Lecture #173: Chemotherapy of Protozoal Infections

What are the major protozoal diseases covered in this lecture?

Amoebiasis, giardiasis, trichomoniasis, African trypanosomiasis, Chagas disease, leishmaniasis, and toxoplasmosis.

How are pathogenic protozoa commonly transmitted?

By insect vectors, fecal-oral transmission, contaminated water, sexual transmission, mammalian reservoirs, or congenital spread.

What is the mechanism of nitroimidazole antiprotozoal drugs?

Activated by parasite pyruvate:ferredoxin oxidoreductase or nitroreductase to toxic nitro free radicals that damage DNA and proteins.

Which drugs are nitroimidazoles?

Metronidazole, tinidazole, secnidazole, fexinidazole, nifurtimox, and benznidazole.

What organisms are treated with metronidazole?

Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, and anaerobic bacteria.

What is metronidazole’s major pharmacokinetic advantage?

Nearly 100% oral bioavailability with excellent tissue and abscess penetration including CSF and liver abscesses.

What is the major advantage of tinidazole over metronidazole?

Longer half-life allowing less frequent dosing and often better tolerability.

What infection is secnidazole primarily used for?

Bacterial vaginosis and trichomoniasis.

What are common metronidazole adverse effects?

Headache, nausea, metallic taste, dry mouth, GI upset, dizziness, and dark urine.

What serious neurologic toxicities can metronidazole rarely cause?

Encephalopathy, convulsions, and paresthesias.

What important drug interaction occurs with metronidazole?

Increased anticoagulant effects of warfarin.

What is paromomycin’s mechanism of action?

Binds 16S rRNA on the 30S ribosome and inhibits protein synthesis.

Why is paromomycin called a luminal amebicide?

It is poorly absorbed orally and remains in the intestinal lumen.

Why are metronidazole and paromomycin used together for amoebiasis?

Metronidazole kills invasive trophozoites while paromomycin eradicates luminal cysts and prevents recurrence.

What are the main adverse effects of paromomycin?

Abdominal cramps, diarrhea, nausea, vomiting, nephrotoxicity, ototoxicity, and muscle weakness.

Which protozoan causes sleeping sickness?

Trypanosoma brucei.

What insect transmits African trypanosomiasis?

The tsetse fly.

Which form of HAT is chronic and more common?

Gambiense HAT caused by T. brucei gambiense.

Which form of HAT is rapidly progressive?

Rhodesiense HAT caused by T. brucei rhodesiense.

What is the preferred oral drug for early-stage HAT?

Fexinidazole.

What makes fexinidazole favorable compared with older HAT drugs?

It is oral, safer, and crosses the blood-brain barrier.

What is the mechanism of fexinidazole?

Activated by parasite nitroreductase to nitro free radicals that damage DNA and proteins.

What are major toxicities of fexinidazole?

Neuropsychiatric effects, neutropenia, nausea, dizziness, and QT prolongation.

Why is long-term follow-up needed after fexinidazole therapy?

Relapse can occur up to 24 months after treatment.

What is the mechanism of pentamidine?

Interferes with kinetoplast DNA, RNA polymerase, ribosomal function, and nucleic acid synthesis.

What are important toxicities of pentamidine?

Hypoglycemia, nephrotoxicity, bone marrow suppression, neuropathy, and electrolyte abnormalities.

What is the mechanism of eflornithine?

Irreversible inhibition of ornithine decarboxylase causing depletion of parasite polyamines.

What is NECT?

Nifurtimox-eflornithine combination therapy used for severe late-stage gambiense HAT.

What are major toxicities of eflornithine?

Diarrhea, leukopenia, anemia, seizures, hearing loss, and bone marrow suppression.

What is the only effective treatment for late-stage rhodesiense HAT?

Melarsoprol.

Why is melarsoprol reserved for severe disease?

It is extremely toxic and can cause fatal reactive encephalopathy.

What is melarsoprol’s mechanism?

Melarsen oxide binds sulfhydryl groups and inhibits trypanothione reductase.

What are major toxicities of melarsoprol?

Encephalopathy, nephrotoxicity, hepatotoxicity, bone marrow toxicity, paralysis, and cardiac toxicity.

What is suramin used for?

Early-stage rhodesiense HAT.

Why should suramin be avoided in patients with Onchocerca volvulus coinfection?

It can trigger severe immunologic reactions.

What is the mechanism of suramin?

Inhibits glycolytic enzymes and disrupts parasite energy metabolism.

What disease is caused by Trypanosoma cruzi?

Chagas disease.

What are the preferred drugs for Chagas disease?

Benznidazole and nifurtimox.

Which Chagas drug is generally preferred?

Benznidazole because it is better tolerated and dosed twice daily.

What is the mechanism of benznidazole and nifurtimox?

Formation of nitro free radicals causing DNA damage and enzyme inactivation.

What are major adverse effects of benznidazole?

Photosensitivity rash, peripheral neuropathy, and rare bone marrow suppression.

What are major adverse effects of nifurtimox?

Nausea, vomiting, insomnia, dizziness, irritability, tremors, and polyneuropathy.

What vector transmits leishmaniasis?

The sand fly.

What cells do Leishmania parasites infect?

Macrophages and other phagocytic cells.

What are the major forms of leishmaniasis?

Cutaneous, mucosal, and visceral leishmaniasis.

What are pentavalent antimonials used for?

First-line treatment of mucosal and many cutaneous forms of leishmaniasis.

What are the pentavalent antimonial drugs?

Sodium stibogluconate and meglumine antimoniate.

What is the mechanism of pentavalent antimonials?

Reduced to toxic Sb3+ species that disrupt ATP/GTP availability, DNA transcription, and metabolic pathways.

What are major toxicities of pentavalent antimonials?

QT prolongation, pancreatitis, hepatotoxicity, nephrotoxicity, anemia, leukopenia, and thrombocytopenia.

What is amphotericin B’s mechanism against leishmania?

Forms pores in parasite membranes by binding ergosterol-like membrane components.

What are major toxicities of amphotericin B?

Infusion reactions, nephrotoxicity, anemia, and hypersensitivity reactions.

What is miltefosine?

The first consistently effective oral drug for visceral and cutaneous leishmaniasis.

Why is miltefosine contraindicated in pregnancy?

It is teratogenic and fetotoxic.

What are common miltefosine adverse effects?

Nausea, vomiting, diarrhea, hepatotoxicity, nephrotoxicity, rash, and decreased sperm quality.

What organism causes toxoplasmosis?

Toxoplasma gondii.

Who are at highest risk for severe toxoplasmosis?

Pregnant patients and immunocompromised HIV/AIDS patients.

What is used for toxoplasmosis during early pregnancy?

Spiramycin before 14 weeks gestation.

What is the standard regimen for fetal toxoplasmosis after 14 weeks gestation?

Pyrimethamine plus sulfadiazine plus leucovorin.

Why is leucovorin given with pyrimethamine?

To reduce folate deficiency and bone marrow toxicity.

What is the mechanism of pyrimethamine?

Inhibits parasitic dihydrofolate reductase.

What is the mechanism of sulfadiazine?

Inhibits dihydropteroate synthase in folate synthesis.

What is the preferred prophylaxis for toxoplasmosis in HIV/AIDS patients?

TMP-SMX.

What common pharmacologic theme links many antiprotozoal drugs?

Generation of reactive oxygen species/free radicals or disruption of essential parasite metabolic pathways.