Drug-Susceptible and Drug-Resistant Tuberculosis (ATS 2025 Guidelines)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Anum Ijaz M.B.B.S., M.D.[2]

Overview:

The updated ATS/CDC/ERS/IDSA tuberculosis treatment guidelines incorporate recent clinical trial data on drug-susceptible and drug-resistant TB in adults and children. The recommendations were developed by a joint multidisciplinary panel in collaboration with American Thoracic Society methodologists, using the GRADE methodology to ensure evidence-based and transparent decision-making.

Recommendations for Drug-Susceptible TB

1.    Treatment of Isoniazid-Susceptible, Rifampin-Susceptible TB in Adults

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. (Conditional Recommendation*; Moderate Certainty of Evidence)

* We conditionally recommend” is analogous to the phrase “we suggest” in the 2016 and 2019 joint panel TB guidelines.

4-Month Rifapentine–Moxifloxacin Regimen
Isoniazid (INH): 300 mg daily × 17 weeks Rifapentine (RPT): 1200 mg daily × 17 weeks Pyrazinamide (PZA): Weight-based × 8 weeks     40–55 kg → 1000 mg   55–75 kg → 1500 mg     75 kg → 2000 mg Moxifloxacin (MOX): 400 mg daily × 17 weeks
Pyridoxine (vitamin B6), 25–50 mg/d, should be given with isoniazid to all patients.

Monitoring & Safety:

Clinical: Monthly review for cough resolution, weight gain, and radiographic improvement.

LFTs: Baseline, repeat if hepatotoxic symptoms appear.

Cardiac: ECG only if cardiac disease, age >50, or QT-prolonging medications.

Drug Resistance: Obtain molecular/phenotypic fluoroquinolone DST before initiation.

Adverse Events: Watch for moxifloxacin-related neuropathy, tendinitis, QT prolongation, dysglycemia.

Adherence: DOT ≥5/7 days weekly preferred.

Pregnancy: Not validated; avoid unless no alternative.

2. Treatment of Nonsevere, Presumed Isoniazid-Susceptible, Rifampin-Susceptible TB in Children

In children and adolescents between 3 months and 16 years of age with nonsevere TB (without suspicion or evidence of MDR/RR-TB), we recommend the use of a 4-month treatment regimen of 2HRZ(E)/2HR rather than the 6-month DS-TB regimen of 2HRZ(E)/4HR ( Strong Recommendation*; Moderate Certainty of Evidence)

*Strong recommendations will apply to most patients for whom these recommendations are made, but they may not apply to all patients in all conditions; no recommendation can take into account all of the unique features of individual patients and clinical circumstances.

4-month standard regimen (2HRZE/2HR)
Intensive Phase (8 weeks): §Isoniazid 10–15 mg/kg + Rifampin 10–20 mg/kg + Pyrazinamide 35 mg/kg ± Ethambutol 20 mg/kg (optional)*. Continuation Phase : Isoniazid + Rifampin × 8 weeks.
§Pyridoxine (vitamin B6), 25–50 mg/d, should be given with isoniazid to all patients. *To avoid potential ocular toxicity, some clinicians exclude ethambutol for children who are HIV-uninfected, have no prior TB treatment history, live in an area of low prevalence of DR-TB, and have no exposure to an individual from an area of high prevalence of DR-TB. Prevalence and risk factors can be difficult to ascertain; therefore, the American Academy of Pediatrics and most experts include ethambutol as part of the intensive phase regimen for children with TB.

Identifying children eligible for 4-month regimens:

Figure developed by the Joint Panel on the basis of data in the SHINE trial and Study 31/A5349 to address eligibility of some children for either the RPT/MOX regimen or the 4-month standard drug regimen.

Monitoring & Special Considerations:

Clinical: Monthly assessment of weight and clinical symptoms.

LFTs: As indicated for HIV, malnutrition, or hepatotoxic symptoms.

Recurrence Surveillance: 3, 6, and 12 months post-treatment.

HIV Co-infection: Acceptable with close follow-up; extend to 6 months if slow response.

Severe Malnutrition or Age <3 months: Use 6-month regimen.

Peripheral Lymph Node TB: Eligible for 4-month regimen; expect slow regression.

Recommendations for Drug-Resistant TB

1. Rifampin-Resistant, Fluoroquinolone-Resistant TB

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. (Strong Recommendation*; Very Low Certainty of Evidence).

* Strong recommendations will apply to most patients for whom these recommendations are made, but they may not apply to all patients in all conditions; no recommendation can take into account all of the unique features of individual patients and clinical circumstances.

BPaL Regimen
Bedaquiline (BDQ): 400 mg daily × 2 weeks, then 200 mg three times weekly × 24 weeks Pretomanid (PA-824): 200 mg daily × 26 weeks Linezolid (LZD): 600 mg daily × 26 weeks
Medications should be administered 7 d/wk with food, with DOT 5 of 7 days per week.

Monitoring & Evaluation:

Baseline: ECG, CBC, LFTs, renal profile, and vision check.

Follow-up: Clinical, radiologic, and laboratory review monthly or as needed.

Hematologic: CBC weekly ×1 month, then monthly (linezolid myelosuppression).

ECG: At baseline, 2, 12, and 24 weeks (QTc from bedaquiline).

Neuropathy: Screen for paresthesias and visual disturbances (linezolid toxicity).

Post-treatment:  Monitor relapse for 12–24 months.

Contraindications:  >1 month prior exposure to bedaquiline/linezolid, pregnancy, hepatic failure.

Special Populations:

  HIV: Use safely regardless of CD4; avoid efavirenz (lowers bedaquiline).

  Children <14 / Pregnant: Use longer regimens until data available.

  Extrapulmonary TB: Only nonsevere EPTB eligible

2. Rifampin-Resistant, Fluoroquinolone-Susceptible TB

In adolescents aged 14 years and older and adults with rifampin-resistant, fluoroquinolone-susceptible pulmonary TB, we recommend the use of a 6-month treatment regimen, composed of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM), rather than the 15-month or longer regimens in patients with MDR/RR-TB. (Strong Recommendation; Very Low Certainty of Evidence)

*Strong recommendations will apply to most patients for whom these recommendations are made, but they may not apply to all patients in all conditions; no recommendation can take into account all of the unique features of individual patients and clinical circumstances.

BPaLM Regimen
Bedaquiline (BDQ): 400 mg daily × 2 weeks, then 200 mg three times weekly × 24 weeks Pretomanid (PA-824): 200 mg daily × 26 weeks Linezolid (LZD): 600 mg daily × 26 weeks Moxifloxacin (MOX): 400 mg daily × 26 weeks
Medications should be administered 7 d/wk with food, avoiding milk, antacids, or other cationic items with DOT 5 of 7 days per week

Monitoring & Evaluation:

Baseline: CBC, LFTs, ECG, vision check.

ECG: Baseline and monthly due to QT risk (bedaquiline + moxifloxacin).

Hematologic: CBC monthly; check for linezolid-induced anemia and thrombocytopenia.

Hepatic: ALT/AST and bilirubin monthly.

Bacteriologic: Sputum weekly → every 2 weeks → monthly until conversion.

DST: Repeat if delayed conversion; use sequencing for resistance mutation detection.

Post-treatment: Relapse surveillance 12–24 months.

Monitoring Plan for Patients Treated with BPaL or BPaLM

Activity

Month of Treatment

Post-Treatment!

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Weight**

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Symptom review***

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DSTW

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CBC!!

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Creatinine§§

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ALT/AST, alkaline phosphatase, bilirubin¶¶

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K+, Ca2+, Mg2+, bicarbonate ±

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Serum drug concentration****

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HIV@

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EKG

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Vision examˆˆ

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Peripheral neuropathy ?

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Arthralgias ??

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Amylase, lipase, TSH F

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● indicates activity is recommended by joint panel opinion. ○ indicates activity that is optional or contingent on other information. Monitoring recommendations may change if treatment regimen or patient status changes When treatment extended to 9 months, monitoring for Months 7-9 (Weeks 27-39) would be "as needed." *Joint panel opinion, adapted by permission from Reference 29. !Recommend clinical assessment (including physical examination and symptom review), sputum collection (two or three specimens), and chest | imaging at 3, 6, 12, 18, and 24 months after treatment completion. !!Split column indicates weekly or biweekly testing. §Obtain three sputa at the start of treatment and every 1-2 weeks until smear conversion, followed by one or two sputa every 2 weeks until culture conversion and then one sputum monthly throughout treatment. ¶Obtain baseline imaging and monitor approximately every 3 months until end of treatment. **Monitor weight monthly and adjust medications as needed. ***Monitor for TB symptoms monthly. WObtain first and second-line DSTs at baseline. Repeat if culture remains positive after 2-3 months of treatment. !!Obtain CBC every 1-2 weeks for the first 6-8 weeks, then monthly while on LZD. A decrease of hemoglobin of greater than 10% or more at 4| weeks of treatment may identify those at high risk for severe anemia . §§Obtain serum creatinine at baseline and monthly while on BPaL or BPaLM. ± Obtain K+, Ca2+, Mg2+, and bicarbonate at baseline and monthly while on BDQ. ¶¶ Obtain ALT, AST, alkaline phosphatase, and bilirubin at baseline and then monthly while on BDQ and Pa. ****Obtain therapeutic drug monitoring (TDM), if possible, of LZD after 1-2 weeks on therapy and if signs of toxicity develop. Recommend collecting an LZD trough concentration if resources allow. TDM may be obtained for other drugs as clinically indicated. @ Obtain baseline HIV test @@Consider baseline and monthly pregnancy test for patients capable of becoming pregnant who decline long-acting forms of birth control (e.g. intrauterine devices or implantable contraception). ˆˆPerform visual acuity (e.g., Snellen) + color discrimination (i.e., Ishihara) examinations at baseline and monthly while on LZD. ?Monitor for peripheral neuropathy at baseline and monthly while on LZD. ??Monitor for arthralgias at baseline and monthly while patient on an FQ. FNote that CDC provisional guidance (3) for use of BPal recommends amylase, lipase, and TSH at baseline. These may not be necessary for all patients, according to joint panel opinion. Consider checking amylase and lipase if underlying concerns for pancreatitis or if symptoms develop. Consider checking TSH if there are concerns for prolonged QT interval on baseline EKG. ALT = alanine aminotransferase; AST = aspartate aminotransferase; EKG = electrocardiogram or ECG; CBC = complete blood count; CXR = chest x-ray; CT = computed tomography: DST = drug susceptibility testing; TSH = thyroid stimulating hormone.