Tuberculosis (TB) remains one of the deadliest infectious diseases worldwide, with an estimated 10.8 million new cases and 1.25 million deaths reported in 2023 alone. China, bearing the third highest TB burden globally, accounts for approximately 6.8% of global cases, including a significant proportion of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB)[1]. Linezolid (LZD), an oxazolidinone antibiotic, has become a cornerstone of MDR-TB regimens due to its potent bactericidal activity against Mycobacterium tuberculosis(Mtb)[2]. However, its utility is severely limited by a high incidence of adverse events (AE), including myelosuppression and neuropathy[3]. These toxicities frequently necessitate dose reduction or discontinued LZD prematurely, which might lead to treatment failure, relapse, and drug-resistance.

Contezolid (Youxitai ®, CZD) is an orally administered novel oxazolidinone antibiotic developed in China[4]. It has been mainly used to treat complicated gram-positive bacteria infections[5–7]. Several vitro studies also demonstrated bactericidal activity against Mtb[8, 9]. Recent clinical case reports also indicate its efficacy for active tuberculosis, with a lower incidence of toxic adverse effects such as bone marrow suppression and neurotoxicity than the first-generation product linezolid[10–12]. As a novel agent with a unique metabolism mechanism, it has been proven to have little interaction with other medicines [13]. The present study assesses the efficacy and safety of CZD in the real-world management of TB. We hope to provide a reference for future anti-TB treatment and research, particularly for patients who are intolerant to LZD or with severe comorbidities.

Demographic, clinical, and laboratory data were obtained from medical records for all eligible patients. The information recorded included patient demographics, medical history, comorbidities, laboratory findings, symptoms, treatment outcomes, and adverse events recorded in the electronic medical system. Laboratory findings included white blood cell (WBC) count, hemoglobin (HGB), platelet(PLT), liver and kidney function, free blood glucose (FBG), HIV, HBV infection, sputum smear, and culture results during anti-Tb treatment.

Descriptive statistics were calculated for each variable. All continuous variables were examined for normality by Shapiro-Wilk test. We present all continuous variables as the median and interquartile range (IQR). Categorical variables were expressed as percentages and frequency. Wilcoxon rank sum or Kruskal-Wallis test was used to compare continuous variables among different groups. Chi-squared tests of independence were used to explore the relationship between the subgroups and categorical variables. P-value < 0.05 was considered statistically significant, and all reported P-values were two-sided.

CZD, a novel oxazolidinone engineered to mitigate hematological and neurological toxicity, might be a breakthrough in TB therapeutics. Unlike LZD, CZD selectively inhibits bacterial ribosomal subunits while sparing mitochondrial protein synthesis, a mechanism hypothesized to reduce off-target effects. Preclinical data of CZD further suggest enhanced intracellular penetration and activity against Mtb [9]. Despite these advantages, real-world evidence on CZD’s efficacy, adverse events, and optimal dosing in different TB populations remains sparse.

Compared with LZD,CZD demonstrated a significantly decreased myelosuppression and neuropathy[14]. In our study, we found myelosuppression persisted in only one patient even after LZD switch to CZD. Most patients achieved LZD associated-AE relief after switching to CZD. This is similar to the retrospective study in China that demonstrated AE relief and improved clinical symptoms in 25 patients who suffered from LZD-associated AE and switched to a CZD-containing regimen[15]. These clinical data demonstrate that CZD exhibits significantly lower incidence of myelosuppression and neurotoxicity compared to LZD, whereas the latter has been associated with a high incidence of toxicities[16]. The toxicity of LZD led to 14.1% permanent discontinuation during long-term tuberculosis treatment regimens[3]. These real-world clinical practices of CZD could be offered as a favorable therapeutic alternative to mitigate adverse effects when LZD-associated-AE develops.

Notably, some clinical cases reported that conetizolid has a satisfactory anti-tuberculosis effect with fewer toxicities[15, 17, 18]. In our study, we found that 10 patients initially combined CZD in their regimen. Most of these patients had a specific health problem or were contrained by commonly used anti-TB drugs or drug interactions of LZD. All of them achieved cultural conversion. The median culture conversion time was at the 8th week after treatment initiation. No myopression and neuropathy were observed during treatment. CZD included regimens that exhibit favorable efficacy and safety profiles in these complex clinical scenarios, demonstrating particular applicability in managing more complicated disease states. These clinical advantages may be attributed to CZD's unique metabolic properties, which are associated with fewer drug-drug interactions compared to conventional anti-mycobacterial agents. Moreover, previous studies of pharmacokinetic characteristics eliminate the requirement for dose adjustment in patients with hepatic or renal impairment[19, 20]. The recommended dosage of CZD for bacterial infections is 800 mg twice daily[4]; however, its optimal dosing regimen for anti-tuberculosis therapy remains undetermined. Our real-world study revealed clinician concerns regarding potential toxicities associated with long-term use, leading to a conservative dosing approach in clinical practice. CZD ranging from 400–800 mg administered once or twice daily demonstrated comparable efficacy in achieving sputum culture conversion and reducing adverse events. Whether lower-dose regimens might predispose to drug resistance induction and whether prolonged high-dose administration could elicit toxicity remains unknown. Comprehensive pharmacokinetic investigations coupled with systematic drug resistance induction studies are therefore warranted to establish the therapeutic window balancing efficacy and safety in tuberculosis treatment.

There are two limitations in our study. Firstly, as a real-world study, the sample size from three TB-designated hospitals was still small. It may not adequately represent broader patient populations in terms of demographic diversity, disease severity, or comorbid conditions. All clinical data were collected from the electronic medical record system. Information regarding symptom improvement including self-reported relief of foot numbness and reduced fatigue was documented by the attending physicians during follow-up visits based on patients’ oral descriptions. No standardized patient-reported outcome (PRO) questionnaire was used at the time of treatment. Secondly, the plasma pharmacokinetics of CZD had not been performed, so the optimal dosage of CZD for patients with TB could not be determined, particularly for those with special clinical problems. Prospective studies for efficacyand dosage of CZD for patients with TB should be conducted in the future. Validated assessment tools such as the neuropathy symptom score or fatigue scales would also be incorporated for evaluation of safety.

In conclusion, CZD may be a very promising and safe drug for the treatment of TB in patients with LZD-associated AE and with special health problems. Further clinical studies are needed to verify this new drug and determine its optimal dosage for TB treatment, particularly in patients with comorbidities.