Naihui Chu

Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) with high mortality. This study evaluated the cerebrospinal fluid (CSF) concentration and safety of the novel oxazolidinone contezolid compared to linezolid in TBM patients. In this randomized prospective study, 10 TBM patients received either a linezolid-containing ( n = 5) or contezolid-containing ( n = 5) anti-TB regimen. CSF and blood concentrations were measured at 2 and 6 h post-dose. Peak (2 h) and trough (6 h) concentrations, area under the concentration-time curve (AUC), and safety were assessed. Contezolid CSF concentrations exceeded the Mycobacterium tuberculosis (Mtb) MIC (0.5 μg/mL) at 2 h (median: 1.0806 μg/mL, range: 0.9295–1.3165 μg/mL) but declined by 6 h (median: 0.7920 μg/mL, range: 0.1867–1.0194 μg/mL). Linezolid CSF concentrations were significantly higher than contezolid at both 2 h (median: 3.251 μg/mL, range: 1.9545–4.9636 μg/mL; P = 0.008) and 6 h (median: 1.623 μg/mL, range: 0.941–1.765 μg/mL; P = 0.016), remaining above MIC in all samples at 6 h. The mean CSF AUC for contezolid (4.637 μg·h/mL, 95% CI: 3.599–5.675) was significantly lower than that for linezolid (12.537 μg·h/mL, 95% CI: 7.8797–17.277; P = 0.008). Blood concentrations were higher than CSF for both drugs at all time points. No serious drug-related adverse events occurred. Contezolid effectively penetrates the blood-CSF barrier in TBM patients, achieving CSF concentrations above the MIC for Mtb. Although its CSF exposure was significantly lower than linezolid, its demonstrated penetration and safety profile suggest contezolid warrants further investigation as a potential treatment option for drug-resistant TBM. IMPORTANCE: Tuberculous meningitis (TBM) is the deadliest form of tuberculosis, especially difficult-to-treat drug-resistant TBM. Finding new, effective, and safe medicines is critical. This study provides evidence in TBM patients that a newer antibiotic, contezolid, successfully reaches the infection site in cerebrospinal fluid (CSF) at levels expected to kill Mycobacterium tuberculosis . While linezolid achieved higher levels in CSF, contezolid still reached concentrations predicted to be effective and caused no serious side effects in our study. This is important because contezolid might offer a safer alternative to linezolid, which can have significant long-term toxicity. These promising results suggest contezolid could become a valuable new weapon against refractory drug-resistant TBM, potentially saving lives where current options are limited or too toxic.

To examine the in vivo distribution of WX-081 alone or in combination with clarithromycin (Clr) or clofazimine (CFZ) in rats infected with Mycobacterium abscessus and evaluate the effects of the interactions of WX-081 with Clr and CFZ on its tissue distribution, the concentrations of WX-081 in plasma, brain, vertebral, and lung tissue of Sprague-Dawley rats at 20 min, 1 h, and 16 h post-treatment with 45 mg/kg WX-081 (Group A), 45 mg/kg WX-081 plus 10 mg/kg Clr (Group B), or 45 mg/kg WX-081 plus 25 mg/kg CFZ (Group C) were determined by liquid chromatography-tandem mass spectrometry. Differences between continuous variables were analyzed using Student’s t -test ( P ≤ 0.05). At 20 min, rats in groups B and C had higher plasma WX-081 concentration than those in Group A (458.7 ng/mL vs. 140.4 ng/mL, P = 0.012; 351.7 ng/mL vs. 140.4 ng/mL, P = 0.022, respectively). At 1 h, only Group B had a higher plasma level than Group A (2,522.3 ng/mL vs. 1,413.2 ng/mL, respectively, P = 0.018), while the WX-081 concentration in Group B lung tissue exceeded that in Group A lung tissue (8,890.9 ng/g vs. 6,666.8 ng/g, respectively, P = 0.041), and that of Group C lungs was lower than that of Group A lung tissue (3,953.4 ng/g vs. 6,666.8 ng/g, respectively, P = 0.014). The lung tissue consistently had the highest WX-081 concentration at all time points. At 20 min, plasma WX-081 levels in groups B and C surpassed that of Group A. At 1 h, Group B had higher plasma and lung WX-081 concentration, while Group C had a lower lung WX-081 concentration than Group A. IMPORTANCE: The study pioneers the exploration of WX-081’s in vivo distribution and drug interactions with Clr or CFZ in a rat Mycobacterium abscessus infection model. It shows that co-administration alters tissue distribution, boosting lung concentrations—key for treating pulmonary infections. These insights guide regimen optimization and underscore WX-081’s potential as a safer alternative, enhancing treatment for non-tuberculous mycobacterial diseases.

Linezolid is an important drug for the treatment of drug-resistant tuberculosis (DR-TB). Acquired linezolid resistance threatens treatment efficacy. This s

Background: Linezolid is essential for drug‐resistant tuberculosis (DR‐TB) treatment but causes frequent hematological toxicity. We developed a time‐dependent nomogram to predict this risk. Methods: A prospective cohort of 201 patients with DR‐TB receiving linezolid (600 mg/day) was enrolled. Blood trough concentration (C _min ) and clinical variables were measured. Multivariable Cox regression identified predictors, with a nomogram constructed to estimate toxicity probability at 1, 3, and 6 months. Model performance was assessed via calibration curves, C‐index, and time‐dependent area under the curve (AUC). Results: Ninety‐six patients (47.8%) developed hematological adverse events (anemia: 26.4%, leukopenia: 14.4%, thrombocytopenia: 7.0%). Five predictors were significant: C _min > 2.08 mg/L [Hazard Ratio (HR) = 2.87, p < 0.001]; lower baseline white blood cells (HR = 0.84, p = 0.003), hemoglobin (HR = 0.99, p = 0.033), and creatinine clearance rate (HR = 0.99, p = 0.001); and initial treatment (HR = 0.56 vs. retreatment, p = 0.011). The nomogram showed good discrimination (C‐index = 0.73) and calibration. Time‐dependent AUCs were 0.74 (1‐month), 0.79 (3‐month), and 0.80 (6‐month). Internal validation via bootstrapping (1000×) confirmed robustness. Conclusions: This nomogram, integrating C _min with baseline clinical factors, enables early identification of patients with DR‐TB at high risk for hematotoxicity and could guide pre‐emptive interventions. However, external validation is required to confirm its generalizability before widespread clinical implementation.

Tuberculosis (TB) is a contagious disease that threatens human health worldwide. Combination chemotherapy is usually recommended for this disease. Recently, 2 nitroimidazole-based agents, namely, delamanid and pretomanid, have been approved by regulatory agencies. JDB0131 is a novel, structurally optimized third-generation nitroimidazole antituberculosis agent that incorporates the advantages of earlier compounds. This multicenter, prospective, randomized phase 2a trial was conducted to evaluate its efficacy and safety in patients with tuberculosis (NCT06224036). In total, 52 patients with newly diagnosed TB were recruited. JDB0131 was tested in a dose escalation manner (cohort 1: 100 mg bid, cohort 2: 200 mg qd, and cohort 3: 200 mg bid). For comparison, delamanid (100 mg bid) and classic fixed-dose combination (FDC) regimens were included as controls. The primary endpoint was logarithmic changes in the number of colony formation units (CFUs) in the solid media culture of sputum TB (log10 CFU). The early bactericidal activity (EBA) of JDB0131 was better than that of delamanid. During the time interval between days 0 and 14, JDB0131 at a dose of 200 mg bid (cohort 3) showed superior efficacy over delamanid. At the end of drug intervention (day 14), JDB0131 (all 3 dose levels) achieved superior time to positivity (TTP) over delamanid. Ninety-one adverse events (AEs), including no serious AEs, were attributed to JDB0131 in 30 patients. This trial identified a promising new drug for the increasing TB burden worldwide.

Purpose: Linezolid is a core drug used to treat rifampicin-resistant tuberculosis (RR-TB) and multidrug-resistant tuberculosis (MDR-TB). However, adverse events (AEs) have limited its clinical application. Safer alternatives to linezolid are needed to address the safety concerns. Patients and Methods: A total of 27 patients with RR-TB (including MDR-TB) were randomly assigned to receive either contezolid (n=14) or linezolid (n=13) in combination with standardized background anti-TB regimens, that is, linezolid-bedaquiline (pyrazinamide)-levofloxacin (moxifloxacin)-cycloserine-clofazimine or contezolid-bedaquiline (pyrazinamide)-levofloxacin (moxifloxacin)-cycloserine-clofazimine. The dosage was 600 mg q12h for linezolid, and 800 mg q12h for contezolid. AE data were collected during the 2-month treatment period to analyze the characteristics, severity, onset time, duration, drug relatedness, management, and outcome of the adverse drug reactions. Results: The median (range) age of contezolid- and linezolid-treated patients was 40.9 (26– 65) and 36.7 (18– 65) years, respectively. The incidence of AEs was 14.3% (2/14) in contezolid-treated patients and 92.3% (12/13) in linezolid group. All drug-related AEs in contezolid group were gastrointestinal reactions (nausea and vomiting one case each). No peripheral neuropathy or myelosuppression AEs were observed. The AEs in linezolid group included anemia (30.8%, 4/13), peripheral neuropathy (53.8%, 7/13), and gastrointestinal reactions (23.1%, 3/13). Dose reduction or discontinuation was required for linezolid in 84.6% (11/13) of patients. The anti-TB efficacy of contezolid and linezolid was comparable in terms of sputum culture conversion rate and imaging-confirmed lesion absorption rate after treatment for 2 months. Conclusion: Contezolid may be a safer alternative to linezolid based on AE incidence in the treatment of multidrug-resistant tuberculosis for two months. Clinical Trial Registration: This study was registered at https://www.chictr.org.cn (identifier: ChiCTR2300074234).

Current TB treatment regimens are hindered by drug resistance, numerous adverse effects, and long treatment durations, highlighting the need for ‘me-better’ treatment regimens. Host-directed therapy (HDT) has gained recognition as a promising approach in TB treatment. It allows the repurposing of existing drugs approved for other conditions and aims to enhance the effectiveness of existing anti-TB therapies, minimize drug resistance, decrease treatment duration, and adverse effects. By modulating the host immune response, HDT ameliorates immunopathological damage and improves overall outcomes by promoting autophagy, antimicrobial peptide production, and other mechanisms. It holds promise for addressing the challenges posed by multiple and extensively drug-resistant Mycobacterium tuberculosis strains, which are increasingly difficult to treat using conventional therapies. This article reviews various HDT candidates, including repurposed drugs, explores their underlying mechanisms such as autophagy promotion and inflammation reduction, while emphasizing their potential to improve TB treatment outcomes and outlining future research directions.

Background: This study aimed to evaluate the efficacy and safety of an all-oral short-term regimen for treating multidrug-resistant tuberculosis (MDR-TB). Methods: In this semirandomized, controlled, multicenter clinical study, patients with MDR-TB who were sensitive to fluoroquinolones were assigned to treatment groups at enrollment. Patients were assigned to group C (4–6 months: bedaquiline + linezolid + clofazimine + moxifloxacin + cycloserine; 5 months: clofazimine + moxifloxacin + cycloserine) unless this protocol was unsuitable or unacceptable, in which case they were randomly assigned to group A (4–6 months: isoniazid + ethambutol + pyrazinamide + protionamide + amikacin + clofazimine + moxifloxacin; 5 months: ethambutol + pyrazinamide + clofazimine + moxifloxacin) or group B (4–6 months: isoniazid + ethambutol + pyrazinamide + protionamide + linezolid + clofazimine + moxifloxacin; 5 months: ethambutol + pyrazinamide + clofazimine + moxifloxacin). The primary outcome was the proportion of patients achieving successful outcomes. Results: From September 2020 to June 2023, 397 patients with MDR-TB were screened and 360 were enrolled. Among them, 90.3% of group C achieved good treatment outcomes, as compared with 57.1% in group A (control) and 75.0% in group B. Group C demonstrated higher sputum culture conversion and pulmonary cavity closure rates than group B, with group A showing the lowest rates. The most common adverse events were skin blackening (29.3%) and hyperuricemia (20.6%). Prolonged QT intervals were observed in 39 participants, predominantly in group C (24.3%). Conclusions: The all-oral 9- to 11-month short-term regimen shows promise as a new treatment option for MDR-TB. Incorporating bedaquiline into an orally administered regimen may improve treatment outcomes and reduce relapse rates. Despite certain limitations, these findings provide valuable insights for developing improved treatments for MDR-TB in China.

SQ109 is a promising candidate drug for the treatment of patients with drug-resistant tuberculosis (DR-TB). The purpose of this study was to investigate the activity of SQ109 against clinical isolates of Mycobacterium tuberculosis (MTB) from patients with multidrug-resistant TB (MDR-TB) and pre-extensively drug-resistant TB (pre-XDR-TB), and to explore new drug-resistant mechanisms of SQ109. We evaluated the in vitro activity of SQ109 against clinical isolates from patients with MDR-TB and pre-XDR-TB using minimal inhibitory concentration (MIC) assay. The drug-resistant gene, mmpL3 of SQ109-resistant strains was sequenced, and a quantitative real-time PCR assay was used to analyze 28 efflux pump genes in SQ109-resistant strains without mmpL3 mutations. The role of candidate efflux pumps mmpL5 and mmpL7 on the MIC of SQ109 was evaluated using recombinantly cloned MmpL5 and MmpL7 expressed in Mycobacterium smegmatis. The MIC90, MIC95 and MIC99 values of SQ109 for 225 clinical isolates of MTB were 0.25 mg/L, 0.5 mg/L and 1.0 mg/L, respectively. Among the pre-XDR strains, six showed resistance to SQ109 despite the absence of gene mutations in mmpL3. In six resistant pre-XDR strains, the MIC of SQ109 decreased with the use of an efflux pump inhibitor, and there was significant upregulation of mmpL5 and mmpL7 in two strains after exposure to SQ109. The presence of MmpL7 in Mycobacterium smegmatis resulted in decreased susceptibility to SQ109, with the MIC increasing from 16 mg/L to 32 mg/L. Our data demonstrated that SQ109 exhibited excellent levels of in vitro activity against MTB. MmpL7 may be a potential gene for MTB resistance to SQ109, providing a useful target for detecting SQ109 resistance in MTB.