What is the difference in treatment approach for a patient with a history of tuberculosis or other infection between Extensively Drug-Resistant (XDR) and Multi-Drug Resistant (MDR) infections?

XDR vs MDR Tuberculosis: Treatment Approach Differences

The critical difference between treating XDR-TB versus MDR-TB is that XDR-TB requires longer treatment duration (15-24 months after culture conversion versus 15-21 months for MDR-TB), has significantly fewer effective drug options available, and carries substantially worse outcomes with mortality rates exceeding those of MDR-TB. 1

Definitions and Clinical Significance

MDR-TB is defined as tuberculosis resistant to at least isoniazid and rifampin, the two most potent first-line agents. 1

XDR-TB is defined as MDR-TB with additional resistance to any fluoroquinolone AND at least one second-line injectable agent (amikacin, kanamycin, or capreomycin). 1

Key Prognostic Differences:

• Mortality rates for MDR-TB typically range from 8-21%, while XDR-TB carries even higher mortality. 1
• Treatment success rates are substantially lower for XDR-TB compared to MDR-TB, with only 47% of XDR-TB patients achieving successful outcomes versus 57% for MDR-TB. 1
• The average number of effective drugs available is critically reduced in XDR-TB, with some patients having fewer than 4 effective agents available. 2

Core Treatment Regimen Differences

MDR-TB Treatment Regimen:

Build a regimen with at least 5 effective drugs during the intensive phase, then 4 drugs during continuation phase. 1, 3, 4

Core drugs (in order of priority): 3, 4

• Bedaquiline (strong recommendation)
• Later-generation fluoroquinolone - levofloxacin or moxifloxacin (strong recommendation)
• Linezolid (conditional recommendation)
• Clofazimine (conditional recommendation)
• Cycloserine or terizidone (conditional recommendation)

Additional agents as needed: 3

• Pyrazinamide (only if susceptible)
• Ethambutol (only if other more effective drugs cannot be assembled)
• Injectable agents: amikacin or streptomycin if susceptible (avoid kanamycin and capreomycin)
• Carbapenems with amoxicillin-clavulanic acid

Duration: 3, 4

• Intensive phase: 5-7 months after culture conversion
• Total duration: 15-21 months after culture conversion

XDR-TB Treatment Regimen:

Use the same core drug regimen as MDR-TB, but treatment must be extended and every available susceptible agent must be utilized. 3, 5

Core drugs (identical to MDR-TB but with critical caveats): 5

• Bedaquiline (strong recommendation)
• Later-generation fluoroquinolone - ONLY if susceptibility confirmed (levofloxacin preferred over moxifloxacin due to fewer adverse events)
• Linezolid (conditional recommendation)
• Clofazimine (conditional recommendation)
• Cycloserine or terizidone (conditional recommendation)

Critical difference: In XDR-TB, the fluoroquinolone may be resistant, eliminating one of the most effective agents. 1

Duration: 5

• Intensive phase: 5-7 months after culture conversion
• Total duration: 15-24 months after culture conversion (note the extended upper limit compared to MDR-TB)

Newer Regimen Option:

The BPaL regimen (bedaquiline, pretomanid, linezolid) for 6-9 months may be considered under operational research conditions for MDR/RR-TB/pre-XDR-TB patients who have not had prior exposure to bedaquiline or linezolid. 5

Critical Management Principles

Drug Selection Algorithm:

1. Perform drug susceptibility testing (DST) on the first isolate from all patients. 3, 4

2. Only include drugs to which the patient's M. tuberculosis isolate has documented or high likelihood of susceptibility. 3, 5

3. For XDR-TB, molecular testing beyond rifampin, isoniazid, fluoroquinolones, and second-line injectables is urgently needed for individualized therapy. 2

4. Never add a single drug to a failing regimen - this leads to acquired resistance. 1, 3, 5

5. When treatment failure occurs, add at least two, preferably three, new drugs to which susceptibility can be inferred. 1, 3, 5

Monitoring Requirements:

Obtain monthly sputum smears and cultures until conversion, then less frequently. 4, 5

Active drug safety monitoring (aDSM) is mandatory given frequent and severe adverse events with DR-TB regimens. 4

Directly observed therapy (DOT) is strongly recommended for all patients to ensure adherence. 3, 5, 6

Patients whose sputum cultures remain positive after 4 months of treatment should be deemed treatment failures and require immediate regimen adjustment. 1

Surgical Considerations

Elective partial lung resection (lobectomy or wedge resection) may be considered for adults with MDR-TB or XDR-TB receiving antimicrobial therapy. 3, 5

Surgery should only be performed by experienced surgeons after the patient has received several months of intensive chemotherapy. 1, 3, 5

Continue chemotherapy for 1-2 years postoperatively to prevent relapse. 1

Common Pitfalls and How to Avoid Them

Pitfall 1: Inadequate Number of Effective Drugs

Using fewer than 5 effective drugs in the intensive phase leads to poorer outcomes. 5

• Solution: Perform comprehensive DST including molecular testing for resistance beyond first-line drugs. 2

Pitfall 2: Premature Treatment Discontinuation

Treating for less than 15 months after culture conversion is associated with higher relapse rates. 5

• Solution: Strictly adhere to the 15-24 month post-conversion duration for XDR-TB. 5

Pitfall 3: Using Ineffective Injectable Agents

Kanamycin and capreomycin are associated with poor outcomes. 3, 5

• Solution: If an injectable is needed, use amikacin or streptomycin only if susceptibility is confirmed. 3

Pitfall 4: Malabsorption in HIV Co-infection

Drug malabsorption is common in patients with concomitant tuberculosis and HIV infection. 6

• Solution: Suspect malabsorption in adherent patients who fail to respond; consider therapeutic drug monitoring. 6

Pitfall 5: Cross-Resistance Between Bedaquiline and Clofazimine

Mutations in Rv0678 can confer cross-resistance between bedaquiline and clofazimine, reducing treatment options. 7

• Solution: Perform molecular testing for Rv0678, pepQ, Rv1979c, and atpE mutations when using these agents. 7

Transmission Control

The majority of XDR-TB cases are due to transmission rather than inadequate treatment of MDR-TB. 8

Three strategies to reduce DR-TB transmission: 4

1. Rapid diagnosis with molecular testing
2. Prompt appropriate treatment
3. Improved airborne infection control

Contact investigation and treatment of latent TB infection is recommended for contacts of MDR-TB and XDR-TB patients using a later-generation fluoroquinolone alone or with a second drug for 6-12 months based on source case susceptibility. 3, 4

Special Populations

HIV Co-infected Patients:

77% of XDR-TB patients have HIV co-infection. 8

• Monitor for malabsorption syndrome and consider therapeutic drug monitoring. 6
• Median CD4+ count in XDR-TB patients is 340 cells/mm³, requiring careful immune reconstitution management. 8

Patients from High-Burden Settings:

In high MDR-TB burden areas like Russia, 40.9% of MDR isolates are pre-XDR and 34.7% are XDR, compared to 14.8% and 1.7% respectively in low-burden settings like Taiwan. 2

• Empiric regimens must account for regional resistance patterns. 2
• 33% of MDR and pre-XDR Russian isolates have fewer than 4 effective drugs available. 2

Consultation Requirements

Early consultation with a specialty center or expert in drug-resistant TB is strongly advised for all XDR-TB cases and MDR-TB treatment failures. 1, 6

Patients with rifampin resistance alone are also at increased risk for treatment failure and should be managed in consultation with an expert. 1