Introduction
The American Thoracic Society, CDC, European Respiratory Society, and IDSA have updated TB treatment guidelines based on recent clinical trial data. In settings with access to advanced diagnostics, new recommendations include a 4-month regimen for drug-susceptible pulmonary TB and nonsevere TB in children. For drug-resistant TB, updated regimens include all-oral combinations with bedaquiline, pretomanid, and linezolid, with or without moxifloxacin. These changes aim to provide shorter, more effective treatment options.
Recommendations
PICO Question 1: In adolescents and adults with DS pulmonary TB, is a 4-month regimen composed of 2 months of isoniazid, rifapentine, pyrazinamide, and moxifloxacin followed by 2 months of isoniazid, rifapentine, and moxifloxacin (2HPZM/2HPM) as efficacious and safe as the standard 6-month DS-TB regimen of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol (2HRZE) followed by 4 months of isoniazid and rifampin (4HR) endorsed by the ATS/CDC/ERS/IDSA guidelines?
- Overview/Background
The standard treatment for drug-susceptible pulmonary TB has been a 6-month regimen. The goal is to find shorter yet effective regimens to improve cure rates, reduce treatment burden, and enhance adherence. The Study 31/A5349 trial evaluated a 4-month regimen (2HPZM/2HPM) using rifapentine and moxifloxacin in adolescents and adults with pulmonary TB. - Evidence Summary: Benefits and Harms
The 4-month RPT-MOX regimen was found to be noninferior to the standard 6-month regimen in terms of cure rates (84.6% vs. 85.4%). No major differences were seen across subgroups (HIV, diabetes, age). Severe adverse events and mortality rates were similar. Limited data existed for older adults, people with HIV, and those with comorbidities. The evidence was based mainly on one large trial and WHO analysis. - Monitoring and Other Considerations
Patients with CNS, bone/joint, miliary, or pericardial TB were excluded and should not use the shorter regimen. Adverse effects related to fluoroquinolones (e.g., QT prolongation) are possible, though ECG monitoring is not routinely required unless clinically indicated. The regimen increases daily pill burden, and DOT was used in the trial, which may not be feasible in all settings. Rifapentine access, cost, and quality (nitrosamine impurities) could be challenges. Fluoroquinolone resistance should be assessed before starting. Pediatric and pregnancy data are limited but evolving. - Certainty of Evidence
The panel, in agreement with WHO, rated the certainty of evidence as high for treatment success, moderate for adverse events, and low for drug resistance and mortality due to few such cases. Since resistance and mortality were not considered critical to the recommendation, the overall certainty of evidence was judged as moderate. - Panel recommendation
In people aged 12 years or older with DS pulmonary tuberculosis, we conditionally recommend the use of a 4-month regimen of isoniazid, rifapentine, moxifloxacin, and pyrazinamide.
PICO Question 2: In children and adolescents with nonsevere DS pulmonary TB, is a 4-month regimen composed of standard-dose 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 2 months of isoniazid and rifampin (2HRZE/2HR) as efficacious and safe as the standard 6-month DS-TB regimen of 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol followed by 4 months of isoniazid and rifampin (2HRZE/4HR) endorsed by the ATS/CDC/ERS/IDSA guidelines?
- Topic/Overview/Background
The SHINE trial evaluated a 4-month treatment regimen versus the standard 6-month regimen for nonsevere TB in children. Nonsevere TB included specific, limited forms of disease. The trial’s findings informed updated recommendations. A literature review found no other relevant trials, so the SHINE trial formed the primary evidence base for this guideline. - Summary of Evidence, Benefits, and Harms
The SHINE trial involved 1,204 children with nonsevere TB and showed similar success rates between the 4-month (97.1%) and 6-month (96.9%) regimens. Adverse events were also similar. The 4-month regimen proved noninferior and offers benefits such as reduced treatment burden and improved adherence. Cost savings are likely, though the exact impact is uncertain. - Monitoring and Additional Considerations
Children diagnosed during contact investigations can also be eligible for the 4-month regimen if they meet criteria and are not suspected to have MDR/RR-TB. Those with severe TB should still receive standard regimens. Monitoring requirements remain the same, with special attention to recurrence and program readiness to implement the shorter regimen. - Certainty of Evidence
The certainty of evidence was rated high for treatment success and moderate for adverse events and mortality. Despite some imprecision, the trial population was considered applicable. Overall, the certainty of the evidence is moderate, consistent with WHO’s evaluation. - Panel Recommendation
For children aged 3 months to 16 years with nonsevere TB (excluding MDR/RR-TB), the panel strongly recommends a 4-month regimen (2HRZ(E)/2HR) over the standard 6-month regimen (2HRZ(E)/4HR), based on moderate-certainty evidence.
PICO Question 3: In adolescents aged 14 and older and adults with rifampin-resistant pulmonary TB, is a 6-month regimen composed of bedaquiline, pretomanid, and linezolid as efficacious and safe as the current 15-month or longer drug-resistant TB regimens composed according to current ATS/CDC/ERS/IDSA DR-TB treatment guidelines?
- Topic/Overview/Background
MDR-TB, RR-TB, and rifampin-intolerant TB cases are harder to treat and often have worse outcomes. Traditional treatment was long and had side effects. The BPaL regimen (bedaquiline, pretomanid, linezolid) showed over 90% success in trials like Nix-TB and ZeNix. WHO reviewed these trials and incorporated findings into guidelines. ZeNix evaluated lower doses of linezolid to reduce side effects. - Summary of Evidence, Benefits, and Harms
ZeNix trial showed that 600 mg of linezolid for 26 weeks had fewer side effects and similar success to higher doses. BPaL showed higher cure rates and lower mortality compared to older regimens, but had more severe side effects. TB-PRACTECAL confirmed similar findings. BPaL was generally more effective and better tolerated. - Certainty of Evidence
The certainty is very low due to small sample sizes, trial differences, potential bias, lack of blinding, and inconsistent outcomes. Observational data may underestimate side effects, making comparisons less reliable. - Monitoring and Additional Considerations
- Patient Selection
BPaL is recommended for confirmed MDR-/RR-TB. Patients must be evaluated for eligibility. Those intolerant to any component need alternative regimens. Minimum age is 14 years. - Subgroup Considerations
- Older adults: May face more side effects due to comorbidities.
- Children, pregnant/lactating individuals: Excluded from trials. Use longer regimens until more safety data are available.
- People with HIV: Can receive BPaL. Monitor closely for immune reconstitution syndrome and drug interactions.
- Extrapulmonary TB: Only nonsevere cases included in trials. Use caution in severe cases.
- Clinical Monitoring
Regular monitoring (clinical, radiologic, lab tests) is essential. ECGs are needed to track QTc changes, especially if other QT-prolonging drugs are used. Post-treatment monitoring for 1–2 years is advised. - Bacteriologic & Drug Susceptibility Testing (DST)
Test sputum regularly for drug resistance. Use molecular tests where available. If resistance is found, switch to alternative regimens with expert consultation. - Drug–Drug Interactions
Avoid efavirenz, QT-prolonging drugs, strong CYP3A4 inducers/inhibitors, antidepressants, and drugs causing myelosuppression. Monitor for interactions carefully. - Regimen Administration & Duration
26 weeks is the recommended duration. DOT remains the standard. In some cases with delayed response, extending treatment to 39 weeks may be considered, though more evidence is needed.
- Patient Selection
- Linezolid dosing
The preferred dose of linezolid is 600 mg daily throughout the regimen. Therapeutic drug monitoring may help guide linezolid dosing with a goal trough of less than 2 μg/ml to minimize adverse reactions - Panel recommendation
In adolescents aged 14 years and older and adults with rifampin-resistant pulmonary TB who have resistance or patient intolerance to fluoroquinolones and either have had no previous exposure to bedaquiline and linezolid or have been exposed for less than 1 month, we recommend the use of the 6-month treatment regimen, composed of bedaquiline, pretomanid, and linezolid (BPaL), rather than more than 15-month regimens
PICO Question 4: In adolescents aged 14 and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, is a 6-month regimen composed of bedaquiline, pretomanid, linezolid, and moxifloxacin as effective and safe as the 15-month or longer DR-TB regimens composed according to current ATS/CDC/ERS/IDSA DR-TB treatment guidelines?
- Topic/Overview/Background:
Multidrug-resistant (MDR-TB), rifampin-resistant TB (RR-TB), and TB in patients intolerant to rifampin are historically associated with prolonged treatment durations and high morbidity and mortality. The TB-PRACTECAL trial investigated a shorter, all-oral 24-week regimen (BPaLM: bedaquiline, pretomanid, linezolid, and moxifloxacin) against standard of care (SoC) regimens that spanned 9 to 24 months. In patients intolerant to linezolid, expert guidance allows for continuation of the remaining regimen components. Surgical intervention for DR-TB remains an option per prior guidance. - Summary of Evidence, Benefits, and Harms:
In the TB-PRACTECAL trial, patients treated with BPaLM had significantly better outcomes than those on SoC. Treatment success was higher (89% vs. 52%), with fewer failures or recurrences (8% vs. 26%), less loss to follow-up (3% vs. 20%), and fewer serious (grade 3–5) adverse events (21% vs. 51%). These findings highlight both the clinical effectiveness and safety profile of the BPaLM regimen. - Certainty of Evidence:
The certainty of evidence supporting BPaLM is rated as very low due to several limitations: imbalance in patient comorbidities, high risk of unmeasured confounders, lack of blinding, small sample sizes, trial termination before completion, and inconsistencies in comparator regimens and outcomes. These factors introduce bias and imprecision, limiting confidence in effect estimates. - Monitoring and Other Considerations:
- Patient Selection: Same criteria as in prior recommendations (PICO 3) apply, but in this case without confirmed fluoroquinolone resistance.
- Subgroup Considerations: Older adults may be more prone to adverse events due to comorbidities. Children under 14 and pregnant/lactating individuals were excluded from the trial; thus, longer regimens are recommended for these groups until more data is available. HIV-positive individuals responded well in trials, but close monitoring is advised in those with low CD4 counts. People with extrapulmonary TB (nonsevere) were included, but those with severe forms were excluded, so caution is advised.
- Clinical Evaluation and Monitoring: Ongoing clinical, radiologic, and lab assessments should be done monthly or as needed. More frequent checks are needed for high-risk patients. Post-treatment follow-up for 1–2 years is recommended. ECGs should be done at baseline and monthly to monitor QT prolongation.
- Bacteriologic Testing and DST: Regular sputum testing is advised—weekly until smear conversion, then biweekly until culture conversion, and monthly thereafter. Molecular and phenotypic drug susceptibility testing (DST) should be used to monitor resistance. If resistance is found, alternative regimens should be considered with expert consultation.
- Drug–Drug Interactions: Significant interactions can occur with drugs like efavirenz, QT-prolonging agents, CYP3A4 modulators, and certain antidepressants. These should be reviewed and managed carefully.
- Regimen Administration: Directly Observed Therapy (DOT) remains standard. The recommended BPaLM regimen duration is 26 weeks. If delayed response is seen, especially with persistent culture positivity, treatment may be extended up to 39 weeks.
- Linezolid Dosing: A dose of 600 mg daily is preferred. Therapeutic drug monitoring is advised to maintain a trough level below 2 µg/ml. If levels are high, dosage or frequency should be adjusted to reduce toxicity.
- Panel Recommendation:
For adolescents aged 14 and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, the panel strongly recommends a 6-month regimen consisting of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) over longer 15-month or more regimens. This recommendation is based on very low certainty of evidence but reflects the regimen’s potential benefits in efficacy, safety, and reduced treatment burden.
Discussion
Shorter, all-oral regimens with fewer drugs, reduced side effects, and lower pill burden are now available for DS-TB and DR-TB. Adults and adolescents with DS-TB can receive a 4-month RPT-MOX regimen. Children with nonsevere TB may also be treated in 4 months. For DR-TB, 6-month BPaL-based regimens are safer, more effective, and may be used in rifampin-intolerant cases.
These regimens can be rolled out through existing programs with proper staff training. Access to drugs, DST, and monitoring needs to be ensured. Patient support and education can improve adherence.
Shorter regimens are acceptable to patients and doctors. BPaL has shown good outcomes in the U.S. since its approval. Access to key drugs and child-friendly FDCs remains a challenge, especially outside global supply chains.
Studies show BPaL/BPaLM are more effective and cost-saving, with fewer side effects than older regimens. A 600 mg linezolid dose is preferred. Access remains difficult in low-burden, high-income countries.
Despite low certainty of evidence on outcomes, strong recommendations are justified due to high-quality evidence showing fewer adverse events. Observational data confirms older regimens cause more on-treatment side effects.
The Joint Panel supports BPaL/BPaLM for being safer, shorter, and easier to tolerate. These regimens are already the preferred choice in well-resourced countries and help with faster recovery and reduced stigma.
BPaLM is preferred for MDR/RR-TB without fluoroquinolone resistance. BPaL is an alternative for rifampin-intolerant cases. DST monitoring remains essential.
Guideline limitations include reliance on WHO data summaries and exclusion of some newer regimens. Some evidence has low certainty, but shorter all-oral treatments are still favored.
Current data is based on limited studies, often excluding older adults, children with severe TB, pregnant women, and patients with severe EPTB. Further research is needed to guide future updates.
