What is atovaquone?

Atovaquone: An Antimicrobial Agent for Opportunistic Infections

Atovaquone is a quinone antimicrobial drug primarily used as an alternative agent for prophylaxis and treatment of Pneumocystis jirovecii pneumonia (PJP) in immunocompromised patients who cannot tolerate first-line therapy. It is also effective as part of combination therapy for malaria prophylaxis and treatment.

Chemical Properties and Formulation

Atovaquone is a yellow crystalline solid with the chemical name trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione 1. It has a molecular weight of 366.84 and is practically insoluble in water. The oral suspension contains 750 mg of atovaquone per 5 mL, formulated with inactive ingredients to enhance absorption 1.

Mechanism of Action

Atovaquone works by:

• Inhibiting parasitic and fungal mitochondrial electron transport by binding to the cytochrome bc1 complex 2
• Disrupting energy production in susceptible organisms
• Providing a mechanism distinct from other antimicrobial agents, which helps explain its effectiveness against drug-resistant pathogens

Clinical Applications

1. Pneumocystis jirovecii Pneumonia (PJP)

Atovaquone is indicated for:

• Treatment of mild to moderately severe PJP in adults (BI evidence level) 3
• Prophylaxis against PJP in immunocompromised patients who cannot tolerate TMP-SMX 3
• Alternative therapy after pentamidine in patients who show clinical improvement after 7-10 days of IV pentamidine therapy (BIII) 3

Dosing for PJP treatment:

• Adults: 750 mg oral suspension twice daily with food
• Children: 30-40 mg/kg/day in 2 divided doses given with fatty foods 3
• Infants aged 3-24 months: Higher dosage of 45 mg/kg/day may be required (AII) 3

2. Malaria Prophylaxis and Treatment

Atovaquone is used in combination with proguanil (Malarone):

• Effective for prevention of Plasmodium falciparum malaria, including drug-resistant strains 4
• Active against both hepatic (pre-erythrocytic) and erythrocytic stages of P. falciparum 4
• Provides causal prophylaxis, eliminating the need for extended post-travel treatment 4
• Treatment efficacy >98% in clinical trials for acute, uncomplicated falciparum malaria 5

Pharmacokinetics

Key pharmacokinetic properties include:

• Bioavailability: Poor and variable between individuals; significantly enhanced when taken with fatty foods (1.4-fold increase) 3, 6
• Distribution: High protein binding
• Metabolism: Minimal hepatic metabolism
• Elimination: Long half-life (50-70 hours) with excretion primarily through feces 7
• Drug interactions: Concentration increased with coadministration of fluconazole and prednisone; decreased by coadministration with acyclovir, opiates, cephalosporins, rifampin, and benzodiazepines 3

Therapeutic Monitoring

Plasma concentrations show wide inter-individual variability:

• Median trough concentration (Cmin) of 11.3 μg/mL has been reported in immunocompromised patients 6
• Nearly 58% of patients may have Cmin below 15 μg/mL, a threshold associated with lower clinical response rates 6
• Therapeutic drug monitoring may be beneficial to identify patients with suboptimal concentrations 6

Adverse Effects

Common adverse reactions include:

• Skin rashes (10-15%)
• Gastrointestinal disturbances (nausea, diarrhea)
• Elevated liver enzymes 3
• Most adverse reactions typically occur after the first week of therapy 3

Clinical Considerations and Caveats

1. Administration with food: Always administer with fatty meals to enhance absorption
2. Patient selection: Best suited for mild to moderate PJP rather than severe disease
3. Monitoring: Consider therapeutic drug monitoring in high-risk patients
4. Resistance: Less likely to develop resistance when used in combination therapy for malaria
5. Cost considerations: More expensive than other oral agents for PJP treatment 7

For PJP prophylaxis in patients who cannot tolerate TMP-SMX, atovaquone is one of several alternatives along with dapsone and aerosolized pentamidine 3. The choice between these agents should be based on patient-specific factors including G6PD status, concomitant medications, and comorbidities.