Second Line Tuberculosis Drugs

Second-line tuberculosis drugs are used when rifampicin or isoniazid cannot be used because of resistance, intolerance or interactions. They are more toxic, more expensive and need longer exposure than first-line drugs, and the best of them (bedaquiline, linezolid, fluoroquinolones, pretomanid) are now oral.

Mechanisms.

• Levofloxacin and moxifloxacin: inhibit DNA gyrase and topoisomerase IV.
• Bedaquiline: inhibits mycobacterial ATP synthase.
• Linezolid: oxazolidinone, binds the 50S ribosome; also inhibits mitochondrial protein synthesis and monoamine oxidase.
• Pretomanid and delamanid: nitroimidazole prodrugs that block mycolic acid synthesis.
• Clofazimine: riminophenazine; mechanism uncertain, accumulates in tissue.
• Cycloserine and terizidone: block D-alanine incorporation into cell walls.
• Ethionamide and prothionamide: thioamides, inhibit mycolic acid synthesis after activation.
• Aminoglycosides (amikacin, streptomycin): bind the 30S ribosome.
• Para-aminosalicylic acid: inhibits folate synthesis.
• Carbapenems with clavulanic acid: inhibit cell wall transpeptidases.

Representative adult doses (all daily unless stated):

• Levofloxacin 750 to 1000 mg by weight band; moxifloxacin 400 mg.
• Bedaquiline 400 mg daily for 2 weeks, then 200 mg three times weekly for 22 weeks (schedules differ between regimens).
• Linezolid 600 mg daily, reduced to 300 mg daily for toxicity or after the first months.
• Pretomanid 200 mg; delamanid 100 mg twice daily for 24 weeks.
• Clofazimine 100 mg; cycloserine 10 to 15 mg/kg in divided doses (maximum 1 g), with pyridoxine 50 mg.
• Ethionamide or prothionamide 15 to 20 mg/kg (maximum 1 g); para-aminosalicylic acid 8 to 12 g in 2 to 3 divided doses.
• Amikacin 15 mg/kg (maximum 1 g) or streptomycin 15 mg/kg (maximum 1 g); in patients over 59 years, 10 mg/kg (maximum 750 mg).
• Meropenem 1 g every 8 hours or imipenem-cilastatin 1 g twice daily, each given with amoxicillin-clavulanate for the clavulanic acid, 30 minutes before.

Differences. Bedaquiline and delamanid prolong the QT interval and act additively. Linezolid is the main marrow and nerve toxic drug. Cycloserine is the main psychiatric toxic drug. Aminoglycosides are ototoxic and nephrotoxic and are the most poorly tolerated. Moxifloxacin prolongs QT more than levofloxacin.

Choosing drugs. Select at least four active drugs at the start, using priority agents first: a fluoroquinolone, bedaquiline and linezolid, then clofazimine, cycloserine, then the remaining companion drugs. Use drug susceptibility results for fluoroquinolones, bedaquiline and linezolid where available.

Fluoroquinolone resistance. Pre-extensively drug-resistant disease (rifampicin plus fluoroquinolone resistance) is treated with bedaquiline, pretomanid and linezolid for 6 to 9 months.

Dose adjustment.

• Renal: levofloxacin 750 to 1000 mg three times weekly when creatinine clearance is under 30 mL/min; cycloserine 250 mg daily or 500 mg three times weekly; ethionamide and linezolid unchanged; aminoglycosides need dosing by level and are best avoided; para-aminosalicylic acid sodium salt is avoided in severe disease.
• Hepatic: avoid pyrazinamide, ethionamide and para-aminosalicylic acid in severe disease; bedaquiline needs caution.
• Weight and age: dose children by weight band; delamanid is used from 3 years in some regimens and pretomanid from 14 years.
• Pregnancy: fluoroquinolones, linezolid, bedaquiline and clofazimine are used when needed, since untreated resistant disease is worse; avoid aminoglycosides, ethionamide and pretomanid where alternatives exist.

Baseline tests. Full blood count, creatinine, electrolytes (potassium, magnesium, calcium), liver enzymes, thyroid function when ethionamide or para-aminosalicylic acid is planned, ECG, visual acuity and colour vision, audiometry for aminoglycosides, HIV status, pregnancy test and glucose.

Ongoing monitoring.

• ECG at 2 weeks, monthly, and when drugs are added. Stop bedaquiline if the QTcF is over 500 ms, and correct potassium (keep over 4 mmol/L), magnesium and calcium first.
• Full blood count weekly for the first month, then monthly with linezolid; reduce the dose or stop for haemoglobin falling or neutrophils under 1.0 x 10^9/L.
• Liver enzymes monthly; creatinine and potassium monthly, and weekly with aminoglycosides.
• Audiometry and creatinine monthly with aminoglycosides.

Serious adverse effects. Linezolid: marrow suppression, peripheral and optic neuropathy, lactic acidosis, serotonin syndrome. Fluoroquinolones: tendon rupture, dysglycaemia, QT prolongation, aortic aneurysm. Aminoglycosides: ototoxicity, nephrotoxicity. Cycloserine: depression, psychosis, seizures. Clofazimine: skin discolouration, QT prolongation. Ethionamide: hypothyroidism, hepatitis, vomiting.

Interactions. Linezolid with serotonergic antidepressants, tramadol or pethidine. Fluoroquinolones with antacids and iron (give 2 hours apart). Bedaquiline with efavirenz (levels fall) and strong CYP3A4 inhibitors. Combined QT drugs: ondansetron, azithromycin, antipsychotics.

Referral and escalation. All patients on second-line regimens need a specialist programme.