Rifampin and Atovaquone Should Not Be Taken Together
Concomitant administration of rifampin and atovaquone is not recommended due to a clinically significant drug interaction that substantially reduces atovaquone concentrations, potentially leading to treatment failure. 1, 2
Mechanism and Clinical Impact
Rifampin is a potent inducer of hepatic drug metabolism that significantly decreases atovaquone plasma concentrations through enhanced drug clearance 1, 2
The FDA drug label for atovaquone explicitly states that concomitant administration with rifampin or rifabutin is known to reduce atovaquone concentrations and is not recommended 1
The rifampin FDA label confirms this interaction, noting that concomitant use decreases atovaquone concentrations while increasing rifampin concentrations, which may increase the risk of rifampin toxicities 2
This bidirectional interaction creates a double problem: inadequate atovaquone levels for treating the target infection (such as Pneumocystis jirovecii pneumonia or malaria) and potentially toxic rifampin levels 2
Guideline Recommendations
The American Thoracic Society/CDC/IDSA clinical practice guidelines for tuberculosis treatment explicitly recommend considering an alternate form of Pneumocystis jirovecii treatment or prophylaxis when rifamycins are being used 3
CDC guidelines note that atovaquone concentration is decreased by coadministration with rifampin, making this combination unsuitable for PCP treatment or prophylaxis 3
Alternative Management Strategies
If a patient requires both tuberculosis treatment (with rifampin) and PCP prophylaxis/treatment:
First-line alternative: Use trimethoprim-sulfamethoxazole (TMP-SMX) instead of atovaquone, as it has no significant interaction with rifampin and is the preferred agent for PCP 3
Second-line alternative: Consider pentamidine (inhaled for prophylaxis or IV for treatment), which does not have documented interactions with rifampin 3
Third-line alternative: Dapsone-based regimens can be used, though monitoring is required 3
If rifabutin can be substituted for rifampin:
Rifabutin also reduces atovaquone concentrations and is similarly not recommended for concomitant use 1
The same alternative agents (TMP-SMX, pentamidine, or dapsone) should be considered 3
Critical Clinical Pitfalls
Do not attempt dose adjustment: Unlike some rifampin interactions where dose increases can compensate, there is no established safe dosing strategy for combining these medications 1, 2
Timing separation does not help: Because rifampin induces hepatic enzymes (an effect that persists for days to weeks), simply separating administration times will not prevent the interaction 4, 5
Monitor for treatment failure: If these drugs are inadvertently combined, patients are at high risk for treatment failure of their atovaquone-targeted infection (PCP or malaria) 1, 2
Consider the indication carefully: Atovaquone is typically used for PCP or malaria; ensure the most appropriate alternative agent is selected based on the specific indication and patient factors 3