Rifampin Drug Interactions with First-Line TB Medications
Rifampin does NOT have clinically significant drug interactions with ethambutol, pyrazinamide, isoniazid, streptomycin, or moxifloxacin when used together for tuberculosis treatment. 1
Direct Evidence from Guidelines
The American Thoracic Society/CDC/IDSA explicitly states that "no contraindication exists for the use of NRTIs, NNRTIs, and protease inhibitors with isoniazid, pyrazinamide, ethambutol, or streptomycin. These first-line antituberculosis medications, in contrast to the rifamycins, are not CYP450 inducers." 1 This confirms these TB drugs do not interact with rifampin through the cytochrome P450 system, which is rifampin's primary mechanism of drug interactions. 1
Standard Combination Regimens
Multiple guidelines recommend using these drugs together without dose adjustments:
The FDA-approved regimen consists of rifampin, isoniazid, and pyrazinamide for 2 months, with either streptomycin or ethambutol added as a fourth drug. 2
This is followed by rifampin and isoniazid for at least 4 additional months. 2
All five drugs (rifampin, isoniazid, pyrazinamide, ethambutol, streptomycin) can be administered together in the initial phase without concern for drug-drug interactions between them. 1, 3
Intermittent Dosing Compatibility
The drugs maintain their lack of interaction even with intermittent dosing schedules:
Twice-weekly or three-times-weekly administration of rifampin with isoniazid, pyrazinamide, ethambutol, and streptomycin has been proven highly effective. 1, 4
A study of 833 patients showed bacteriological relapse rates of 2% or less for all pyrazinamide-containing regimens given three times weekly. 4
Moxifloxacin Considerations
Moxifloxacin (a fluoroquinolone) can be safely added to rifampin-containing regimens for drug-resistant TB or extensive disease. 1
Fluoroquinolones are recommended to strengthen regimens for patients with more extensive disease or isoniazid resistance. 1
The interaction concern with fluoroquinolones relates to absorption interference by metal cations, not rifampin. 5, 6
Hepatotoxicity: Additive, Not Interactive
The primary concern when combining these drugs is additive hepatotoxicity, not drug-drug interactions:
Rifampin may enhance isoniazid hepatotoxicity through enzyme induction, causing early transaminase elevation (within 15 days). 7
The combination of isoniazid, rifampin, and pyrazinamide has a clinical hepatitis rate of 2.7%, compared to 0.6% for isoniazid alone. 1
This represents additive toxicity rather than a pharmacokinetic interaction that would require dose adjustment. 7
Monitoring Requirements
Monitor serum transaminases twice weekly during the first 2 weeks, every 2 weeks during the first 2 months, then monthly thereafter. 7
Stop all three drugs (isoniazid, rifampin, pyrazinamide) if transaminases exceed 3 times the upper limit of normal. 7
After normalization, reintroduce isoniazid at low dose without rifampin initially; do not reintroduce pyrazinamide due to poor prognosis of pyrazinamide-induced hepatitis. 7
Important Caveat
Rifampin's major drug interactions occur with OTHER drug classes (antiretrovirals, oral contraceptives, anticoagulants, immunosuppressants) through CYP450 induction, NOT with standard TB medications. 1, 8, 9