Pre-XDR TB and XDR TB

Definitions (WHO 2021 - Updated)

Old (pre-2021) definitions still appear in many textbooks: "Pre-XDR" was MDR-TB + resistance to a fluoroquinolone OR a second-line injectable (amikacin, kanamycin, capreomycin); "XDR" required resistance to both a fluoroquinolone AND a second-line injectable. The new definitions reflect that injectables have been largely abandoned and bedaquiline/linezolid are now the key second-line drugs. - Fishman's Pulmonary Diseases and Disorders, p. 2289

Spectrum of Drug Resistance in TB

Drug-susceptible TB
       ↓
Isoniazid-monoresistant TB
       ↓
MDR-TB (INH + RIF resistant)
       ↓
Pre-XDR-TB (MDR + fluoroquinolone resistant)
       ↓
XDR-TB (MDR + fluoroquinolone + BDQ or LZD resistant)

Epidemiology

• In 2019, >360,000 cases of MDR-TB were reported globally (3.3% of new cases, 18% of relapses)
• 12,350 XDR-TB cases were reported in 2019 (by the older definition)
• High-burden regions: Eastern Europe (ex-Soviet states), India, China, South Africa
• Persons with XDR-TB are 64% more likely to die during treatment than those with drug-susceptible TB
• Jawetz Melnick & Adelberg's Medical Microbiology, Treatment section

Risk Factors for Drug Resistance

• Prior TB treatment (especially without DOT)
• Contact with known MDR/XDR-TB case
• Immigrant from high-resistance-burden country (ex-Soviet states, India, China, South Africa)
• Treatment with a non-standard or incomplete regimen
• Lack of culture conversion by months 3-4
• HIV-positive with intermittent regimen use

Rapid Diagnostics

• GeneXpert MTB/RIF - detects M. tuberculosis AND rifampin resistance simultaneously; results in ~2 hours
• Confirms RIF resistance (a marker for MDR-TB) quickly
• Drug susceptibility testing (DST) for second-line drugs should follow
• Fluoroquinolone resistance testing is required whenever INH resistance is found
• Molecular detection of drug resistance is available via CDC for INH, RIF, and second-line drugs

Key Principles of Treatment (Drug-Resistant TB)

1. Expert consultation is mandatory - never manage alone
2. Use only drugs with documented or likely susceptibility
3. Never add a single new drug to a failing regimen - this selects for resistance to that new drug
4. Include multiple new active drugs simultaneously
5. Monitor bacteriologically with monthly sputum cultures for pulmonary TB
6. If cultures remain positive after 3 months, repeat full DST

Treatment Regimens

MDR-TB (the backbone of pre-XDR/XDR treatment)

• Intensive phase (5-7 months): 5 active drugs
• Continuation phase: 4 active drugs, total duration 15-21 months after culture conversion
• Preferred oral drugs: levofloxacin or moxifloxacin + bedaquiline + linezolid + clofazimine + cycloserine
• If fluoroquinolone-susceptible, it is a backbone drug

Pre-XDR-TB

• Treatment parallels MDR-TB principles but fluoroquinolones are not usable (or usable at very limited capacity)
• Total duration: 15-24 months after culture conversion
• Build regimen from remaining active Group A (bedaquiline, linezolid) and Group B/C drugs

XDR-TB Treatment Options

• Intensive (4-6 months): moxifloxacin + kanamycin + ethionamide + clofazimine + high-dose INH + pyrazinamide + ethambutol (7 drugs)
• Continuation (5-6 months): moxifloxacin + clofazimine + pyrazinamide + ethambutol (4 drugs)

Key Drugs Used in DR-TB and Their Mechanisms

Outcomes

• XDR-TB has significantly worse outcomes than MDR-TB or drug-susceptible TB
• The BPaL regimen has improved outcomes substantially for XDR-TB (success rates ~90% in trials vs. historical <50%)
• Surgery (partial resection) can be considered for localized pulmonary disease that fails medical therapy
• A comprehensive review on MDR-TB management is available: Dheda et al., Nature Reviews Disease Primers, 2024 (PMID: 38523140)

Important Note on Evolving Definitions

• Group A drugs (the most potent second-line drugs) are bedaquiline and linezolid - these now define XDR
• Group A drugs may change as new drugs emerge or resistance profiles evolve
• Second-line injectables (kanamycin, amikacin, capreomycin) have been downgraded to Group C due to toxicity and the availability of better oral options