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In Mycobacterium tuberculosis (MTB) control, whole genome sequencing-based molecular drug susceptibility testing (molDST-WGS) has emerged as a pivotal tool. However, the current reliance on a single-strain reference limits molDST-WGS's true potential. To address this, we introduce a new pan-lineage reference genome, 'MtbRf'. We assembled 'unmapped' reads from 3,614 MTB genomes (751 L1; 881 L2; 1,700 L3; and 282 L4) into 35 shared, annotated contigs (54 coding sequences [CDSs]). We constructed MtbRf through: (1) searching for contig homologues among genome database that precipitate results uniquely within Mycobacteria genus; (2) comparing genomes with H37Rv ('lift-over') to define 18 insertions; and (3) filling gaps in H37Rv with insertions. MtbRf adds 1.18% sequences to H37rv, salvaging >60% of previously unmapped reads. Transcriptomics confirmed gene expression of new CDSs. The new variants provided a moderate DST predictive value (AUROC 0.60–0.75). MtbRf thus unveils previously hidden genomic information and lays the foundation for lineage-specific molDST-WGS. [ABSTRACT FROM AUTHOR]

Rationale: The clinical implications of trehalose 6,6′-dimycolate (TDM) in nontuberculous mycobacterial pulmonary disease have not been studied. Objectives: To examine the presence of TDM in clinical isolates obtained from patients with Mycobacterium avium complex (MAC) pulmonary disease (PD) and its impact on disease severity and treatment outcomes. Methods: We analyzed clinical isolates from patients with diagnoses of MAC PD at Seoul National University Hospital between January 1, 2019, and December 31, 2021. The lipids were extracted from clinical isolates obtained at the time of diagnosis using mass spectrometry. Mass peaks between 300 and 3,500 m/z were obtained, and the peak patterns of the total lipids were analyzed. Results: TDM was identified in clinical isolates from 176 of 343 patients. Cavities were more prevalent in patients with TDM-negative isolates (19.8%) than in those with TDM-positive isolates (10.2%) (P = 0.015). The time to antibiotic treatment was shorter in patients with TDM-negative isolates (4 mo [interquartile range, 2–10 mo]) than in those with TDM-positive isolates (7 mo [interquartile range, 3–16 mo]) (P = 0.032). Patients with TDM-negative isolates had a significantly lower proportion of culture conversions (P = 0.012). TDM was associated with higher likelihood of culture conversion (adjusted hazard ratio, 2.29; P = 0.035). Conclusions: TDM-negative isolates were linked to a higher occurrence of cavities, earlier initiation of treatment, and worse treatment outcome in patients with MAC PD. [ABSTRACT FROM AUTHOR]

Background Improving health-related quality of life (HRQOL) has emerged as a priority in the management of nontuberculous mycobacterial pulmonary disease (NTM-PD). We aimed to evaluate HRQOL and its changes after 6 months' treatment in patients with NTM-PD. Methods The NTM-KOREA is a nationwide prospective cohort enrolling patients initiating treatment for NTM-PD in 8 institutions across South Korea. We conducted the Quality of Life–Bronchiectasis (QOL-B) at 6-month intervals and evaluated baseline scores (higher scores indicate better quality of life) and changes after 6 months' treatment. Multivariate logistic regression was performed to identify factors associated with improvement in the QOL-B physical functioning and respiratory symptoms domains. Results Between February 2022 and August 2023, 411 patients were included in the analysis. Baseline scores (95% confidence interval [CI]) for physical functioning and respiratory symptoms were 66.7 (46.7–86.7) and 81.5 (70.4–92.6), respectively. Among 228 patients who completed the QOL-B after 6 months' treatment, improvements in physical functioning and respiratory symptoms were observed in 61 (26.8%) and 71 (31.1%) patients, respectively. A lower score (adjusted odds ratio; 95% CI) for physical functioning (0.93; 0.91–0.96) and respiratory symptoms (0.92; 0.89–0.95) at treatment initiation was associated with a greater likelihood of physical functioning and respiratory symptom improvement, respectively; achieving culture conversion was not associated with improvement in physical functioning (0.62; 0.28–1.39) or respiratory symptoms (1.30; 0.62–2.74). Conclusions After 6 months of antibiotic treatment for NTM-PD, HRQOL improved in almost one-third, especially in patients with severe initial symptoms, regardless of culture conversion. Clinical Trials Registration ClinicalTrials.gov identifier: NCT03934034. [ABSTRACT FROM AUTHOR]

The article discusses the diagnosis of a disseminated infection caused by Mycobacterium avium subspecies avium (MAA) in a 57-year-old male Asian elephant at the Seoul Zoo, Gyeonggi, South Korea. Polymerase chain reaction-restriction enzyme polymorphism analysis (PCR-RFLP) of the genes was performed from multiple organs and cultured bacteria to confirm mycobacterial infection. In addition, the elephant may have become infected through contamination of soil and feed by free-living birds infected with MAA.

The global incidence of Mycobacterium abscessus (Mabc), a rapidly growing nontuberculous mycobacterial strain that causes treatment-refractory pulmonary diseases, is increasing. Despite this, the host factors that allow for protection against infection are largely unknown. In this study, we found that sirtuin 3 (SIRT3), a mitochondrial protein deacetylase, plays a critical role in host defense against Mabc infection. Mabc decreased SIRT3 and upregulated mitochondrial oxidative stress in macrophages. SIRT3 deficiency led to increased bacterial loads, histopathological and mitochondrial damage, and pathological inflammation during Mabc infection. Administration of scavengers of mitochondrial reactive oxygen species significantly decreased the in vivo Mabc burden and excessive inflammation, and induced SIRT3 expression in infected lungs. Notably, SIRT3 agonist (resveratrol) significantly decreased Mabc growth and attenuated inflammation in mice and zebrafishes, indicating the key role for SIRT3 in metazoan host defense. Collectively, these data strongly suggest that SIRT3 is a host-directed therapeutic target against Mabc infection by controlling mitochondrial homeostasis. [ABSTRACT FROM AUTHOR]

Background: Mycobacterium avium complex pulmonary disease (MAC-PD) is a chronic lung condition with rapidly increasing prevalence worldwide. Macrolides like azithromycin and clarithromycin are the backbone of long-term antibiotic therapy for progressive MAC-PD. The impact of minimum inhibitory concentrations (MICs), especially within the susceptible range, for macrolides on treatment responses remains unclear., Methods: We analyzed adult patients who started treatment for MAC-PD between 1 March 2009 and 1 March 2022 at Seoul National University Hospital. Patients were categorized into four groups according to the clarithromycin MICs of their causative strains at treatment initiation. Logistic regression was employed to evaluate the impact of clarithromycin MICs on the microbiological cure rate. Companion drugs and their MICs, alongside clinical characteristics like age, sex, body mass index, cavity presence, acid-fast bacilli smear positivity, causative species, and erythrocyte sedimentation rate were adjusted in multivariable analysis., Results: Four-hundred thirty-six patients (median age, 65 years; 34% men) were included. Microbiological cure rates were 51.8%, 51.9%, 50.0%, and 18.2% for patients with clarithromycin MICs ≤0.5, 1-2, 4-8, and ≥32 µg/mL, respectively (P=0.181). No significant differences in microbiological cure rates were observed across varying levels of clarithromycin MICs within the susceptible range (≤8 µg/mL). Relative to patients with clarithromycin-susceptible strains, patients with MICs ≥32 µg/mL had an odds ratio of 0.25 for achieving microbiological cure (95% confidence interval, 0.06-1.07; P=0.06)., Conclusions: Treatment responses were comparable among patients with strains having clarithromycin MICs within the susceptible range, but were likely to be worse for patients with strains having MICs ≥32 µg/mL., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: This study aimed to determine whether a shorter high-dose rifampicin regimen is non-inferior to the standard 6-month tuberculosis regimen., Method: This multicenter, randomized, open-label, non-inferiority trial enrolled participants with respiratory specimen positivity by Xpert MTB/RIF assay or Mycobacterium tuberculosis culture without rifampicin-resistance. Participants were randomized at 1:1 to the investigational or control group. The investigational group received high-dose rifampicin (30 mg/kg/day), isoniazid, and pyrazinamide until culture conversion, followed by high-dose rifampicin and isoniazid for 12 weeks. The control group received the standard 6-month regimen. The primary outcome was the rate of unfavorable outcomes at 18 months post-randomization. The non-inferiority margin was set at <6% difference in unfavorable outcomes rates., Results: Between 4 November 2020 and 3 January 2022, 76 participants were enrolled. Of these, 58 were included in the modified intention-to-treat analysis. Unfavorable outcomes occurred in 10 (31.3%) of 32 in the control group and 10 (38.5%) of 26 in the investigational group. The difference was 7.2% (95% confidence interval, ∞ to 31.9%), failing to prove non-inferiority. Serious adverse events and grade 3 or higher adverse events did not differ between the groups., Conclusions: The shorter high-dose rifampicin regimen failed to demonstrate non-inferiority but had an acceptable safety profile. Trial registration ClinicalTrials.gov NCT04485156.

Although the incidence of Mycobacterium abscessus infection has recently increased significantly, treatment is difficult because this bacterium is resistant to most anti-tuberculosis drugs. In particular, M. abscessus is often resistant to available macrolide antibiotics, so therapeutic options are extremely limited. Hence, there is a pressing demand to create effective drugs or therapeutic regimens for M. abscessus infections. The aim of the investigation was to assess the capability of isoegomaketone (iEMK) as a therapeutic option for treating M. abscessus infections. We determined the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of iEMK for both reference and clinically isolated M. abscessus strains. In addition to time-kill and biofilm formation assays, we evaluated iEMK's capability to inhibit M. abscessus growth in macrophages using an intracellular colony counting assay. iEMK inhibited the growth of reference and clinically isolated M. abscessus strains in macrophages and demonstrated effectiveness at lower concentrations against macrophage-infected M. abscessus than when used to treat the bacteria directly. Importantly, iEMK also exhibited anti-biofilm properties and the potential to mitigate macrolide-inducible resistance, underscoring its promise as a standalone or adjunctive therapeutic agent. Overall, our results suggest that further development of iEMK as a clinical drug candidate is promising for inhibiting M. abscessus growth, especially considering its dual action against both planktonic bacteria and biofilms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kim, Lee, Yu, Yoon, Kang, Lee, Park, Lee, Whang and Kim.)

A novel duplex PCR method based on variable-number tandem-repeat targets to discriminate among Mycobacterium abscessus complex isolates was developed and evaluated in 85 clinical isolates. The assay accuracy was confirmed by a multiple-target sequence analysis. The duplex PCR assay is a one-step, reliable, and accurate assay for discriminating M. abscessus species.