Tuberculosis remains a major global public health problem. The World Health Organization estimated approximately 10.7 million incident TB cases and about 1.23 million deaths in 2024. China carries a high burden of both tuberculosis and multidrug‑resistant/rifampicin‑resistant tuberculosis (MDR/RR‑TB). Introduction and expanded clinical use of new and repurposed anti‑tuberculosis agents—such as bedaquiline and linezolid—and accumulating evidence for all‑oral shorter regimens have created clinical practices that are not fully reflected in existing domestic prescribing information.
Off‑label use is defined as using a drug outside the approved indication, dose, route, duration, or target population. Such use is increasingly common for both newer and established anti‑tuberculosis drugs—examples include higher doses or extended durations of isoniazid, alternative rifamycin applications, fluoroquinolone use in MDR/RR‑TB, and carbapenems in complex resistance scenarios. The guideline aims to standardize off‑label use within evidence‑based, legal, and safety‑monitoring frameworks.
The Tuberculosis Branch of the Chinese Medical Association developed this guideline building on the Expert Consensus on Off‑Label Use of Anti‑Tuberculosis Drugs (2023 update). The guideline employed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and adhered to the Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement.
Comprehensive literature searches covered databases from inception through June 10, 2025, and the panel formulated 25 recommendations addressing off‑label indications, dosing, treatment duration, routes of administration, target populations, and safety monitoring for 13 commonly used anti‑tuberculosis drugs.
Off‑label use should be supported by adequate medical evidence and used only when no appropriate approved alternative is available. Appropriate review and documented informed consent are required (Recommendation 1).
An individualized safety monitoring plan must be developed for each off‑label regimen. Plans should consider drug‑specific toxicities, patient characteristics, concomitant medications, and potential drug–drug interactions (Recommendation 2).
Where applicable, therapeutic drug monitoring (TDM) and genotype‑inferred pharmacogenetic information (for example, NAT2 acetylator status) may support individualized dosing, efficacy assessment, and safety monitoring.
High‑dose isoniazid may be considered for patients with low‑level isoniazid resistance and as part of selected shorter regimens for MDR/RR‑TB when activity is likely retained (Recommendation 3).
A daily dose of isoniazid 10–15 mg/kg may be used when low‑level resistance with retained activity is suspected (Recommendation 4). In select severe or refractory tuberculous meningitis (TBM) or when central nervous system exposure is inadequate, higher dosing can be considered; for children and adolescents, 15–20 mg/kg once daily with pyridoxine, toxicity monitoring, and TDM as needed is suggested (Recommendation 4).
Local (direct) administration of isoniazid can be cautiously and individually considered as an adjunct to systemic therapy after specialist evaluation and safety monitoring (Recommendation 5).
TDM is recommended where available for patients receiving high‑dose isoniazid, those with inadequate response, suspected malabsorption, significant drug interactions, high hepatotoxicity risk, or altered pharmacokinetics. NAT2 genotype‑inferred acetylator phenotype can support individualized dosing alongside TDM and clinical assessments (Recommendation 6).
Off‑label rifampicin uses include established shorter preventive regimens such as isoniazid plus rifampicin for 3 months (3HR) and a 4‑month rifampicin regimen (4R) for tuberculosis preventive treatment (Recommendation 7).
Individualized high‑dose rifampicin may be considered in TBM or investigational use in drug‑susceptible pulmonary TB; local administration is reserved as an adjunct (Recommendation 7).
For tuberculosis preventive treatment, a 3‑month twice‑weekly regimen combining isoniazid 500–600 mg plus rifapentine 450–600 mg (3H2P2) is recommended based on pharmacokinetic and safety data in Chinese populations (Recommendation 8).
Use of rifampicin during pregnancy, including early pregnancy, may be considered after individualized benefit–risk assessment (Recommendation 7).
Levofloxacin is a key drug for fluoroquinolone‑susceptible MDR/RR‑TB and may be used for rifampicin‑susceptible, isoniazid‑resistant TB or as an individualized alternative when first‑line drugs are not usable (Recommendations 9, 11).
Levofloxacin may be used in children of any age with MDR/RR‑TB; dosing should be age‑ and weight‑adjusted with appropriate safety monitoring (Recommendation 10).
Moxifloxacin can be used for fluoroquinolone‑susceptible MDR/RR‑TB. In drug‑resistant TBM, individualized use may be considered but routine use of 800 mg/day is not recommended. ECG and electrolyte monitoring are advised during prolonged or high‑dose use or when combined with other QT‑prolonging drugs (Recommendation 12).
Fluoroquinolone TDM is suggested during high‑dose or prolonged treatment or when exposure is uncertain. Empirical Cmax reference ranges cited are levofloxacin 8–12 mg/L and moxifloxacin 3–5 mg/L; these are references rather than fixed targets (Recommendation 13).
Linezolid is recommended off‑label for MDR/RR‑TB (including pre‑XDR and XDR), drug‑resistant or refractory TBM, and eligible non‑severe extrapulmonary MDR/RR‑TB. Adult dosing commonly used is 600 mg once daily; pediatric dosing is age‑ and weight‑based; treatment duration depends on the overall regimen (Recommendation 14).
Prolonged linezolid treatment requires monitoring for myelosuppression, optic and peripheral neuropathy, and lactic acidosis. Dose reduction, treatment interruption, or discontinuation should follow toxicity severity; concurrent serotonergic medications should be avoided where possible (Recommendation 15).
TDM is recommended in prolonged linezolid treatment, particularly for inadequate response, serious toxicity, organ dysfunction, extreme body weight, or important drug interactions (Recommendation 16).
Contezolid may be considered as an alternative oxazolidinone for patients who cannot tolerate linezolid or are at high risk of linezolid‑related toxicity (for example, baseline myelosuppression or neurologic disease) when an oxazolidinone is needed to construct an effective regimen (Recommendation 17).
Clofazimine may be used in longer MDR/RR‑TB regimens as a WHO Group B drug and in selected 6‑ and 9‑month regimens, with duration aligned to the complete regimen and fluoroquinolone susceptibility results (Recommendation 18).
Patients receiving clofazimine should be counseled about potential skin, mucosal, and body fluid discoloration and monitored for gastrointestinal toxicity and Fridericia‑corrected QT interval (QTcF) prolongation (Recommendation 19).
Bedaquiline is a core drug for MDR/RR‑TB. Off‑label uses include adult RR‑TB, children of any age with MDR/RR‑TB, treatment beyond 24 weeks, use during pregnancy after benefit–risk assessment, and extrapulmonary MDR/RR‑TB (Recommendation 20).
During bedaquiline treatment, monitoring should focus on QTcF prolongation, hepatic dysfunction, and other adverse reactions. Increased ECG monitoring is advised for older patients, those with underlying cardiac disease or electrolyte abnormalities, and patients receiving concurrent QT‑prolonging drugs (Recommendation 21).
Delamanid off‑label uses mirror those for bedaquiline: adult RR‑TB within an appropriate combination regimen, children of any age with MDR/RR‑TB, treatment beyond 24 weeks, use during pregnancy after individualized assessment, and extrapulmonary MDR/RR‑TB (Recommendation 22).
Delamanid requires monitoring of QTcF interval, electrolytes, and serum albumin; its use should be avoided if baseline serum albumin is <28 g/L (Recommendation 22).
Amikacin may be considered in selected MDR/RR‑TB cases, retreatment, or when regimen modification is required due to intolerance; it is a consideration for severe, refractory, or drug‑resistant TBM during the intensive phase. Local administration can be used adjunctively in select situations after specialist evaluation (Recommendation 23).
Renal function, urinalysis, and auditory/vestibular function should be monitored during amikacin therapy. Dose or dosing interval adjustments are needed for renal impairment. TDM is advised when available, especially for high‑risk or prolonged treatments to individualize dosing (Recommendation 24).
The guideline emphasizes that off‑label use must be evidence‑supported, accompanied by informed consent, and implemented with individualized safety monitoring plans.
Specialist evaluation is recommended for local drug administration and for tailoring regimens in complex resistance or special population scenarios (children, pregnancy, TBM, extrapulmonary disease).
TDM and pharmacogenetic tools (for example, NAT2 genotype) are recommended where available to support individualized dosing decisions and to reduce the risk of toxicity or therapeutic failure.
All authors declared no competing interests.