Latest Guidelines for Pulmonary Tuberculosis Treatment
Drug-Susceptible Pulmonary Tuberculosis
For drug-susceptible pulmonary tuberculosis, 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
Initial Intensive Phase (First 2 Months)
- Four-drug regimen required: Isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) for 2 months 1, 2, 4
- Daily dosing is strongly recommended over intermittent regimens for optimal efficacy 2
- 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, 4
- Rifampin dosing: Adults <50 kg receive 450 mg daily; adults ≥50 kg receive 600 mg daily 2
Continuation Phase (Next 4 Months)
- Isoniazid and rifampin (HR) for 4 months after completing the intensive phase 1, 2
- The continuation phase begins once susceptibility to isoniazid and rifampin is confirmed 2
Extended Treatment Durations
- For cavitary pulmonary TB with positive cultures at 2 months: Extend continuation phase to 7 months (total 9 months of therapy) 2, 4
- For TB meningitis and CNS tuberculosis: Extend treatment to 12 months total (2 months HRZE followed by 10 months HR) 2
- If pyrazinamide cannot be included: Extend total treatment duration to 9 months 2
Critical Pitfall to Avoid
Do not use shortened 4-month fluoroquinolone-containing regimens (moxifloxacin or gatifloxacin replacing ethambutol or isoniazid) as they substantially increase relapse rates compared to standard 6-month therapy (RR 3.56 for moxifloxacin regimens, RR 2.11 for gatifloxacin regimens) 5
Multidrug-Resistant Tuberculosis (MDR-TB)
For MDR-TB meeting specific criteria, use the shorter 6-month all-oral bedaquiline-containing regimen; otherwise, use an individualized longer regimen of 18 months duration. 1
Shorter 6-Month BPaLM/BPaL Regimens (Preferred When Eligible)
Eligibility criteria for shorter regimens: 1
- MDR/RR-TB or pre-XDR-TB confirmed
- No resistance to fluoroquinolones
- No extensive TB (spinal/CNS/miliary)
- Not pregnant
- Age >6 years
- No prior exposure to bedaquiline or linezolid (defined as <2 weeks)
BPaLM regimen composition: 1
- Bedaquiline
- Pretomanid
- Linezolid
- Moxifloxacin
- Duration: 6 months total
BPaL regimen (without moxifloxacin): 1
- Bedaquiline
- Pretomanid
- Linezolid
- Duration: 6-9 months under operational research conditions
Longer Individualized MDR-TB Regimens (18 Months)
Use longer regimens for: 1
- Extensive pulmonary disease
- Severe extrapulmonary TB
- Additional fluoroquinolone resistance
- Prior exposure to second-line medicines >1 month
Regimen construction using WHO drug prioritization: 1, 3, 6
Group A drugs (include at least 3): 1
- Levofloxacin OR moxifloxacin (levofloxacin preferred for fewer adverse events and less QTc prolongation)
- Bedaquiline (strongly recommended in every regimen unless contraindicated)
- Linezolid
Group B drugs (include at least 1): 1
- Clofazimine
- Cycloserine OR terizidone
Group C drugs (add only if Groups A and B insufficient): 1
- Ethambutol
- Delamanid
- Pyrazinamide
- Imipenem-cilastatin OR meropenem with amoxicillin/clavulanate
- Amikacin (or streptomycin)
- Ethionamide OR prothionamide
- Para-aminosalicylic acid
Duration: 18 months total (15 months after culture conversion) 1, 6
Intensive phase: 5-7 months after culture conversion 3, 6
Alternative Longer Regimen (When BPaLM/BPaL Not Available)
For patients not eligible for shorter regimens: 1
- Intensive phase (4-6 months): Bedaquiline (6 months total)-levofloxacin/moxifloxacin-clofazimine-pyrazinamide-ethambutol-high dose isoniazid-ethionamide, given daily
- Continuation phase (5 months): Levofloxacin/moxifloxacin-clofazimine-pyrazinamide-ethambutol, given daily
- Bedaquiline dosing: Daily for first 2 weeks, then three times weekly for remaining 22 weeks 1
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
- For HIV-infected patients NOT receiving ART: Extend continuation phase to 7 months (total 9 months of therapy) 1
- Critical drug interaction: For patients receiving protease inhibitors or NNRTIs, substitute rifabutin for rifampin with appropriate dose adjustments 2, 3
- Avoid intermittent regimens (twice or thrice weekly) in HIV-infected patients due to high relapse rates and emergence of rifamycin resistance 1
- All MDR-TB regimens (BPaLM, BPaL, 9-month, and longer treatments) can be used in people living with HIV with CD4 count <100/mm³, with careful evaluation of drug-drug interactions 1
Pregnancy
- Use the standard regimen: Rifampin, isoniazid, ethambutol, and pyrazinamide can all be used during pregnancy 1, 4
- Avoid streptomycin due to ototoxicity to the fetus 1, 4
- Add prophylactic pyridoxine (vitamin B6) 10-25 mg daily to prevent neurological side effects 1, 2
- Bedaquiline should be included in MDR-TB regimens even during pregnancy 1
Children
- Use the same regimen as adults: HRZE for 2 months, followed by HR for 4 months 1, 4
- Ethambutol is not used routinely in children younger than 4 years due to inability to monitor visual acuity 1
- For disseminated TB and TB meningitis in infants and children: Extend treatment to 12 months 1
- Bedaquiline should be included in MDR-TB regimens for all age groups, even in children below 6 years 1
Renal Insufficiency
- Adjust dosages for streptomycin, ethambutol, and isoniazid according to creatinine clearance 1
- For hemodialysis patients: Administer all medications after dialysis to avoid premature drug removal 1
Pre-existing Liver Disease
- Use rifampin, pyrazinamide, and isoniazid even with pre-existing liver disease, but perform frequent clinical and laboratory monitoring 1
- These drugs can cause hepatitis but remain essential for effective TB treatment 1
Monitoring and Safety
Treatment Response Monitoring
- Monitor with follow-up sputum smear microscopy and culture for pulmonary TB 2
- Consider rifampin blood level monitoring if poor response due to under-dosing or malabsorption is suspected 2
Adverse Event Monitoring
- Monitor for hepatotoxicity, especially during the first 2 months of treatment 2, 3
- For MDR-TB regimens: Accurately record and manage all adverse events, particularly with new drugs and regimens 1
- Monitor for QTc prolongation with bedaquiline, delamanid, and fluoroquinolones 1
- Monitor for peripheral neuropathy with linezolid 3
- Monitor for optic neuritis with ethambutol 3
Drug Interactions
- Rifampin interacts extensively with oral contraceptives, anticoagulants, and antiretroviral drugs, requiring careful medication review and potential dose adjustments 2, 3
Treatment Adherence
- Directly observed therapy (DOT) is the standard of care for pulmonary TB 1, 4
- Fixed-dose combinations (two, three, or four drugs) provide a more convenient form of administration and improve adherence 2
- A patient-centered approach is essential to ensure adherence, including comprehensive health education and counseling 1, 2