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Second-Line Anti-TB Drugs: Details and Use in DR-TB

(MD Examination Answer — 15 Marks)

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INTRODUCTION

1. Treatment of drug-resistant TB (DR-TB)
2. Patients intolerant or allergic to first-line agents
3. When first-line supplemental agents are unavailable

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WHO GROUPING OF SECOND-LINE ATT DRUGS

Note: Kanamycin and capreomycin are NOT to be included in longer regimens.

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GROUP A DRUGS — DETAILED PHARMACOLOGY

1. Fluoroquinolones (Levofloxacin / Moxifloxacin)

• Well absorbed orally; high serum levels; distribute well into body tissues and fluids
• Absorption decreased by co-ingestion with multivalent cations (antacids, calcium, iron)

• Levofloxacin: ≥750 mg/day (optimal dose under active study)
• Moxifloxacin: 400 mg/day (800 mg in standardized shorter MDR-TB regimens)

• Both levofloxacin and moxifloxacin are used effectively in MDR-TB treatment
• Moxifloxacin combined with rifapentine showed non-inferiority to standard 6-month regimen in TBTC Study 31 (for DS-TB)
• Despite resistance to earlier fluoroquinolones (ofloxacin, ciprofloxacin), later-generation fluoroquinolones remain associated with favorable outcomes
• Ciprofloxacin and ofloxacin are no longer recommended for TB

• GI intolerance, rashes, dizziness, headache (0.5–10%)
• QTc prolongation — rare but monitored; risk compounded with bedaquiline, delamanid, clofazimine
• Risk of tendon rupture/cartilage damage in children (traditionally avoided)

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2. Bedaquiline (Diarylquinoline — TMC207/R207910)

• 400 mg/day for 2 weeks, then 200 mg three times weekly — total 24 weeks (6 months)
• Oral bioavailability is excellent; food increases bioavailability 2-fold

• Very large volume of distribution (>10,000 L) — accumulates intracellularly
• Terminal half-life: ~5.5 months (mainly redistribution from tissues)
• Metabolized by CYP3A4 to M2 (N-monodesmethyl metabolite; ~20% activity)
• A single dose can inhibit M. tuberculosis growth for up to 1 week

• Integral part of all shorter-course, all-oral MDR-TB regimens (WHO endorsed)
• In phase 2 RCT: 8-week sputum conversion ~50% vs. 9% with background regimen alone
• BPaL regimen (Bedaquiline + Pretomanid + Linezolid): highly effective against XDR-TB (Nix-TB, ZeNix trials)
• BPaLM regimen (BPaL + Moxifloxacin): WHO recommended preferred regimen for MDR/RR-TB (2022)

• Rifampin lowers bedaquiline levels by ~50% (CYP3A4 induction)
• Efavirenz (CYP3A4 inducer): reduces bedaquiline levels; avoid co-administration
• Protease inhibitors interact significantly
• Avoid strong CYP3A4 inducers

• Nausea (26%), diarrhea (13%) — rarely treatment-limiting
• QT interval prolongation (via M2 metabolite) — serial ECG monitoring mandatory
• Black box FDA warning for QT prolongation; earlier trial showed higher mortality (11.4% vs. 2.5%) — not confirmed in subsequent studies

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3. Linezolid (Oxazolidinone)

• Nearly 100% oral bioavailability
• Good penetration into tissues and fluids, including CSF

• ~80% of MDR-TB patients can be successfully treated with linezolid-containing individualized regimens based on DST
• Key component of BPaL and BPaLM regimens
• Evaluated for replacement of ethambutol for 2–4 weeks in intensive phase of DS-TB for faster sputum conversion

• Optic neuropathy and peripheral neuropathy (dose-dependent)
• Pancytopenia (myelosuppression)
• Lactic acidosis
• Serotonin syndrome — weak MAO inhibitor; dangerous with SSRIs/serotonergic drugs

Sutezolid — modified oxazolidinone with higher early bactericidal activity; in Phase 2A trials.

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GROUP B DRUGS

4. Clofazimine

• Used in both 9-month and 6-month MDR-TB regimens
• Important in BDLLfxCfz (6-month) and BLLfxCfZZ (9-month) regimens
• Cross-resistance with bedaquiline can occur via efflux pump mutations (Rv0678)

• Skin discoloration (red-brown to black pigmentation) — reversible but cosmetically distressing
• GI intolerance
• QTc prolongation — important when combined with bedaquiline and fluoroquinolones
• Ichthyosis with prolonged use

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5. Cycloserine / Terizidone

• Part of longer MDR-TB regimens (Group B)
• Terizidone is a combination of two molecules of cycloserine — fewer CNS effects

• Seizures (major concern — avoid in epilepsy)
• Psychosis, depression, suicidal ideation
• Pyridoxine (Vitamin B6) supplementation is mandatory (reduces neurotoxicity)
• Peripheral neuropathy

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GROUP C DRUGS

6. Delamanid (Bicyclic Nitroimidazole)

• Licensed by EMA for MDR-TB treatment; used in Group C when Group A/B drugs cannot be used
• 6-month BDLLfxCfz regimen (bedaquiline + delamanid + linezolid + levofloxacin ± clofazimine) — non-inferior to 9-month/longer regimens
• Safe to use in children, adolescents, and pregnant/breastfeeding women (unlike pretomanid)

• Headache, insomnia
• QTc prolongation — monitoring required when combined with other QT-prolonging drugs

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7. Pretomanid (New Nitroimidazole)

• FDA-approved as part of BPaL regimen (Bedaquiline + Pretomanid + Linezolid) for XDR-TB and treatment-intolerant or non-responsive MDR-TB
• BPaLM = BPaL + Moxifloxacin — WHO preferred regimen for MDR/RR-TB
• Contraindicated in pregnancy (incomplete safety data)

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8. Injectable Aminoglycosides (Amikacin / Streptomycin)

• Ototoxicity (irreversible — cochlear and vestibular)
• Nephrotoxicity
• Monitoring: renal function, audiometry

Note: Injectables are now Group C only — preferred to use oral regimens. Kanamycin and capreomycin are no longer recommended in longer MDR-TB regimens.

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9. Ethionamide / Prothionamide

• Severe GI intolerance (nausea, vomiting) — major compliance issue
• Hepatotoxicity
• Hypothyroidism with prolonged use
• Cross-resistance with high-level isoniazid resistance (both target InhA)

Included only if bedaquiline, linezolid, clofazimine, or delamanid are not used, or if better options are not possible.

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10. p-Aminosalicylic Acid (PAS)

• Severe GI intolerance (nausea, diarrhea)
• Hypothyroidism (interferes with iodine uptake)
• Hepatotoxicity
• Malabsorption syndrome

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DR-TB: WHO-RECOMMENDED TREATMENT REGIMENS (2022/2024)

1. Preferred — BPaLM Regimen (6 months, all oral)

• Success rate: ~90%
• For MDR/RR-TB and pre-XDR-TB, age ≥14 years, regardless of HIV status
• Not for disseminated, CNS, or osteoarticular TB
• No prior exposure to bedaquiline, pretomanid, linezolid (or <1 month)
• Not for pregnant/breastfeeding women

2. Alternative 6-Month Regimen — BDLLfxCfz

• Non-inferior to 9-month/longer regimens
• Safe in children, adolescents, pregnant/breastfeeding women
• Fluoroquinolone omitted if resistant; clofazimine omitted if FQ-susceptible

3. 9-Month All-Oral Regimens (in order of preference)

• For FQ-susceptible MDR/RR-TB with no prior second-line exposure

4. Longer 18–20 Month Individualized Regimen

• Include all 3 Group A drugs (FQ + Bdq + Lzd) ensuring ≥4 likely effective agents
• Include at least 1 Group B drug
• Supplement with Group C drugs to reach total of 4–5 active drugs

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XDR-TB TREATMENT

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MONITORING DURING DR-TB TREATMENT

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SUMMARY TABLE

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