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Poly Drug Resistant Tuberculosis (PDR-TB) — Complete MD Exam Answer (15 Marks)

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1. INTRODUCTION & SPECTRUM OF DRUG RESISTANCE IN TB

PDR-TB key point: PDR-TB includes strains resistant to, for example, H+E, or H+Z, or R alone — but NOT both H+R simultaneously (that would be MDR-TB). It is NOT the same as MDR-TB. This distinction is frequently tested.

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2. EPIDEMIOLOGY

• ~500,000 new cases of MDR/RR-TB occur annually worldwide (WHO)
• Highest burden: countries of the former Soviet Union, China, India, South Africa
• India alone contributes ~27% of the global MDR-TB burden
• PDR-TB is most common with isoniazid monoresistance (~7–8% in North America; higher in high-burden countries)
• Primary resistance = patient infected from the start with a resistant strain
• Acquired resistance = resistance develops during treatment (usually due to inadequate therapy)

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3. PATHOGENESIS / MECHANISMS OF RESISTANCE

Why resistance develops:

• Monotherapy or inadequate regimen selection
• Poor-quality drugs / subtherapeutic levels
• Non-adherence (missed doses)
• Interrupted treatment
• Lack of Directly Observed Therapy (DOT)
• HIV coinfection (especially intermittent regimens)

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4. CLASSIFICATION OF FIRST-LINE ANTI-TB DRUGS

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5. CLINICAL FEATURES

• Clinically indistinguishable from drug-susceptible TB
• Suspect PDR/MDR-TB when:
  • No culture conversion by months 3–4 of treatment
  • Worsening symptoms or imaging despite treatment
  • No DOT throughout course
  • Nonstandard or inappropriate regimen used
  • Previous treatment failure, relapse, or incomplete treatment
  • Contact with a known DR-TB patient
  • HIV co-infection on intermittent therapy
  • History of treatment for drug-resistant TB

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6. DIAGNOSIS

6A. Sputum Smear Microscopy

• AFB smear: identifies mycobacteria but cannot assess drug susceptibility

6B. Culture & Drug Susceptibility Testing (DST)

• Solid media (Löwenstein-Jensen): 3–8 weeks
• Liquid broth (MGIT BACTEC): 1–3 weeks (faster)
• Minimum inhibitory concentration (MIC)-based testing

6C. Rapid Molecular Tests (Priority)

• GeneXpert MTB/RIF (Xpert): Detects MTB and rifampicin resistance via rpoB mutation within 2 hours — now the WHO-recommended first test
• Line Probe Assay (LPA/Hain GenoType MTBDRplus): Detects H and R resistance (katG, inhA, rpoB) within 1–2 days
• Whole Genome Sequencing (WGS): Gold standard for comprehensive resistance profiling, increasingly used
• TrueNat MTB/MTB Plus: Point-of-care test for R resistance

6D. Radiology

• Chest X-ray: Upper lobe cavitation, consolidation, bilateral involvement — suggest extensive disease but not drug resistance per se
• CT chest: Better delineation of cavities, extent of disease (guides surgical decisions)

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7. TREATMENT

7A. General Principles (CRITICAL for exam)

1. Expert consultation is mandatory for all forms of DR-TB
2. Use only drugs to which the patient's isolate has documented or high likelihood of susceptibility
3. NEVER add a single drug to a failing regimen — always add ≥2 new active drugs
4. Treatment response monitored clinically, radiologically, and bacteriologically (cultures monthly)
5. If cultures remain positive at 3 months → repeat susceptibility testing
6. All-oral regimens are now preferred over injectable-containing regimens (WHO 2022 guidelines)
7. Directly Observed Therapy (DOT) is essential

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7B. Treatment of Isoniazid Mono/Poly Resistance (Non-MDR PDR-TB)

• Discontinue isoniazid
• Replace with moxifloxacin (400 mg/day) or levofloxacin (750 mg/day) if susceptible
• Regimen: Rifampicin + Ethambutol + Pyrazinamide + Fluoroquinolone × 6 months
• If non-cavitary pulmonary / extrapulmonary: pyrazinamide may be shortened to 8 weeks
• If fluoroquinolone resistance also present: expert consultation required

• Tailored regimen based on DST results
• Substitute resistant drugs with susceptible alternatives
• Duration generally 9–12 months depending on drug combination

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7C. MDR-TB Treatment (Resistance to H + R)

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7D. Key Drug Mechanisms (Second-Line)

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7E. Pre-XDR-TB and XDR-TB Treatment

• Pre-XDR-TB (MDR + fluoroquinolone resistance): total duration 15–24 months after culture conversion
• XDR-TB: Parallels MDR-TB principles but with restricted drug options

• Bedaquiline + Pretomanid + Linezolid (BPaL)
• FDA approved 2019
• 6-month all-oral regimen
• Protocol: Bedaquiline 400 mg/day × 2 wk → 200 mg 3×/wk × 24 wk; Pretomanid 200 mg/day × 26 wk; Linezolid 1200 mg/day (reduce to 600 → 300 mg for toxicity)
• Used for XDR-TB or treatment-intolerant/non-responsive MDR-TB
• WHO 2024 rapid communication: New 6-month regimens incorporating BDQ+DLM+LZD ± Lfx/Cfz also under evaluation

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8. DRUG TOXICITY MONITORING

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9. SURGERY

• Medical therapy alone carries a high risk of treatment failure or relapse
• Localized pulmonary disease with adequate contralateral lung reserve
• Surgery is performed along with a recommended MDR/XDR-TB medical regimen
• Bacteriologic and radiographic data support resectability

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10. PREVENTION AND PUBLIC HEALTH

• DOT (Directly Observed Therapy) — mandatory for all DR-TB
• Prompt diagnosis and treatment to interrupt transmission
• Negative-pressure isolation rooms with HEPA filtration; patient wears surgical mask; health care workers wear N95 respirators
• Contact tracing of household contacts
• Active case-finding in high-risk populations
• Treat latent TB infection (reduces active TB risk by 75–90%)
• Address structural factors: poverty, overcrowding, drug stockouts
• BCG vaccination: protects against severe forms of TB in children but has limited efficacy against pulmonary TB in adults

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11. OUTCOMES

• Untreated or inadequately treated MDR-TB: mortality approaches that of pre-antibiotic era
• With optimal regimens: 55–70% treatment success in MDR-TB; lower in XDR-TB
• BPaL regimen showed ~90% treatment success in XDR-TB in clinical trials (ZeNix, TB-PRACTECAL trials)
• Poor prognostic factors: bilateral cavitary disease, HIV co-infection, malnutrition, no culture conversion at 2 months

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SUMMARY SCHEMA

PDR-TB
  = Resistance to >1 first-line drug
    BUT NOT both H + R together
  ≠ MDR-TB

Spectrum:
Mono-R → PDR-TB → RR-TB → MDR-TB → Pre-XDR-TB → XDR-TB

Treatment PDR-TB (non-MDR):
  INH mono-R: Rfx/Lfx + R + E + Z × 6 months

Treatment MDR-TB:
  Step 1–3: Lfx/Mfx + BDQ + LZD + Cfz + Cs (5 oral drugs)
  Duration: 15–21 months

Treatment XDR-TB:
  BPaL (Bedaquiline + Pretomanid + Linezolid) × 6 months

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• Murray & Nadel's Textbook of Respiratory Medicine, 7th Ed. — Drug-Resistant Tuberculosis chapter
• Harrison's Principles of Internal Medicine, 22nd Ed. (2025) — Drug-Resistant TB
• Goldman-Cecil Medicine, International Ed. — Drug-Resistant Tuberculosis
• Lippincott Illustrated Reviews: Pharmacology — Anti-TB drugs
• WHO Rapid Communication on DR-TB Treatment Updates, June 2024