Rifamycins

Rifamycins (rifampicin, rifabutin, rifapentine, rifaximin and rifamycin SV) are semisynthetic ansamycins that inhibit bacterial RNA synthesis. They are bactericidal against Mycobacterium tuberculosis and many Gram-positive cocci, and they penetrate biofilm, cells and bone. They are first-line drugs for tuberculosis and leprosy and are used for prosthetic-material infection and chemoprophylaxis. Resistance appears in a single step, so they are never used as monotherapy for active infection.

Mechanism. Binding to the beta subunit of bacterial DNA-dependent RNA polymerase (rpoB) blocks initiation of RNA transcription. Resistance arises by rpoB mutation.

Pharmacokinetics. Rifampicin: oral absorption about 90 percent (reduced by food, so taken on an empty stomach); half-life 2 to 5 hours, falling with repeated dosing because of autoinduction; hepatic deacetylation and biliary excretion; good CSF penetration with inflamed meninges. Rifapentine has a half-life of about 13 hours. Rifabutin has a half-life of 32 to 67 hours. Rifaximin is minimally absorbed and acts in the gut lumen.

Enzyme induction. Rifampicin is a strong inducer of CYP3A4, CYP2C9, CYP2C19, P-glycoprotein and glucuronyltransferases, with effects starting within days and lasting about 2 weeks after stopping. Rifabutin is a weaker inducer; rifapentine is intermediate; rifaximin has negligible systemic effect.

• Rifampicin: the core drug for tuberculosis, leprosy, brucellosis (with doxycycline) and staphylococcal device infection (with another active agent).
• Rifabutin: alternative when interactions with antiretroviral protease inhibitors prohibit rifampicin; used in Mycobacterium avium complex disease and Helicobacter pylori rescue therapy.
• Rifapentine: weekly or daily regimens in tuberculosis and preventive therapy.
• Rifaximin: non-absorbed gut antibacterial for hepatic encephalopathy, travellers’ diarrhoea and some bowel conditions.

Adult regimens (normal renal function).

• Tuberculosis: rifampicin 10 mg/kg once daily (usually 600 mg if 50 kg or more, 450 mg if under 50 kg), on an empty stomach, with isoniazid, pyrazinamide and ethambutol for the first 2 months. Higher-dose regimens are being studied.
• Latent tuberculosis: rifampicin 600 mg daily for 4 months; rifapentine with isoniazid weekly for 12 weeks.
• Meningococcal prophylaxis: 600 mg every 12 hours for 2 days (children 10 mg/kg, infants under 1 year 5 mg/kg, every 12 hours).
• Prosthetic joint and device infection caused by staphylococci: 300 to 450 mg every 12 hours added only after bacteraemia is cleared and an effective companion drug is established.
• Brucellosis: 600 to 900 mg daily with doxycycline for 6 weeks.
• Leprosy: 600 mg once monthly with dapsone and clofazimine.
• Rifabutin: 300 mg daily (150 mg daily with strong CYP3A inhibitors such as boosted protease inhibitors).
• Rifaximin: 550 mg every 12 hours for hepatic encephalopathy prophylaxis; 200 mg three times daily for 3 days for travellers’ diarrhoea.
• Children: rifampicin 10 to 20 mg/kg once daily (maximum 600 mg) in tuberculosis.

Selection. First line for drug-susceptible tuberculosis. Rifampicin resistance defines MDR tuberculosis and changes the regimen. In HIV co-infection, choose the antiretroviral regimen around the interaction (interactions are listed under safety).

Contraindications. Hypersensitivity to rifamycins; jaundice or acute hepatitis; co-administration with drugs whose levels fall to ineffective levels and cannot be adjusted (for example, boosted protease inhibitors, bictegravir, tenofovir alafenamide at usual doses).

Serious effects. Hepatitis (usually within 2 months; risk rises with alcohol, pre-existing liver disease and isoniazid or pyrazinamide); flu-like syndrome, thrombocytopenia and haemolysis with intermittent dosing; acute kidney injury; hypersensitivity; orange discolouration of urine, sweat, tears and contact lenses; uveitis (rifabutin); rifaximin-associated C. difficile infection (rare).

Interactions.

• Antiretrovirals: dolutegravir is given at 50 mg every 12 hours; efavirenz and nevirapine levels change; boosted protease inhibitors are contraindicated with rifampicin (rifabutin is substituted).
• Warfarin and direct oral anticoagulants (reduced effect), combined oral contraceptives (non-hormonal contraception advised), antiepileptics, azole antifungals, calcineurin inhibitors, methadone, corticosteroids (increase dose), sulphonylureas, beta-blockers, opioids, statins, tacrolimus.

Monitoring. Baseline liver tests and again at 2 weeks and at symptoms; stop if transaminases exceed 5 times the upper limit (3 times with symptoms) or bilirubin rises; full blood count; INR when co-prescribed.

Special groups. Pregnancy: used where needed (tuberculosis); give vitamin K to the newborn if used near term. Breastfeeding: compatible. Hepatic impairment: caution, with monitoring. Renal impairment: no adjustment. Region: tuberculosis and HIV overlap in East Africa makes rifampicin interactions a daily prescribing issue.