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Antimicrobial Agents and Chemotherapy Jun 2024Individuals with compromised lung function and immunity are susceptible to developing chronic infection. Current treatment recommendations typically involve using one...
Individuals with compromised lung function and immunity are susceptible to developing chronic infection. Current treatment recommendations typically involve using one β-lactam antibiotic in combination with non-β-lactam antibiotics. However, a recent case study (B. Becken, K. M. Dousa, J. L. Johnson, S. M. Holland, and R. A. Bonomo, Antimicrob Agents Chemother 68:e00319-24, 2024, https://doi.org/10.1128/aac.00319-24) demonstrated successful treatment of chronic lung disease in a child using two β-lactam antibiotics simultaneously. This commentary reviews the emerging evidence and outstanding questions regarding dual β-lactam therapy for infections.
PubMed: 38837394
DOI: 10.1128/aac.00585-24 -
Tuberculosis and Respiratory Diseases Jun 2024Chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are increasingly being treated with inhaled corticosteroids (ICS). However,...
BACKGROUND
Chronic airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), are increasingly being treated with inhaled corticosteroids (ICS). However, ICSs carry potential infection risks, particularly nontuberculous mycobacteria (NTM). This study investigated the association between ICS use and NTM infection risk using national insurance data, particularly for individuals with chronic airway diseases.
METHODS
We conducted a nationwide population-based study using data from the National Health Insurance Service-National Sample Cohort in South Korea from 2002 to 2019. The cohort included 57,553 patients diagnosed with COPD or asthma. To assess the risk of NTM infection, we used Cox proportional hazards models and propensity score-based inverse probability treatment weighting (IPTW) to ensure a balanced analysis of covariates.
RESULTS
Of the 57,553 patients (mean age: 56.0 years, 43.2% male), 16.5% used ICS and 83.5% did not. We identified 63 NTM infection cases, including 9 among ICS users and 54 among non-users. Before and after IPTW, ICS use was associated with a higher risk of NTM infection (adjusted hazard ratio [HR], 4.01; 95% confidence interval [CI]: 7.48-15.58). Higher risks were significant for patients ≥65 years (adjusted HR: 6.40, 95% CI: 1.28-31.94), females (adjusted HR: 10.91, 95% CI: 2.24-53.20), never-smokers (adjusted HR: 6.31, 95% CI: 1.49-26.64), systemic steroid users (adjusted HR: 50.19, 95% CI: 8.07-312.19), and those with higher comorbidity scores (adjusted HR: 6.64, 95% CI: 1.19-37.03).
CONCLUSION
ICS use in patients with chronic airway diseases might increase the risk of NTM infection, particularly in older females, never-smokers, and systemic steroid users.
PubMed: 38835294
DOI: 10.4046/trd.2024.0038 -
Drug Discovery Today Jun 2024Tuberculosis (TB) is a significant global health threat, and cases of infection with non-tuberculous mycobacteria (NTM) causing lung disease (NTM-LD) are rising.... (Review)
Review
Tuberculosis (TB) is a significant global health threat, and cases of infection with non-tuberculous mycobacteria (NTM) causing lung disease (NTM-LD) are rising. Bacteriophages and their gene products have garnered interest as potential therapeutic options for bacterial infections. Here, we have compiled information on bacteriophages and their products that can kill Mycobacterium tuberculosis or NTM. We summarize the mechanisms whereby viable phages can access macrophage-resident bacteria and not elicit immune responses, review methodologies of pharmaceutical product development containing mycobacteriophages and their gene products, mainly lysins, in the context of drug regulatory requirements and we discuss industrially relevant methods for producing pharmaceutical products comprising mycobacteriophages, emphasizing delivery of mycobacteriophages to the lungs. We conclude with an outline of some recent case studies on mycobacteriophage therapy.
PubMed: 38830505
DOI: 10.1016/j.drudis.2024.104049 -
Journal of Clinical Tuberculosis and... Aug 2024There are different tuberculosis diagnostic tools available that detect an antigen-specific immune response. The present study aims to evaluate the potential of...
There are different tuberculosis diagnostic tools available that detect an antigen-specific immune response. The present study aims to evaluate the potential of cross-reactive responses of a CFP-10 and ESAT-6 antigen-based TB test using bioinformatics tools. The study found that the presence of the sequences coding for the CFP-10 and ESAT-6 antigens in mycobacterial genomes is not associated with their pathogenicity, and not even consistent within a single species among its strains, which can lead to either false positive or false negative test results. The data that was analyzed included genome assemblies of all available mycobacterial strains obtained from the NCBI Genome database, while the standalone BLAST and tblastn programs were utilized to detect the presence of the CFP-10 and ESAT-6 sequences. The findings revealed that a number of non-pathogenic mycobacteria contained the aforementioned sequences, while some pathogenic mycobacteria did not, indicating that a standard tuberculin skin test should be more preferable for detecting various pathogenic mycobacteria compared to antigen-specific tests. In the complex (MTBC), the proportion of positive strains varied within individual species, indicating a complex relationship. Among non-tuberculous mycobacteria (NTMB), more than half of the analyzed species did not contain these sequences which is consistent with their non-pathogenicity. Further research is necessary to fully comprehend the relationship between MTBC pathogenicity and the CFP-10 and ESAT-6 sequences. This could lead to a conclusion that a standard tuberculin skin test, although non-specific due to the undefined antigen content, may be able to detect various pathogenic mycobacteria in a more reliable manner than antigen-specific tests.
PubMed: 38828192
DOI: 10.1016/j.jctube.2024.100436 -
International Journal of Biological... Jun 2024Due to the uniqueness and essentiality of MEP pathway for the synthesis of crucial metabolites- isoprenoids, hopanoids, menaquinone etc. in mycobacterium, enzymes of...
Due to the uniqueness and essentiality of MEP pathway for the synthesis of crucial metabolites- isoprenoids, hopanoids, menaquinone etc. in mycobacterium, enzymes of this pathway are considered promising anti-tubercular drug targets. In the present study we seek to understand the consequences of downregulation of three of the essential genes- DXS, IspD, and IspF of MEP pathway using CRISPRi approach combined with transcriptomics in Mycobacterium smegmatis. Conditional knock down of either DXS or IspD or IspF gene showed strong bactericidal effect and a profound change in colony morphology. Impaired MEP pathway due to downregulation of these genes increased the susceptibility to frontline anti-tubercular drugs. Further, reduced EtBr accumulation in all the knock down strains in the presence and absence of efflux inhibitor indicated altered cell wall topology. Subsequently, transcriptional analysis validated by qRT-PCR of +154DXS, +128IspD, +104IspF strains showed that modifying the expression of these MEP pathway enzymes affects the regulation of mycobacterial core components. Among the DEGs, expression of small and large ribosomal binding proteins (rpsL, rpsJ, rplN, rplX, rplM, rplS, etc), essential protein translocases (secE, secY and infA, infC), transcriptional regulator (CarD and SigB) and metabolic enzymes (acpP, hydA, ald and fabD) were significantly depleted causing the bactericidal effect. However, mycobacteria survived under these damaging conditions by upregulating mostly the genes needed for the repair of DNA damage (DNA polymerase IV, dinB), synthesis of essential metabolites (serB, LeuA, atpD) and those strengthening the cell wall integrity (otsA, murA, D-alanyl-D-alanine dipeptidase etc.).
Topics: Bacterial Proteins; Mycobacterium smegmatis; Gene Expression Regulation, Bacterial; Antitubercular Agents; Microbial Viability; Metabolic Networks and Pathways
PubMed: 38823743
DOI: 10.1016/j.ijbiomac.2024.132727 -
International Journal of Infectious... May 2024Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune...
Clinical features and treatment outcomes of bone and joint nontuberculous mycobacterial infections according to immune status: a 9-year retrospective observational cohort.
OBJECTIVES
Nontuberculous mycobacteria (NTM) bone and joint infections (BJIs) are uncommon. We evaluated the characteristics of BJIs and identified differences according to immune status.
METHODS
We performed a multicenter retrospective study in France involving patients with documented NTM BJI over a 9-year period. We collected the clinical and microbiological characteristics, management, and clinical outcomes of the patients.
RESULTS
Overall, 95 patients were included, of whom 50.5% (48/95) were immunosuppressed. Tenosynovitis was more frequent in the immunocompetent group, and native arthritis more common in the immunosuppressed group. Mycobacerium marinum and M. abscessus complex were significantly more frequent in the immunocompetent group, and M. avium and M. xenopi were significantly more frequent in the immunosuppressed group. The combination of antibiotherapy with surgery tended to be more frequent in the immunocompetent than the immunosuppressed group (63.8% (30/47) vs 47.8% (22/46), respectively); of the latter, 45.7% (21/46) received antimicrobial therapy alone, a higher frequency than in the immunocompetent group (23.4%, 11/47). The median duration of antimicrobial treatment was similar in the two groups (11 months). Mortality was significantly higher in the immunosuppressed group.
CONCLUSIONS
Although the clinical presentations and the NTM species involved in BJI differed according to immune status, most recovered completely after treatment.
PubMed: 38823623
DOI: 10.1016/j.ijid.2024.107122 -
International Journal of Infectious... May 2024Non-tuberculous mycobacteria (NTM) frequently colonize the airways of patients with bronchiectasis; however, there has been limited research into airway microbiota...
OBJECTIVES
Non-tuberculous mycobacteria (NTM) frequently colonize the airways of patients with bronchiectasis; however, there has been limited research into airway microbiota composition and predisposing factors for NTM detection during acute bronchiectasis exacerbations.
METHODS
This study enrolled 34 patients with bronchiectasis experiencing acute exacerbations. Metagenomic next-generation sequencing was used to detect microbiota in bronchoalveolar lavage fluid (BALF), and bioinformatics methods were used for the comparative analysis of meaningful microbiota in the BALF of patients with acute exacerbations of bronchiectasis. A correlation analysis was conducted to identify susceptibility factors for NTM in patients with bronchiectasis.
RESULTS
Compared with patients with community-acquired pneumonia, patients with bronchiectasis had higher detection rates of NTM (38.2%), Pseudomonas aeruginosa, and Haemophilus influenzae. Patients with NTM-positive bronchiectasis had lower body mass index and lipid profiles than patients who were NTM-negative. Metagenomic next-generation sequencing of BALF revealed patients who were NTM-positive had increased relative abundance of Rothia and other anaerobic genera compared with patients who were NTM-negative. Patients who were NTM-positive also showed higher levels of Streptococcus parasanguinis at the species level. Elevated Rothia mucilaginosa and S. parasanguinis correlated with decreased percentages of clusters of differentiation 3+ T lymphocytes and clusters of differentiation 3+ T-cell subgroups in peripheral blood.
CONCLUSIONS
NTM colonization increases the risk of acute bronchiectasis exacerbations. Low body mass index, lipid levels, and isolation of R. mucilaginosa and S. parasanguinis in BALF are susceptibility factors for NTM colonization in patients with bronchiectasis.
PubMed: 38821186
DOI: 10.1016/j.ijid.2024.107120 -
Therapeutic Advances in Respiratory... 2024Ukraine remains a high World Health Organization priority country for drug-resistant tuberculosis (TB). Rifampicin-resistant TB (RR-TB) has a more protracted, more... (Observational Study)
Observational Study
Impact of line probe assay-based molecular testing on individualized treatment in patients with rifampicin-resistant tuberculosis: data from the prospective INNOVA4TB cohort study in Ukraine.
BACKGROUND
Ukraine remains a high World Health Organization priority country for drug-resistant tuberculosis (TB). Rifampicin-resistant TB (RR-TB) has a more protracted, more complicated, and more expensive treatment. In 2021, Ukraine reported 4025 RR-TB cases - 5.4 times more (751) than all 30 European Union/ European Economic Area countries together.
OBJECTIVES
The objective of the study was to determine the diagnostic accuracy of line probe assay (LPA), AID Autoimmun Diagnostika GmbH, for detecting resistance to anti-TB drugs and its clinical application for selecting treatment regimens.
DESIGN
A prospective observational cohort study.
METHODS
From May 2019 to June 2020, we consecutively enrolled patients with active TB hospitalized at the Regional Phthisiopulmonology Center (Vinnytsia, Ukraine), aged between 18 and 82 years. The LPA was performed in the Genetic Research Laboratory at National Pirogov Memorial Medical University, Vinnytsia, Ukraine.
RESULTS
A total of 84 clinical specimens and 97 culture isolates from 126 TB patients were tested during the study. Accuracy (95% confidence interval) of LPA for clinical samples in comparison with phenotypic drug susceptibility test (DST) was 80.1 (68.5-89.0) for isoniazid (H), 74.7 (62.4-84.6) for rifampicin (R), 74.4 (62.5-84.1) for ethambutol, 71.4 (41.9-91.6) for streptomycin, 84.6 (62.4-96.5) for prothionamide/ethionamide, and 84.6 (73.6-92.3) for levofloxacin (Lfx), respectively. We found a significantly higher sensitivity of LPA for H, R, and Lfx for the culture isolates compared to clinical specimens ( < 0.05). LPA detected different mutations in 6 out of 17 (35.5%) patients susceptible to R by Xpert. A shorter treatment regimen with an injectable agent demonstrated a low suitability rate of 5% (8/156) in a cohort of RR-TB patients from Ukraine.
CONCLUSION
Initial LPA testing accurately identifies resistance to anti-TB drugs and facilitates the selection of an appropriate treatment regimen, minimizing exposure to empirical therapy.
Topics: Humans; Prospective Studies; Adult; Ukraine; Rifampin; Male; Middle Aged; Tuberculosis, Multidrug-Resistant; Female; Mycobacterium tuberculosis; Young Adult; Aged; Adolescent; Antitubercular Agents; Microbial Sensitivity Tests; Aged, 80 and over; Antibiotics, Antitubercular; Predictive Value of Tests; Precision Medicine; Reproducibility of Results
PubMed: 38817020
DOI: 10.1177/17534666241249841 -
Cureus Apr 2024Mycobacterium avium complex (MAC) is often observed in immunocompromised individuals. However, when pulmonary MAC infection occurs in immunocompetent individuals,...
Mycobacterium avium complex (MAC) is often observed in immunocompromised individuals. However, when pulmonary MAC infection occurs in immunocompetent individuals, particularly elderly females, characteristically involving the middle lobe and lingula lobe of the lung, it is known as Lady Windermere syndrome (LWS). A 64-year-old female patient with no significant comorbidities presented with a history of low-grade intermittent fever and dry cough for one-month duration complicated with hemoptysis for two days. Her initial investigations and imaging were negative, except for the high-resolution CT (HRCT) finding of bronchiectasis involving the middle lobe and lingula lobe suggestive of MAC infection, which was further confirmed by positive sputum culture for MAC. LWS is a condition that is rarely encountered in clinical settings and seldom described in the literature. Especially in resource-limited settings, arriving at a diagnosis is further hindered by the scarce availability of advanced imaging such as HRCT. In clinical settings where pulmonary tuberculosis is endemic, the differentiation of the two conditions is of paramount importance as the treatment regimens for the two conditions are quite different.
PubMed: 38813313
DOI: 10.7759/cureus.59272 -
International Journal of Systematic and... May 2024A rapidly growing nontuberculous mycobacterium was isolated from diseased koi carp in Niigata, Japan, which was identified as representing a novel species through whole...
A rapidly growing nontuberculous mycobacterium was isolated from diseased koi carp in Niigata, Japan, which was identified as representing a novel species through whole genome sequence analysis. The bacterial isolates (NGTWS0302, NGTWS1803 and NGTWSNA01) were found to belong to the genus through phylogenetic analysis using whole genome sequences of mycobacteria species. The bacterial colony was smooth, moist and non-chromogenic on 1% Ogawa medium at 30 °C. In biochemical characteristic tests, the bacterial isolates showed positive reactions for catalase activity, Tween 80 hydrolysis and tellurite reduction. The isolates were sensitive to 2-4 µg ml ampicillin, kanamycin and rifampicin. Based on these results, we propose a novel species, sp. nov. The type strain is NGTWS1803 (=JCM 35117=ATCC TSD-289).
Topics: Animals; Phylogeny; Carps; Japan; Bacterial Typing Techniques; DNA, Bacterial; RNA, Ribosomal, 16S; Sequence Analysis, DNA; Fish Diseases; Anti-Bacterial Agents; Fatty Acids; Microbial Sensitivity Tests; Whole Genome Sequencing; Base Composition
PubMed: 38809248
DOI: 10.1099/ijsem.0.006404