What are the definitions and treatment options for Pre-Extensively Drug-Resistant (Pre-XDR) Tuberculosis (TB) and Extensively Drug-Resistant (XDR) TB?

Definitions of Pre-XDR TB and XDR TB

According to the World Health Organization (WHO), pre-extensively drug-resistant tuberculosis (pre-XDR TB) is defined as multidrug-resistant TB (MDR-TB) with additional resistance to any fluoroquinolone, while extensively drug-resistant tuberculosis (XDR TB) is defined as TB resistant to rifampicin, plus any fluoroquinolone, plus at least one further priority A drug (bedaquiline or linezolid). 1

Detailed Definitions

• MDR-TB: TB resistant to both isoniazid and rifampicin, the two most powerful first-line anti-TB drugs 1
• RR-TB: TB resistant to rifampicin only 1
• Pre-XDR TB: MDR-TB with additional resistance to any fluoroquinolone 1
• XDR TB: TB resistant to rifampicin, plus any fluoroquinolone, plus at least one further priority A drug (bedaquiline or linezolid) 1

Epidemiology

• Of an estimated 500,000 new cases of RR-TB in 2020, only about one-third were detected and treated 1
• In 2020,157,903 new cases of DR-TB were detected (132,222 cases of MDR/RR-TB and 25,681 cases of pre-XDR-TB or XDR-TB) 1
• XDR-TB has been reported in 84 countries, with approximately 9% of MDR-TB cases having additional resistance qualifying as XDR-TB 1
• These highly resistant infections are more difficult to eradicate and carry worse outcomes for infected individuals 1

Diagnostic Approaches

• Rapid molecular tests like GeneXpert, whole genome sequencing, and Myc-TB offer solutions for rapid detection of resistance 1
• Testing for rifampicin resistance has increased globally, with 71% of bacteriologically confirmed pulmonary TB cases tested in 2020 1
• Testing for fluoroquinolone resistance remains significantly lower at around 50% worldwide 1
• Conventional culture-based methods for detecting XDR-TB generally take several weeks, though progress is being made in developing rapid molecular tests 2

Treatment Recommendations for Pre-XDR TB

• For pre-XDR TB, treatment should include at least 5 effective drugs in the intensive phase and 4 drugs in the continuation phase 1
• The intensive phase should last between 5-7 months after culture conversion 1
• Total treatment duration should be between 15-21 months after culture conversion 1
• Core drugs to include:
  • Bedaquiline (strongly recommended) 1, 3
  • Linezolid (suggested as an important component) 1, 3
  • Clofazimine (suggested) 1, 3
  • Cycloserine (suggested) 1, 3
  • Pyrazinamide (only if susceptibility is confirmed) 1, 3, 4

Treatment Recommendations for XDR TB

• For XDR TB, treatment should include at least 5 effective drugs in the intensive phase and 4 drugs in the continuation phase 1, 3
• The intensive phase should last between 5-7 months after culture conversion 1
• Total treatment duration should be between 15-24 months after culture conversion 1, 3
• Core drugs to include:
  • Bedaquiline (strongly recommended) 1, 3
  • Linezolid (suggested as a core component) 1, 3
  • Clofazimine (suggested) 1, 3
  • Cycloserine (suggested) 1, 3
  • Carbapenems with amoxicillin-clavulanate may be considered 3

Drugs to Avoid

• Kanamycin or capreomycin are not recommended due to poor outcomes 3
• Macrolides such as azithromycin and clarithromycin are not recommended due to lack of efficacy 3
• Amoxicillin-clavulanate alone should not be included in treatment regimens except when used with carbapenems 1, 3

Treatment Outcomes

• Treatment success rates for XDR-TB are generally 30-50%, with very poor outcomes in HIV-infected patients 2
• The use of bedaquiline and/or linezolid has been shown to improve treatment outcomes regardless of resistance to fluoroquinolones and/or second-line injectable drugs 5
• Among patients with XDR-TB, compared to those receiving no group A drugs, the adjusted odds ratios for unfavorable outcomes were 0.37 with linezolid only, 0.40 with bedaquiline only, and 0.21 with both drugs 5

Common Pitfalls and Challenges

• Using fewer than five effective drugs in the intensive phase leads to poorer outcomes 3
• Treating for less than 15 months after culture conversion for XDR-TB is associated with higher relapse rates 3
• Delay in diagnosis and improper treatment create a vicious cycle that fuels the MDR-TB/XDR-TB epidemic 6
• Approximately two-thirds of individuals who develop MDR/RR-TB each year are not receiving appropriate treatment 1

Emerging Approaches

• Shorter regimens (9-12 months) are being studied but are not yet recommended for XDR-TB 3
• New diagnostics, drugs, and vaccines are required to meet the challenge of difficult MDR-TB/XDR-TB 6
• Surgical intervention, such as elective partial lung resection, may be considered in selected cases where medical therapy alone may be insufficient 3