What is the recommended treatment approach for resistant tuberculosis?

Treatment of Resistant Tuberculosis

For multidrug-resistant tuberculosis (MDR-TB), build a regimen with at least 5 effective drugs in the intensive phase using bedaquiline, a later-generation fluoroquinolone (levofloxacin or moxifloxacin), and linezolid as mandatory core agents, supplemented with clofazimine and/or cycloserine, treating for 18-20 months total or 15-21 months after culture conversion. 1, 2, 3

Core Drug Selection: The Three Mandatory Agents

The foundation of MDR-TB treatment requires three Group A drugs that must all be included unless contraindicated:

• Bedaquiline (strong recommendation) - this newer agent has the lowest adverse event profile leading to discontinuation (1.7%) and is strongly recommended for all adults ≥18 years 1, 3, 4
• Later-generation fluoroquinolone - specifically levofloxacin or moxifloxacin (strong recommendation), with levofloxacin having only 1.3% discontinuation rate due to adverse events 1, 2, 3, 4
• Linezolid (strong recommendation despite higher toxicity at 14.1% discontinuation rate) - essential for efficacy but requires close monitoring 1, 3, 4

Completing the Regimen: Additional Agents

After the three mandatory drugs, add at least one (preferably two) additional effective agents to reach a minimum of 5 drugs in the intensive phase:

• Clofazimine (conditional recommendation) - low adverse event rate of 1.6%, making it an excellent fourth agent 1, 2, 4
• Cycloserine or terizidone (conditional recommendation) - effective but requires monitoring for neuropsychiatric effects 1, 2
• Pyrazinamide - include only when susceptibility is confirmed and the isolate is not resistant 1, 2
• Ethambutol - use only when other more effective drugs cannot be assembled to reach 5 total drugs 1, 2

Treatment Duration

The intensive phase and total duration depend on culture conversion:

• Intensive phase: 5-7 months after culture conversion with at least 5 drugs 1, 2
• Continuation phase: reduce to 4 drugs after intensive phase 1, 2
• Total duration: 18-20 months total, or alternatively 15-21 months after culture conversion, whichever is longer 1, 3
• For pre-XDR and XDR-TB: extend total duration to 15-24 months after culture conversion 1, 2

Shorter Regimen Option: BPaLM

For eligible patients, a 6-month all-oral regimen may be considered:

• Composition: Bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) 5, 3
• Eligibility criteria: No documented fluoroquinolone or bedaquiline resistance, no previous exposure to second-line TB drugs for >1 month, no extensive pulmonary disease or severe extrapulmonary TB 5
• Advantage: Dramatically shorter duration (6 months vs 18-20 months) with all-oral therapy 5

Drugs to Explicitly AVOID

These agents should NOT be used in MDR-TB regimens:

• Injectable agents kanamycin and capreomycin - high toxicity (7.5-10.2% discontinuation rates) without superior efficacy when oral alternatives exist 1, 2, 3, 4
• Macrolides (azithromycin and clarithromycin) - strong recommendation against use 1, 2
• Amoxicillin-clavulanate alone - only use with carbapenems (imipenem-cilastatin or meropenem) 1, 2
• Ethionamide/prothionamide - avoid if more effective drugs are available 2
• p-aminosalicylic acid - very high discontinuation rate (11.6%) and should be avoided if other options exist 2, 4

Critical Monitoring Requirements

Baseline assessment before treatment initiation:

• ECG for QTc interval - bedaquiline, moxifloxacin, and clofazimine all prolong QT 3, 6
• Electrolytes (potassium, magnesium, calcium) - correct before starting QT-prolonging agents 3
• Complete blood count - baseline for linezolid toxicity monitoring 3
• Visual acuity and color vision - baseline for linezolid optic neuropathy screening 3
• Sputum culture with drug susceptibility testing - essential for fluoroquinolones, bedaquiline, and linezolid 3, 6

Ongoing monitoring during treatment:

• Monthly sputum cultures - to document culture conversion and guide duration 5, 3
• ECG monitoring - repeat regularly when using multiple QT-prolonging agents 3
• Complete blood count - monitor for linezolid-induced myelosuppression 3
• Visual screening - monthly for linezolid optic neuropathy 3

Common Pitfalls and How to Avoid Them

Using fewer than 5 effective drugs in the intensive phase increases treatment failure risk substantially - always count only drugs to which the organism is susceptible based on testing or treatment history 2, 3

Omitting any of the three Group A agents (fluoroquinolone, bedaquiline, or linezolid) compromises regimen efficacy - only exclude if documented resistance or absolute contraindication exists 3

Insufficient treatment duration (stopping before 15 months after culture conversion) dramatically increases relapse risk - resist pressure to shorten therapy prematurely 2, 3

Using injectable agents when oral alternatives are available adds ototoxicity risk (permanent hearing loss) without improving outcomes - reserve amikacin/streptomycin only for cases where oral options are exhausted and susceptibility is confirmed 1, 2, 3

Combining multiple QT-prolonging agents without monitoring - bedaquiline, moxifloxacin, and clofazimine together can excessively prolong QTc interval, requiring regular ECG surveillance and electrolyte correction 3, 6

Starting treatment without drug susceptibility testing risks using ineffective drugs, particularly dangerous for fluoroquinolones where undetected resistance can lead to bedaquiline resistance acquisition 6

Special Considerations for Isoniazid-Resistant TB

For isoniazid-resistant TB that is NOT multidrug-resistant (rifampin-susceptible):

• Regimen: 6-month course of rifampin, ethambutol, pyrazinamide, plus a later-generation fluoroquinolone 2, 5
• Duration: 6 months total (not 18-20 months like MDR-TB) 2, 5

Adjunctive Surgical Therapy

Consider elective partial lung resection alongside medical therapy for:

• Patients at high risk of treatment failure based on extensive cavitary disease 3
• Patients at high risk of relapse based on bacteriological and radiographic data 3
• Surgical intervention is adjunctive only - medical therapy remains the cornerstone 3