Metronidazole — Nitroimidazole Class
Mechanism
Anaerobic Reductive Activation
- Prodrug: reduced by ferredoxin in anaerobic organisms
- Reactive nitroso radical → DNA strand breaks
- Mammalian cells lack ferredoxin → selective toxicity
- Tinidazole: same mechanism, longer half-life, single-dose options
Key Clinical Points
Spectrum and Interactions
- Protozoa: Giardia, Entamoeba, Trichomonas
- Bacteria: Bacteroides, Clostridium, anaerobes
- Amebic liver abscess: add luminal agent (diloxanide or iodoquinol)
- Alcohol: disulfiram-like reaction (acetaldehyde accumulation)
- Warfarin: potentiated via CYP2C9 inhibition
Human African Trypanosomiasis (HAT) — Stage-Dependent Treatment
Treatment by Stage and Subspecies
| Stage |
T. b. gambiense |
T. b. rhodesiense |
Key Mechanism |
| Stage 1 (blood) |
Pentamidine |
Suramin |
No blood-brain barrier penetration needed |
| Stage 2 (CNS) |
NECT (nifurtimox + eflornithine) |
Melarsoprol |
Blood-brain barrier penetration required |
Eflornithine Selectivity
Irreversible ornithine decarboxylase inhibitor → blocks polyamine synthesis. T. b. gambiense has slower ornithine decarboxylase turnover than T. b. rhodesiense → sustained inhibition in gambiense only. Melarsoprol: arsenic binds trypanothione → kills both subspecies in stage 2 but causes post-treatment reactive encephalopathy.
Chagas Disease and the Trypanothione System
Chagas Disease
Benznidazole / Nifurtimox
- Benznidazole: nitroimidazole; reductive activation by T. cruzi nitroreductases → DNA/protein damage
- Nifurtimox: nitrofuran; generates reactive oxygen species → overwhelms trypanothione
- Acute phase and congenital disease: high cure rates
- Chronic cardiomyopathy: reduces PCR positivity; cardiac benefit unproven (BENEFIT trial)
- Both agents: teratogenic — contraindicated in pregnancy
Shared Vulnerability
Trypanothione System
- Trypanosoma and Leishmania use trypanothione (not glutathione) as primary antioxidant
- Absent in mammalian cells → selective drug target
- Melarsoprol: arsenic binds trypanothione directly
- Nifurtimox: reactive oxygen species overwhelm trypanothione
- Antimonials (Sb III): inhibit trypanothione reductase
- Eflornithine: depletes polyamine precursors for trypanothione synthesis
Leishmaniasis — Drug Selection by Form and Region
First-Line Visceral
Liposomal Amphotericin B
- Binds Leishmania membrane sterols → lethal ion flux
- Liposomal: targets reticuloendothelial system where amastigotes live
- Reduced nephrotoxicity vs conventional form
- HIV coinfection: indefinite secondary prophylaxis required
First Oral Agent
Miltefosine
- Alkylphosphocholine → disrupts Leishmania membrane phospholipids
- First-line in South Asia (antimonial resistance prevalent)
- Teratogenic — contraception mandatory during and after treatment
- Long half-life: resistance selection risk
Legacy Agents
Antimonials / Pentamidine
- Antimonials (Sb V → Sb III): inhibit trypanothione reductase; resistance high in South Asia
- Pentamidine: disrupts kinetoplast DNA; severe hypoglycemia risk
- Antimonials still active in East Africa and parts of South America
Toxoplasmosis — Sequential Folate Blockade
Standard Treatment
Pyrimethamine + Sulfadiazine
- Sulfadiazine: inhibits DHPS (early folate synthesis step)
- Pyrimethamine: inhibits DHFR (downstream folate step)
- Sequential double blockade → synergistic antiparasitic effect
- Folinic acid (leucovorin) mandatory: bypasses DHFR block in human cells
- Folic acid does NOT substitute — cannot bypass DHFR block
Prophylaxis
Trimethoprim-Sulfamethoxazole
- Preferred primary prophylaxis in HIV with advanced immunosuppression
- Also covers Pneumocystis jirovecii pneumonia simultaneously
- Discontinue after sustained immune reconstitution on antiretroviral therapy
- Spiramycin: reduces vertical transmission in pregnancy (does not treat established fetal infection)