Notes · Microbiology · 9 November 2026

Tuberculosis – MDR, XDR & RR patterns

Definition

• Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex.
• Multidrug‑resistant TB (MDR‑TB): resistance to at least isoniazid (INH) and rifampicin (RIF), the two most potent first‑line drugs.
• Rifampicin‑resistant TB (RR‑TB): resistance to RIF with or without resistance to INH; all RR‑TB are treated as MDR‑TB because RIF resistance predicts poor response to standard regimens.
• Extensively drug‑resistant TB (XDR‑TB): MDR‑TB plus resistance to any fluoroquinolone (e.g., levofloxacin, moxifloxacin) and at least one of the three injectable second‑line drugs (amikacin, kanamycin, capreomycin).

Epidemiology

• In 2023 WHO reported ~450,000 new MDR‑TB cases globally; ~6% of all TB cases.
• RR‑TB accounts for ~8% of all TB cases; most are also INH‑resistant, thus classified as MDR‑TB.
• XDR‑TB remains rare, ~6% of MDR‑TB cases, but is concentrated in Eastern Europe, Central Asia, and parts of South Africa.
• India contributes ~27% of global MDR‑TB burden; high population density and treatment interruptions are key drivers.
• HIV co‑infection raises risk of MDR/XDR‑TB by 2–3‑fold due to frequent health‑system contact and drug‑interaction complexities.

Aetiology (Mechanisms of Drug Resistance)

• Spontaneous chromosomal mutations during bacterial replication are the primary source; no plasmid‑mediated transfer in M. tuberculosis.
• Isoniazid resistance: mutations in katG (encoding catalase‑peroxidase) → loss of drug activation; or in the inhA promoter → over‑expression of the target enzyme.
• Rifampicin resistance: mutations in the rpoB gene (β‑subunit of RNA polymerase) within the 81‑bp Rifampicin‑Resistance‑Determining Region (RRDR).
• Fluoroquinolone resistance: mutations in gyrA and gyrB (DNA gyrase subunits).
• Injectable drug resistance: mutations in rrs (16S rRNA) and eis promoter (affecting aminoglycoside acetyltransferase).
• Compensatory mutations may restore fitness, allowing resistant strains to transmit efficiently.

Pathophysiology (Impact of Resistance)

• Resistant bacilli survive despite standard therapy, leading to persistent bacterial load and ongoing lung tissue destruction.
• Prolonged infection promotes caseating necrosis, cavitation, and higher bacillary burden, which in turn increases the chance of further mutations.
• Host immune response remains similar (cell‑mediated Th1 response), but the delayed bacterial clearance results in more extensive disease and higher transmission potential.

Clinical Features

• Symptoms are indistinguishable from drug‑susceptible TB: chronic cough, weight loss, night sweats, fever, hemoptysis.
• Clues suggesting MDR/XDR‑TB:
  • History of previous TB treatment (especially >2 months of first‑line regimen).
  • Persistent positive sputum smear after ≥2 months of appropriate therapy.
  • Relapse within 6 months of completing treatment.
  • Close contact with a known MDR/XDR‑TB case.
• Extrapulmonary involvement (e.g., lymph node, pleural, skeletal) occurs at similar rates but may be more common in HIV‑positive patients.

Investigations

Management (WHO 2023 Guidelines)

General Principles

• Treat all RR‑TB as MDR‑TB; use an all‑oral, shorter, individualized regimen when possible.
• Aim for ≥4 effective drugs in the intensive phase, including at least one fluoroquinolone (if susceptible) and one injectable (if needed).
• Directly Observed Therapy (DOT) and robust adherence support are mandatory.

MDR‑TB Regimen (2023)

1. Intensive phase (≥4–6 months)

   • Bedaquiline 400 mg daily for 2 weeks, then 200 mg three times per week.
   • Levofloxacin 750 mg daily (or moxifloxacin 400 mg if susceptible).
   • Linezolid 600 mg daily (dose may be reduced to 300 mg after 2–3 months to limit toxicity).
   • Clofazimine 100 mg daily.
   • Cycloserine 500 mg daily (or terizidone 500 mg twice daily).
   • Pyrazinamide 1500 mg daily (if susceptible).

2. Continuation phase (≥12 months)

   • Bedaquiline (up to 6 months total exposure), levofloxacin, linezolid (dose adjusted), clofazimine, cycloserine.

• Total treatment duration: minimum 18 months after culture conversion; many programs use 20 months.

XDR‑TB Regimen (2023)

• Same core drugs as MDR‑TB plus:
  • Delamanid 100 mg twice daily (if not already used).
  • Pretomanid (in the BPaL regimen) 200 mg daily combined with bedaquiline and linezolid for 6 months, followed by continuation phase with bedaquiline and linezolid.
• Injectables (amikacin, kanamycin, capreomycin) are now optional; WHO recommends avoiding them due to ototoxicity unless no alternative exists.

Monitoring & Adverse‑Effect Management

• Baseline ECG: monitor QTc; bedaquiline, delamanid, clofazimine can prolong QT.
• Monthly CBC: linezolid may cause anemia, thrombocytopenia.
• Liver function tests: pyrazinamide, bedaquiline, and clofazimine are hepatotoxic.
• Audiometry: if injectable used.
• Therapeutic drug monitoring (TDM): recommended for linezolid and bedaquiline in select cases.

Treatment of RR‑TB in Special Populations

• Pregnancy: avoid bedaquiline and delamanid; use levofloxacin (category C) only if benefits outweigh risks; prioritize injectable‑free regimen.
• Children: pediatric formulations of bedaquiline and delamanid now approved; dosing based on weight (mg/kg).
• Renal impairment: dose‑adjust cycloserine; most other drugs are hepatically cleared.

Complications

• Treatment failure: persistent culture positivity after ≥4 months of adequate regimen; may indicate additional resistance or poor adherence.
• Relapse: recurrence of disease within 12 months of cure; higher in XDR‑TB.
• Drug toxicity: peripheral neuropathy (linezolid), optic neuritis (ethambutol, rarely used), QT prolongation, ototoxicity (injectables).
• Transmission: MDR/XDR‑TB patients remain infectious longer; infection‑control measures (negative pressure rooms, N95 masks) are critical.
• Psychosocial impact: prolonged therapy leads to stigma, loss of income, and mental health issues; multidisciplinary support improves outcomes.

High‑Yield Exam Points

• MDR‑TB = INH + RIF resistance; RR‑TB = RIF resistance (with/without INH); XDR‑TB = MDR‑TB + any fluoroquinolone + at least one injectable resistance.
• rpoB mutation → rifampicin resistance; detected by Xpert MTB/RIF.
• WHO 2023 regimen: all‑oral, 6‑drug intensive phase (bedaquiline, fluoroquinolone, linezolid, clofazimine, cycloserine, pyrazinamide).
• Injectables are no longer core drugs; reserved for rare cases where oral options are exhausted.
• BPaL regimen (bedaquiline + pretomanid + linezolid) is the preferred 6‑month regimen for XDR‑TB or non‑responsive MDR‑TB.
• Treatment duration: at least 18 months after culture conversion; shorter regimens only under strict programmatic conditions.
• Key mutation sites: katG (INH), inhA promoter (INH), rpoB RRDR (RIF), gyrA/B (fluoroquinolones), rrs (injectables).
• Adverse‑effect monitoring: QTc (bedaquiline, delamanid, clofazimine), CBC (linezolid), LFTs (pyrazinamide, bedaquiline).

Practice questions

1. A 35‑year‑old man with a history of incomplete TB treatment presents with persistent cough. Sputum Xpert MTB/RIF shows M. tuberculosis and a mutation in the rpoB gene but no mutation in katG. Which of the following is the most appropriate initial classification?
   Answer: RR‑TB — because rifampicin resistance is present regardless of isoniazid status.

2. According to the WHO 2023 guidelines, which drug is not part of the recommended all‑oral regimen for MDR‑TB?
   A) Bedaquiline
   B) Levofloxacin
   C) Amikacin
   D) Clofazimine
   Answer: C — amikacin is an injectable and is no longer a core drug in the recommended regimen.

3. A patient with confirmed XDR‑TB is started on the BPaL regimen. Which drug in this regimen is a nitro‑imidazooxazine that specifically targets mycolic acid synthesis?
   Answer: Pretomanid — it is the nitro‑imidazooxazine component of BPaL.

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