Antiprotozoal therapies

INTRODUCTION — Protozoan parasites belong to four distinct groups: the amebae, the flagellates, the ciliates, and the sporozoa. Protozoa are single-celled organisms that replicate by various mechanisms within the infected host. The mechanisms of action of the various agents used to treat protozoan parasites are relatively poorly understood [1,2].

In the United States, the antiprotozoal drugs eflornithine, melarsoprol, and suramin are available through the Centers for Disease Control and Prevention (CDC) Drug Service, Atlanta, GA 30333 (telephone 404-639-3670; [email protected]).

Agents with activity against protozoal parasites will be reviewed here; their use for treatment of specific protozoal infections is discussed in detail separately. Antimalarial agents are discussed in detail separately, as are agents with activity against helminths. (See "Antimalarial drugs: An overview" and "Anthelminthic therapies".)

ALBENDAZOLE — Albendazole binds to tubulin and affects cytoskeletal microtubules and is a well-established therapy treatment of helminthic infections [3]. (See "Anthelminthic therapies".)

Albendazole also has activity against some protozoan infections, including most microsporidial species, particularly Encephalitozoon infections. However, it is not as active against Enterocytozoon bieneusi [4-11]. (See "Microsporidiosis".)

Absorption of albendazole is enhanced by taking it with fatty meals. Albendazole should be taken with fatty foods for treatment of invasive systemic parasitic infections; it should be taken with no food (eg, on an empty stomach) for treatment of intraluminal parasitic infections with no systemic involvement.

ATOVAQUONE — Atovaquone is a hydroxynaphthoquinone agent active against several protozoan parasites [12].

For the treatment of Pneumocystis jirovecii (formerly carinii) pneumonia (PCP), atovaquone is well tolerated but less effective than pentamidine or trimethoprim-sulfamethoxazole (TMP-SMX). Atovaquone is an alternative agent for prophylaxis against PCP for patients who are unable to tolerate TMP-SMX. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Treatment and prevention of Pneumocystis infection in patients with HIV".)

Atovaquone-pyrimethamine is an alternative agent for treatment and long-term maintenance therapy of Toxoplasma encephalitis in AIDS patients intolerant of sulfonamides. (See "Overview of prevention of opportunistic infections in patients with HIV" and "Toxoplasmosis in patients with HIV".)

Atovaquone-proguanil may be used for malaria chemoprophylaxis and is also effective in the treatment of Plasmodium falciparum malaria. (See "Antimalarial drugs: An overview".)

Atovaquone-azithromycin may be used for treatment of babesiosis. (See "Babesiosis: Clinical manifestations and diagnosis".)

Atovaquone suspension is twice as well absorbed as the tablet form, and consumption of atovaquone with a fatty meal enhances absorption [13].

BENZNIDAZOLE — Benznidazole is a nitroimidazole derivative with activity against Trypanosoma cruzi trypomastigotes and amastigotes. Side effects include rash, nausea, and peripheral neuritis. (See "Chagas disease: Antitrypanosomal drug therapy".)

EFLORNITHINE — Eflornithine inhibits parasite growth by selective and irreversible inhibition of ornithine carboxylase, an enzyme required for cellular proliferation and differentiation [14,15]. It is effective in the early and late central nervous system stage of infections with Trypanosoma brucei gambiense but not T. b. rhodesiense. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)

Frequent side effects include diarrhea, anemia, leukopenia, and hair loss.

FEXINIDAZOLE — Fexinidazole, a nitroimidazole derivate, was approved for treatment of gambiense human African trypanosomiasis (HAT) by the European Medicines Agency in 2018, under a mechanism for drugs intended for use outside the European Union [16,17]. It was approved by the US Food and Drug Administration in 2021 [18].

Oral administration is a major advantage of fexinidazole, with greater convenience and lower cost relative to other agents for treatment of HAT that require intravenous or intramuscular administration. (See "Human African trypanosomiasis: Treatment and prevention".)

FUMAGILLIN — Fumagillin is an antibiotic released by Aspergillus fumigatus. The mechanism of action of fumagillin has not been established, but the drug can suppress proliferation of microsporidia in vitro [19].

Topical fumagillin therapy has been successful in several cases of microsporidial keratoconjunctivitis in patients with AIDS. Fumagillin has also been used to treat intestinal E. bieneusi infections in immunocompromised patients; neutropenia and thrombocytopenia are common complications. (See "Microsporidiosis".)

FURAZOLIDONE — Furazolidone is a nitrofuran derivative used as an alternative drug for giardiasis. Adverse effects include nausea, vomiting, and allergic reactions [20]. The drug is a monoamine oxidase inhibitor and also causes a disulfiram-like reaction when taken with alcohol. Furazolidone is not bitter (unlike other drugs for giardiasis) and is available in a liquid form useful for young children. (See "Giardiasis: Treatment and prevention".)

MELARSOPROL — Melarsoprol is a trivalent arsenical compound used to treat late-stage African trypanosomiasis involving the central nervous system [21]. Melarsoprol appears to act by binding to essential thiol groups of trypanosomes, preventing trophozoite multiplication [14,22]. Severe adverse effects are common, including myocarditis, encephalopathy, and hypersensitivity reactions [23]. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)

METRONIDAZOLE — Metronidazole is a 5-nitroimidazole with potent activity against several protozoa including Entamoeba histolytica, Giardia duodenalis, and Trichomonas vaginalis. Metronidazole is the drug of choice for giardiasis and intestinal and extraintestinal amebiasis and trichomoniasis. (See "Intestinal Entamoeba histolytica amebiasis" and "Extraintestinal Entamoeba histolytica amebiasis" and "Giardiasis: Treatment and prevention" and "Trichomoniasis: Clinical manifestations and diagnosis".)

Metronidazole is generally well tolerated; adverse effects include mild abdominal pain, headache, nausea, and metallic taste. It produces a disulfiram-like reaction when taken with alcohol. (See "Metronidazole: An overview".)

NIFURTIMOX — Nifurtimox is a synthetic nitrofuran compound for treatment of acute T. cruzi infection. The drug has little effect in chronic Chagas disease. (See "Chagas gastrointestinal disease" and "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Antitrypanosomal therapy'.)

Nifurtimox can be used in combination with eflornithine or melarsoprol for treatment of African trypanosomiasis due to T. b. gambiense. (See "Human African trypanosomiasis: Treatment and prevention".)

Adverse reactions are common and dose dependent, including nausea, vomiting, insomnia, headache, vertigo, tremor, paresthesias, and convulsions [23].

NITAZOXANIDE — Nitazoxanide is a nitrothiazolyl-salicylamide derivative useful for treatment diarrhea due to Cryptosporidium parvum in children and for the treatment of giardiasis in children and adults [24]. It is generally well tolerated. (See "Giardiasis: Treatment and prevention".)

Nitazoxanide has not been shown to be more effective than placebo in HIV-infected patients; prolonged therapy at higher doses may be required. (See "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis".)

PAROMOMYCIN — Paromomycin is an oral poorly absorbed aminoglycoside. It is used as a secondary drug for treatment of noninvasive amebiasis. (See "Intestinal Entamoeba histolytica amebiasis".)

It may also be used for the treatment of giardiasis during pregnancy when the disease is not severe enough to require definitive therapy with metronidazole or quinacrine. (See "Giardiasis: Treatment and prevention".)

PENTAMIDINE — Pentamidine isethionate is an aromatic diamine compound active against Pneumocystis and several protozoal pathogens including Leishmanii spp and T. b. gambiense [25]. Pentamidine has poor cerebrospinal fluid penetration; therefore, its use is limited to first-stage trypanosomiasis (without central nervous system involvement).

Adverse reactions of parenteral pentamidine are common, including reversible nephrotoxicity, acute hypotension, pancreatitis, hypoglycemia, cardiac arrhythmias, blood dyscrasias, and sterile abscesses at the injection site [26,27].

Aerosolized pentamidine used for the prophylaxis of Pneumocystis pneumonia in susceptible patients is associated with local adverse effects, including sore throat, oral paresthesias, metallic taste, cough, and bronchospasm.

PYRIMETHAMINE — Pyrimethamine-sulfadiazine is used in the treatment of toxoplasmosis. The high doses required for this treatment often result in significant folate deficiency, requiring folinic acid replacement. Abdominal symptoms and rashes are also common. (See "Toxoplasmosis in patients with HIV".)

Pyrimethamine-dapsone is used for prophylaxis of Pneumocystis pneumonia. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Treatment and prevention of Pneumocystis infection in patients with HIV".)

Pyrimethamine is effective for acute treatment and maintenance suppression of Isospora belli infections [28]. (See "Management of Cystoisospora (Isospora) infections".)

QUINACRINE — Quinacrine is an acridine dye with activity against giardiasis. It is well absorbed and may impart a yellow color to the urine and rarely to the skin or sclerae. Adverse effects include headache, dizziness, vomiting, diarrhea, and, less commonly, psychotic episodes.

SPIRAMYCIN — Spiramycin has activity against toxoplasmosis and is an alternative to antifolates. In the setting of intrauterine infection, spiramycin is administered throughout pregnancy until delivery. (See "Toxoplasmosis and pregnancy".)

SURAMIN — Suramin is a polysulfonated naphthylamine derivative of urea. The mechanism of action is not fully understood; it is thought to act by inhibition of enzymes associated with DNA metabolism and protein synthesis in trypanosomal parasites. Suramin is used for treating the early stage of East African trypanosomiasis due to T. b. rhodesiense. It must be given intravenously and is excreted very slowly. Adverse effects are common and can be severe, including cutaneous eruptions, vomiting, paresthesias, photophobia, peripheral neuropathy, anaphylaxis, and renal damage. (See "Human African trypanosomiasis: Epidemiology, clinical manifestations, and diagnosis".)

TETRACYCLINE — Tetracycline has activity against B. coli and D. fragilis enteric infections. (See "Balantidium coli infection" and "Dientamoeba fragilis".)

TINIDAZOLE — Tinidazole has activity against amebiasis, giardiasis, and vaginal trichomoniasis and may be better tolerated than metronidazole. (See "Intestinal Entamoeba histolytica amebiasis" and "Extraintestinal Entamoeba histolytica amebiasis" and "Giardiasis: Treatment and prevention" and "Trichomoniasis: Clinical manifestations and diagnosis".)

TRIMETHOPRIM-SULFAMETHOXAZOLE — Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred treatment for Pneumocystis pneumonia and is used for prophylaxis against this infection in immunocompromised patients. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV" and "Treatment and prevention of Pneumocystis infection in patients with HIV".)

TMP-SMX is effective in treating enteric infections with Isospora belli and is used as long-term maintenance therapy to prevent relapse in patients with AIDS. (See "Epidemiology, clinical manifestations, and diagnosis of Cystoisospora (Isospora) infections".)

TMP-SMX also has activity against enteric infection due to Cyclospora. (See "Cyclospora infection".)

Adverse effects are primarily due to the sulfamethoxazole and include skin, liver, and bone marrow toxicity.

SUMMARY

●Treatment for giardiasis – Antiprotozoal agents with activity against giardiasis include metronidazole, nitazoxanide, tinidazole, furazolidone, and quinacrine. (See 'Metronidazole' above and 'Nitazoxanide' above and 'Tinidazole' above and 'Furazolidone' above and 'Quinacrine' above.)

●Treatment for pneumocystis pneumonia – Antiprotozoal agents with activity against Pneumocystis include trimethoprim-sulfamethoxazole, atovaquone, pentamidine, and pyrimethamine-dapsone. (See 'Trimethoprim-sulfamethoxazole' above and 'Atovaquone' above and 'Pentamidine' above and 'Pyrimethamine' above.)

●Treatment for amebiasis – Antiprotozoal agents with activity against amebiasis include metronidazole, tinidazole, and paromomycin. (See 'Metronidazole' above and 'Tinidazole' above and 'Paromomycin' above.)

●Treatment for Dientamoeba fragilis and Balantidium coli – Tetracycline and iodoquinol have activity against both Dientamoeba fragilis and Balantidium coli. (See 'Tetracycline' above.)

●Details of treatment regimens – The use of antiprotozoal therapies for treatment of specific protozoal infections is discussed in detail separately. (See related topics.)