Amebicidal Drugs

In Lecturio - Amebiasis is an infection of the colon caused by Entamoeba histolytica. Infection occurs by ingestion of water and food contaminated with feces (containing cysts of Entamoeba histolytica). In this article, we will study in detail the various amebicides, their mechanism of action, adverse effects/toxicity, contraindications, drug interactions and drugs of choice. Other important therapeutic aspects of individual drugs will also be studied.

Table of Contents

• Overview of Amebiasis
• Functional and Chemical Classification of Amebicides
• Amebicidal Drugs
• Summary of Antiamebicidal Drug Treatment
• Review Questions
• References

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Image: “This micrograph stained with chlorazol black revealed an Entamoeba histolytica cyst.” by CDC/ Dr. George Healy – This media comes from the Centers for Disease Control and Prevention’s Public Health Image Library (PHIL), with identification number #1474. License: Public Domain

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Overview of Amebiasis

Amebiasis is an infection of the intestine caused by Entamoeba histolytica. It is a protozoan parasite. Human beings and other non-human primates are the main hosts. Infection occurs by ingestion of water and food contaminated with feces. The contaminated food/water contains the cysts of Entamoeba histolytica. It can cause extra-intestinal invasive infections.

E. dispar and E. histolytica are the only pathogenic amoebas known to humans. The protozoan enters the digestive tract and multiplies in the terminal ileum or colon to the trophozoite stage. Trophozoite of E. Histolytica is a motile form.

Inside the intestine, it causes necrosis and perforation of the intestinal wall. It can also penetrate the intestinal wall and reach the liver via the portal vein, where it may cause a fatal liver abscess.

Cysts are excreted into the feces. The life cycle of E. histolytica is completed at this stage. It can survive in the environment for weeks to months. Factors that increase the chances of amebiasis are travel to an endemic area, consumption of contaminated food/water and anal intercourse. The infection can cause an asymptomatic disease to mild to moderate intestinal cases (ulcers, dysentery) to severe or chronic cases.

Amebiasis is prevalent highly in developing countries where general sanitation hygiene is not available.

The classic symptoms of amebiasis are bloody or watery diarrhea, fever (10—30 % patients), anorexia, and weight loss. Rectal bleeding can occur without diarrhea in children. It remains asymptomatic in most individuals and resolves on its own. Invasive infections result when E. histolytica reaches organs such as the liver via the systemic circulation. If the infection is limited to the intestine it is called non-invasive infection.

Treatment is therefore directed at disinfecting luminal trophozoites (non-invasive infection), as well as those in the tissue (invasive infection) if the infection has spread to that extent. Not all drugs can disinfect the cysts of E. histolytica. Drugs are usually active either in the tissues or in the intestinal lumen, thereby necessitating a combination therapy for symptomatic amebiasis.

Patients should be educated to avoid contaminated food/water or undercooked food.

Functional and Chemical Classification of Amebicides

Tissue amebicides

• Nitro-imidazoles: Metronidazole, Tinidazole, etc.
• Alkaloid derivatives: Emetine and Dehydroemetine

Luminal amebicides

• Amide: Diloxanide furoate, Nitazoxanide
• 8-Hydroxyquinolines: Iodoquinol
• Antibiotics: Tetracycline and Erythromycin

Amebicidal Drugs

Tissue amebicides

Metronidazole

• A nitro-imidazole
• Selectively toxic to anaerobic microorganisms
• Half-life of metronidazole is 7.5 hours.

Mechanism of action	The nitro-group of nitro-imidazoles undergoes bioactivation by ferredoxin (which is present only in anaerobic microorganisms) to form reactive toxic metabolites (nitro radicals) that inhibit nucleic acid synthesis. This occurs by nitro-radicals competing with the energy metabolism pathway of anaerobic microorganisms.
Clinical uses	Amebiasis: drug of choice. It kills the tissue and intestinal trophozoites; however, it is not effective against cysts of E. histolytica. also indicated for an invasive type of amebiasis Giardiasis: drug of choice Trichomoniasis: drug of choice (a single dose of 2 g) Pseudomembranous colitis (caused by Clostridium difficile): drug of choice Effective against Helicobacter pylori. However, this should only be used in combination with another antibiotic (e.g., amoxicillin) and a proton pump inhibitor (e.g., omeprazole). Effective as treatment or prophylaxis of peri- and post-operative anaerobic infections (usually in combination with cephalosporins for a broad-spectrum coverage). Acute necrotizing ulcerative gingivitis (ANUG): drug of choice (in combination with amoxycillin, tetracycline, or erythromycin)
Adverse effect/toxicity	Nausea, vomiting, abdominal cramps, metallic taste, oral moniliasis, headache, dark urine Rare: neurotoxicity; if occurs, the drug should be discontinued. Rare: opportunistic infections may occur. Resistance to nitro-imidazoles develops when the microorganisms become deficient in the pathway that generates nitro-radicals.
Drug interactions	Alcohol should not be used during metronidazole therapy because a disulfiram-like reaction can occur. Cimetidine can reduce metronidazole metabolism. If administered together, dose adjustment is required. Metronidazole reduces warfarin metabolism. Metronidazole decreases renal excretion of lithium.
Contraindications	Blood dyscrasias Neurological disease Chronic alcoholism Not contraindicated in pregnancy, but should be used with caution.

Tinidazole

Tinidazole is  a second-generation nitro-imidazole. Its efficacy equals that of metronidazole, but it has a shorter course of treatment (3 days vs. 10 days for metronidazole), has a longer half-life (12—14 hours), and is more expensive.

Mechanism of action	Similar to metronidazole
Clinical uses	Amebiasis: drug of choice along with metronidazole. However, it must be used with a luminal agent. Giardiasis: drug of choice along with metronidazole. Trichomoniasis: can be used either as the first-line drug or in cases of metronidazole resistance. Effective against Helicobacter pylori. However, this should only be used in combination (see Metronidazole for details). Acute necrotizing ulcerative gingivitis (ANUG): drug of choice (in combination with amoxicillin, tetracycline, or erythromycin)
Adverse effect/toxicity	Similar to metronidazole
Drug interactions	Similar to metronidazole
Contraindications	Similar to metronidazole

Other nitro-imidazoles

• Secnidazole, ornidazole, and satranidazole
• They are similar to metronidazole/tinidazole but with a longer half-life.
• Satranidazole has much better tolerability (lower side effects).

Nitazoxanide

Nitazoxanide is a new nitrothiazole antiparasitic drug and Prodrug – gets converted to tizoxanide. Effective against numerous intestinal protozoa and helminths

Mechanism of action	Inhibits pyruvate: ferredoxin oxidoreductase enzyme (PFOR), which is essential for electron transport energy metabolism in anaerobic organisms.
Clinical uses	Amebic dysentery Approved by US FDA only for diarrhea caused by Cryptosporidiumand Giardia intestinalis. Shown to be effective against many other organisms such as Ascaris,Trichomonas vaginalis, tapeworms, several helminthic infections, etc.
Adverse effect/toxicity	Usually extremely well tolerated. GI symptoms such as abdominal pain, nausea, vomiting, and diarrhea (dose-dependent)
Drug interactions	None documented. However, the active metabolite tizoxanide is highly protein-bound. Therefore, its use with other highly protein-bound drugs must be avoided or done with caution.

Emetine & Dehydroemetine

Because of toxicity concerns rarely used. For example, severe amebiasis when metronidazole cannot be used. These act only against the trophozoites but not against the cysts.

In the setting of severe amebiasis, these drugs should be administered s.c. or i.m. (and not i.v.) for at least 3—5 days.

Mechanism of action	Block ribosomal movement along mRNA
Adverse effect/toxicity	Dose/time-dependent GI symptoms: nausea, vomiting, diarrhea Pain and tenderness at the injection site; muscle weakness; minor ECG changes Severe effects involve cardiotoxicity, e.g., arrhythmias. Dehydroemetine is somewhat better tolerated than emetine.
Contraindications	Absolute: cardiac disease and renal disease Relative: younger children and pregnant women

Luminal amebicides

Diloxanide furoate

• Amide
• Directly kills luminal trophozoites
• It does not kill the tissue trophozoites.
• No antibacterial action
• Prodrug (releases free diloxanide as the active metabolite)

Mechanism of action	Unknown
Clinical uses	Asymptomatic intestinal infection (alone). Amebic colitis (in conjunction with a nitro-imidazole; can be used alone in very mild cases) Less effective in invasive dysentery, because of poor tissue amebicidal action Although one course is usually sufficient, some chronic cases may require repeat courses for eradication. Please note diloxanide furoate is not available in the USA.
Adverse effect/toxicity	Usually well tolerated Flatulence, nausea, itching Rare: urticaria
Drug interactions	No known interactions

Iodoquinol

Directly kills amebic trophozoites, thereby inhibiting cyst production. Ineffective as tissue amebicide.

Mechanism of action	Unknown
Clinical uses	Asymptomatic intestinal infection (alone) Amebic colitis (in conjunction with a nitro-imidazole; can be used alone in very mild cases) Giardiasis Local treatment of monilial and trichomonas vaginitis
Adverse effect/toxicity	Usually well tolerated Nausea, transient greenish discoloration of stool, pruritus Thyroid enlargement, possible neurotoxic effects (related to iodine after considerable systemic absorption, e.g., due to high doses)
Contraindications	Pregnancy Hepatic insufficiency Hypersensitivity to iodine

Paromomycin

• Aminoglycoside
• May be superior to diloxanide in asymptomatic infection.
• It is only active as luminal amebicide.

Mechanism of action	Protein synthesis inhibitor by interacting with the 16S ribosomal subunit.
Clinical uses	Asymptomatic intestinal infection (alone) Amebic colitis (in conjunction with a nitro-imidazole; can be used alone in very mild cases) Cryptosporidiosis in AIDS patients Visceral leishmaniasis
Adverse effect/toxicity	Headaches, dizziness, rashes, arthralgia (due to considerable systemic absorption, e.g., in a patient with renal insufficiency)
Contraindications	Known hypersensitivity Intestinal obstruction

Other antibiotics

Some antibiotics can be used in the treatment of intestinal amebiasis. Examples include erythromycin and tetracycline.

Summary of Antiamebicidal Drug Treatment

Form of amebiasis	Treatment
Asymptomatic intestinal infection	Luminal agent (i.e., Diloxanide furoate*, 500 mg 3 times daily × 10 days or Iodoquinol, 650 mg 3 times daily × 21 days or Paromomycin, 10 mg/kg 3 times daily × 7 days)
Amebic colitis (mild to moderate)	Metronidazole, 750 mg 3 times daily (or 500 mg i.v. every 6 hours) × 10 days or Tinidazole, 2 g daily × 3 days plus Luminal agent
Amebic colitis (severe)	Metronidazole (same as above) or Tinidazole, 2 g daily × 3 days plus Luminal agent
Extraintestinal amebiasis	Metronidazole (same as above)or Tinidazole, 2 g daily × 5 days plus Luminal agent

*Diloxanide furoate is not available in the United States.

Review Questions

The correct answers can be found below the references.

1. Which of the following statements regarding amebicides is correct?

1. Diloxanide furoate is the drug of choice in hepatic amebiasis.
2. Iodoquinol inhibits the protein synthesis of E. histolytica.
3. Paromomycin is a diaminopyrimidine derivative.
4. Tinidazole is ineffective in cases of metronidazole resistance.
5. Metronidazole is used for amebiasis as well as postoperative prophylactic antibiotic therapy.

2. Which of the following is the mechanism of action of metronidazole?

1. Prevents the conversion of heme to hemozoin
2. Inhibits the nucleic acid synthesis
3. Inhibits the pyruvate synthesis
4. Damages the plasma membrane of amoeba
5. Inhibits the ATP synthesis in amoeba

3. Which of the following is the first-line drug for invasive amebiasis?

1. Metronidazole
2. Paromomycin
3. Diloxanide Furoate
4. Nitazoxanide
5. Iodoquinol