What medications are given for resistant pulmonary tuberculosis (PTB)?

Medications for Resistant Pulmonary Tuberculosis

For multidrug-resistant (MDR) or rifampicin-resistant (RR) pulmonary tuberculosis, treatment requires at least five effective drugs selected from a prioritized classification system, with Group A drugs (levofloxacin/moxifloxacin, bedaquiline, and linezolid) forming the backbone of all regimens. 1

Drug Classification and Selection Priority

The WHO classifies anti-TB drugs into prioritized groups for building MDR/RR-TB regimens 1:

Group A (Priority Drugs - Include All Three if Possible)

• Levofloxacin or moxifloxacin (levofloxacin preferred due to fewer adverse events and less QTc prolongation) 1, 2
• Bedaquiline 1
• Linezolid 1

Group B (Add at Least One)

• Clofazimine 1
• Cycloserine or terizidone 1

Group C (Add if Needed to Reach Five Drugs)

• Ethambutol 1
• Delamanid 1
• Pyrazinamide 1
• Imipenem-cilastatin or meropenem with amoxicillin/clavulanate 1
• Amikacin (or streptomycin) 1
• Ethionamide or prothionamide 1, 3
• p-aminosalicylic acid 1

Treatment Regimen Options

Shorter All-Oral Regimen (9-11 Months)

This regimen is recommended for eligible MDR/RR-TB patients who meet ALL of the following criteria 1:

• Confirmed rifampicin resistance with fluoroquinolone resistance excluded 1, 2
• No previous exposure to second-line drugs for >1 month 1, 2
• No extensive bilateral cavitary disease or extensive parenchymal damage 1, 2
• No severe extrapulmonary TB (miliary TB or TB meningitis) 1
• Not pregnant 1
• Age >6 years 2

Regimen composition 1:

• Intensive phase (4-6 months): Bedaquiline, levofloxacin/moxifloxacin, clofazimine, pyrazinamide, ethambutol, high-dose isoniazid, ethionamide/prothionamide 1, 2
• Continuation phase (5 months): Levofloxacin/moxifloxacin, clofazimine, pyrazinamide, ethambutol 1, 2, 4

Individualized Longer Regimen (18-24 Months)

This regimen is required for patients with 1, 2:

• Fluoroquinolone resistance 1, 2
• Extensive pulmonary disease 1, 2
• Prior exposure to second-line drugs >1 month 1, 2
• Severe extrapulmonary TB 1
• Pregnancy 1

Build the regimen using this algorithm 1:

1. Include all three Group A drugs (levofloxacin/moxifloxacin, bedaquiline, linezolid) to which the isolate is susceptible 1
2. Add at least one Group B drug (cycloserine/terizidone and/or clofazimine) 1
3. If fewer than five effective drugs, add Group C agents 1
4. Continue intensive phase for minimum 8 months 1, 2
5. Total duration 18-24 months 1, 2

BPaL Regimen (6-9 Months)

For extensively drug-resistant (XDR) TB or pre-XDR-TB with limited options 1, 5:

• Bedaquiline, pretomanid, and linezolid for 6-9 months 1, 5
• Only for patients with <2 weeks prior exposure to bedaquiline or linezolid 1
• Should be used under operational research conditions or as last resort when effective regimen cannot be assembled 1
• Requires intensive monitoring for adverse events 1, 5

Critical Management Principles

Drug Susceptibility Testing Requirements

• Never add only one effective drug to a failing regimen 1
• Use only drugs to which the isolate is documented susceptible or has high likelihood of susceptibility 1
• Perform second-line DST to confirm resistance patterns and guide treatment 1

Adverse Event Monitoring

Common toxicities requiring close monitoring 1, 6:

• Linezolid: Peripheral neuropathy (81% of patients) and myelosuppression (48%) - often requires dose reduction 5
• Fluoroquinolones: QTc prolongation, tendinopathy 1, 6
• Bedaquiline: QTc prolongation 6
• Aminoglycosides: Nephrotoxicity and ototoxicity 6
• Cycloserine: CNS toxicity including psychosis 6
• Ethionamide: Severe gastrointestinal toxicity 3, 6

Expert Consultation Requirement

All treatment decisions should be managed by a multidisciplinary team or TB consilium, not individual physicians 1. This minimizes errors, shares responsibility, and ensures optimal drug selection 1.

Drugs No Longer Recommended

The following should NOT be included in MDR-TB regimens 1:

• Capreomycin and kanamycin 1
• Amoxicillin/clavulanate when used without a carbapenem 1
• Azithromycin and clarithromycin 1

Special Considerations

Injectable Agents

• Amikacin and streptomycin should only be used when the isolate is documented susceptible and when five effective oral drugs cannot be assembled 1
• Injectable agents are no longer obligatory in MDR-TB treatment 1

High-Dose Isoniazid

• Can be considered despite low-level isoniazid resistance but NOT with high-level resistance 1
• Mutations in inhA with katG mutations confer resistance to any dose of isoniazid 1

Ethionamide/Prothionamide

• Mutations in inhA region confer cross-resistance to ethionamide/prothionamide and isoniazid 1, 3
• Should only be used when isolate is documented susceptible 1, 3