Anti-Protozoal Drugs Used in Pediatrics

1. Classification of Antiprotozoal Agents

1.1 Based on Target Organisms

• Antimalarial agents
  • 4-aminoquinolines (Chloroquine, Hydroxychloroquine)
  • 8-aminoquinolines (Primaquine)
  • Artemisinin derivatives
  • Antifolates (Pyrimethamine)
• Antiamoebic agents
  • Nitroimidazoles (Metronidazole, Tinidazole)
  • Luminal agents (Diloxanide furoate)
  • Mixed agents (Chloroquine)
• Anti-giardiasis agents
  • Nitroimidazoles
  • Nitazoxanide
  • Benzimidazoles
• Anti-trypanosomal agents
  • Pentamidine
  • Suramin
  • Benznidazole
• Anti-leishmaniasis agents
  • Pentavalent antimonials
  • Amphotericin B
  • Miltefosine

2. Mechanism of Action

2.1 DNA Synthesis Inhibitors

• Metronidazole and other nitroimidazoles:
  • Reduction of nitro group by ferredoxin-linked processes
  • Formation of toxic intermediates
  • DNA strand breakage
  • Cell death through oxidative stress

2.2 Membrane Function Disruptors

• Amphotericin B:
  • Binds to ergosterol
  • Creates transmembrane channels
  • Increases membrane permeability

2.3 Metabolic Process Inhibitors

• Artemisinin compounds:
  • Generation of free radicals
  • Alkylation of parasite proteins
  • Interference with heme detoxification

3. Pharmacokinetics in Pediatric Population

3.1 Age-Specific Considerations

• Neonates and Infants:
  • Reduced hepatic metabolism
  • Lower plasma protein binding
  • Increased volume of distribution
  • Prolonged half-life of many agents
• Young Children:
  • Enhanced hepatic metabolism
  • Higher clearance rates
  • May require more frequent dosing
• Adolescents:
  • Similar to adult parameters
  • Weight-based dosing often appropriate

3.2 Critical Pharmacokinetic Considerations

Drug Class	Absorption	Distribution	Metabolism	Elimination
Chloroquine	Good oral bioavailability (75-80%)	Large Vd, tissue accumulation	Hepatic CYP450	Renal (50% unchanged)
Metronidazole	Almost complete absorption	Good tissue penetration	Hepatic oxidation	Renal (60-80%)
Artemisinin derivatives	Variable (40-90%)	Moderate Vd	Extensive first-pass	Mainly biliary

4. Clinical Indications and Pediatric Dosing

4.1 Malaria Treatment

Drug	Age/Weight	Dosing	Duration	Special Considerations
Artemether-Lumefantrine	5-14kg	20/120mg 1 tab BID	3 days	Take with fatty meal
Artesunate	All pediatric	2.4mg/kg IV at 0,12,24h	Minimum 24h	Severe malaria only
Chloroquine	All ages	10mg base/kg, then 5mg/kg at 24,48h	3 days	Only sensitive strains

4.2 Intestinal Protozoa

Condition	First-line	Alternative	Duration
Giardiasis	Metronidazole 15mg/kg/day divided TID	Nitazoxanide 100-200mg BID	5-7 days
Amoebiasis	Metronidazole 30-50mg/kg/day divided TID	Tinidazole 50mg/kg/day	7-10 days
Cryptosporidiosis	Nitazoxanide (>12mo) 100mg BID	Paromomycin	3 days

5. Contraindications and Safety

5.1 Absolute Contraindications

• Chloroquine/Hydroxychloroquine:
  • Retinopathy
  • Known hypersensitivity
  • Pre-existing cardiac conduction abnormalities
• Metronidazole:
  • First trimester pregnancy
  • Active CNS disease
  • Severe hepatic dysfunction

5.2 Major Drug Interactions

Antiprotozoal	Interacting Drug	Effect	Management
Quinine	Macrolides	↑ QT prolongation risk	ECG monitoring
Artemether	CYP3A4 inducers	↓ effectiveness	Dose adjustment
Metronidazole	Antiepileptics	↓ anticonvulsant levels	Level monitoring

6. Special Populations and Considerations

6.1 Neonates (0-28 days)

• Reduced hepatic metabolism capacity
• Higher risk of kernicterus with some agents
• Need for careful dose adjustment
• Regular monitoring of liver function

6.2 Immunocompromised Children

• Higher risk of severe manifestations
• Extended treatment duration often needed
• Regular monitoring for adverse effects
• Prophylaxis may be indicated

6.3 Renal Impairment

Drug	GFR Adjustment	Monitoring
Chloroquine	50% if GFR <10	Renal function, K+
Metronidazole	50% if GFR <10	Clinical response

7. Emerging Therapies and Future Directions

7.1 Novel Drug Development

• New Chemical Entities:
  • KAF156 (Imidazolopiperazines) - Phase 3 trials
  • DSM265 (Selective DHODH inhibitor) - Phase 2
  • MMV390048 (PI4K inhibitor) - Phase 1
• Novel Delivery Systems:
  • Long-acting injectable formulations
  • Pediatric-friendly formulations
  • Taste-masked preparations

7.2 Research Priorities

• Clinical Needs:
  • Better safety data in young children
  • Age-appropriate formulations
  • Simplified dosing regimens
  • Drug resistance surveillance
• Implementation Challenges:
  • Cost-effectiveness studies
  • Access in resource-limited settings
  • Point-of-care diagnostics

8. Monitoring and Follow-up

8.1 Required Monitoring

Drug Class	Parameter	Frequency	Critical Values
Quinolines	Ophthalmologic exam	Baseline, then yearly	Any retinal changes
Antimonials	ECG, LFTs	Weekly	QTc >500ms
Amphotericin B	K+, Cr, Mg	2-3x weekly	K+ <3.0, Cr ×2

8.2 Treatment Response Assessment

• Clinical Parameters:
  • Fever clearance time
  • Symptom resolution
  • Weight gain/growth
• Laboratory Markers:
  • Parasitemia clearance
  • Inflammatory markers
  • Organ function tests