What is the treatment approach for a patient with suspected Multidrug-Resistant (MDR) versus Extensively Drug-Resistant (XDR) tuberculosis (TB) infection?

Treatment Approach for MDR vs XDR Tuberculosis

For suspected MDR-TB, immediately consult a TB expert and initiate an all-oral regimen with at least 5 effective drugs including bedaquiline, a later-generation fluoroquinolone (levofloxacin or moxifloxacin), linezolid, and clofazimine; for XDR-TB, use the same core regimen but extend treatment duration to 15-24 months after culture conversion. 1, 2, 3

Immediate Actions Upon Suspicion

• Obtain rapid molecular drug susceptibility testing (DST) for rifampin and isoniazid resistance first, then immediately test for fluoroquinolone and aminoglycoside resistance if rifampin resistance is detected 1, 2
• Consult a TB expert immediately through CDC-supported TB Centers of Excellence, local health department TB control programs, or international MDR-TB expert groups 1
• Initiate treatment empirically while awaiting full susceptibility results if clinical suspicion is high, but only with drugs likely to be effective based on resistance patterns 1

Defining the Resistance Pattern

MDR-TB Definition

• Resistance to at least isoniazid AND rifampin 1
• Requires 18-24 months of treatment with second-line drugs 1

XDR-TB Definition (Updated 2021)

• The current evidence-based definition is MDR-TB with additional resistance to any fluoroquinolone PLUS resistance to bedaquiline and/or linezolid 4
• The older definition (MDR-TB plus fluoroquinolone and second-line injectable resistance) is outdated given that injectables are no longer recommended 4
• XDR-TB carries significantly worse outcomes with adjusted odds ratio of 1.91 for treatment failure compared to MDR-TB 4

Regimen Construction for MDR-TB

Intensive Phase (Until Culture Conversion)

Use at least 5 effective drugs from the following priority groups: 1, 2

Group A (Core drugs - include ALL if susceptible):

• Bedaquiline (strongly recommended, 400 mg daily for 2 weeks, then 200 mg three times weekly for total 24 weeks) 1, 2, 3
• Later-generation fluoroquinolone - levofloxacin or moxifloxacin (strongly recommended if susceptible) 1, 2, 3
• Linezolid (conditionally recommended, highly effective but monitor for toxicity) 1, 2, 3

Group B (Add to reach 5 drugs):

• Clofazimine (suggested as important component) 1, 2, 3
• Cycloserine/terizidone (suggested if needed) 1, 3

Group C (Add if needed to reach 5 drugs):

• Ethambutol (only if susceptibility confirmed) 1
• Pyrazinamide (only if susceptibility confirmed) 1, 3
• Carbapenems (imipenem or meropenem) ALWAYS with amoxicillin-clavulanate 1, 3
• Delamanid (limited evidence but may consider) 1, 3

Continuation Phase (After Culture Conversion)

• Continue at least 4 effective drugs from the intensive phase regimen 1, 2
• Total treatment duration: 15-21 months after culture conversion for MDR-TB 2, 3

Regimen Construction for XDR-TB

Core Approach

Use the same drug classes as MDR-TB but with critical modifications: 5, 3

• Intensive phase: At least 5 effective drugs 3
• Continuation phase: At least 4 effective drugs 3
• Total duration: 15-24 months after culture conversion (longer than MDR-TB) 2, 3

Drug Selection Strategy

• Bedaquiline is mandatory as a core component even if resistance is present, as it improves outcomes (adjusted OR 0.40 for unfavorable outcome) 3, 4
• Linezolid is critical for XDR-TB (adjusted OR 0.37 for unfavorable outcome when used alone, 0.21 when combined with bedaquiline) 3, 4
• Add all susceptible drugs from Groups B and C to reach required number 3
• Consider adjunctive surgical resection (lobectomy or wedge resection) for patients at high risk of treatment failure based on bacteriological and radiographic data 1, 2

Drugs to Absolutely Avoid

• Kanamycin and capreomycin - associated with poor outcomes and should not be used 2, 3
• Macrolides (azithromycin, clarithromycin) - lack efficacy for TB 2, 3
• Amoxicillin-clavulanate alone - only use with carbapenems 3
• Ethionamide/prothionamide - avoid if more effective drugs available due to poor tolerability 3

Shorter Regimen Option for Selected MDR-TB Cases

For MDR-TB patients WITHOUT fluoroquinolone resistance and limited prior second-line drug exposure: 2

• Use all-oral bedaquiline-containing regimen for 9-12 months total duration 2
• Regimen includes: bedaquiline, later-generation fluoroquinolone, linezolid, and clofazimine 2
• This shorter regimen is NOT recommended for XDR-TB 3

Treatment Monitoring

• Monthly sputum cultures and smears to identify early treatment failure 1, 2, 5
• Repeat DST if cultures remain positive after 3 months or if bacteriological reversion occurs 1
• Active drug safety monitoring for QTc prolongation (bedaquiline, fluoroquinolones), peripheral neuropathy (linezolid), tendon rupture (fluoroquinolones), and hepatotoxicity 2
• Monthly weight checks and assessment of clinical response (cough, systemic symptoms) 1

Critical Pitfalls to Avoid

• Using fewer than 5 effective drugs in intensive phase leads to treatment failure and death (hazard ratio 0.52 for aggressive regimen vs inadequate regimen) 3, 6
• Treating for less than 15 months after culture conversion for XDR-TB increases relapse rates 3
• Including drugs with known resistance based on DST or epidemiological data - even 1% resistance on solid media culture will lead to treatment failure 1
• Failing to obtain fluoroquinolone susceptibility testing when isoniazid resistance is detected 1

Special Populations

HIV-Positive Patients

• Initiate antiretroviral therapy within first 8 weeks of starting anti-TB treatment 2
• Extend MDR-TB treatment to at least 9 months and for at least 6 months beyond culture conversion 2

Contacts of MDR-TB Patients

• Offer latent TB infection treatment rather than observation alone 1, 5
• Use 6-12 months of later-generation fluoroquinolone alone or with a second drug based on source case susceptibility 1, 5
• Do NOT routinely use pyrazinamide as the second drug due to increased toxicity and discontinuations 1