What is the role of Atovaquone in Pneumocystis jirovecii pneumonia (PJP) prophylaxis?

Atovaquone for PJP Prophylaxis

Atovaquone 1500 mg daily is an effective second-line agent for PJP prophylaxis in patients who cannot tolerate trimethoprim-sulfamethoxazole, though it is less effective than TMP-SMX and requires administration with food to ensure adequate absorption. 1, 2

Indications and Patient Selection

• Atovaquone is FDA-approved for PJP prophylaxis in adults and adolescents aged 13 years and older who cannot tolerate TMP-SMX 2
• The European League Against Rheumatism and National Comprehensive Cancer Network recommend atovaquone 1500 mg daily as a first-line alternative when TMP-SMX is not tolerated 1, 3
• All alternative agents, including atovaquone, are less effective than TMP-SMX, which remains the gold standard 1

Dosing and Administration

• The FDA-approved prophylaxis dose is 1500 mg (10 mL) once daily, administered with food 2
• Food increases atovaquone bioavailability 1.4-fold compared to fasting state; failure to take with food may result in subtherapeutic levels and prophylaxis failure 4, 2
• For treatment of mild-to-moderate PCP (not prophylaxis), the dose is 750 mg twice daily for 21 days 2

Critical Administration Pitfall

• Atovaquone must be taken with food—this is non-negotiable for adequate absorption 2
• Consider alternative agents (dapsone or aerosolized pentamidine) in patients with gastrointestinal disorders, malabsorption, or inability to take medications with food 2

Evidence on Low-Dose Atovaquone

There is conflicting evidence regarding lower doses:

• A 2023 study in hematologic malignancy patients showed that 750 mg once daily prevented PJP in 85 patients over a median 150 days, with zero breakthrough infections 5
• However, a 2004 report documented prophylaxis failures in transplant recipients receiving low-dose atovaquone 6
• A 2017 pharmacokinetic study found that 58% of immunocompromised patients on standard dosing had trough levels <15 μg/mL, a threshold associated with poor treatment response 7

Given the FDA approval and pharmacokinetic concerns, the standard 1500 mg daily dose should be used rather than lower doses, particularly in high-risk populations like transplant recipients. 2, 6

Bioavailability Concerns

• Atovaquone exhibits wide inter-individual variability in absorption, with more than half of immunocompromised patients achieving subtherapeutic levels even on standard dosing 7
• Plasma concentrations are not affected by co-administration with valaciclovir or cyclosporine, nor by graft-versus-host disease 7
• The unpredictable absorption raises questions about therapeutic drug monitoring, though this is not routinely performed in clinical practice 7

Comparison to Other Alternatives

When TMP-SMX cannot be used, the hierarchy of alternatives is:

• Dapsone 100 mg daily is the most well-established alternative per the National Comprehensive Cancer Network, but requires G6PD testing and monitoring for methemoglobinemia 1
• Aerosolized pentamidine 300 mg monthly via Respirgard II nebulizer is effective but requires monthly healthcare visits 1
• Atovaquone 1500 mg daily offers the convenience of oral daily dosing without the hematologic monitoring required for dapsone 1, 2

Duration of Prophylaxis

• Continue prophylaxis for the duration of immunosuppression 3
• For HIV patients: until CD4+ count >200 cells/μL for at least 3 months 1
• For transplant recipients: at least 6-12 months post-transplantation 1, 3
• For patients on corticosteroids: while receiving ≥20 mg prednisone daily or equivalent 1, 3

Re-challenge Considerations

• A 2017 study in kidney transplant recipients showed that patients switched to atovaquone for non-hypersensitivity reasons (such as cytopenias or renal dysfunction) could be successfully re-challenged with TMP-SMX 8
• Consider re-challenging with TMP-SMX after the initial adverse event resolves, as TMP-SMX provides superior efficacy and additional protection against bacterial infections 1, 8

Adverse Effects

• Common adverse reactions include skin rashes (10-15%), nausea, and diarrhea, typically occurring after the first week of therapy 4
• Elevated liver enzymes may occur; cases of cholestatic hepatitis and fatal liver failure have been reported 2
• Atovaquone is contraindicated in patients with history of hypersensitivity reactions including angioedema, bronchospasm, throat tightness, or urticaria 2

Limitations

• Atovaquone does not provide the additional protection against common bacterial infections that TMP-SMX offers 1
• Clinical experience is limited to mild-to-moderate PCP; efficacy in severe PCP or salvage therapy after TMP-SMX failure has not been established 2
• One case report from 2023 described successful treatment of severe PCP with atovaquone in an HIV-negative patient, but this remains investigational 9