Azo-Naphthalene Drugs

Trypan blue was one of the first compounds used to treat babesiosis. Because local irritation and abscesses develop after subcutaneous injection, it is administered intravenously. Trypan blue does not completely eliminate Babesia organisms, but infected animals recover from illness and remain in a state of premunition. They must be treated with aromatic diamidines (see Aromatic Diamidines) within 1 month to be cured. A disadvantage of trypan blue is that it stains all body tissues and secretions for several weeks.

Acridine Dyes

Quinacrine, developed as a human antimalarial drug, has been administered to dogs as an alternative treatment to nitroimidazoles for giardiasis. It becomes incorporated into the DNA of the organism and inhibits nucleic acid synthesis. Evidence of toxicity includes vomiting, fever, pruritus, neurologic signs, yellow discoloration of urine and tissues, and hepatic dysfunction. It is no longer available in the United States.

Quinoline and Quinolone Derivatives

Diiodohydroxyquin and iodochlorhydroxyquin are halogenated oxyquinolines that have been provided as topical antifungal drugs. They are also amebicidal when administered orally. They are not absorbed systemically and have relatively low toxicity. Signs of toxicity are abdominal pain, diarrhea, and neurologic signs, all of which have been reported in dogs. Atovaquone is a closely related hydroxynaphthoquinone derivative licensed to treat Pneumocystis species infections. It has been used in combination with azithromycin to treat babesiosis in humans and dogs (see Chapter 76).⁷⁹ Buparvaquone, which has been used to treat theileriosis in herbivores, has not effectively treated leishmaniasis or cytauxzoonosis in dogs or cats, respectively.¹⁶⁵ Decoquinate, a hydroxyquinolone licensed for treating coccidiosis in poultry, is effective in ameliorating the signs of hepatozoonosis (see Chapter 74 and the Drug Formulary in the Appendix).⁹⁴

Aromatic Diamidines

Phenamidine, pentamidine, diminazene, amicarbalide, and imidocarb, which are diamidine derivatives, are the drugs of choice for treating Babesia, Cytauxzoon, and African Trypanosoma species infections in dogs and cats. They also effectively treat some other protozoa (see Table 71-1) by interfering with nucleic acid metabolism. These drugs are formulated as salts to reduce irritation after parenteral (intramuscular or subcutaneous) injection. Pentamidine has also been used to treat leishmaniasis.¹³⁵ Derivatives of pentamidine have shown high in vitro efficacy against a North American isolate of Leishmania.¹³⁹ Aromatic diamidines have some of the highest activity against Babesia gibsoni infection; however, drug resistance can develop.^70a,101 Although imidocarb has been recommended to treat Hepatozoon canis and Cytauxzoon felis infections, incomplete responses have been noted^26a,144a, and other drugs should be considered first (see Table 71-1).

Diamidines are rapidly effective and usually resolve clinical signs and parasitemia within 24 hours. They do not completely eradicate the organisms but have residual activity after a single injection. The drugs become highly concentrated in parenchymal organs such as the liver and brain and are slowly metabolized or excreted unchanged. The slow metabolism and elimination of diamidines contribute to their prophylactic effects for many weeks after a single injection. Subtherapeutic dosages may allow organisms to develop resistance to these drugs.

Nitroimidazoles

Nitroimidazoles are effective against anaerobic enteric protozoa that cause trichomoniasis, amebiasis, giardiasis, and balantidiasis. They can be used to treat intraintestinal and invasive parasites. The nitro group within anaerobic protozoa and bacteria undergoes a reduction to produce various unstable metabolites, some of which have antimicrobial activity. The drugs are generally much less effective against microaerophilic or aerobic microorganisms. Metronidazole, tinidazole, ronidazole, ipronidazole, nimorazole, dimetridazole, secnidazole, and ornidazole are close structural analogs marketed in various regions of the world. Fexinidazole is in clinical trials for treatment of African trypanosomiasis.^160b See the Drug Formulary in the Appendix for further information on tinidazole, ronidazole, ipronidazole, and metronidazole. Metronidazole is the most widely used of these compounds. For example, it has no in vitro activity against nonanaerobic protozoa such as Leishmania. It has shown therapeutic benefit, especially in resolution of cutaneous lesions in infected dogs, when used in combination with other drugs such as enrofloxacin.^14,17 In addition to protozoa, it is active against obligate spore-forming anaerobes such as Clostridium, some non-spore-forming anaerobes such as Campylobacter, and microaerophilic organisms such as species belonging to the Enterobacteriaceae. Metronidazole is generally preferred for treating giardiasis.¹⁵⁰ Giardia infections that are resistant to metronidazole have been effectively treated by combining treatment with quinacrine.¹¹³ Metronidazole is the drug of choice for treating invasive amebiasis in humans.

Metronidazole is almost completely absorbed after oral administration. Food does not reduce the extent of absorption but may delay the rate. Intravenous administration of metronidazole may be preferable in severely ill patients but is expensive and potentially more neurotoxic. The drug is distributed widely and penetrates body tissues, extracellular fluids, and even pus-filled cavities. Metronidazole achieves good concentrations in the central nervous system even in the absence of inflammation. It is extensively metabolized in the liver, but renal excretion of active drug also occurs.

Metronidazole has been administered alone and with spiramycin to treat periodontal disease and stomatitis and leishmaniasis¹²⁴ and in combination with aminoglycosides to treat mixed infections associated with bowel perforation and intra-abdominal sepsis (see Chapter 88). In humans the drug effectively treats intra-abdominal, pelvic, pleuropulmonary, central nervous system, and bone and joint infections.

Side effects of metronidazole include gastrointestinal irritation with signs of vomiting and anorexia, glossitis, and stomatitis. Neurologic signs may be seen in dogs and cats after 7 to 10 days of treatment with high dosages (greater than 66 mg/kg/day) and may be resolved when therapy is discontinued.²³ Some dogs have developed fatal encephalopathy, persistent seizures, or cerebellar and central vestibular ataxia after therapy; diazepam helped the dogs recover (see the Drug Formulary in the Appendix).³⁸ Metronidazole is also mutagenic,^150a as are other members of this class of drugs, and precautions must be taken to avoid their use in pregnant or neonatal animals.

Benzimidazoles

Fenbendazole and albendazole are broad-spectrum benzimidazoles that are used to treat a wide range of infections with helminths and selected protozoa. They affect microtubule synthesis in the protozoal cytoskeleton. Both drugs have been effective in the treatment of intestinal giardiasis and are often more potent than metronidazole.⁵⁶ Fenbendazole is relatively safe, and dosages used for treating helminths (50 mg/kg for 3 days) are effective in treating giardiasis.^56,149,149 The drug was not as effective in cats that were co-infected with Cryptosporidium.⁷⁶ Fenbendazole use was associated with development of granulocytopenia as an idiosyncratic reaction in one dog.⁴⁵ Myelotoxicity has been caused by albendazole use in dogs and cats¹⁵⁷ but can be reversed after treatment is discontinued. Febantel, which is metabolized to fenbendazole, is one component of an anthelmintic combination that is effective against Giardia.^10,123

Azoles

The antifungal drugs ketoconazole, fluconazole, and terbinafine have some antileishmanial activity, because the infecting organism has ergosterol in its cell wall. In experimental animal models, these drugs have been less effective than other antiprotozoal drugs. The newer triazoles, such as posaconazole, have activity against Trypanosoma cruzi, as does a newer more potent derivative, albaconazole, that has been used in infected dogs.⁵⁸ Another antifungal, amphotericin B (AMB), has been more effective (see Miscellaneous Drugs, later).

Ionophores

Ionophores are compounds that form lipid-soluble complexes with cations, which facilitate transport of the ions across biologic membranes. They are antibiotics isolated from Streptomyces spp. and are provided primarily as coccidiostats. Monensin, lasalocid, and salinomycin, the compounds used in veterinary medicine, cause accumulation of intracellular ions within the parasite, interfering with its metabolism. They have been used primarily as growth promoters in food animal practice, although monensin has been effective in reducing shedding of Toxoplasma oocysts by cats. The ionophores also have antibacterial activity and have been used experimentally to treat endotoxic shock in dogs. Because of their stimulatory effects on cardiac contractility and myocardial perfusion, their toxicity may be increased by concurrent administration of cardiac glycosides.

Antimonials

Sodium stibogluconate and meglumine antimoniate are pentavalent antimony compounds and two of the main agents used in the treatment of leishmaniasis.52,151,160–162 The dosage is based on the amount of antimony compound administered. Treatment with these drugs is not curative, and two or three courses may be necessary. Combination therapy with other drugs has been recommended.¹⁵⁴ Side effects include anorexia, vomiting, nausea, myalgia, and lethargy. Electrocardiogram abnormalities and nephrotoxicity can develop at higher dosages. Although these antimonials are often given parenterally, a cyclodextrin formulation was found to have good bioavailability in mice.²⁹ Liposomal formulations have been investigated as a means of improving efficacy and reducing toxicity (see the Drug Formulary in the Appendix).¹³⁶

Antibacterials

Paromomycin (aminosidine) and furazolidone are nonabsorbable antibacterials (previously discussed; see Chapter 30. They are effective in treating some intestinal protozoal infections. Because of potential intestinal absorption and nephrotoxicity, paromomycin—an aminoglycoside—must be administered with caution when treating amebiasis or trichomoniasis when bowel lesions are extensive. Paromomycin has also been used to treat leishmaniasis. Furazolidone and sulfonamides are effective in treating intestinal coccidial infections. Nifurtimox, a nitrofuran derivative, can suppress but not cure T. cruzi infections. Nausea, vomiting, and convulsions may be side effects.

Quinolones, such as marbofloxacin and enrofloxacin, have been used, often in combination, to treat dogs with leishmaniasis and babesiosis.88,117

Trimethoprim, an antibacterial diaminopyrimidine compound that inhibits folic acid synthesis, has broad-spectrum antimicrobial activity (see Chapter 30). Combined with sulfonamides, it has been used to treat Pneumocystis and coccidial infections. Pyrimethamine is closely related to trimethoprim but is more effective against protozoa. It has been used in combination with sulfonamides to treat infections with Neospora and Toxoplasma organisms.

Several newer antifolate drugs under development may also be active against these two protozoa. Clindamycin, a lincosamide antimicrobial drug, and certain macrolides (azithromycin, clarithromycin) are also active against these two protozoa (see Chapter 79).^26a,33

Spiramycin, a macrolide antibiotic, has an antibacterial spectrum similar to that of erythromycin but is less effective. Absorption after oral administration is adequate for therapeutic purposes. It is widely distributed and reaches high concentrations in tissues, from which it is slowly eliminated in the bile and urine. Its usefulness has been limited for treating bacterial infections in veterinary medicine, but it is now marketed in combination with metronidazole, primarily to treat periodontal and oral infections. Spiramycin has been found to be somewhat effective for treating intestinal cryptosporidiosis and has been given to humans to treat acute toxoplasmosis. (See the Drug Formulary in the Appendix.)