Agents Used toTreat Parasitic Infections¶
Chapter 229 | Part 5: Infectious Diseases · Part 5 – Infectious Diseases: Parasitic · Chapter 229
Key Clinical Points¶
- G6PD deficiency testing is mandatory before administering Primaquine or Tafenoquine to prevent hemolysis.
- Albendazole absorption increases 5-fold with a high-fat meal (approximately 40 g); its metabolite albendazole sulfoxide crosses the blood-brain barrier.
- Artemisinin derivatives are first-line for severe falciparum malaria but are not active against intrahepatic forms; they are cleared rapidly and are not suitable for prophylaxis.
- Antimonials (SbV) are first-line for leishmaniasis but require prolonged parenteral treatment and monitoring for cardiotoxicity.
- Mefloquine and Halofantrine have fatal QTc prolongation risks; avoid concomitant use within 3 weeks.
- Amphotericin B formulations (lipid complex, ABLC, liposomal) have reduced nephrotoxicity compared to deoxycholate.
- Pregnancy categories range from A (safe) to X (contraindicated); FDA categories apply to US usage.
- Drug resistance (e.g., artemisinin resistance in Uganda) and counterfeit medications are major challenges in global control efforts.
1. DEFINITION & OVERVIEW¶
• Overview: Parasitic infections affect over half the world's population, with significant health burdens in underdeveloped nations. • Drivers of Expansion: Linked to deforestation, climate change, and global warming. • Control Methods: Chemotherapy remains the most effective control method despite challenges from drug resistance and counterfeit medications.
1.1 Global Burden & Control¶
• Successes: Global initiatives against malaria, tuberculosis, and AIDS show success. • Innovation: New antiparasitic agents are being developed through repurposing of existing drugs.
1.2 Mechanism of Action: Albendazole¶
• Binding: Binds to beta-tubulin in nematodes. • Effect: Inhibits glucose uptake → causes nematode starvation. • Scope: Effective against a wide range of parasitic diseases.
1.3 Mechanism of Action: Artemisinin Derivatives¶
• Efficacy: Rapidly effective against asexual blood forms of Plasmodium. • Concentration: Concentrated in parasitized erythrocytes (100x higher than uninfected). • Active Metabolite: Dihydroartemisinin generates free radicals via heme/iron interaction.
1.4 Mechanism of Action: Antimonials¶
• Reduction: Pentavalent SbV reduced to trivalent Sb(III) form in vivo. • Inhibition: Inhibits trypanolithine reductase (Leishmania-specific enzyme). • Scope: Effective against all leishmaniasis forms.
2. EPIDEMIOLOGY¶
• Distribution: Parasitic infections vary by organ system and geography (see Table 228-1). • Clinical Rule: Malaria must be considered in any patient from malarious areas.
2.1 Organ System Distribution¶
• Muscular System: Trichinella (worldwide) → palpebral swelling. • Bloodstream: ◦ Plasmodium (tropics/subtropics) ◦ Babesia (New England, USA) ◦ T. brucei (Sub-Saharan Africa) → painful chancre, adenopathy, cyclical fevers ◦ Filariae (Asia, India) → periodic fever, eosinophilia, lymphangitis ◦ L. donovani complex (tropics/subtropics) → hepatosplenomegaly, wasting.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Pathogens: Caused by protozoa, helminths, and arthropods. • Pathogenesis: Involves tissue invasion, nutrient competition, and immune evasion. • Resistance Mechanisms: ◦ Target site modification (e.g., artemisinin resistance in Uganda). ◦ Efflux pumps.
4. CLINICAL FEATURES¶
• General Signs: Fever, myalgias, eosinophilia, hepatosplenomegaly, lymphadenopathy. ◦ Specific signs: palpebral swelling (Trichinella), retinal injury (Chloroquine), QTc prolongation (Mefloquine/Halofantrine). • Systemic Symptoms: ◦ Fever without localizing symptoms → malaria, trypanosomiasis. ◦ Myalgias/myositis → Trichinella infection. ◦ Hepatosplenomegaly/wasting → L. donovani complex (Kala-azar). • Drug-Induced Clinical Features: ◦ Chloroquine: pruritus, nausea, vomiting, hair depigmentation, corneal opacity; rare retinal injury. ◦ Mefloquine: lightheadedness, nightmares, QTc prolongation; rare psychosis/convulsions. ◦ Artemisinin derivatives: neurotoxicity (ataxia), nausea, contact dermatitis.
5. DIFFERENTIAL DIAGNOSIS¶
• Fever in travelers from malarious areas: Consider malaria vs Babesia/Leishmaniasis/Trypanosomiasis. • Myalgias: Trichinella or other myositis causes. • Hepatosplenomegaly with fever: Leishmaniasis, Malaria, L. donovani complex.
6. INVESTIGATIONS & DIAGNOSIS¶
- Initial Assessment: Clinical suspicion based on symptoms and travel history.
- Pre-treatment Screening: ◦ For Primaquine or Tafenoquine → Mandatory G6PD testing to prevent hemolysis.
- Monitoring during treatment: ◦ Mefloquine/Halofantrine → ECG monitoring for QTc prolongation. ◦ Albendazole/Amphotericin B → Liver function tests (LFTs) to monitor hepatotoxicity and nephrotoxicity.
6.1 Laboratory Monitoring¶
• G6PD Testing: Mandatory before Primaquine/Tafenoquine. • ECG Monitoring: Required for Mefloquine/Halofantrine. • Liver Function Tests: During Albendazole/Amphotericin B therapy.
6.2 Diagnostic Criteria & Thresholds¶
• Monitoring Protocols: Follow specific thresholds for drug monitoring and adverse effect detection as per Harrison's guidelines.
7. MANAGEMENT & TREATMENT¶
- Antimalarial Agents: ◦ Artemisinin derivatives: First-line for severe falciparum malaria; not suitable for prophylaxis due to rapid clearance and lack of activity against intrahepatic forms. ◦ Chloroquine: Used in chloroquine-sensitive regions; note interactions with antacids/kaolin (reduced absorption) and Cimetidine (increased levels). ◦ Mefloquine: Avoid concurrent use with QTc prolonging agents (e.g., Halofantrine) within 3 weeks.
- Antihelminthic Agents: ◦ Albendazole: Broad-spectrum for nematodes and cestodes; note that high-fat meal (approximately 40 g) increases absorption 5-fold; metabolite albendazole sulfoxide crosses blood-brain barrier. ◦ Ivermectin: Used for onchocerciasis, lymphatic filariasis. ◦ Praziquantel: Broad-spectrum antischistosomal agent.
- Antiprotozoal Agents: ◦ Amphotericin B: Use liposomal formulations (AmBisome) or lipid complex (Abelcet) for leishmaniasis to reduce nephrotoxicity compared to deoxycholate. ◦ Metronidazole: First-line for amebiasis and giardiasis. ◦ Miltefosine: Oral treatment for leishmaniasis.
7.1 Antimalarial Agents¶
• Artemisinin derivatives: First-line for severe malaria; not suitable for prophylaxis due to rapid clearance and lack of activity against intrahepatic forms. • Chloroquine: Used in sensitive regions; note interactions with antacids/kaolin (reduced absorption) and Cimetidine (increased levels). • Mefloquine: Contraindicated with QTc prolonging agents.
7.2 Antihelminthic Agents¶
• Albendazole: Effective against nematodes/cestodes; metabolite albendazole sulfoxide crosses blood-brain barrier. • Ivermectin: Onchocerciasis, lymphatic filariasis. • Praziquantel: Antischistosomal agent.
7.3 Antiprotozoal Agents¶
• Amphotericin B: Liposomal formulations preferred for leishmaniasis; avoid deoxycholate due to nephrotoxicity. • Metronidazole: Ameardiasis and giardiasis. • Miltefosine: Oral treatment for leishmaniasis.
8. PROGNOSIS & COMPLICATIONS¶
• Drug Resistance: Major challenge (e.g., artemisinin resistance in Uganda). • Adverse Effects: ◦ QTc prolongation (Mefloquine/Halofantrine). ◦ Nephrotoxicity (Amphotericin B deoxycholate). ◦ Hemolysis (Primaquine in G6PD deficiency). • Disease-specific sequelae: e.g., Kala-azar.
9. SPECIAL CONSIDERATIONS¶
• Pregnancy Categories: Range from A (safe) to X (contraindicated); FDA categories apply to US usage. • Breastfeeding Safety: Varies by drug class; some agents are contraindicated.
9.1 Pregnancy Categories¶
• Assessment: Based on fetal risk (A-X) as listed in Table 229-1.
9.2 Breastfeeding Safety¶
• Safety Profile: Varies by drug class and specific formulation.
10. KEY PEARLS & CLINICAL TRAPS¶
• G6PD Check: Mandatory for Primaquine/Tafenoquine. • Artemisinin Limitations: Not suitable for prophylaxis; rapid clearance; no intrahepatic activity. • QTc Risk: Mefloquine and Halofantrine (no co-use within 3 weeks). • Amphotericin Choice: Lipid formulations are safer than deoxycholate. • Albendazole Tip: High-fat meal (approximately 40 g) increases absorption 5-fold.
Reference Tables¶
TABLE 228-1 Parasitic Infections, by Organ System and Signs/Symptoms a¶
Harrison's 22e, p.1740
| ORGAN SYSTEM, MAJOR SIGN(S)/SYMPTOM(S) |
PARASITE(S) | GEOGRAPHIC DISTRIBUTION | COMMENTS |
|---|---|---|---|
| Muscular System | |||
| Myalgias, myositis | Trichinella | Worldwide | Palpebral swelling; high-level eosinophilia |
| Bloodstream | |||
| Plasmodium | Tropics and subtropics | ||
| Babesia | New England, United States | ||
| T. brucei rhodesiense, T. brucei gambiense |
Sub-Saharan Africa | ||
| Filariae | Asia, India | ||
| L. donovani complex | Tropics and subtropics |
TABLE 229-1 Overview of Agents Used for the Treatment of Parasitic Infections¶
Harrison's 22e, p.1741
| DRUGS BY CLASS | PARASITIC INFECTION(S) | ADVERSE EFFECTS | MAJOR DRUG–DRUG INTERACTIONS |
PREGNANCY CLASSa |
BREAST MILK |
|---|---|---|---|---|---|
| 4-Aminoquinolines | |||||
| Amodiaquine | Malariab | Agranulocytosis, hepatotoxicity | No information | Not assigned | Yesc |
| Chloroquine | Malariab | Occasional: pruritus, nausea, vomiting, headache, hair depigmentation, exfoliative dermatitis, reversible corneal opacity Rare: irreversible retinal injury, nail discoloration, blood dyscrasias |
Antacids and kaolin: reduced absorption of chloroquine Ampicillin: bioavailability reduced by chloroquine Cimetidine: increased serum levels of chloroquine Cyclosporine: serum levels increased by chloroquine |
Not assignedd | Yesc |
| Piperaquine | Malariab | Occasional: GI disturbances | None reported | Not assigned | Yes |
| Malariab Malariab |
Frequent: hemolysis in patients with G6PD deficiency Occasional: methemoglobinemia, GI disturbances Rare: CNS symptoms Frequent: hemolysis in patients with G6PD deficiency, mild GI upset Occasional: methemoglobinemia, headache |
Quinacrine: potentiated toxicity of primaquine No information |
Contraindicated Not assigned |
||
| Aminoalcohols | |||||
| Halofantrine | Malariab | Frequent: abdominal pain, diarrhea Occasional: ECG disturbances (dose-related prolongation of QTc and PR interval), nausea, pruritus; contraindicated in persons who have cardiac disease or who have taken mefloquine in the preceding 3 weeks |
Concomitant use of agents that prolong QTc interval contraindicated |
C | No information |
| Lumefantrine | Malariab | Occasional: nausea, vomiting, diarrhea, abdominal pain, anorexia, headache, dizziness |
Plasma levels increased by darunavir and nevirapine, decreased by etravirine |
Not assigned | No information |
| Amebiasis,b infection with Dientamoeba fragilis, giardiasis, cryptosporidiosis, leishmaniasis |
Frequent: GI disturbances (oral dosing only) Occasional: nephrotoxicity, ototoxicity, vestibular toxicity (parenteral dosing only) |
No major interactions | Oral: B Parenteral: not assignedd |
||
| Amphotericin B Amphotericin B deoxycholate Amphotec (InterMune) Amphotericin B lipid complex, ABLC (Abelcet) Amphotericin B, liposomal (AmBisome) |
Leishmaniasis,e amebic meningoencephalitis |
Frequent: fever, chills, hypokalemia, hypomagnesemia, nephrotoxicity Occasional: vomiting, dyspnea, hypotension |
Antineoplastic agents: renal toxicity, bronchospasm, hypotension Glucocorticoids, ACTH, digitalis: hypokalemia Zidovudine: increased myelo- and nephrotoxicity |
B | No information |
| Leishmaniasis | Frequent: arthralgias/myalgias, pancreatitis, ECG changes (QT prolongation, T-wave flattening or inversion) |
Antiarrhythmics and tricyclic antidepressants: increased risk of cardiotoxicity |
Not assigned | ||
| Artemisinin and derivatives |
Malariag | Occasional: neurotoxicity (ataxia, convulsions), nausea, vomiting, anorexia, contact dermatitis |
|||
| Arteether | No information | Not assigned | Yesc | ||
| Artemether | Artemether levels decreased by darunavir, etravirine, and nevirapine |
C | Yesc | ||
| Artesunateh | Mefloquine: levels decreased and clearance accelerated by artesunate |
C | Yesc | ||
| Dihydroartemisinin | Mefloquine: increased absorption | Not assigned | Yesc |