinol.48,49 Complete clearance of the infec- tion may not always occur.52 After subcutaneous administration, more than 80% of meglumine antimoniate is eliminated by the kidneys. Pain at the site of injection is the most common adverse effect, and cutaneous abscesses or cellulitis may also occur.53 Systemic adverse effects such as lethargy, vomiting, diarrhea, inappetence, and increased serum liver enzyme activities may be more likely to occur in the presence of renal failure, which can be a complication of leishmaniosis. Of concern, the administration of meglumine antimoniate to healthy dogs has led to renal tubu- lar necrosis, in the absence of azotemia.54 In human patients, other adverse effects include generalized arthralgias, abdominal pain, mild cytopenias, cardiotoxicity, and chemical pancreati- tis.21 Novel formulations of antimony compounds are being developed for treatment of leishmaniasis, including lipid formu- lations and preparations that could be administered orally.50 TABLE 10-3 Suggested Doses of Drugs Primarily Used to Treat Leishmaniosis or C Drug Dose (mg/kg) Interval (hours) Route Duration (days) Meglumine antimoniate 75-100 24 SC 30-60 Allopurinol 10 12 PO At least 6-12 months Miltefosine 2 24 PO 28 Benznidazole 5-10 24 PO 60 more likely to occur in human patients with renal insufficiency. At usual doses, allopurinol treatment leads to improvement in kidney lesions in dogs with leishmaniosis that have renal insufficiency.60 Nevertheless, careful monitoring for adverse effects is indicated in these dogs (see Table 10-3). Serious drug interactions can occur when allopurinol is administered with azathioprine. Miltefosine Miltefosine is an effective alternative to pentavalent antimonials for treatment of leishmaniosis.61 It is a phospholipid analogue that activates cellular proteases in Leishmania spp., which results in apoptosis. Miltefosine is the first highly active oral drug for treatment of leishmaniosis. Nevertheless, despite clinical improve- ment in treated dogs, elimination of the parasite may not always occur.62,63 Resistance to miltefosine can result from increased P-glycoprotein–mediated drug efflux and decreased drug uptake. Because miltefosine has a long half-life and must be administered for 28 days, selection for resistant isolates has been a concern. The World Health Organization has recommended that veteri- nary use of miltefosine in dogs with leishmaniosis be avoided in order to minimize the rate of selection for resistant strains.64 Over 90% of miltefosine is absorbed from the gastrointestinal tract of dogs after oral administration.54 The half-life of miltefo- sine in the dog is approximately 6 days, so it accumulates until a hagas’ Disease in Dogs Comments Leishmaniosis. Use with allopurinol. Available in ampules. Dose based on concentration of meglumine antimoniate. Caution in dogs with renal insufficiency. Leishmaniosis. Use with meglumine or miltefosine. Monitor CBC and serum chemistry in dogs with hepatic and renal insufficiency. Leishmaniosis. Use with allopurinol. Chagas’ disease rashes, peripheral neuropathy, and less commonly bone mar- row suppression. It also has the potential to be carcinogenic. Nifurtimox Nifurtimox is a nitrofuran derivative used to treat Chagas’ dis- ease in humans. It has limited efficacy, with 70% parasitologic cure for acute disease and at best 20% for chronic disease.18 As with benznidazole, metabolic reduction of the nitro group by a trypanosome-specific nitroreductase leads to the forma- tion of toxic metabolites. In human patients, it is well absorbed orally and undergoes hepatic metabolism. Gastrointestinal and neurologic signs are the primary adverse effects of nifurtimox, and like benznidazole, it has carcinogenic properties.68 Severe adverse effects have precluded the use of nifurtimox in dogs.69 SUGGESTED READING Rossignol JF. Cryptosporidium and Giardia: treatment options and prospects for new drugs. Exp Parasitol. 2010;124(1):45-53. REFERENCES 1. McKellar QA, Galbraith EA, Baxter P. Oral absorption and bio- availability of fenbendazole in the dog and the effect of concurrent ingestion of food. J Vet Pharmacol Ther. 1993;16:189-198. 2. Gary AT, Kerl ME, Wiedmeyer CE, et al. 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Canine Chagas’ disease (American trypanosomia- sis) in North America. Vet Clin North Am Small Anim Pract. 2009;39:1055-1064:v-vi. 10 - Antiprotozoal Drugs Introduction Antiprotozoal Drugs Used Primarily for Gastrointestinal Infections Amprolium Benzimidazoles Fenbendazole and Albendazole Nitroimidazoles Metronidazole Tinidazole Ronidazole Nitozoxanide Antibacterial Drugs with Broad-Spectrum Antiprotozoal Activity Folic Acid Antagonists Pyrimethamine Macrolides and Lincosamides Paromomycin Tetracyclines and Ciprofloxacin Antiprotozoal Drugs Used for Systemic Protozoal Infections Quinolone Derivatives Atovaquone Decoquinate Aromatic Diamines Imidocarb Dipropionate Diminazene Aceturate Triazine Antiprotozoals (Toltrazuril and Ponazuril) Antileishmanial Antiprotozoal Drugs Antifungal Agents Amphotericin B Azole Antifungals Antimony Compounds Allopurinol Miltefosine Antiprotozoal Drugs for Treatment of Chagas’ Disease Benznidazole Nifurtimox Suggested Reading References