Chemotherapy for Amebiasis

• The topic involves the use of antiprotozoal drugs to treat diseases caused by protozoan parasites, which are prevalent in tropical and subtropical regions due to poor sanitation and vector control
• Protozoal infections are difficult to treat because protozoan cells share metabolic processes with human hosts
• Many antiprotozoal drugs have toxic effects, especially on highly active cells, and are generally unsafe for pregnant patients

Chemotherapy for Amebiasis

• Amebiasis, or amebic dysentery, is an intestinal tract infection caused by Entamoeba histolytica, which is endemic in developing countries
• Transmission is via the fecal-oral route or through contaminated food or water
• Most infected individuals are asymptomatic
• Diagnosis is by isolating E. histolytica from feces
• Treatments are classified as luminal, systemic, or mixed amebicides based on the site of action

Mixed Amebicides

• Mixed amebicides include metronidazole and tinidazole

Metronidazole

• Metronidazole is a nitroimidazole and the preferred mixed amebicide for amebic infections
• It is also used to treat infections caused by Giardia lamblia, Trichomonas vaginalis, anaerobic cocci, gram-negative bacilli (e.g., Bacteroides), and gram-positive bacilli (e.g., Clostridioides difficile)
• It acts as an electron acceptor, leading to cytotoxic compounds that bind to proteins and DNA, causing the death of E. histolytica trophozoites
• Orally administered metronidazole is rapidly and completely absorbed, with widespread distribution in body tissues and fluids, including vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid
• It is metabolized in the liver
• The drug accumulates in severe hepatic disease
• It is excreted in urine
• Adverse effects include nausea, vomiting, epigastric distress, abdominal cramps, and a metallic taste
• It may lead to oral yeast infections and potentially prolong the QT interval
• Combining metronidazole with alcohol can trigger a disulfiram-like reaction

Tinidazole

• Tinidazole is a second-generation nitroimidazole with a similar spectrum of activity and absorption as metronidazole
• It is used to treat amebiasis, amebic liver abscess, giardiasis, and trichomoniasis
• Its efficacy is comparable to metronidazole but at a higher cost
• It is metabolized by CYP3A4
• Its concentrations can be influenced by strong inducers or inhibitors of this enzyme
• Common adverse effects include gastrointestinal upset and a metallic taste
• Alcohol consumption is advised against during therapy

Luminal Amebicides

• Luminal amebicides include iodoquinol, diloxanide furoate, and paromomycin

Iodoquinol

• Iodoquinol is effective against luminal trophozoite and cyst forms of E. histolytica
• Adverse effects include rash, diarrhea, and dose-related peripheral neuropathy, including rare optic neuritis
• Long-term usage of iodoquinol is not advised

Paromomycin

• Paromomycin is an aminoglycoside antibiotic specifically effective against luminal forms of E. histolytica
• It is poorly absorbed from the gastrointestinal tract
• Its direct amebicidal action and reduction of intestinal flora contribute to its anti-amebic effects
• The main adverse effects include gastrointestinal distress and diarrhea

Systemic Amebicides

• Systemic amebicides include chloroquine

Chloroquine

• Chloroquine is effective in treating extraintestinal amebiasis, including liver abscesses and intestinal wall infections caused by amebas
• It is often combined with metronidazole or used as a substitute for nitroimidazoles in cases of intolerance to treat amebic liver abscesses
• Chloroquine eliminates trophozoites in liver abscesses but is not effective against luminal amebiasis, necessitating follow-up with a luminal amebicide
• Chloroquine is effective in treating malaria

Antimalarial drugs

• Four species of plasmodium typically cause human malaria: P. falciparum, P. vivax, P. malariae, and P. ovale
• Classification of drugs include tissue schizonticides and blood schizonticides

Tissue Schizonticides

• Includes primaquine

Primaquine

• Eradicates primary exoerythrocytic forms of P. falciparum and P. vivax and the secondary exoerythrocytic forms of recurring malarias (P. vivax and P. ovale)
• Leads to radical cures of the P. vivax and P. ovale malarias, which may remain in the liver in the exoerythrocytic form after the erythrocytic form of the disease is eliminated
• Destroys the sexual (gametocytic) forms of all four plasmodia in the plasma or prevents them from maturing later in the mosquito, interrupting the transmission of the disease
• Not effective against the erythrocytic stage of malaria and is often used in conjunction with a blood schizonticide, such as chloroquine, quinine, mefloquine, or pyrimethamine
• Metabolites of primaquine act as oxidants responsible for the schizonticidal action as well as for the hemolysis and methemoglobinemia encountered as toxicities
• Well absorbed on oral administration
• Rapidly oxidized to metabolites which appear in the urine
• Hemolytic anemia (in patient’s low levels of glucose-6- phosphate)
• Abdominal discomfort (with large doses) especially when administered in combination with chloroquine
• Methemoglobinemia
• Granulocytopenia (rarely)
• Contraindicated during pregnancy
• All Plasmodium species may develop resistance to primaquine

Blood Schizonticides

• Includes chloroquine, mefloquine, quinine and quinidine, and pyrimethamine

Chloroquine

• The mainstay of antimalarial therapy and the drug of choice in the treatment of erythrocytic P. falciparum malaria
• Less effective against P. vivax malaria
• Highly specific for the asexual form of plasmodia
• Also effective in the treatment of extraintestinal amebiasis
• Rapidly and completely absorbed following oral administration
• 4 days of therapy suffice to cure the disease
• Concentrates in erythrocytes, liver, spleen, kidney, lung, melanin-containing tissues, and leukocytes
• Some metabolic products have antimalarial activity
• Excretion by urine is enhanced as is acidified
• Higher doses, many more toxic effects occur, such as gastrointestinal upset, pruritus, headaches, and blurring of vision
• Discoloration of the nail beds and mucous membranes may be seen on chronic administration
• Electrocardiographic changes occur because it has a quinidine-like effect
• Dermatitis is produced by gold or phenylbutazone therapy
• Patients with psoriasis or porphyria should not be treated with chloroquine, because an acute attack may be provoked

Mefloquine

• An effective single agent for suppressing and curing infections caused by multidrug-resistant forms of P. falciparum
• Its exact mechanism of action remains to be determined, but like quinine, it can apparently damage the parasite's membrane
• Absorbed well after oral administration and concentrates in the liver and lung
• Has a long half-life (17 days) because of its concentration in various tissues and its continuous circulation through the enterohepatic and enterogastric systems
• The drug undergoes extensive metabolism
• Its major excretory route is the feces
• Adverse reactions at high doses range from nausea, vomiting, and dizziness to disorientation, hallucinations, and depression
• Electrocardiographic abnormalities and cardiac arrest are possible if mefloquine is taken concurrently with quinine or quinidine

Quinine and quinidine

• Interfere with heme polymerization, resulting in death of the erythrocytic form of the plasmodial parasite
• These drugs are reserved for severe infestations and for malarial strains that are resistant to other agents, such as chloroquine
• Taken orally, quinine is well distributed throughout the body and can reach the fetus
• Alkalinization of the urine decreases its excretion
• Major adverse effects of quinine include cinchonism (syndrome causing nausea, vomiting, tinnitus, and vertigo) and a positive Coombs' test for hemolytic anemia
• Quinine is fetotoxic
• Potentiates neuromuscular-blocking agents
• Elevates digoxin levels if taken concurrently with quinine
• Quinine absorption is retarded when the drug is taken with aluminum-containing antacids

Pyrimethamine

• Inhibits plasmodial dihydrofolate reductase at much lower concentrations than those needed to inhibit the mammalian enzyme
• The inhibition deprives the protozoan of tetrahydrofolate cofactor required in the de-novo biosynthesis of purines and pyrimidines
• It is also used against P. malariae and toxoplasma gondii
• If megaloblastic anemia occurs with pyrimethamine treatment, it may be reversed with leucovorin

Chemotherapy for Trypanosomiasis

• Only four drugs are available for the chemotherapy of human African trypanosomiasis or sleeping sickness; Suramin, pentamidine, melarsoprol and eflornithine
• African trypanosomiasis (sleeping sickness) and American trypanosomiasis (Chagas disease) are two chronic and, eventually, fatal diseases caused by species of Trypanosoma
• In African sleeping sickness, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense initially live and grow in the blood
• The parasite later invades the CNS, causing inflammation of the brain and spinal cord that produces the characteristic lethargy and, eventually, continuous sleep
• Chagas disease is caused by Trypanosoma cruzi and is endemic in Central and South America

Pentamidine

• Pentamidine is utilized to treat African trypanosomiasis caused by T. brucei gambiense in the early hemolymphatic stage without CNS involvement
• It is an alternative for preventing or treating infections caused by the atypical fungus P. jirovecii, especially in immunocompromised individuals
• It is considered in cases where sulfonamides are contraindicated and is an alternative for treating leishmaniasis
• The drug's mechanism of action involves concentration in T. brucei through an energy-dependent uptake system, potentially interfering with parasite synthesis of RNA, DNA, phospholipids, and proteins
• Pentamidine is administered intravenously or intramuscularly for trypanosomiasis and P. jirovecii pneumonia
• It carries risks of serious reversible renal dysfunction upon discontinuation
• Adverse effects such as hyperkalemia, hypotension, pancreatitis, ventricular arrhythmias, and hyperglycemia
• Monitoring plasma glucose is crucial due to the potential for life-threatening hypoglycemia

Suramin

• Primarily employed in the early stage of African trypanosomiasis caused by T. brucei rhodesiense, especially when there is no central nervous system (CNS) involvement
• Its mechanism of action involves inhibiting various enzymes, particularly those related to energy metabolism, which contributes to its trypanocidal activity
• Administered intravenously, suramin binds to plasma proteins, poorly penetrates the blood-brain barrier, and exhibits a prolonged elimination half-life (over 40 days)
• Primarily excreted unchanged in urine
• Adverse reactions, though rare, may encompass nausea, vomiting, shock, loss of consciousness, acute urticaria, blepharitis, and neurologic issues such as paresthesia, photophobia, and hyperesthesia of the hands and feet
• Renal insufficiency, if present, tends to resolve upon discontinuation of treatment, and acute hypersensitivity reactions are also possible

Melarsoprol

• A trivalent arsenical compound, is the primary treatment for late-stage African trypanosome infections with CNS involvement from T. brucei rhodesiense
• The drug interacts with sulfhydryl groups, affecting pyruvate kinase enzymes in both the organism and host
• Administration through slow IV injection is crucial to reduce the risk of resistance, potentially associated with decreased transporter uptake
• Associated with CNS toxicity, particularly reactive encephalopathy, resulting in a 10% fatality rate
• Co-administration of corticosteroids can help mitigate the risk of encephalopathy
• Adverse effects include peripheral neuropathy, hypertension, hepatotoxicity, albuminuria, hypersensitivity reactions, and febrile reactions post-injection
• Individuals with glucose-6-phosphate dehydrogenase deficiency may experience hemolytic anemia as a side effect

Eflornithine

• A crucial component in the treatment of late-stage African trypanosomiasis when combined with nifurtimox
• The intravenous form is used, but frequent dosing is required due to its short half-life
• Additionally, topical eflornithine is employed to manage unwanted facial hair in women
• Potential adverse reactions include anemia, thrombocytopenia, seizures, and temporary hearing loss

Nifurtimox

• This drug, when combined with eflornithine, is employed to treat advanced infections of T. brucei gambiense and T. cruzi (Chagas disease)
• Functioning as a nitroaromatic compound, it undergoes reduction, generating toxic oxygen radicals that are detrimental to T. cruzi
• Administered orally, the drug is excreted through urine
• Adverse effects include hypersensitivity reactions, gastrointestinal problems, and peripheral neuropathy

Benznidazole

• A nitroimidazole derivative akin to nifurtimox, is the preferred treatment for Chagas disease due to its improved tolerability compared to nifurtimox
• Adverse effects, such as dermatitis, peripheral neuropathy, insomnia, and anorexia, are common
• Both benznidazole and nifurtimox are cautioned against during pregnancy due to the potential risk of harm to the fetus

Chemotherapy for Leishmaniasis

• Leishmaniasis, caused by various Leishmania species and transmitted by infected sand flies, presents in three forms: cutaneous, mucocutaneous, and visceral (potentially fatal if untreated)
• Treatments for visceral leishmaniasis include amphotericin B, pentavalent antimonials (sodium stibogluconate or meglumine antimoniate), pentamidine, and paromomycin
• Miltefosine, an orally active agent, is also effective
• Sodium stibogluconate, administered parenterally, is a prodrug with an unknown mechanism of action, and resistance has developed
• Miltefosine interferes with parasitic cell membrane components and induces apoptosis, but its use is cautioned during pregnancy due to teratogenic effects
• Adverse reactions for both treatments include various side effects such as injection site pain, gastrointestinal upset, and cardiac arrhythmias

Chemotherapy for Toxoplasmosis

• Toxoplasmosis, a common human infection caused by the protozoan T. gondii, is transmitted through consumption of raw or undercooked infected meat, contaminated water, or accidental ingestion of oocysts from cat feces
• Pregnant women can transmit the infection to their fetus, and immunocompromised patients may develop severe disseminated disease
• Current treatments focus on the tachyzoite stage, with pyrimethamine, particularly in combination with sulfadiazine, being the most effective
• Leucovorin is often administered to prevent folate deficiency
• Alternative treatments include pyrimethamine with clindamycin or trimethoprim/sulfamethoxazole
• Prophylaxis against toxoplasmosis in immunocompromised patients involves the use of trimethoprim/sulfamethoxazole
• Discontinuation of pyrimethamine is advised at the first sign of a rash due to potential severe hypersensitivity reactions

Chemotherapy for Giardiasis

• Giardia lamblia, the most commonly diagnosed intestinal parasite in the United States, is typically contracted through fecally contaminated water or food
• Infections involve trophozoites in the small intestine, occasionally forming cysts passed in stools
• While some cases are asymptomatic, severe diarrhea, particularly in immunocompromised individuals, can occur
• The preferred treatment is a single oral dose of tinidazole, with oral metronidazole as an alternative for 5 days
• Nitazoxanide, approved for giardiasis and cryptosporidiosis, is administered as a 3-day oral therapy for giardiasis
• Albendazole and paromomycin may also be effective, with paromomycin considered for pregnant patients