Multidrug Resistant Tuberculosis Pharmacotherapy

Multidrug resistant tuberculosis is disease caused by organisms resistant to at least isoniazid and rifampicin; rifampicin-resistant disease is managed identically. Pre-extensively drug-resistant disease adds fluoroquinolone resistance, and extensively drug-resistant disease adds resistance to bedaquiline or linezolid. Cure now relies on all-oral regimens of 6 to 20 months, which have replaced injectable-based regimens.

Pharmacology. Treatment depends on four principles: at least four drugs likely to be active, a core of bedaquiline, linezolid and a fluoroquinolone or pretomanid, no single drug added to a failing regimen, and drug susceptibility testing for every drug in the regimen where it exists.

Detection. Rapid molecular testing detects rifampicin resistance in under 2 hours and is done on every new sputum sample. Line probe or sequencing assays then identify isoniazid and fluoroquinolone resistance.

• Core drugs: bedaquiline, linezolid, levofloxacin or moxifloxacin, pretomanid.
• Add-ons: clofazimine, cycloserine or terizidone, delamanid, ethambutol, pyrazinamide, high-dose isoniazid when isoniazid resistance is low-level (typically an inhA mutation), ethionamide.
• Injectables: amikacin and streptomycin, now a last resort.
• Rescue drugs: carbapenems with clavulanic acid, para-aminosalicylic acid.

Six-month regimen (BPaLM). For adults and adolescents aged 14 years and over with rifampicin-resistant disease and no fluoroquinolone resistance:

• Bedaquiline 400 mg daily for 2 weeks, then 200 mg three times weekly (length follows the regimen used).
• Pretomanid 200 mg daily for 26 weeks.
• Linezolid 600 mg daily for 26 weeks, reduced to 300 mg for toxicity.
• Moxifloxacin 400 mg daily for 26 weeks.

Fluoroquinolone resistance. Use the same regimen without moxifloxacin (BPaL) for 26 weeks, extendable to 9 months.

Nine-month all-oral regimen. For patients unsuitable for the six-month regimen, including some children and pregnant women: bedaquiline for 6 months with levofloxacin or moxifloxacin, clofazimine, ethambutol, pyrazinamide, high-dose isoniazid (10 to 15 mg/kg) and ethionamide for the first 4 months, extendable to 6 months if smear remains positive; the continuation phase is levofloxacin or moxifloxacin, clofazimine, ethambutol and pyrazinamide for 5 months.

Longer individualised regimens. For extensive disease, resistance beyond these regimens, or intolerance: 18 to 20 months, with bedaquiline for at least 6 months (longer if tolerated), linezolid, a fluoroquinolone, clofazimine and cycloserine as the core, adding delamanid, carbapenems or others when drugs cannot be used. Stop drugs only after the regimen is judged stable.

Tuberculous meningitis and central nervous system disease. Drugs with poor penetration (bedaquiline, clofazimine) are less reliable; use linezolid, fluoroquinolone, cycloserine and high-dose isoniazid in a specialist-designed regimen.

Children and pregnancy. Children under 14 years: individualised regimens based on weight-banded doses of the same drugs. Pregnancy: data for pretomanid are limited, so the nine-month or individualised regimens are usual with specialist input.

Region. In East Africa, access to rapid molecular testing, pretomanid, bedaquiline and linezolid monitoring (blood counts, eye review) varies by programme and decides which regimen is feasible.

Monitoring schedule. ECG, full blood count, creatinine, electrolytes and liver enzymes at baseline, at 2 weeks, monthly, and after any drug change. Visual acuity and colour vision monthly with linezolid or ethambutol. Sputum culture monthly until two negative results.

Stop rules and adjustments.

• QTcF over 500 ms: stop QT-prolonging drugs, correct electrolytes, repeat ECG.
• Neutrophils under 1.0 x 10^9/L or platelets under 50 x 10^9/L: hold linezolid, then restart at 300 mg daily once recovered.
• Optic neuritis or progressive neuropathy: stop linezolid permanently.
• Alanine aminotransferase more than 3 times the upper limit with symptoms, or more than 5 times without: hold hepatotoxic drugs.

Treatment support. Directly observed therapy, nutritional support, HIV treatment, adverse effect management and psychosocial support all affect cure.

Referral and escalation. All patients need a specialist programme. Escalate for culture positivity at month 4 to 6, new resistance, intolerance of core drugs, or relapse.