What are the definitions of Multi-Drug Resistant (MDR) and Extensively Drug-Resistant (XDR) Tuberculosis (TB)?

MDR and XDR Tuberculosis Definitions

Multidrug-resistant tuberculosis (MDR-TB) is defined as TB caused by Mycobacterium tuberculosis resistant to at least isoniazid AND rifampin, while extensively drug-resistant tuberculosis (XDR-TB) is defined as MDR-TB with additional resistance to any fluoroquinolone AND at least one of the priority A drugs (bedaquiline or linezolid). 1, 2

MDR-TB Definition

MDR-TB requires documented resistance to both isoniazid (INH) and rifampin (RIF), the two most powerful first-line anti-tuberculosis drugs. 1, 2

• This resistance pattern necessitates treatment with second-line drugs for 18-24 months after sputum culture conversion, using regimens of 5-6 medications that are less effective, more toxic, and more costly than standard first-line therapy 1
• Globally, approximately 3.7% of newly diagnosed TB cases and 20% of previously treated TB cases meet MDR-TB criteria 1
• Mortality rates for MDR-TB typically exceed 10% (range: 8-21%), substantially higher than drug-susceptible TB 1

XDR-TB Definition

The current WHO definition of XDR-TB (updated in 2020) requires three components: resistance to rifampin, PLUS resistance to any fluoroquinolone, PLUS resistance to at least one priority A drug (bedaquiline or linezolid). 2, 3, 4

• This updated definition replaced the older 2006 definition that required resistance to fluoroquinolones and second-line injectable drugs (kanamycin, amikacin, or capreomycin) 4
• The change was evidence-based: resistance to fluoroquinolones significantly increases odds of unfavorable treatment outcomes (adjusted OR 1.91,95% CI 1.63-2.23), while second-line injectables are no longer recommended due to poor outcomes 3, 4
• Approximately 9% of MDR-TB cases have additional resistance qualifying as XDR-TB 1, 3
• XDR-TB has been reported in 84 countries worldwide 1, 3

Pre-XDR TB Definition

Pre-extensively drug-resistant TB (pre-XDR TB) is defined as MDR-TB with additional resistance to any fluoroquinolone, but not meeting full XDR-TB criteria (i.e., lacking resistance to bedaquiline or linezolid). 2, 3

• This intermediate category represents a critical surveillance point, as these patients are at high risk for developing full XDR-TB if treatment is inadequate 2, 3
• In 2020,25,681 cases of pre-XDR-TB or XDR-TB were detected globally 3

Related Resistance Patterns to Distinguish

Other important resistance patterns that must be differentiated from MDR-TB and XDR-TB include: 2

• Rifampicin-resistant TB (RR-TB): Resistance to rifampin alone, often treated similarly to MDR-TB 2, 3
• Mono-resistant TB: Resistance to only one first-line drug 2
• Polyresistant TB: Resistance to more than one first-line drug, but not both isoniazid and rifampin 2

Clinical Significance and Outcomes

The distinction between these definitions has critical implications for treatment complexity, duration, and outcomes. 2

• MDR-TB requires 18-24 months of treatment with at least 5 effective drugs in the intensive phase and 4 drugs in continuation phase 2
• XDR-TB requires 15-24 months after culture conversion with every available susceptible agent, often including newer drugs like bedaquiline and linezolid 5, 2, 3
• Treatment outcomes worsen progressively: drug-susceptible TB has the best outcomes, followed by MDR-TB, pre-XDR TB, and XDR-TB with the worst outcomes 1, 4
• Among XDR-TB patients receiving both bedaquiline and linezolid, the adjusted odds ratio for unfavorable outcome was 0.21 (95% CI 0.12-0.38) compared to those receiving neither drug 4

Common Diagnostic Pitfalls

Rapid molecular testing is essential for timely diagnosis, as approximately two-thirds of individuals who develop MDR/RR-TB globally are not receiving appropriate treatment. 2, 3

• Testing for rifampicin resistance has increased to 71% of bacteriologically confirmed pulmonary TB cases, but fluoroquinolone resistance testing remains at only 50% worldwide 3
• Drug susceptibility testing must be performed on the first isolate from all patients to guide appropriate therapy 5
• Failure to test for second-line drug resistance in MDR-TB patients delays recognition of pre-XDR or XDR-TB, leading to inadequate treatment regimens 3