Rifampicin

Rifampicin is the key sterilising drug for tuberculosis, and is also used for leprosy, brucellosis, staphylococcal device infection and prophylaxis after meningococcal exposure. It is the most potent enzyme inducer in clinical use, so interactions decide how it is prescribed.

Classification. Rifamycin.

Mechanism. Binds the beta subunit of bacterial DNA-dependent RNA polymerase and blocks transcription; bactericidal.

Spectrum. Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium kansasii, Staphylococcus aureus (including MRSA, never as monotherapy), Neisseria meningitidis, Haemophilus influenzae, Brucella, Legionella, Chlamydia. Resistance develops rapidly if used alone.

Pharmacokinetics. Oral bioavailability about 90%, reduced by food. Half-life 2 to 5 hours, shortening with repeated dosing by autoinduction. Protein binding about 80%. Excellent tissue, CSF and intracellular penetration. Hepatic metabolism with biliary excretion. Colours urine, sweat, tears and saliva orange to red.

Maximum 600 mg daily in most regimens (higher doses under specialist direction).

Adults, oral or IV, once daily, on an empty stomach.

• Tuberculosis: 10 mg/kg (range 8 to 12 mg/kg), usually 450 mg if under 50 kg and 600 mg if 50 kg or more, daily for 6 months, with isoniazid, pyrazinamide and ethambutol in the first 2 months. Drug-susceptible disease only; use as part of a fixed regimen.
• Tuberculous meningitis (specialist): 15 to 20 mg/kg daily in some regimens; high-dose use only with monitoring.
• Latent tuberculosis: 600 mg daily for 4 months, or 600 mg with isoniazid 300 mg daily for 3 months.
• Leprosy: 600 mg once a month, supervised, as part of a multidrug regimen.
• Brucellosis: 600 to 900 mg daily for 6 weeks with doxycycline 100 mg every 12 hours.
• Staphylococcal prosthetic joint, bone and device infection (always combined with another active drug): 300 to 450 mg every 12 hours.
• Meningococcal prophylaxis in contacts: 600 mg every 12 hours for 2 days.
• Haemophilus influenzae type b prophylaxis: 600 mg once daily for 4 days.

Children.

• Tuberculosis: 15 mg/kg once daily (range 10 to 20 mg/kg; maximum 600 mg), for 4 to 6 months depending on the regimen.
• Meningococcal prophylaxis: 10 mg/kg every 12 hours for 2 days (5 mg/kg under 1 year; maximum 600 mg a dose).

Alternatives. Rifabutin, rifapentine (tuberculosis); ceftriaxone, ciprofloxacin (meningococcal prophylaxis).

Contraindications. Rifamycin hypersensitivity; jaundice; concurrent use with atazanavir, saquinavir with ritonavir or nevirapine, or other drugs whose levels cannot be safely adjusted; acute porphyria.

Adverse effects. Orange body fluids (harmless; stains soft contact lenses), nausea, vomiting, abdominal pain, flushing, pruritus, rash, headache.

Serious adverse effects:

• Hepatotoxicity (cholestatic or hepatocellular; higher with isoniazid, alcohol, old age, malnutrition and chronic liver disease).
• Thrombocytopenia, haemolytic anaemia, and flu-like syndrome (intermittent dosing).
• Acute kidney injury and hypersensitivity.
• Adrenal crisis in adrenal insufficiency (cortisol clearance).
• Clostridioides difficile infection.

Interactions. Strong induction of CYP3A4, CYP2C9, CYP2C19 and P-glycoprotein lowers levels of many drugs.

• Antiretrovirals: dolutegravir (increase to 50 mg every 12 hours), efavirenz (usual dose), lopinavir/ritonavir (avoid or double dose with monitoring), atazanavir and darunavir (avoid), nevirapine (avoid), tenofovir alafenamide (avoid).
• Hormonal contraception (failure: use an intrauterine device or injectable depot medroxyprogesterone acetate).
• Warfarin and direct oral anticoagulants (avoid or monitor INR).
• Antiepileptics (phenytoin, carbamazepine, lamotrigine) and corticosteroids (increase dose).
• Digoxin, methadone, ciclosporin and tacrolimus, calcium channel blockers, beta-blockers, sulphonylureas.
• Azole antifungals, artemether-lumefantrine and other antimalarials, voriconazole, levothyroxine, statins.
• Drugs raising hepatic risk: isoniazid, pyrazinamide, alcohol.

Common prescribing errors. Missing contraception failure, not adjusting antiretroviral therapy, using it as monotherapy for staphylococci, giving with food, missing liver tests, and stopping all tuberculosis drugs at the first rise in transaminases without a plan to reintroduce.

Special groups.

• Pregnancy: acceptable and used for tuberculosis. Give vitamin K 10 mg to the mother near term and vitamin K to the newborn (haemorrhagic risk).
• Breastfeeding: compatible.
• Older adults: higher hepatotoxicity risk; monitor liver tests.
• Kidney impairment: no adjustment; creatinine clearance under 10 mL/min maximum 600 mg daily.
• Liver impairment: avoid in active hepatitis or decompensated disease. If the drug is needed in compensated chronic liver disease, use it under specialist direction with weekly liver tests at first.
• Region: cornerstone of tuberculosis programmes in East Africa, mostly as a fixed-dose combination. The dolutegravir dose increase matters in HIV co-infection.

Preparation. Oral on an empty stomach, 30 to 60 minutes before food or 2 hours after (with food only if gastrointestinal upset). IV: reconstitute 600 mg vial with the supplied diluent, dilute in 500 mL of 5% glucose and infuse over 3 hours; use within 4 hours.

Baseline and monitoring. - Baseline: liver tests, full blood count, creatinine, HIV status, pregnancy test, full medication review for interacting drugs. - During treatment: liver tests at 2, 4 and 8 weeks (more often in risk groups, with symptoms); full blood count if bleeding or bruising; review adherence and orange urine as an adherence check.

Stop rules. Stop and refer for jaundice, transaminases over 3 times the upper limit with symptoms (or over 5 times without symptoms), thrombocytopenia with bleeding, haemolysis, anaphylaxis or severe skin reaction. Reintroduce drugs one at a time under specialist direction.

Referral and escalation. Refer for drug-induced liver injury, drug-resistant tuberculosis, tuberculous meningitis, drug interactions with antiretrovirals and anticoagulants, and treatment failure.