Clinical characteristics and antimicrobial susceptibility profiles of Mycobacterium abscessus and Mycobacterium massiliense pulmonary infection.

INTRODUCTION: Mycobacterium abscessus complex (MABC) is the most common rapidly growing Mycobacterium species in structural pulmonary diseases and can be life-threatening. This study aimed to assess the clinical characteristics and drug susceptibility statuses of different Mycobacterium abscessus (MAB) subspecies. METHODS: DNA sequencing was used to differentiate clinical MABC subspecies isolates. The Clinical and Laboratory Standards Institute guidelines were used to determine vitro susceptibility of imipenem-relebactam, omadacycline, and other conventional antibiotics. Patient's clinical characteristics were collected and analysed. RESULTS: There were 139 M. abscessus, 39 M. massiliense, and 1 M. bolletii, accounting for 77.7%, 21.8%, and 0.5% of the MABC isolates, respectively. Patients with M. abscessus pulmonary disease (M.ab-PD) had higher proportions of older adults, tuberculosis history, chronic pulmonary disease, and malignancy than those with M. massiliense pulmonary disease (M.ma-PD). Patients with M.ab-PD had higher rates of bilateral middle- and lower-lobe involvement than patients with M.ma-PD. Both subspecies showed high resistance rates to doxycycline and moxifloxacin, and clarithromycin-induced resistance was more common in M.ab than in M.ma. Relebactam with imipenem resulted in a 2-fold reduction in the minimum inhibitory concentration (MIC) value compared to imipenem alone among MAB; furthermore, the MIC was lower in M.ab than in M.ma. Omadacycline and tigecycline had comparable in vitro susceptibility, and the MIC showed no statistically significant difference between M.ab and M.ma. CONCLUSIONS: M.ab is the most prevalent MABC subspecies in the Zhejiang Province. Patients with M.ab-PD have complex underlying diseases and broader lobar lesions. Imipenem-relebactam and omadacycline are promising antibiotics for MABC infection treatment.

Concentration of contezolid in cerebrospinal fluid and serum in a patient with tuberculous meningoencephalitis: A case report.

Central nervous system (CNS) tuberculosis (TB) is a devastating and often life-threatening disease caused by Mycobacterium tuberculosis. Contezolid, a new oxazolidinone, has demonstrated potent antimycobacterial activity in both in-vivo and in-vitro studies, with lower toxicity than linezolid. However, pharmacokinetic data are still not available for contezolid in the CNS of patients with CNS TB. This article reports the steady-state concentrations of contezolid in serum and cerebrospinal fluid (CSF) of a patient receiving contezolid as part of multi-drug treatment for tuberculous meningoencephalitis. At weeks 7 and 11 (7 h post-dose) after initiation of contezolid therapy, the serum concentrations of contezolid were 9.64 mg/L and 9.36 mg/L, respectively. In CSF, the observed concentrations of contezolid were 0.54 mg/L and 1.15 mg/L, respectively. The CSF:serum concentration ratios were 0.056 and 0.123 at weeks 7 and 11, respectively. The observed concentrations in CSF were above the minimum inhibitory concentration of contezolid against M. tuberculosis, and were close to the estimated serum unbound fraction of contezolid (10%), suggesting that unbound contezolid has high CSF permeability.

Randomized control study of the use of faropenem for treating patients with pulmonary tuberculosis.

OBJECTIVES: Faropenem has antituberculosis activity in vitro but its utility in treating patients with tuberculosis (TB) is unclear. METHODS: We conducted an open-label, randomized trial in China, involving newly diagnosed, drug-susceptible pulmonary TB. The control group was treated with the standard 6-month regimen. The experimental group replaced ethambutol with faropenem for 2 months. The primary outcome was the treatment success rate after 6 months of treatment. Noninferiority was confirmed if the lower limit of a 95% one-sided confidence interval (CI) of the difference was greater than -10%. RESULTS: A total of 227 patients eligible for the study were enrolled in the trial group and the control group in a ratio of 1:1. Baseline characteristics of participants were similar in both groups. In the modified intention-to-treat population, 88.18% of patients in the faropenem group achieved treatment success, and 85.98% of those in the control group were successfully treated, with a difference of 2.2% (95% CI, -6.73-11.13). In the per-protocol population, treatment success was 96.04% in the faropenem group and 95.83% in the control group, with a difference of 2.1% (95% CI, -5.31-5.72). The faropenem group showed noninferiority to the control group in the 6-month treatment success rates. The faropenem group had significantly fewer adverse events (P <0.01). CONCLUSIONS: Our study proved that oral faropenem regimen can be used for the treatment of TB, with fewer adverse events. (Chinese Clinical Trial Registry, ChiCTR1800015959).

Oral Bacteria Dysbiosis in Patients with Linezolid-Induced Black Hairy Tongue: A Case Series.

Linezolid-induced black hairy tongue is a self-limiting benign disease that is rare. Here, we report three patients who developed black hairy tongue after linezolid treatment. The severe dysbiosis of oral bacterial communities was observed in all these patients. Proteobacteria was the most prevalent phylum (over 90%) at the black tongue stage. Furthermore, the dramatic oral bacterial alteration took a long time to reverse after the BHT resolved.

Aortic Involvement in Disseminated Tuberculosis - Challenges Beyond the Diagnosis.

Tuberculous aortitis (TA) is a rare disease with a high mortality rate. Aortic pseudoaneurysm is the most common vascular pattern of TA, and isolated arterial wall thickening and arterial stenosis can also be seen in TA. We report two cases of disseminated tuberculosis involving the aorta with clinical improvement after treatment. One patient who had an aortic ulcer and intermural hematoma received anti-tuberculosis along with steroids therapy. The other patient, who developed a tubercular abdominal aortic pseudoaneurysm during anti-tuberculosis therapy, successfully received endovascular stent implantation. Clinicians should be aware that TA should be considered in patients with aortitis and active tuberculosis.

Prevalence trends of latent tuberculosis infection at the global, regional, and country levels from 1990-2019.

OBJECTIVES: To track the prevalence trends of latent tuberculosis infection (LTBI) at the global, regional, and national levels. METHODS: Data on the prevalence of LTBI were extracted from the Global Burden of Disease database. The average annual percent change (AAPC) was estimated by joinpoint regression and was used to evaluate the epidemic of the disease. RESULTS: Globally, the prevalence rate of LTBI decreased from 30.66% in 1990 to 23.67% in 2019, with an AAPC of -0.9%. The prevalence rate of LTBI varied from 5.02% (Jordan) to 48.35% (Uganda) in 1990 and from 2.51% (Jordan) to 43.75% (Vietnam) in 2019 at the country level. The prevalence decreased in all the six World Health Organization (WHO) regions and in most countries, with the AAPC ranging from -0.5% in the Western Pacific Region to -2.1% in the European Region and from -4.3% (Bhutan) to -0.1% (Malaysia, Myanmar, South Africa, Tokelau, and Vietnam), respectively. Disparities were also observed among different sex and age groups. CONCLUSION: The prevalence of LTBI decreased slightly worldwide in the last three decades, but the decrease is slow and not sufficient to meet the targets of WHO tuberculosis elimination. Much more effort and progress should be made in order to decrease the prevalence of LTBI.

Epidemic Trends in High Tuberculosis Burden Countries During the Last Three Decades and Feasibility of Achieving the Global Targets at the Country Level.

Objective: To estimate the epidemic trends of tuberculosis (TB) in 30 high burden countries (HBCs) over the past 30 years, which is crucial for tracking the status of disease control, especially at the country level. Methods: Annual data on incidence and mortality of TB in these 30 HBCs were extracted from the Global Burden of Disease database. The average annual percent change (AAPC) was used to evaluate the trends of incidence and mortality. The trajectory analysis was used to identify different trends among the subgroup countries. The predicted incidence and mortality rates in 2025, 2030, and 2035 were also calculated. Results: The incidence and mortality decreased in most of the HBCs. The AAPCs of incidence ranged between -4.0 (Indonesia) and -0.2% (DR Congo) (all p < 0.05). The incidence trends in Lesotho (AAPC: 0%, 95% CI: -0.4, 0.3, p = 0.8) and South Africa (AAPC: -0.2%, 95% CI: -0.5, 0, p = 0.1) were stable, and increased in Kenya with AAPC of 0.1% (95% CI: 0.1, 0.2, p < 0.05). The AAPCs for mortality ranged between -5.8 (Ethiopia) and -0.6% (Central African Republic) (all p < 0.05). The mortality trends in DPR Korea (AAPC: 0.1%, 95% CI: -0.3, 0.4, p = 0.6) and Russian Federation (AAPC: -0.5%, 95% CI: -1.9, 0.9, p = 0.5) were stable, and increased in Lesotho and Zimbabwe with AAPC of 1.3% (95% CI: 1.1, 1.4, p < 0.05) and 1.6% (95% CI: 1.0, 2.2, p < 0.05), respectively. Trajectory analysis showed that the Central African Republic, Lesotho, Cambodia, Namibia, and South Africa had higher incidences, and the Central African Republic had higher mortality. Brazil and China had relatively lower rates of incidence and mortality. Predictions showed that reduction rates of incidence and mortality could hardly be reached compared with those set for the global targets for the majority HBCs. Conclusions: The disease burden of TB has been reduced among the majority HBCs over the last three decades. According to the current control levels, achieving the ambitious global targets at the country level for these 30 HBCs is challenging.

The Application of Whole-Exome Sequencing in Patients With FUO.

BACKGROUND: Fever of unknown origin (FUO) is still a challenge for clinicians. Next-generation sequencing technologies, such as whole exome sequencing (WES), can be used to identify genetic defects in patients and assist in diagnosis. In this study, we investigated the application of WES in individuals with FUO. METHODS: We performed whole-exome sequencing on 15 FUO patients. Clinical information was extracted from the hospital information system. RESULTS: In 7/15 samples, we found positive results, including potentially causative mutations across eight different genes: CFTR, CD209, IRF2BP2, ADGRV 1, TYK2, MEFV, THBD and GATA2. CONCLUSIONS: Our results show that whole-exome sequencing can promote the genetic diagnosis and treatment of patients with FUO.

Mycobacterium Intracellulare Infection Associated with TYK2 Deficiency: A Case Report and Review of the Literature.

Individuals with genetic defects show an increased susceptibility to poorly pathogenic mycobacteria including nontuberculous mycobacteria and Bacillus Calmette-Guerin (BCG). In previous studies, defects in multiple genes were identified to be associated with mycobacterium infection including tyrosine kinase 2 (TYK2). The mutations lead to insufficient production of interferon (IFN)-γ or an insufficient response to IFN-α/ß, interleukin (IL)-6, IL-10, IL-12 and IL-23. Herein, we describe a case of Mycobacterium intracellulare infection in a male with abdominal pain and diarrhea. Whole exome sequencing of the genomes revealed a compound heterozygous mutation (c.3083A>G/c.2590C>T, p.N1028S/p.R864C) in the TYK2 gene. The patient recovered after two years of anti-mycobacterial treatment and no relapse was observed so far. We also reviewed 24 cases of mycobacterial infection associated with TYK2 deficiency which provides evidence of how personalised genomics can improve outcomes.

Profiling the mRNA and miRNA in Peripheral Blood Mononuclear Cells in Subjects with Active Tuberculosis.

PURPOSE: To identify candidate hub genes and miRNAs associated with active tuberculosis (ATB) and reveal the potential molecular mechanisms of disease progression. PATIENTS AND METHODS: The expression of mRNA and miRNA was evaluated in peripheral blood mononuclear cells (PBMC) from 4 ATB patients and 4 healthy donors (HD) using high throughput sequencing (HTS) and bioinformatics analysis. Moreover, differentially expressed miRNAs were validated with 35 ATB patients and 35 HDs using reverse transcription quantitative real-time PCR (RT-qPCR). RESULTS: A total of 2658 significantly differentially expressed genes (DEG) including 1415 up-regulated genes and 1243 down-regulated genes were identified in the ATB group compared with HDs, and the DEGs enriched in immune-related pathways, especially in TNF signaling pathway, cytokine-cytokine receptor interaction, mitogen-activated protein kinase (MAPK) signaling pathways and tuberculosis. Additionally, 10 hub genes were acquired according to protein-protein interaction (PPI) analysis of DEGs. Moreover, 26 differentially expressed miRNAs were found in ATB group compared with HDs. Furthermore, RT-qPCR results showed that hsa-miR-23a-5p (P=0.0106), hsa-miR-183-5p (P=0.0027), hsa-miR-193a-5p (P=0.0021) and hsa-miR-941(P=0.0001) were significantly increased in the ATB patients compared with HD group, and the hsa-miR-16-1-3p was significantly decreased (P=0.0032). CONCLUSION: Our research provided a characteristic profile of mRNAs and miRNAs expressed in ATB subjects, and 10 hub genes related with ATB were found, which will contribute to explore the role of miRNAs and hub genes in the pathogenesis of ATB, and improve the ability of differential diagnosis and treatment for the disease.

Risk factors for negative T-SPOT.TB assay results in patients with confirmed active tuberculosis: A retrospective study.

INTRODUCTION: The interferon-γ release assays as potent adjunct tools for the quick detection of TB in high burden countries is feasible. In this retrospective study, we aimed to identify the risk factors for negative T-SPOT results in confirmed active tuberculosis. METHODOLOGY: We consecutively enrolled 1,021 patients who were positive for acid-fast bacilli smear staining or culture-confirmed mycobacterial infection and simultaneously tested with the T-SPOT.TB assay. All of the included specimens were used to discriminate the Mycobacterium species using the biochip assay. We collected basic clinical characteristics and laboratory results for further analysis. RESULTS: Of the 1,021 patients enrolled in the study, 89 patients were identified as having nontuberculous mycobacteria (NTM). Ninety-nine patients were excluded from the analysis because of indeterminate T-SPOT.TB results, while the remaining 833 patients were identified as having Mycobacterium tuberculosis infection. In total, 159 patients had false-negative T-SPOT.TB results (19.1% of 833). The concordance rate between the T-SPOT.TB results and final diagnoses in females was always lower than that in males. Multivariate logistic regression analysis showed that female sex (OR 1.81; 95% CI 1.19, 2.7; p = 0.006), age (OR 1.02; 95% CI 1.01, 1.03; p = 0.003), acid-fast bacilli (AFB) smear-negative (OR 5.45; 95% CI 3.62, 8.19; p < 0.001), HIV coinfection (OR 6.83; 95% CI 2.73, 17.10; p < 0.001) were associated with negative T-SPOT.TB result. CONCLUSIONS: Female is another independent risk factor of negative T-SPOT.TB results, besides to elder, HIV co-infection, acid-fast bacilli (AFB) smear-negative who are suspected of having active TB infection.

Epidemic Trends of Tuberculosis in China from 1990 to 2017: Evidence from the Global Burden of Disease Study.

PURPOSE: Tuberculosis remains a major public health problem globally, especially in undeveloped countries. This study aimed to evaluate and review the long-term epidemic trends of tuberculosis in China. METHODS: Data were extracted from the Global Health Data Exchange. Metrics (prevalence, incidence and mortality) and Joinpoint regression were used to identify the epidemic trends. RESULTS: From 1990 to 2017, decreasing trends in prevalence (average annual percent change, AAPC: -0.5%, 95% CI: -0.6% to -0.5%), incidence (-3.2%, 95% CI: -3.5% to -2.9%), and mortality (-5.7%, 95% CI: -6.2% to -5.3%) of tuberculosis were observed. The incidence and mortality of multidrug-resistant tuberculosis (MDR-TB) decreased with AAPC of -2.3% (-3.1% to -1.4%) and -4.9% (-5.4% to -4.5%), respectively, while the prevalence increased with an AAPC of 1.2% (0.3% to 2.0%). The burden of extensively drug-resistant tuberculosis (XDR-TB) increased with an AAPC of 12.5% (11.9% to 13.2%) in prevalence, 7.6% (6.5% to 8.7%) in incidence, and 4.5% (3.6% to 5.4%) in mortality. The disease burden of tuberculosis increased with age and peaked among those aged over 70. CONCLUSION: The epidemic of tuberculosis decreased in China, while the disease burden was still challenging to control. MDR-TB and XDR-TB should be emphasized along with the epidemic. It will certainly be a difficult task to achieve the post-2015 global targets by 2025 and 2035.

Multicenter evaluation of the biochip assay for rapid detection of mycobacterial isolates in smear-positive specimens.

OBJECTIVES: The objective of this study was to conduct a multicentre evaluation of the performance of the biochip assay in the rapid identification of mycobacteria in smear-positive sputum specimens. METHODS: A total of 1751 sputum specimens were obtained from 7 cities in Zhejiang, China. All of the specimens were used for the discrimination of Mycobacterium species using the biochip assay, and the results were compared to the golden standard method of culture, hsp65, 16S rRNA and rpoB sequence analysis. RESULTS: In the 1751 sputum specimens, 1685 samples were cultured successfully; among these samples, 1361 were Mycobacterium tuberculosis, 323 were NTM and 1 was Nocadia farcinica. Of the 323 NTM, most of them were Mycobacterium intracellulare(52.5%) followed by Mycobacterium abscessus (20.7%), Mycobacterium avium (11.7%), Mycobacterium kansasii (9.6%) and Mycobacterium fortuitum (1.9%). The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the biochip assay to differentiate TB and NTM from AFB positive specimens were 99.8%, 99.7%, 99.9%, 99.1%, 98.8%, 1, 1, and 99.7%, respectively. The concordance between the biochip assay and mycobacterial culture for the identification of NTM species was 95.4%. CONCLUSIONS: The biochip assay is a reliable tool for the rapid identification of most mycobacteria in clinical sputum specimens. This assay can be helpful for physicians in the early diagnosis and treatment of mycobacterium infections.