What are the current Programmatic Management of Drug‑Resistant Tuberculosis (PMDT) guidelines for treating rifampicin‑resistant or multidrug‑resistant tuberculosis, including recommended drug regimen, treatment duration, monitoring, and management of adverse events?

Current Treatment Guidelines for Drug-Resistant Tuberculosis (PMDT)

The WHO now recommends the 6-month BPaLM regimen (bedaquiline + pretomanid + linezolid 600 mg daily + moxifloxacin) as the preferred first-line treatment for all eligible adults with MDR/RR-TB, replacing older 9-month and 18-20 month regimens. 1, 2

Diagnostic Approach and Initial Classification

• CBNAAT (GeneXpert) is the WHO-recommended first-line test for all persons with suspected tuberculosis; it simultaneously detects Mycobacterium tuberculosis and rifampicin resistance. 1
• When rifampicin resistance is detected, the case is classified as RR-TB and standard HRZE must not be started. 1
• Comprehensive drug susceptibility testing (DST) for fluoroquinolones and all second-line drugs is required to inform regimen selection, though treatment should not be delayed awaiting results. 1, 2
• Fluoroquinolone DST is pivotal for deciding between BPaLM, BPaL, the 9-month all-oral regimen, or longer individualized regimens. 1

Baseline Evaluation Before Initiating MDR/RR-TB Therapy

Prior to any MDR/RR-TB regimen, obtain: 1

• Complete blood count, liver function tests, renal function tests
• ECG with QTc measurement
• Electrolytes (potassium, magnesium, calcium) to evaluate QTc-prolongation risk
• Visual acuity testing and audiometry (when injectable agents might be used)
• Weight, HIV status, pregnancy status
• Detailed history of prior TB drug exposure (>30 days is critical for BPaLM eligibility)

Treatment Regimen Hierarchy (WHO 2023)

The WHO hierarchy for MDR/RR-TB regimens from most to least preferred: 1

1. BPaLM Regimen (6 months) – FIRST-LINE OPTION

Composition: Bedaquiline + pretomanid + linezolid 600 mg daily + moxifloxacin (no pyrazinamide or ethambutol). 1, 2

Eligibility criteria: 1, 2

• Age ≥14 years
• No fluoroquinolone resistance
• No resistance to bedaquiline, pretomanid, or linezolid
• No prior exposure >30 days to component drugs
• Not pregnant or breastfeeding (pretomanid safety unknown)

Can be used in: 1, 2

• Extensive pulmonary disease with cavities (no longer a contraindication)
• People living with HIV
• Patients with low BMI (<17) with close monitoring
• Most forms of extrapulmonary TB

Absolute contraindications: 1, 2

• Central nervous system TB
• Miliary (disseminated) TB
• Osteoarticular TB
• Pregnancy or breastfeeding
• Age <14 years

Duration: Exactly 6 months (26 weeks); must not be extended beyond this. 1, 2 If poor response is suspected, switch to an 18-20 month individualized regimen rather than prolonging BPaLM. 1

Critical adjustment: If fluoroquinolone resistance is detected after starting BPaLM, immediately stop moxifloxacin and continue as BPaL (without moxifloxacin) for a total of 9 months. 1, 2

2. BPaL Regimen (6-9 months) – FOR PRE-XDR TB

Composition: Bedaquiline + pretomanid + linezolid (moxifloxacin omitted). 1

Indication: MDR-TB that is fluoroquinolone-resistant (pre-XDR). 1, 2

Duration: 6 months, extendable to 9 months if sputum cultures remain positive between months 4-6. 1

3. 9-Month All-Oral Regimen – WHEN BPaLM/BPaL NOT FEASIBLE

Eligibility: 1

• Fluoroquinolone-sensitive disease
• No prior >1 month exposure to second-line drugs
• Not pregnant
• No CNS/miliary/osteoarticular disease

Typical composition: 1

• Intensive phase (4-6 months): Bedaquiline + linezolid/ethionamide + fluoroquinolone (levofloxacin or moxifloxacin) + clofazimine + pyrazinamide + ethambutol + high-dose isoniazid (if applicable)
• Continuation phase (≈5 months): Fluoroquinolone + clofazimine + pyrazinamide + ethambutol

Important: Ethionamide should not be used in pregnancy; substitute with a linezolid-based variation. 1

4. Long Individualized Regimen (18-20 months) – LAST RESORT

When used: If BPaLM, BPaL, or the 9-month regimen cannot be applied due to drug resistance, intolerance, or contraindications. 1, 3

Core requirements: 4, 1, 3

• ≥5 effective drugs in the intensive phase
• ≥4 drugs in the continuation phase
• Intensive phase: 5-7 months after culture conversion
• Total duration: 15-21 months after culture conversion (18-24 months for pre-XDR/XDR)

Drug selection by WHO grouping: 1, 3

• Group A (preferred, include all three if possible): Levofloxacin or moxifloxacin, bedaquiline, linezolid
• Group B (add when at least one Group A drug is used): Clofazimine, cycloserine/terizidone
• Group C (add as needed to reach ≥5 drugs): Ethambutol, delamanid, pyrazinamide, imipenem-cilastatin or meropenem (with amoxicillin-clavulanate), amikacin (only if no oral alternatives)

Drugs NOT recommended: 3

• Kanamycin or capreomycin (poor outcomes, high toxicity)
• Macrolides (azithromycin, clarithromycin)
• Amoxicillin-clavulanate alone (only with carbapenems)
• Ethionamide/prothionamide (if more effective drugs available)
• p-aminosalicylic acid (if more effective drugs available)

Critical Treatment Principles

Standardized regimens (BPaLM, BPaL, 9-month) must not be altered; adding or removing drugs increases the risk of failure and resistance amplification. 1

Never add a single drug to a failing MDR-TB regimen—this creates functional monotherapy and markedly increases acquired resistance; at least two susceptible drugs must be added when modifying a regimen. 1

Only drugs to which the patient's M. tuberculosis isolate has documented, or high likelihood of, susceptibility should be included in an effective treatment regimen. 4

Monitoring and Safety During DR-TB Treatment

ECG Monitoring for QTc Prolongation

• Baseline, weeks 2,4,8,12, then monthly to detect QTc prolongation from bedaquiline, moxifloxacin, and clofazimine. 1, 2
• Discontinue bedaquiline if QTcF >500 ms or clinically significant ventricular arrhythmia develops. 2
• Weekly ECG monitoring is required in high-risk patients (those on multiple QTc-prolonging drugs or with cardiac disease). 2

Hematologic Monitoring

• Monthly complete blood count to identify linezolid-induced myelosuppression (anemia, thrombocytopenia). 1, 2
• If linezolid toxicity occurs, reducing the dose to 300 mg daily is an acceptable strategy that preserves efficacy. 1, 2

Neurologic Monitoring

• Monthly assessment for peripheral neuropathy (linezolid) and optic neuropathy (linezolid, ethambutol). 1
• Patients with pre-existing Grade III-IV peripheral neuropathy can receive BPaLM but other regimens are preferred. 2

Hepatotoxicity Monitoring

• Monitor AST, ALT, bilirubin, and alkaline phosphatase at baseline, monthly, and if symptomatic. 2
• More frequent monitoring is needed with other hepatotoxic medications or underlying liver disease. 2

Bacteriologic Monitoring

• Regular sputum smear and culture monitoring at 2,4, and 6 months is essential to assess treatment response. 1

Active drug-safety monitoring (aDSM) is mandatory for all DR-TB patients. 1

Role of Individual Drugs in MDR-TB

• MDR-TB is defined as resistance to isoniazid + rifampicin only; pyrazinamide and ethambutol may remain active and should be retained if DST shows susceptibility. 4, 1
• Pyrazinamide should be included in MDR-TB regimens when the isolate has not been found resistant to pyrazinamide. 4

Injectable Second-Line Drugs

• WHO no longer recommends routine use of injectable agents (amikacin, kanamycin, capreomycin). 1, 3
• Amikacin or streptomycin may be included only when an adequate number of effective oral drugs cannot be assembled and susceptibility is confirmed. 1, 3
• Kanamycin and capreomycin are strongly discouraged due to poor outcomes and high toxicity. 1, 3

Common Pitfalls and How to Avoid Them

Do not use fewer than five effective drugs in the intensive phase of long regimens; this predisposes to treatment failure. 1, 3

Do not discontinue therapy early even after culture conversion; complete the full prescribed duration (6,9, or 18-20 months). 1

Do not give BPaLM to children <14 years (pretomanid not studied); opt for the 9-month regimen instead. 1

Do not delay BPaLM waiting for fluoroquinolone susceptibility results; start empirically and switch to BPaL if resistance is documented. 2

Do not extend BPaLM beyond 6 months; if poor response is suspected, switch to an 18-20 month individualized regimen. 1, 2

**Prior brief exposure (<30 days) to component drugs is not a contraindication**; only exposure >30 days requires ruling out resistance before proceeding. 2

Special Populations

Isoniazid-Resistant TB (Not MDR)

• Add a later-generation fluoroquinolone to a 6-month regimen of daily rifampin, ethambutol, and pyrazinamide. 3

Contacts of MDR-TB Patients

• Consider LTBI treatment with a later-generation fluoroquinolone alone or with a second drug based on source-case susceptibility. 3
• For children, the 9-month isoniazid regimen (9H) is the only WHO-recommended preventive therapy. 1

People Living with HIV

• HIV status does not preclude use of BPaLM; these patients are eligible. 2
• In the presence of HIV infection, it is critically important to assess clinical and bacteriologic response; if there is evidence of slow or suboptimal response, therapy should be prolonged. 5