What is the appropriate treatment regimen for a patient with tuberculosis (TB) requiring third-line anti-tuberculosis (anti-TB) drugs due to resistance to first and second-line treatments?

Third-Line Anti-TB Drugs

Definition and Context

Third-line anti-TB drugs are not formally classified as a distinct category in current WHO or major guideline frameworks; rather, drug-resistant TB treatment uses a hierarchical selection system where "third-line" typically refers to Group C and Group D agents used when first-line drugs (HRZE) and second-line drugs (fluoroquinolones, injectables, bedaquiline, linezolid) cannot be used due to resistance or intolerance. 1, 2

WHO Drug Classification System for Drug-Resistant TB

The WHO organizes anti-TB drugs into prioritized groups for building MDR/RR-TB regimens:

Group A (Backbone - Use All Three If Possible)

• Levofloxacin (750-1000 mg daily) or Moxifloxacin (400 mg daily) - levofloxacin preferred due to fewer adverse events and less QTc prolongation 1, 2
• Bedaquiline (400 mg daily × 2 weeks, then 200 mg three times weekly for ≥22 weeks, extendable beyond 6 months with monitoring) 1, 2
• Linezolid (600 mg daily, reducible to 300 mg if myelosuppression or neuropathy develops) 1, 2

Group B (Add to Reach 4-5 Effective Drugs)

• Clofazimine (100 mg daily) 2, 3
• Cycloserine/Terizidone (10-15 mg/kg daily, maximum 1000 mg) 2, 3

Group C (Add When Groups A & B Insufficient)

• Ethambutol (when other more effective drugs cannot be used) 3
• Delamanid 3
• Pyrazinamide (if isolate susceptible) 3
• Imipenem-cilastatin or Meropenem (with clavulanate)
• Amikacin (15 mg/kg daily) or Streptomycin (only when documented susceptible and five effective oral drugs cannot be assembled) 1, 3

Group D (Least Effective - Use Only When Necessary)

• Para-aminosalicylic acid (PAS)
• Ethionamide/Prothionamide (only when isolate documented susceptible; mutations in inhA confer cross-resistance with isoniazid) 1
• High-dose isoniazid (can be considered despite low-level resistance, but not with high-level resistance) 1

Treatment Regimen Construction Principles

Critical Rule: Never Add Only One Drug to a Failing Regimen

Adding a single drug to failing therapy rapidly leads to acquired resistance to that new agent. 4, 2, 3, 5 Always add at least 3 new effective drugs when treatment fails. 4

Regimen Composition Requirements

• Minimum 5 effective drugs during intensive phase (including pyrazinamide and four core second-line drugs) 4, 3
• Maintain at least 3-4 effective drugs throughout treatment, even after bedaquiline discontinuation 2
• Use only drugs with documented susceptibility or high likelihood of susceptibility based on drug susceptibility testing (DST) 1, 2, 3

Drug Selection Algorithm

1. Include all three Group A drugs if possible 1, 2
2. Add Group B drugs to reach 4-5 effective medications 2
3. If insufficient, add Group C drugs 3
4. Group D drugs only when Groups A-C cannot provide adequate regimen 1

Treatment Duration

• Standard longer regimen: 18-24 months total, or 15-17 months after culture conversion, whichever is longer 4, 2, 3
• Shorter all-oral regimen (9-12 months): For eligible patients without fluoroquinolone resistance, extensive disease, prior second-line drug exposure, severe extrapulmonary TB, or pregnancy 4, 1, 2
• BPaL regimen (6-9 months): Bedaquiline, pretomanid, linezolid for fluoroquinolone-resistant MDR-TB under operational research conditions with ≤2 weeks prior bedaquiline/linezolid exposure 4, 2

Critical Monitoring Requirements

Cardiac Monitoring

• Baseline and monthly ECGs to detect QTc prolongation (fluoroquinolones, bedaquiline, delamanid, clofazimine all prolong QT interval) 2
• Avoid combining multiple QT-prolonging agents when possible 2

Hematologic Monitoring

• Monthly complete blood counts to detect linezolid-induced myelosuppression 2
• Dose reduction to 300 mg may be necessary 2

Neurologic Monitoring

• Regular visual acuity and color vision evaluation for optic neuropathy (ethambutol, linezolid) 2
• Monitor for peripheral neuropathy (linezolid, cycloserine, ethionamide) 2
• Pyridoxine 100-200 mg daily with cycloserine 2

Microbiologic Monitoring

• Monthly sputum culture until conversion, then less frequently 4, 2, 3
• Second-line DST to confirm resistance patterns and guide treatment 4, 1

Special Populations

HIV Co-infection

• Start antiretroviral therapy within first 8 weeks of anti-TB treatment initiation, regardless of CD4 count 4, 2
• Monitor drug-drug interactions, particularly bedaquiline and delamanid with protease inhibitors and efavirenz (CYP450 metabolism) 2
• HIV co-infected patients have up to fourfold higher mortality risk 2

Pregnancy

• Individualized longer regimen required (shorter regimen not recommended) 1

Common Pitfalls to Avoid

• Never use empirical regimens except for culture-negative TB - always base treatment on confirmed drug susceptibility patterns 4
• Do not administer drugs with documented resistance (either molecular or phenotypic DST) 4
• Avoid monotherapy or adding single drugs to failing regimens 4, 2, 3
• Do not use injectable agents without documented susceptibility and only when five effective oral drugs cannot be assembled 1, 3
• Recognize cross-resistance: inhA mutations confer resistance to both ethionamide/prothionamide and isoniazid 1

Treatment Support Measures

• Directly observed therapy (DOT) strongly recommended to ensure adherence 3
• Health education and counseling on disease and treatment adherence should be provided 4
• Psychosocial support, material support, and patient education are essential given complex, prolonged regimens 4