Latest Guidelines for Pulmonary Tuberculosis Treatment
Drug-Susceptible Pulmonary Tuberculosis
For drug-susceptible PTB, use a 6-month regimen consisting of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) for 2 months, followed by isoniazid and rifampin (HR) for 4 months, given daily. 1, 2, 3
Intensive Phase (First 2 Months)
- Administer isoniazid, rifampin, pyrazinamide, and ethambutol daily for 8 weeks 1, 2
- Rifampin dosing: Adults <50 kg receive 450 mg daily; adults ≥50 kg receive 600 mg daily 1, 4
- Isoniazid dosing: Adults receive 5 mg/kg up to 300 mg daily; children receive 10-15 mg/kg up to 300 mg daily 3
- Ethambutol can be discontinued once drug susceptibility testing confirms full susceptibility to isoniazid and rifampin, particularly in patients with low risk for drug resistance (community isoniazid resistance ≤4%) 1, 2
Continuation Phase (Months 3-6)
- Continue with isoniazid and rifampin daily for 4 months after completing the intensive phase 1, 2
- All medications should be taken 1 hour before or 2 hours after a meal with a full glass of water 4
Critical Monitoring Points
- Hepatotoxicity monitoring is essential, especially during the first 2 months of treatment 1, 2
- Perform follow-up sputum smear microscopy and culture for pulmonary TB 1
- Monitor for optic neuritis with ethambutol 2
- Treatment should be continued longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive 4
Important Caveat on Shortened Regimens
Four-month fluoroquinolone-containing regimens are NOT recommended as they substantially increase relapse rates compared to standard 6-month treatment (RR 3.56 for moxifloxacin regimens, RR 2.11 for gatifloxacin regimens) despite similar treatment success and adverse event rates 5. The 8-month ethambutol-based regimen (2EHRZ/6HE) is also inferior to the standard 6-month regimen with significantly higher unfavorable outcomes (10% vs 5%) 6.
Multidrug-Resistant Tuberculosis (MDR-TB)
For MDR-TB meeting specific eligibility criteria, use the 6-month all-oral BPaLM regimen (bedaquiline, pretomanid, linezolid, and moxifloxacin); otherwise, use individualized longer regimens lasting 18 months. 7, 1
BPaLM Regimen (6 Months)
Eligibility criteria for the 6-month BPaLM regimen include: 7, 1
- MDR/RR-TB or pre-XDR-TB confirmed
- No resistance to fluoroquinolones on drug susceptibility testing
- No extensive pulmonary TB disease (cavities) or severe extrapulmonary TB (spinal/CNS/miliary)
- Not pregnant
- Age >14 years (due to lack of safety data on pretomanid in younger children)
Regimen composition: Bedaquiline, pretomanid, linezolid, and moxifloxacin for 6 months (26 weeks) 7, 1
Dosing schedule: 7
- Bedaquiline: Daily for first 2 weeks, then three times weekly for remaining 22 weeks
- All other drugs: Daily throughout treatment
- Complete 26 weeks of prescribed doses within an overall period of 7 months to account for any missed doses
Extension criteria: For BPaL (without moxifloxacin), extend to 9 months (39 weeks) if sputum cultures remain positive between months 4 and 6 7
9-Month All-Oral Regimen (Alternative to BPaLM)
For patients with MDR/RR-TB without fluoroquinolone resistance who are not eligible for BPaLM, use the 9-month all-oral bedaquiline-containing regimen 7
Two variations exist: 7
- Ethionamide variation: 4-6 months of bedaquiline (6 months total), fluoroquinolone, clofazimine, pyrazinamide, ethambutol, high-dose isoniazid, and ethionamide; followed by 5 months of fluoroquinolone, clofazimine, pyrazinamide, and ethambutol
- Linezolid variation (preferred for pregnancy): Same as above but linezolid (600 mg daily for maximum 2 months) replaces ethionamide
Key points: 7
- Intensive phase is 4 months but may extend to 6 months if bacteriological conversion not achieved by month 4
- Bedaquiline is always given for 6 months total
- Levofloxacin is often preferred over moxifloxacin due to lower cardiotoxicity risk
- This regimen can be used in children of all ages (unlike BPaLM)
Longer Regimens (18-20 Months)
Use longer individualized regimens when: 7
- Severe extrapulmonary TB (spinal/CNS/miliary/osteoarticular)
- Additional resistance to key medicines of the BPaLM or 9-month regimen (except moxifloxacin)
- Lack of response to shorter treatment regimens
- Drug intolerance to component medicines of shorter regimens
- Pregnant/lactating women or children <14 years (for BPaLM specifically)
WHO Drug Classification for Building Longer Regimens: 7
Group A (prioritize these):
- Levofloxacin or moxifloxacin
- Bedaquiline
- Linezolid
Group B (add at least one):
- Clofazimine
- Cycloserine or terizidone
Group C (use if Groups A/B insufficient):
- Ethambutol, delamanid, pyrazinamide
- Imipenem-cilastatin or meropenem with amoxicillin/clavulanate
- Amikacin (or streptomycin)
- Ethionamide or prothionamide
- p-aminosalicylic acid
Regimen construction principles: 7
- Include at least three Group A agents (bedaquiline, levofloxacin/moxifloxacin, and linezolid)
- Add at least one Group B agent (cycloserine/terizidone and/or clofazimine)
- Use minimum of 4 drugs total to improve efficacy and prevent further resistance
- Duration: 18 months total
Critical safety consideration: Active tuberculosis drug safety monitoring (aDSM) must be implemented as frequent and severe adverse events are common with DR-TB regimens 7
Special Populations
HIV Co-infection
- For HIV-infected patients receiving antiretroviral therapy (ART): Use the standard 6-month daily regimen (2 months HRZE, 4 months HR) 1, 2
- For HIV-infected patients NOT receiving ART: Extend continuation phase to 7 months (total 9 months of therapy) 1, 2
- Pyridoxine (vitamin B6) 25-50 mg daily should be administered to all HIV-infected patients receiving isoniazid to prevent neurological side effects 2
- For HIV-positive patients receiving protease inhibitors or NNRTIs, substitute rifabutin for rifampin with appropriate dose adjustments 2
Pregnancy and Breastfeeding
- Use the standard regimen: Rifampin, isoniazid, ethambutol, and pyrazinamide can all be used during pregnancy 1
- For MDR-TB in pregnancy: Use the 9-month regimen with linezolid variation instead of ethionamide, as ethionamide is contraindicated in pregnancy 7
- Streptomycin is contraindicated as it interferes with in utero ear development and may cause congenital deafness 7
Pediatric Patients
- Children receive appropriately adjusted doses: Isoniazid 10-15 mg/kg up to 300 mg daily; rifampin 10-20 mg/kg up to 600 mg daily 3, 4
- The 9-month all-oral MDR-TB regimen can be used in children of all ages 7
- Ethambutol should not be used in children whose visual acuity cannot be monitored 3
- Levofloxacin has been associated with musculoskeletal disorders in pediatric populations, though it remains an option when needed 7
Culture-Negative Pulmonary TB
For HIV-uninfected adults with culture-negative pulmonary TB, a 4-month treatment regimen is adequate (conditional recommendation) 7
- Initiate with 2 months of HRZE daily
- If all cultures on adequate samples are negative and there is clinical/radiographic response after 2 months, shorten continuation phase to 2 months (HR)
- Assess clinical and radiographic response at end of treatment to determine if extension to full 6 months is needed 7
- This shortened approach is supported by very low relapse rates (1.9% among 940 patients) in clinical trials 7
Critical Drug Interactions and Safety Monitoring
Hepatotoxicity
- Monitor liver function tests, especially during the first 2 months 1, 2
- Hepatotoxicity is the most common serious adverse event requiring treatment modification
Cardiac Monitoring
- Monitor for QTc prolongation with bedaquiline, delamanid, and fluoroquinolones 1, 2
- Levofloxacin is generally preferred over moxifloxacin for fewer adverse events and less QTc prolongation 7
Drug Interactions
- Rifampin has extensive drug interactions with oral contraceptives, anticoagulants, and antiretroviral drugs requiring dose adjustments 2
- Consider rifampin blood level monitoring if poor response due to under-dosing or malabsorption is suspected 1
Patient-Centered Care
- Directly observed therapy (DOT) or video observed therapy (VOT) should be considered, as patient noncompliance is a major cause of drug-resistant tuberculosis 7, 3
- All DR-TB cases should be discussed at a local, regional, or national consilium 7
- Provide comprehensive health education, counseling, and shared decision-making regarding treatment 7