Contezolid

Tuberculosis (TB) remains a major global public health problem. According to the World Health Organization (WHO) Global Tuberculosis Report 2025, an estimated 10.7 million people developed TB and approximately 1.23 million died from the disease in 2024. China continues to face a high burden of both TB and multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). The introduction and expanded use of new and repurposed anti-tuberculosis drugs, including bedaquiline and linezolid, together with accumulating evidence supporting all-oral shorter regimens, have resulted in evidence-based uses that are not yet fully reflected in current Chinese prescribing information. Meanwhile, off-label doses, treatment durations, and alternative uses of established anti-tuberculosis drugs and repurposed anti-infective agents, including isoniazid, rifamycins, fluoroquinolones, and carbapenems, are common in patients with complex drug resistance, drug intolerance, or other special clinical conditions. Standardized guidance is therefore needed within evidence-based, legal, and safety-monitoring frameworks.Building on the Expert Consensus on Off-Label Use of Anti-Tuberculosis Drugs (2023 Update), the Tuberculosis Branch of the Chinese Medical Association developed this guideline using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement. Focusing on 13 commonly used anti-tuberculosis drugs, the guideline systematically evaluates evidence regarding off-label indications, dosing, treatment duration, routes of administration, target populations, and safety monitoring. Comprehensive literature searches were conducted from database inception through June 10, 2025, and a total of 25 recommendations were formulated. Major updates in this guideline address newly approved and repurposed drugs and all-oral shorter regimens, optimized dosing and alternative applications of established agents, treatment considerations for children and patients with extrapulmonary tuberculosis, local drug administration, drug-safety monitoring, and therapeutic drug monitoring (TDM). The guideline aims to provide practical, standardized, and evidence-based recommendations to support the rational and safe off-label use of anti-tuberculosis drugs in clinical practice.The 25 recommendations are summarized as follows.Recommendation 1: Off-label use of anti-tuberculosis drugs should be supported by adequate medical evidence and limited to situations in which no appropriate approved alternative is available. Appropriate review and informed consent are required (1, B).Recommendation 2: An individualized safety monitoring plan should be developed according to drug-specific toxicities, patient characteristics, concomitant medications, and potential drug-drug interactions (1, B).Recommendation 3: High-dose isoniazid may be considered for patients with low-level isoniazid resistance and as a component of selected shorter regimens for MDR/RR-TB when isoniazid is likely to retain activity (2, C).Recommendation 4: Isoniazid, 10-15 mg/kg once daily, may be used for MDR/RR-TB with low-level resistance and retained activity (2, B). In selected cases of severe or refractory TBM, or when CNS exposure is inadequate, higher isoniazid dosing may be used; for children/adolescents, 15-20 mg/kg once daily with pyridoxine, toxicity monitoring, and TDM as needed (2, C).Recommendation 5: Local isoniazid administration may be cautiously and individually considered in selected cases as an adjunct to standardized systemic therapy, following specialist evaluation and appropriate safety monitoring (2, D).Recommendation 6: Where available, TDM may be considered for patients receiving high-dose isoniazid or those with an inadequate response, suspected malabsorption, clinically important drug interactions, a high risk of hepatotoxicity, or altered pharmacokinetics. NAT2 genotype-inferred acetylator phenotype may support individualized dose adjustment together with TDM, efficacy, and safety assessments (2, B).Recommendation 7: Off-label rifampicin use includes a 3-month regimen of isoniazid and rifampicin (3HR) (1, B) or a 4-month regimen of rifampicin (4R) (2, B) for tuberculosis preventive treatment; individualized high-dose use in TBM or investigational use in drug-susceptible pulmonary tuberculosis (2, C); local administration as adjunct therapy only (2, D); and use during pregnancy, including early pregnancy, after individualized benefit-risk assessment (2, C).Recommendation 8: Based on pharmacokinetic and safety data from Chinese populations, the 3H₂P₂ regimen-isoniazid 500-600 mg, plus rifapentine, 450-600 mg, twice weekly for 3 months-is recommended for tuberculosis preventive treatment (1, B).Recommendation 9: Levofloxacin is a key drug for fluoroquinolone-susceptible MDR/RR-TB (1, B); it may also be used for rifampicin-susceptible, isoniazid-resistant TB (2, D) or as an individualized alternative when first-line drugs cannot be used (2, C).Recommendation 10: Levofloxacin may be used in children of any age with MDR/RR-TB, and when first-line drugs cannot be used, as an individualized alternative for drug-susceptible TB. Dosing should be adjusted according to age and body weight, accompanied by appropriate safety monitoring (2, B).Recommendation 11: Oral levofloxacin administered once daily for 6 months is recommended for eligible close contacts of patients with MDR/RR-TB after active TB has been excluded and fluoroquinolone susceptibility of the source case has been assessed (1, B).Recommendation 12: Moxifloxacin may be used in fluoroquinolone-susceptible MDR/RR-TB (1, B). In drug-resistant TBM, individualized use may be considered, but 800 mg/day should not be routinely used (2, D). ECG and electrolyte monitoring is recommended during prolonged or high-dose use or concomitant QT-prolonging therapy (1, C).Recommendation 13: Fluoroquinolone TDM may be considered during high-dose or prolonged treatment or when drug exposure is uncertain. Levofloxacin Cmax 8-12 mg/L and moxifloxacin Cmax 3-5 mg/L are empirical reference ranges rather than fixed targets (2, B).Recommendation 14: Off-label linezolid use includes MDR/RR-TB, including pre-XDR-TB and XDR-TB (1, B); drug-resistant or refractory tuberculous meningitis (2, D); and eligible non-severe extrapulmonary MDR/RR-TB (2, C). Adults typically receive 600 mg once daily; children receive age-and weight-based dosing, with duration determined by the regimen (1, C).Recommendation 15: During prolonged linezolid treatment, monitoring should be performed for myelosuppression, optic and peripheral neuropathy, and lactic acidosis. The dose should be reduced, treatment interrupted, or linezolid discontinued according to toxicity severity, and concomitant serotonergic medications should be avoided whenever possible (1, B).Recommendation 16: TDM should be considered during prolonged linezolid treatment, particularly in patients with an inadequate response, serious toxicity, organ dysfunction, extreme body weight, or clinically important drug interactions (2, B).Recommendation 17: Contezolid may be considered as an alternative for patients with MDR/RR-TB who cannot tolerate linezolid or are at high risk of linezolid toxicity due to baseline myelosuppression, neurologic disease, or other factors, when an oxazolidinone is required to construct an effective regimen (2, D).Recommendation 18: Off-label clofazimine use includes longer MDR/RR-TB regimens as a WHO group B drug and selected 6-and 9-month regimens: its duration should follow the complete regimen and fluoroquinolone susceptibility results (1, B).Recommendation 19: Patients receiving clofazimine should be counseled regarding discoloration of the skin, mucosa, and body fluids and they should be monitored for gastrointestinal toxicity and Fridericia-corrected QT interval (QTcF) prolongation (1, B).Recommendation 20: Bedaquiline is a core drug for MDR/RR-TB. Off-label use includes adult RR-TB (2, C), children of any age with MDR/RR-TB (2, D), treatment beyond 24 weeks (2, C), use during pregnancy after benefit-risk assessment (2, C), and extrapulmonary MDR/RR-TB (2, C).Recommendation 21: During bedaquiline treatment, monitoring should be performed for QTcF prolongation, hepatic dysfunction, and other adverse reactions. More frequent ECG monitoring is recommended for older patients, those with underlying heart disease or electrolyte abnormalities, and those receiving concurrent QT-prolonging medications (1, B).Recommendation 22: Off-label delamanid use includes adult RR-TB as part of an appropriate combination regimen (2, C), children of any age with MDR/RR-TB (2, D), treatment extending beyond 24 weeks (2, C), use during pregnancy after benefit-risk assessment (2, C), and extrapulmonary MDR/RR-TB (2, C). Monitoring of QTcF interval, electrolytes, and serum albumin is required; its use should be avoided if the baseline serum albumin is <28 g/L (1, B).Recommendation 23: Amikacin may be considered for selected MDR/RR-TB, retreatment TB, or TB requiring regimen modification due to drug intolerance, and for severe, refractory, or drug-resistant TBM during the intensive phase (2, C). Local administration may be used as adjunctive therapy in selected cases (2, D).Recommendation 24: Monitor renal function, urinalysis, and auditory/vestibular function during amikacin treatment. Adjust the dose or dosing interval for renal impairment. TDM is advised when available, particularly for high-risk or prolonged treatment, to support individualized dosing (1, B).Recommendation 25: Meropenem or imipenem/cilastatin, each combined with clavulanate, may be considered as a Group C option for MDR/RR-TB when Group A and B drugs cannot form an effective regimen (2, D). In drug-resistant, severe, or refractory TBM, individualized use may be considered only when other effective options are unavailable; meropenem is preferred for children and patients at high risk of seizures (2, D).