Rifabutin for Tuberculosis

Rifabutin is a spiropiperidyl rifamycin used when rifampicin cannot be given, mainly because of interactions with antiretrovirals or other essential drugs. It is a weaker enzyme inducer than rifampicin and itself a substrate of CYP3A4, so its dose changes with the interacting drug. Uveitis and neutropenia are its characteristic toxicities.

Class. Rifamycin antimycobacterial.

Mechanism. Inhibits RNA polymerase (rpoB). Most rifampicin-resistant isolates are cross-resistant, so it does not rescue rifampicin-resistant disease.

Pharmacokinetics. About 20% oral bioavailability, peak at 2 to 4 hours, half life 32 to 67 hours, large volume of distribution with high tissue concentrations. Hepatic metabolism with active metabolite; renal and biliary elimination.

Drug-susceptible tuberculosis when rifampicin is unsuitable. - Usual: 5 mg/kg (range 5 to 10) once daily; adults 300 mg daily; maximum 300 mg daily without efavirenz. - With ritonavir- or cobicistat-boosted protease inhibitors: 150 mg once daily (or 300 mg three times weekly). - With efavirenz: 450 to 600 mg once daily. - Duration: equal to the regimen it replaces, usually 6 months. Loading dose: none.

Titration. Reduce for uveitis, neutropenia or drug-level rise with CYP3A4 inhibitors; increase only with inducers.

Children. 5 mg/kg daily; data are limited.

Main alternative. Rifampicin with adjusted antiretrovirals is preferred where feasible; rifabutin is an alternative when interactions cannot be managed.

Contraindications. Hypersensitivity to rifamycins, severe neutropenia and severe liver disease. Caution with other drugs that cause uveitis.

Serious adverse effects. Uveitis (dose and interaction related, notably with clarithromycin, fluconazole and protease inhibitors), neutropenia, thrombocytopenia, hepatitis, arthralgia and skin discolouration.

Common adverse effects. Orange urine and secretions, rash, nausea and pseudojaundice.

Interactions. - Boosted protease inhibitors, clarithromycin and azoles raise rifabutin levels; reduce the dose and watch for uveitis. - Efavirenz lowers levels; increase the dose. - It lowers voriconazole, warfarin, methadone and contraceptive levels, but less than rifampicin. - Dolutegravir needs no dose change; bictegravir is not advised.

Common prescribing errors. Full dose with boosted protease inhibitors, no eye review after visual symptoms, and substituting it for resistant disease.

Special groups. - Pregnancy: limited data; used only when benefit outweighs risk. - Breastfeeding: limited data. - Children: weight-based use under specialist care. - Older adults: usual dose; watch counts. - Kidney impairment: with CrCl under 30 mL/min, reduce the dose by half. - Liver impairment: caution; monitor liver tests.

Formulations. Capsules 150 mg.

Administration. Once daily, with or without food; food improves tolerance.

Baseline. Full blood count, liver tests, creatinine, eye assessment if prior uveitis, drug and contraception review.

Monitoring. Full blood count at baseline, 2 weeks, then monthly; liver tests at baseline and when symptomatic; ask about eye pain, redness and blurred vision at every visit.

Stopping thresholds. Stop for uveitis, neutrophils under 0.5 x 10^9/L or hepatitis (ALT over three times the upper limit of normal with symptoms, or over five times without).

Referral and escalation. Urgent ophthalmology for eye symptoms; specialist review for interactions and unexplained cytopenia.