New generation fluoroquinolone sitafloxacin could potentially overcome the majority levofloxacin and moxifloxacin resistance in multidrug-resistant Mycobacterium tuberculosis.

Introduction. Pre-existing fluoroquinolones (FQs) resistance is a major threat in treating multidrug-resistant (MDR) tuberculosis. Sitafloxacin (Sfx) is a new broad-spectrum FQ.Hypothesis. Sfx is more active against drug-resistant Mycobacterium tuberculosis (Mtb) isolates.Aim. To determine whether there is cross-resistance between Sfx and ofloxacin (Ofx), levofloxacin (Lfx) and moxifloxacin (Mfx) in MDR Mtb.Methods. A total of 106 clinical Mtb isolates, including 23 pan-susceptible and 83 MDR strains, were analysed for Sfx, Lfx and Mfx resistance using MIC assay. The isolates were also subjected to whole-genome sequencing to analyse drug-resistant genes.Results. Sfx exhibited the most robust inhibition activity against Mtb clinical isolates, with a MIC50 of 0.0313 µg ml-1 and MIC90 of 0.125 µg ml-1, which was lower than that of Mfx (MIC50 = 0.0625 µg ml-1, MIC90 = 1 µg ml-1) and Lfx (MIC50 = 0.125 µg ml-1, MIC90 = 2 µg ml-1). We determined the tentative epidemiological cut-off values as 0.5 µg ml-1 for Sfx. Also, 8.43% (7/83), 43.37% (36/83), 42.17% (35/83) and 51.81% (43/83) MDR strains were resistant to Sfx, Mfx, Lfx and Ofx, respectively. Cross-resistance between Ofx, Lfx and Mfx was 80.43% (37/46). Only 15.22% (7/46) of the pre-existing FQs resistance isolates were resistant to Sfx. Among the 30 isolates with mutations in gyrA or gyrB, 5 (16.67%) were Sfx resistant. The combination of Sfx and rifampicin could exert partial synergistic effects, and no antagonism between Sfx and six clinically important anti-Mtb antibiotics was evident.Conclusion. Sfx exhibited superior activity against MDR isolates comparing to Lfx and Mfx, and could potentially overcome the majority pre-existing FQs resistance in Mtb strains.

In vitro activity of tubercidin against Mycobacterium tuberculosis and nontuberculosis Mycobacteria.

Tubercidin is an adenosine analogue that has been shown to exhibit good activity against some tumours and parasites. In this study, the in vitro activity of tubercidin was evaluated against Mycobacterium tuberculosis (Mtb) and nontuberculosis Mycobacteria (NTM). For determining the MICs of tubercidin, 23 fully drug-sensitive (DS) Mtb strains, 33 multi-drug resistance tuberculosis (MDR-TB) strains, 29 pre-extensively drug-resistant tuberculosis (pre-XDR-TB) strains, 21 extensively drug-resistant tuberculosis (XDR-TB) strains, 17 rapidly growing mycobacteria (RGM) and nine slowly growing mycobacteria (SGM) references strains were tested by microplate-based Alamar Blue assay (MABA) method. The results indicate that tubercidin has high in vitro activity against some drug-resistance Mtb strains and NTM reference strains, which warrants further investigation on the actions of tubercidin and its derivatives as potential drugs for mycobacterial infections.

An anti-LpqH human monoclonal antibody from an asymptomatic individual mediates protection against Mycobacterium tuberculosis.

Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (Mtb). Whilst a functional role for humoral immunity in Mtb protection remains poorly defined, previous studies have suggested that antibodies can contribute towards host defense. Thus, identifying the critical components in the antibody repertoires from immune, chronically exposed, healthy individuals represents an approach for identifying new determinants for natural protection. In this study, we performed a thorough analysis of the IgG/IgA memory B cell repertoire from occupationally exposed, immune volunteers. We detail the identification and selection of a human monoclonal antibody that exhibits protective activity in vivo and show that it targets a virulence factor LpqH. Intriguingly, protection in both human ex vivo and murine challenge experiments was isotype dependent, with most robust protection being mediated via IgG2 and IgA. These data have important implications for our understanding of natural mucosal immunity for Mtb and highlight a new target for future vaccine development.

Single-cell profiling reveals distinct immune response landscapes in tuberculous pleural effusion and non-TPE.

Background: Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and remains a major health threat worldwide. However, a detailed understanding of the immune cells and inflammatory mediators in Mtb-infected tissues is still lacking. Tuberculous pleural effusion (TPE), which is characterized by an influx of immune cells to the pleural space, is thus a suitable platform for dissecting complex tissue responses to Mtb infection. Methods: We employed singe-cell RNA sequencing to 10 pleural fluid (PF) samples from 6 patients with TPE and 4 non-TPEs including 2 samples from patients with TSPE (transudative pleural effusion) and 2 samples with MPE (malignant pleural effusion). Result: Compared to TSPE and MPE, TPE displayed obvious difference in the abundance of major cell types (e.g., NK, CD4+T, Macrophages), which showed notable associations with disease type. Further analyses revealed that the CD4 lymphocyte population in TPE favored a Th1 and Th17 response. Tumor necrosis factors (TNF)-, and XIAP related factor 1 (XAF1)-pathways induced T cell apoptosis in patients with TPE. Immune exhaustion in NK cells was an important feature in TPE. Myeloid cells in TPE displayed stronger functional capacity for phagocytosis, antigen presentation and IFN-γ response, than TSPE and MPE. Systemic elevation of inflammatory response genes and pro-inflammatory cytokines were mainly driven by macrophages in patients with TPE. Conclusion: We provide a tissue immune landscape of PF immune cells, and revealed a distinct local immune response in TPE and non-TPE (TSPE and MPE). These findings will improve our understanding of local TB immunopathogenesis and provide potential targets for TB therapy.

The species distribution and antimicrobial resistance profiles of Nocardia species in China: A systematic review and meta-analysis.

BACKGROUND: Nocardia species can cause local or disseminated infection. Prompt diagnosis and appropriate treatment of nocardiosis are required, because it can cause significant morbidity and mortality. Knowledge of local species distribution and susceptibility patterns is important to appropriate empiric therapy. However, knowledge on the epidemiology and antimicrobial susceptibility profiles of clinical Nocardia species remains limited in China. METHODS: The data of isolation of Nocardia species were collected from databases such as Pubmed, Web of Science, Embase as well as Chinese databases (CNKI, Wanfang and VIP). Meta-analysis was performed using RevMan 5.3 software. Random effect models were used and tested with Cochran's Q and I2 statistics taking into account the possibility of heterogeneity between studies. RESULTS: In total, 791 Nocardia isolates were identified to 19 species levels among all the recruited studies. The most common species were N. farcinica (29.1%, 230/791), followed by N. cyriacigeorgica (25.3%, 200/791), N. brasiliensis (11.8%, 93/791) and N. otitidiscaviarum (7.8%, 62/791). N. farcinica and N. cyriacigeorgica were widely distributed, N. brasiliensis mainly prevalent in the south, N. otitidiscaviarum mainly distributed in the eastern coastal provinces of China. Totally, 70.4% (223/317) Nocardia were cultured from respiratory tract specimens, 16.4% (52/317) from extra-pulmonary specimens, and 13.3% (42/317) from disseminated infection. The proportion of susceptible isolates as follows: linezolid 99.5% (197/198), amikacin 96.0% (190/198), trimethoprim-sulfamethoxazole 92.9% (184/198), imipenem 64.7% (128/198). Susceptibility varied by species of Nocardia. CONCLUSIONS: N. farcinica and N. cyriacigeorgica are the most frequently isolated species, which are widely distributed in China. Pulmonary nocardiosis is the most common type of infection. Trimethoprim-sulfamethoxazole can still be the preferred agent for initial Nocardia infection therapy due to the low resistance rate, linezolid and amikacin could be an alternative to treat nocardiosis or a choice in a combination regimen.

Trends and Species Diversity of Non-tuberculous Mycobacteria Isolated From Respiratory Samples in Northern China, 2014-2021.

Background: Pulmonary non-tuberculous mycobacteria (NTM) infection has become a public health concern in China and around the world. The objective of this study was to describe the longitudinal changes in the frequency and diversity of NTM in northern China. Methods: We retrospectively analyzed data on mycobacterium species in Beijing Chest Hospital from January 2014 to December 2021. The isolates were identified to species level by targeted DNA sequencing. Results: After excluding duplicates, 1,755 NTM strains were analyzed, which were from 27 provinces in China over 8 years. Among all mycobacteria, the proportion of NTM increased each year, from 4.24% in 2014 to 12.68% in 2021. Overall, 39 different NTM species were identified, including 23 slow growing mycobacteria (SGM) and 16 rapid growing mycobacteria (RGM). The most common species were M. intracellulare (51.62%), M. abscessus (22.22%), M. kansasii (8.32%), M. avium (7.75%) and M. fortuitum (2.05%). The number of NTM species identified also increased each year from 9 in 2014 to 26 in 2021. Most species showed stable isolation rates over the years; however, the proportion of M. avium increased from 3.85 to 10.42% during the study period. Besides, 81 non-mycobacteria strains, including Gordonia (21 isolates), Nocardia (19 isolates) and Tsukamurella (17 isolates), etc., were also discovered. Conclusion: The proportion of NTM and species diversity increased considerably in northern China from 2014 to 2021. M. intracellulare was the most common NTM isolated among respiratory specimens, followed by M. abscessus and M. kansasii. Rare NTM species and non-mycobacteria pathogens also need attention.

In vitro activity of fidaxomicin against nontuberculosis mycobacteria.

Introduction. Nontuberculous mycobacteria (NTM) infections are increasing worldwide and are relatively resistant to many of the first- and second-line drugs to treat tuberculosis. Macrolide antibiotics, such as clarithromycin and azithromycin, are the key drugs for treating NTM infections. Fidaxomicin is a macrolide antibiotic that is widely used in treating Clostridium difficle (C.difficile) infections, and has high in vitro activity against Mycobacterium tuberculosis especially multidrug-resistant tuberculosis (MDR-TB) and has no cross-resistance with rifampicin.Hypothesis. Fidaxomicin may have in vitro activity against NTM strains.Aim. To find that whether the macrolide antibiotic fidaxomicin has in vitro activity against NTM strains.Methodology. Fidaxomicin used in this study was firstly tested on C. difficile reference strains and has shown to be effective and workable. And then 28 rapidly growing mycobacteria (RGM), 12 slowly growing mycobacteria (SGM) reference strains and 103 NTM clinical isolates were tested by the microplate-based AlamarBlue assay (MABA) method to determine the MICs. Fidaxomicin, rifampicin and clarithromycin were tested against M. abcessus complex subspecies 14 M. abscessus and 5 M. massiliense strains for inducible resistance determination.Results. In total, 21 out of 28 RGM and 9 of 12 SGM reference strains have the MICs of fidaxomicin at or below 1 µg ml-1. Fidaxomicin also showed low MIC values for some clinical isolates including M. abscessus complex, M. avium complex, M. fortuitum, M. kansasii and M. parascrofulaceum. Fidaxomicin also has no inducible macrolide resistance in M. abscessus complex in comparison with clarithromycin.Conclusion. Fidaxomicin has high in vitro activity against most of the NTM reference strains and some prevalent NTM clinical isolates. This promising finding warrants further investigation on the actions of fidaxomicn in vivo and as a potential antibiotic for NTM treatment.

Extremely high levels of central nervous system involvement in miliary tuberculosis.

BACKGROUND: Miliary tuberculosis (TB) is one of the severest manifestations of TB that can be lethal when concomitant with the central nervous system (CNS) involvement. Bacteriological, biochemical and radiological methods for find CNS comorbidity in miliary TB was evaluated in this study. METHODS: Consecutive miliary TB adults were retrospectively enrolled from two designated TB hospitals in China. The capacities of examinations of cerebrospinal fluid (CSF), cerebral computed tomography (CT) and magnetic resonance imaging (MRI) for diagnosis of CNS involvement were assessed. RESULTS: Assessment of CNS involvement with a lumbar puncture and/or neuroimaging was undertaken in 282 out of 392 of acute miliary TB. Of these 282 patients, 87.59% (247/282) had CNS involvement. Cerebral contrast-enhanced MRI (96.05%, 170/177) and MRI (93.15%, 204/219) yielded significantly higher sensitivities over CSF examination (71.92%, 146/203, P < 0.001) and CT (34.69%, 17/49, P < 0.001). The sensitivity of CSF examination was superior to CT scan (P < 0.001). Although 59.65% (134/225) miliary TB patients acquired bacteriological evidence with sputum examination, the positivity was only 8.82% (21/238) for CSF examination by conventional and molecular tests. CONCLUSION: Almost all miliary TB had CNS involvement and MRI demonstrated outstanding potential over other methods. Therefore, a routinely screening of CNS TB should be strongly suggested in miliary TB and MRI could be used as the initial approach in resources rich settings.

Fidaxomicin has high in vitro activity against Mycobacterium tuberculosis.

This study aimed to evaluate whether the antibiotic fidaxomicin has in vitro activity against Mycobacterium tuberculosis (Mtb). 38 fully drug-sensitive Mtb strains and 34 multidrug-resistant tuberculosis (MDR-TB) strains were tested using the microplate alamar blue assay (MABA) method to determine the minimum inhibitory concentrations (MICs) for fidaxomicin and rifampicin. Fidaxomicin has high in vitro activity against Mtb and is a potential drug to treat Mtb, and MDR-TB infections in particular.

An overview of advanced reduction processes for bromate removal from drinking water: Reducing agents, activation methods, applications and mechanisms.

Bromate (BrO3-) is a possible human carcinogen regulated at a strict standard of 10µg/L in drinking water. Various techniques to eliminate BrO3- usually fall into three main categories: reducing bromide (Br-) prior to formation of BrO3-, minimizing BrO3- formation during the ozonation process, and removing BrO3- from post-ozonation waters. However, the first two approaches exhibit low degradation efficiency and high treatment cost. The third workaround has obvious advantages, such as high reduction efficiency, more stable performance and easier combination with UV disinfection, and has therefore been widely implemented in water treatment. Recently, advanced reduction processes (ARPs), the photocatalysis of BrO3-, have attracted much attention due to improved performance. To increase the feasibility of photocatalytic systems, the focus of this work concerns new technological developments, followed by a summary of reducing agents, activation methods, operational parameters, and applications. The reaction mechanisms of two typical processes involving UV/sulfite homogeneous photocatalysis and UV/titanium dioxide heterogeneous photocatalysis are further summarized. The future research needs for ARPs to reach full-scale potential in drinking water treatment are suggested accordingly.