What is atovaquone (Mepron) primarily used for, particularly in patients with weakened immune systems, such as those with Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS) or those exposed to malaria?

What is Atovaquone Used For?

Atovaquone is primarily used as an alternative treatment for mild-to-moderate Pneumocystis jirovecii pneumonia (PCP) and as prophylaxis against PCP in immunocompromised patients who cannot tolerate trimethoprim-sulfamethoxazole (TMP-SMZ). 1, 2 Additionally, atovaquone combined with proguanil is highly effective for malaria prophylaxis and treatment. 3

Primary Indications

Pneumocystis Jirovecii Pneumonia (PCP)

Treatment of Mild-to-Moderate PCP:

• Atovaquone is recommended as an alternative for mild-to-moderate PCP when TMP-SMZ cannot be tolerated or when clinical treatment fails after 5-7 days of TMP-SMZ therapy 1, 2
• The recommendation strength is BI for adults and AII for children 1, 2
• Critical limitation: Atovaquone is NOT recommended for severe PCP (defined as PaO2 <70 mmHg or alveolar-arterial gradient >35 mmHg) due to insufficient evidence 1, 4
• Adult dosing: 750 mg twice daily with food for 21 days 1, 2
• Pediatric dosing: 30-40 mg/kg/day in 2 divided doses; infants 3-24 months may require 45 mg/kg/day 1, 2

PCP Prophylaxis:

• Atovaquone is an alternative prophylactic agent when TMP-SMZ cannot be tolerated 1
• Indicated for HIV-infected patients with CD4+ counts <200 cells/µL 1
• Dosing: 1,500 mg once daily with food 1, 2
• Atovaquone may provide cross-protection against toxoplasmosis, though data are limited 1

Toxoplasmosis

Primary Prophylaxis:

• Atovaquone possibly provides protection against toxoplasmosis in HIV-infected patients with CD4+ counts <100 cells/µL 1, 5
• Can be used with or without pyrimethamine 1
• However, TMP-SMZ remains the preferred agent for dual protection against both PCP and toxoplasmosis 5

Treatment:

• Atovaquone has been used in patients with toxoplasmosis who are unresponsive to or intolerant of conventional agents 6
• Historical data showed complete or partial radiological response rates of 37-87.5% in small studies 6
• Not considered first-line therapy; pyrimethamine plus sulfadiazine remains the gold standard 5

Malaria

Prophylaxis and Treatment:

• Atovaquone combined with proguanil (as Malarone) is highly effective for prevention of Plasmodium falciparum malaria, including drug-resistant strains 3
• Prophylactic efficacy is estimated at 95-100% in both immune and non-immune individuals 3
• Both agents are active against hepatic stages, providing causal prophylaxis and eliminating the need for extended post-travel treatment beyond 7 days 3, 7
• Well-tolerated with fewer gastrointestinal and neuropsychiatric adverse events compared to alternatives like mefloquine or chloroquine plus proguanil 3

Critical Administration Requirements

Food Dependency:

• Atovaquone MUST be administered with food, particularly fatty foods 1, 2, 4
• Bioavailability increases 1.4-fold when taken with food compared to fasting state 1, 2, 4
• Failure to take with food may result in suboptimal plasma concentrations and treatment failure 2, 4
• Dietary fat increases absorption two- to threefold for AUC and fivefold for Cmax 7

Absorption Variability:

• Wide inter-individual variability in atovaquone bioavailability exists 8
• In one study, 58% of immunocompromised patients had plasma concentrations below the threshold associated with optimal clinical response 8
• Patients with gastrointestinal disorders may have limited absorption resulting in suboptimal concentrations 2

Drug Interactions

Decreased Atovaquone Concentrations:

• Rifampin, rifabutin, acyclovir, opiates, cephalosporins, tetracycline, metoclopramide, and benzodiazepines all decrease atovaquone levels 1, 2, 4

Increased Atovaquone Concentrations:

• Fluconazole and prednisone increase atovaquone concentrations 1, 2, 4

Adverse Effects

Common Adverse Reactions:

• Rash (10-15%, most common reason for discontinuation at 6%) 1, 2, 9
• Gastrointestinal effects: nausea (4-26%), diarrhea (3-42%), vomiting (2-14%) 1, 9
• Elevated liver enzymes 1, 2
• Most adverse reactions occur after the first week of therapy 1

Serious Adverse Reactions (Postmarketing):

• Methemoglobinemia, thrombocytopenia 9
• Hypersensitivity reactions including angioedema, bronchospasm, throat tightness, urticaria 9
• Hepatitis, fatal liver failure 9
• Pancreatitis 9

Tolerability Advantage:

• Atovaquone has superior tolerability compared to TMP-SMZ and pentamidine 6
• Treatment-limiting adverse effects: 7% with atovaquone vs. 20% with TMP-SMZ and 4% vs. 36% with pentamidine 6

Important Clinical Caveats

Limitations in Severe Disease:

• Atovaquone should not be used as first-line therapy for severe PCP 4
• For severe PCP when TMP-SMZ cannot be used, clindamycin plus primaquine is preferred over atovaquone 4
• One case report described successful treatment of severe PCP with atovaquone in an HIV-negative patient, but this remains investigational 10

Monitoring Considerations:

• The unpredictable absorption variability raises the question of therapeutic drug monitoring to identify patients with low concentrations who might benefit from regimen adaptation or alternatives 8
• Plasma concentrations <15 μg/mL are associated with lower rates of clinical response in PCP treatment 8

Special Populations:

• Children aged 3-24 months may require higher doses (45 mg/kg/day) due to different pharmacokinetics 1, 2, 4
• Elimination half-life is 2-3 days in adults but only 1-2 days in children 7
• No dose adjustments needed for race, gender, elderly patients, or mild-to-moderate renal or hepatic impairment 7