Chapter: Drugs for Leishmaniasis and Trypanosomiasis

1. Introduction/Overview

Leishmaniasis and trypanosomiasis represent two distinct groups of parasitic diseases that continue to impose a significant burden in endemic regions worldwide. Leishmaniasis is caused by protozoa of the genus Leishmania and manifests as cutaneous, mucocutaneous, or visceral disease. Trypanosomiasis is subdivided into human African trypanosomiasis (HAT) and Chagas disease (American trypanosomiasis), each with unique epidemiological features and clinical courses. Both diseases are transmitted by vectors (sandflies for leishmaniasis, tsetse flies for HAT, and triatomine bugs for Chagas disease) and pose therapeutic challenges due to drug toxicity, resistance patterns, and limited treatment options.

Clinical relevance is underscored by the potential for severe morbidity and mortality if treatment is delayed or inadequate. The emergence of drug-resistant strains further complicates management, necessitating a comprehensive understanding of available pharmacotherapies, mechanisms of action, and patient-specific considerations.

Learning objectives

• Identify the principal pharmacological agents employed in the treatment of leishmaniasis and trypanosiasis.
• Describe the mechanisms of action underlying key antileishmanial and antitrypanosomal drugs.
• Summarize pharmacokinetic properties, dosing strategies, and therapeutic monitoring guidelines for these agents.
• Recognize adverse effect profiles and potential interactions that influence clinical decision making.
• Apply special patient considerations, including pregnancy, renal/hepatic impairment, and pediatric/geriatric populations, to optimize therapy.

2. Classification

2.1 Antimonial Compounds

Pentavalent antimonials, including sodium stibogluconate and meglumine antimoniate, constitute a foundational class of antileishmanial drugs. Their hydrophilic nature necessitates parenteral administration, typically via intramuscular or intravenous routes. For HAT and Chagas disease, pentamidine and suramin represent distinct pentavalent agents with divergent pharmacologic profiles.

2.2 Amphotericin B Formulations

Amphotericin B, a polyene macrolide, is available in conventional, liposomal, lipid complex, and lipid-associated formulations. Lipid-based preparations are designed to reduce nephrotoxicity while preserving antileishmanial activity.

2.3 Alkylphosphocholines

Miltefosine, an alkylphosphocholine, is orally administered and exhibits a unique mechanism targeting phospholipid metabolism. Its mechanism of action distinguishes it from other antileishmanial classes.

2.4 Aminoglycoside Antibiotics

Paromomycin, an aminoglycoside, is formulated for topical or intramuscular use and operates by binding ribosomal RNA.

2.5 Nucleophilic and Oxidative Agents

Agents such as pentamidine, suramin, melarsoprol, eflornithine, nifurtimox, benznidazole, and fexinidazole fall under this category, each with distinct mechanisms involving oxidative stress, enzyme inhibition, or DNA intercalation.

2.6 Novel Prodrugs

Fexinidazole, a prodrug activated by hepatic metabolism, and the nitroimidazole benznidazole are noteworthy for their oral bioavailability and activity against both acute and chronic Chagas disease.

3. Mechanism of Action

3.1 Pentavalent Antimonials

Pentavalent antimonials are believed to undergo intracellular reduction to the trivalent form, which subsequently interferes with parasite protein synthesis by inhibiting trypanothione reductase, a key enzyme in maintaining redox balance. This inhibition leads to accumulation of reactive oxygen species and subsequent parasite death. The exact interaction with host cells remains incompletely elucidated, but evidence suggests modulation of host immune responses as a contributory factor.

3.2 Amphotericin B

Amphotericin B exerts its antileishmanial activity by binding to ergosterol-like sterols in parasite membranes, creating pores that disrupt ionic gradients. In host cells, the drug binds to cholesterol, leading to toxicity. Lipid formulations alter the biodistribution, favoring accumulation in macrophages and reducing renal exposure.

3.3 Miltefosine

Miltefosine disrupts phosphatidylserine flip-flop and phospholipid asymmetry, leading to altered membrane dynamics and apoptosis-like cell death in Leishmania parasites. Additionally, it interferes with fatty acid synthesis pathways, further compromising parasite viability.

3.4 Paromomycin

Paromomycin binds to the 28S ribosomal subunit of the parasite, inhibiting protein synthesis. Its selective affinity for the parasite ribosome over mammalian ribosomes accounts for its therapeutic window.

3.5 Pentamidine

Pentamidine intercalates into parasite DNA and inhibits nucleic acid synthesis. It also acts as an inhibitor of trypanothione reductase, thereby inducing oxidative damage. The drug’s lipophilic characteristics facilitate penetration across the blood–brain barrier, making it useful in HAT stage 2.

3.6 Suramin

Suramin blocks multiple parasite enzymes, including phosphodiesterases and polyphosphate kinases. By preventing the hydrolysis of ATP and the formation of polyphosphate, suramin disrupts energy metabolism within the parasite.

3.7 Melarsoprol

Melarsoprol, an arsenical, alkylates sulfhydryl groups on parasite proteins, leading to enzyme inactivation and impaired cellular functions. Its high lipophilicity allows penetration into the central nervous system, essential for treating late-stage HAT.

3.8 Eflornithine

Eflornithine competitively inhibits ornithine decarboxylase, an enzyme critical for polyamine synthesis in parasites. Inhibition of polyamine production hampers DNA replication and cell growth.

3.9 Nifurtimox and Benznidazole

Both nitroimidazole and nitroimidazotriazole agents generate reactive oxygen species via nitroreduction within the parasite. The generated radicals inflict oxidative damage on essential biomolecules, culminating in parasite death.

3.10 Fexinidazole

Fexinidazole is a prodrug that undergoes hepatic biotransformation to yield an active metabolite. This metabolite interferes with DNA synthesis by forming DNA adducts and also generates oxidative stress, thereby exerting antitrypanosomal effects.

4. Pharmacokinetics

4.1 Pentavalent Antimonials

Absorption is limited to parenteral routes, with bioavailability approaching 100% when administered intramuscularly. Distribution is extensive, but penetration into the central nervous system is variable, necessitating higher doses for CNS involvement. Metabolism involves reduction to the trivalent state, followed by renal excretion. The terminal half-life is approximately 8–12 hours, requiring frequent dosing over 20–30 days.

4.2 Amphotericin B

Conventional amphotericin B is poorly absorbed orally and is administered intravenously. It distributes widely, with high concentrations in the liver, spleen, and kidneys. Lipid formulations modify the pharmacokinetic profile, extending the half-life to 2–3 days and reducing peak plasma concentrations that correlate with nephrotoxicity. Metabolism is minimal; excretion is predominantly renal.

4.3 Miltefosine

Orally administered, miltefosine exhibits a bioavailability of approximately 70%. Peak plasma concentrations are reached within 2–3 hours. The drug distributes widely, with significant penetration into skin and mucosal tissues. Metabolism occurs via hepatic glucuronidation, and excretion is primarily fecal. The terminal half-life ranges from 30 to 40 days, necessitating extended treatment courses.

4.4 Paromomycin

When administered intramuscularly, paromomycin achieves peak concentrations in the bloodstream within 1–2 hours. Its distribution is limited due to high protein binding. The drug undergoes minimal metabolism and is excreted unchanged by the kidneys. The elimination half-life is approximately 1–2 hours, requiring daily dosing.

4.5 Pentamidine

Pentamidine is typically administered via intramuscular or intravenous routes. Peak plasma concentrations are achieved rapidly, and the drug distributes extensively into tissues. Metabolism is negligible; excretion occurs primarily via the kidneys. The half-life is approximately 4–5 hours, allowing for dosing every 12 hours.

4.6 Suramin

Suramin is administered intravenously, with a large volume of distribution and prolonged plasma persistence. The drug is not metabolized and is excreted unchanged through glomerular filtration. The half-life is 18–30 days, necessitating careful monitoring of renal function.

4.7 Melarsoprol

Melarsoprol is given intravenously, with peak plasma concentrations achieved within minutes. Distribution is extensive; the drug penetrates the blood–brain barrier effectively. Metabolism involves hepatic conjugation and subsequent renal excretion. The elimination half-life is approximately 4–6 hours, requiring multiple daily administrations.

4.8 Eflornithine

Eflornithine is given intravenously, with rapid attainment of therapeutic concentrations. It distributes widely but does not cross the blood–brain barrier efficiently; thus, it is combined with nifurtimox for late-stage HAT. The drug is excreted unchanged by the kidneys, with a half-life of about 2 hours.

4.9 Nifurtimox and Benznidazole

Both agents are orally absorbed; bioavailability is approximately 60–80%. Distribution is extensive, with significant penetration into cardiac tissue. Metabolism occurs via hepatic biotransformation to active metabolites, and excretion is mainly renal. Half-lives are 10–15 hours for nifurtimox and 20–30 hours for benznidazole, necessitating daily dosing over months.

4.10 Fexinidazole

Fexinidazole is orally administered, with a bioavailability exceeding 80%. It is rapidly absorbed, and the active metabolite is generated via hepatic reduction. Distribution is wide, including penetration into the central nervous system. The drug is excreted primarily in the urine and feces. The terminal half-life of the active metabolite is approximately 12 hours, enabling once-daily dosing.

5. Therapeutic Uses/Clinical Applications

5.1 Leishmaniasis

Antimonials remain first-line therapy for cutaneous leishmaniasis in many endemic regions, with dosing regimens ranging from 20 to 30 mg/kg/day for 20–30 days. Liposomal amphotericin B is preferred for visceral leishmaniasis, especially in patients with renal dysfunction, with doses of 3–5 mg/kg/day for 5–7 days. Miltefosine is employed in uncomplicated visceral leishmaniasis and cutaneous forms, administered at 2.5 mg/kg/day for 28–30 days. Paromomycin is used topically for localized cutaneous lesions and intramuscularly for visceral disease in combination regimens. Combination therapies, such as paromomycin plus liposomal amphotericin B, are increasingly utilized to mitigate resistance.

5.2 Human African Trypanosomiasis (HAT)

Early-stage HAT (stage 1) is treated with pentamidine or suramin, administered intravenously every other day for 12–14 doses. Late-stage HAT (stage 2) requires agents that cross the blood–brain barrier. Melarsoprol, given at 3 mg/kg/day intravenously for 10 days, remains a standard but is associated with high toxicity. Eflornithine, often combined with nifurtimox (NECT regimen), is preferred due to reduced adverse effects; dosing involves 15 mg/kg intravenously every 6 hours for 14 days. Novel oral therapies such as fexinidazole (100 mg twice daily for 10 days) are now approved for both stages, offering simplified regimens.

5.3 Chagas Disease

Benznidazole, administered at 5–7 mg/kg/day orally for 60 days, constitutes the first-line treatment for acute Chagas disease. Nifurtimox, given at 10–15 mg/kg/day for 60–90 days, is an alternative, particularly in regions where benznidazole is unavailable. In chronic disease, the efficacy of both agents declines, yet treatment is still recommended for younger patients and those with severe cardiomyopathy.

5.4 Off-Label Uses

Miltefosine has been employed off-label for refractory mucocutaneous leishmaniasis and visceral disease in patients intolerant to antimonials. Amphotericin B lipid formulations are occasionally used for severe drug reactions or in patients with renal impairment. Paromomycin has seen limited use in combination with other agents for multidrug-resistant visceral leishmaniasis.

6. Adverse Effects

6.1 Pentavalent Antimonials

• Cardiotoxicity: arrhythmias, conduction abnormalities.
• Pancreatitis: abdominal pain, elevated pancreatic enzymes.
• Hepatotoxicity: elevations in transaminases, jaundice.
• Peripheral neuropathy: sensory deficits, paresthesias.
• Hypersensitivity reactions: rash, anaphylaxis.

6.2 Amphotericin B

• Nephrotoxicity: acute tubular necrosis, electrolyte disturbances.
• Infusion reactions: fever, chills, hypotension.
• Hypokalemia, hypomagnesemia.
• Severe allergic reactions in rare cases.

6.3 Miltefosine

• Gastrointestinal: nausea, vomiting, diarrhea.
• Teratogenicity: embryotoxicity, fetal malformations.
• Hepatotoxicity: elevated transaminases.
• Peripheral neuropathy: mild sensory disturbances.

6.4 Paromomycin

• Ototoxicity: hearing loss, tinnitus (rare).
• Nephrotoxicity: minimal due to low systemic exposure.
• Local irritation at injection site.

6.5 Pentamidine

• Hyperglycemia, hypoglycemia.
• Cardiotoxicity: arrhythmias, hypotension.
• Acute renal failure in susceptible patients.

6.6 Suramin

• Hypersensitivity reactions: anaphylaxis, urticaria.
• Renal impairment: acute tubular necrosis.
• Hematologic: anemia, thrombocytopenia.

6.7 Melarsoprol

• Neurotoxicity: encephalopathy, seizures (post‑treatment reactive encephalopathy).
• Arsenic toxicity: skin lesions, neuropathy.
• Renal dysfunction.

6.8 Eflornithine

• Gastrointestinal upset: nausea, vomiting.
• Ocular toxicity: conjunctivitis, photophobia.
• Hematologic: anemia, leukopenia.

6.9 Nifurtimox and Benznidazole

• Gastrointestinal upset: nausea, vomiting, abdominal pain.
• Neurologic: tremor, peripheral neuropathy.
• Dermatologic: rash, photosensitivity.
• Hepatotoxicity: elevated transaminases.

6.10 Fexinidazole

• Headache, dizziness.
• Gastrointestinal: nausea, diarrhea.
• Viral hepatitis reactivation in chronic carriers.

7. Drug Interactions

7.1 Pentavalent Antimonials

• Digoxin: potentiation of cardiotoxicity.
• Warfarin: increased bleeding risk due to hepatic metabolism interference.
• Other nephrotoxic agents: cumulative renal injury.

7.2 Amphotericin B

• Calcineurin inhibitors: enhanced nephrotoxicity.
• Diuretics: risk of electrolyte imbalance.
• Other nephrotoxic drugs (e.g., aminoglycosides): additive renal damage.

7.3 Miltefosine

• Other teratogenic agents: additive embryotoxicity.
• Drugs with overlapping hepatotoxic profiles: risk of hepatic injury.

7.4 Paromomycin

• Aminoglycosides: additive nephrotoxicity and ototoxicity.
• Other drugs affecting renal excretion: increased systemic exposure.

7.5 Pentamidine

• Glucose-lowering agents: risk of hypoglycemia.
• Other cardiotoxic drugs: additive arrhythmogenic potential.

7.6 Suramin

• Drugs with renal clearance: potential competition leading to altered pharmacokinetics.

7.7 Melarsoprol

• Arsenic-containing medications: cumulative toxicity.
• Drugs affecting hepatic metabolism: altered clearance.

7.8 Eflornithine

• Drugs affecting polyamine metabolism: potential synergistic or antagonistic effects.

7.9 Nifurtimox and Benznidazole

• Anticonvulsants: possible reduction in efficacy due to hepatic induction.
• Drugs with CNS penetration: additive central nervous system side effects.

7.10 Fexinidazole

• Hepatotoxic agents: risk of compounded liver injury.
• Antifibrinolytics: potential interference with prodrug activation.

8. Special Considerations

8.1 Pregnancy and Lactation

• Antimonials and amphotericin B are generally considered acceptable during pregnancy; however, data remain limited. Miltefosine is contraindicated due to teratogenicity. Paromomycin can be used with caution.
• Pentamidine is contraindicated in pregnancy because of potential fetal toxicity. Suramin and melarsoprol are also contraindicated.
• Chagas disease agents (benznidazole, nifurtimox) are contraindicated in pregnancy; alternative therapies are limited.
• Fexinidazole has insufficient data for use during pregnancy; lactation is not recommended due to potential drug excretion in breast milk.

8.2 Pediatric Considerations

• Dosage adjustments are required for children based on weight. Antimonials are dosed at 20–30 mg/kg/day, while miltefosine is dosed at 2.5 mg/kg/day. Liposomal amphotericin B is often preferred for children with renal compromise.
• Safety data for fexinidazole in children are emerging; current guidelines recommend caution until more evidence is available.

8.3 Geriatric Considerations

• Reduced renal clearance necessitates dose adjustments for antimonials, amphotericin B, and pentamidine. Monitoring of renal function is essential.
• Polypharmacy increases the risk of drug interactions; careful review of concomitant medications is advised.

8.4 Renal and Hepatic Impairment

• Antimonials: caution in hepatic impairment; monitor transaminases. Renal impairment increases risk of toxicity; dose adjustments may be required.
• Amphotericin B: lipid formulations are preferred in renal impairment; monitor for nephrotoxicity.
• Miltefosine: hepatic impairment leads to prolonged half-life; dose reduction may be necessary.
• Paromomycin: minimal systemic exposure reduces hepatic concerns; however, renal function monitoring remains critical.
• Pentamidine: dose adjustment in renal impairment; monitor for hypoglycemia.
• Suramin: contraindicated in severe renal impairment due to accumulation.
• Melarsoprol: hepatic metabolism may be altered; renal function monitoring is essential.
• Eflornithine: renal excretion necessitates dose adjustment in renal impairment.
• Nifurtimox and benznidazole: hepatic metabolism requires caution in hepatic disease; renal excretion necessitates monitoring.
• Fexinidazole: hepatic activation may be impaired; dose adjustments pending further data.

9. Summary/Key Points

• Pentavalent antimonials and amphotericin B remain foundational for visceral leishmaniasis, while miltefosine offers an oral alternative with distinct safety considerations.
• HAT treatment requires stage-specific agents; melarsoprol and eflornithine/nifurtimox combinations target CNS involvement, whereas fexinidazole offers a simplified oral regimen.
• Chagas disease management relies on benznidazole and nifurtimox, with limited efficacy in chronic disease; emerging therapies such as fexinidazole may broaden options.
• Adverse effect profiles vary widely; renal and hepatic function, pregnancy status, and age dictate therapeutic choices and dosing.
• Drug interactions are common, particularly with agents affecting renal excretion or hepatic metabolism; vigilant monitoring and dose adjustments mitigate risk.
• Special populations—including pregnant women, children, and the elderly—demand individualized therapy plans incorporating pharmacokinetic and safety data.

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