What are rifamycins?

Rifamycins: A Class of Critical Antimicrobial Agents

Rifamycins are a class of antibiotics that inhibit bacterial RNA polymerase and are essential components in the treatment of tuberculosis and other mycobacterial infections, with varying properties that affect their clinical applications and drug interaction profiles. 1

Types of Rifamycins

The primary rifamycins used in clinical practice include:

• Rifampin (Rifampicin): The most widely used rifamycin and most potent CYP450 enzyme inducer in the class 1
• Rifabutin: Has substantially less CYP450 enzyme induction activity compared to rifampin 1
• Rifapentine: A newer rifamycin with intermediate CYP450 induction activity 1
• Rifaximin: A non-absorbed rifamycin used for gastrointestinal disorders 2

Mechanism of Action

Rifamycins work by:

• Binding to the β-subunit of bacterial RNA polymerase 3
• Inhibiting transcription by blocking the RNA exit tunnel 3
• Exhibiting bactericidal activity against many Gram-positive and Gram-negative bacteria 4

Clinical Applications

Rifamycins are primarily used for:

• Tuberculosis treatment: Core components of first-line regimens for drug-susceptible TB 1
• HIV-related tuberculosis: With specific considerations for drug interactions 1
• Other mycobacterial infections: Including Mycobacterium avium complex (MAC) 2
• Gram-positive infections: Particularly prosthetic joint and valve infections with biofilm formation 2

Pharmacokinetic Properties

Key pharmacokinetic characteristics include:

• Absorption: Variable effects of food on absorption; rifampin absorption is decreased by food while rifapentine absorption is increased 5
• Protein binding: Rifapentine has high protein binding (97%) which may affect its efficacy 5
• Metabolism: Primarily through the cytochrome P450 system 6

Drug Interactions

Rifamycins have significant drug interactions due to their effects on the CYP450 enzyme system:

• Relative potency as CYP450 inducers: Rifampin > Rifapentine > Rifabutin 1, 5
• Antiretroviral medications:
  • Protease inhibitors: Rifampin significantly reduces blood levels of protease inhibitors 1, 7
  • NNRTIs: Different interactions based on specific agent; efavirenz can be used with rifampin but requires dose adjustment 1, 7
  • INSTIs: Require dose adjustments when used with rifampin 7
  • NRTIs: Generally safe to use with rifamycins 1

Special Considerations in HIV-TB Coinfection

For patients with HIV and TB coinfection:

• Rifabutin is preferred over rifampin when used with protease inhibitors 1, 7
• Dose adjustments are critical:
  • Rifabutin dose should be reduced to 150mg two or three times weekly when used with ritonavir 1
  • Rifabutin dose should be increased to 450-600mg daily or 600mg two to three times weekly when used with efavirenz 1
• Intermittent rifamycin therapy (once or twice weekly) is contraindicated in HIV patients with advanced immunosuppression due to risk of acquired rifamycin resistance 1, 8

Resistance Mechanisms

Resistance to rifamycins occurs through:

• Target modification: Point mutations in RNA polymerase (most common in TB) 3
• Enzymatic inactivation: Including ADP ribosyltransferases, glycosyltransferases, phosphotransferases, and monooxygenases 3
• Reduced drug uptake: Cytoplasmic exclusion 4

Adverse Effects

Common adverse effects include:

• Hepatotoxicity, especially when combined with other hepatotoxic drugs like isoniazid 6
• Hypersensitivity reactions, particularly with higher doses and less frequent administration 5
• Discoloration (yellow, orange, red, brown) of bodily fluids including urine, sweat, tears, and sputum 6

Clinical Pearls and Pitfalls

• Critical pitfall: Never use rifampin with most protease inhibitors due to significant reduction in antiretroviral drug levels 7
• Important consideration: Rifabutin dose must be adjusted when used with CYP450 inhibitors like ritonavir to prevent toxicity 1
• Monitoring requirement: Regular liver function tests are essential when using rifamycins, especially in combination with other potentially hepatotoxic drugs 6
• Drug selection: Choice of rifamycin should be based on concomitant medications, particularly in HIV-infected patients on antiretroviral therapy 1, 7

Rifamycins remain cornerstone drugs for tuberculosis treatment, but their complex pharmacokinetics and significant drug interaction potential require careful clinical management, particularly in patients with HIV coinfection.