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Cell Nov 2023Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse...
Mycobacterium tuberculosis (Mtb) cultured axenically without detergent forms biofilm-like cords, a clinical identifier of virulence. In lung-on-chip (LoC) and mouse models, cords in alveolar cells contribute to suppression of innate immune signaling via nuclear compression. Thereafter, extracellular cords cause contact-dependent phagocyte death but grow intercellularly between epithelial cells. The absence of these mechanopathological mechanisms explains the greater proportion of alveolar lesions with increased immune infiltration and dissemination defects in cording-deficient Mtb infections. Compression of Mtb lipid monolayers induces a phase transition that enables mechanical energy storage. Agent-based simulations demonstrate that the increased energy storage capacity is sufficient for the formation of cords that maintain structural integrity despite mechanical perturbation. Bacteria in cords remain translationally active despite antibiotic exposure and regrow rapidly upon cessation of treatment. This study provides a conceptual framework for the biophysics and function in tuberculosis infection and therapy of cord architectures independent of mechanisms ascribed to single bacteria.
Topics: Animals; Mice; Biofilms; Lung; Mycobacterium tuberculosis; Tuberculosis; Virulence; Biomechanical Phenomena
PubMed: 37865090
DOI: 10.1016/j.cell.2023.09.016 -
Clinical Microbiology and Infection :... Jun 2024Nontuberculous mycobacteria (NTM) are highly abundant in soil, dust, and water sources, making human-pathogen contact frequent and recurrent. NTM represents over 200... (Review)
Review
BACKGROUND
Nontuberculous mycobacteria (NTM) are highly abundant in soil, dust, and water sources, making human-pathogen contact frequent and recurrent. NTM represents over 200 species/subspecies; some are considered strict or opportunistic pathogens. Mycobacterium abscessus, often regarded as one of the most antibiotic-resistant mycobacteria, is the second most frequent NTM pulmonary disease pathogen.
OBJECTIVES
To describe the epidemiology of M. abscessus through a literature review focusing on clinical aspects.
SOURCES
We conducted searches on PubMed and Web of Knowledge for articles published from 2010 to the present using the keywords 'Mycobacterium abscessus', 'Nontuberculous mycobacteria', and 'epidemiology'. Our search prioritized original reports on the occurrence of NTM and M. abscessus infection/disease.
CONTENT
Advanced molecular and genetic diagnostic techniques have refined the M. abscessus complex (MABC) microbiological classification over the last few decades. MABC can adhere to surfaces and form a biofilm. This characteristic and its resistance to common disinfectants allow these microorganisms to persist in the water distribution systems, becoming a constant reservoir. The frequency and manifestation of NTM species vary geographically because of environmental conditions and population susceptibility differences. MABC lung disease, the most frequent site of NTM infection in humans, is often seen in patients with underlying lung diseases such as bronchiectasis, whereas MABC disseminated disease is related to immunosuppression. Skin and soft tissue infections are associated with surgical or injection procedures. Epidemiological evidence suggests an overall increase in MABC infection and disease in the last decade.
IMPLICATIONS
Establishing the burden of this disease is challenging because of varying measures of incidence and prevalence, referral bias, and differences in medical practices and reporting. Furthermore, environmental and structural determinants, infection routes, and MABC pulmonary disease mechanisms require additional investigation. This review contributes to a better understanding of the epidemiology of MABC, which could inform clinical practice and future research.
Topics: Humans; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous
PubMed: 37778416
DOI: 10.1016/j.cmi.2023.08.035 -
Clinics in Chest Medicine Dec 2023Nontuberculous mycobacterial (NTM) isolation and pulmonary disease (NTM-PD) have continued to increase in most regions of the world, driven mainly by Mycobacterium... (Review)
Review
Nontuberculous mycobacterial (NTM) isolation and pulmonary disease (NTM-PD) have continued to increase in most regions of the world, driven mainly by Mycobacterium avium. Single-center studies also support increasing trends as well as a persistent burden of undiagnosed NTM among persons suspected of having tuberculosis (TB), in countries with moderate-to-high TB prevalence. Cumulative exposure to water and soil presents an increased risk to susceptible hosts, and trace metals in water supply are recently recognized risk factors. Establishing standard case definitions for subnational and national surveillance systems with mandatory notification of NTM-PD are needed to allow comparisons within and across countries and regions.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Lung; Lung Diseases; Tuberculosis
PubMed: 37890910
DOI: 10.1016/j.ccm.2023.08.012 -
Open-Label Trial of Amikacin Liposome Inhalation Suspension in Mycobacterium abscessus Lung Disease.Chest Oct 2023Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M...
BACKGROUND
Mycobacterium abscessus is the second most common nontuberculous mycobacterium respiratory pathogen and shows in vitro resistance to nearly all oral antimicrobials. M abscessus treatment success is low in the presence of macrolide resistance.
RESEARCH QUESTION
Does treatment with amikacin liposome inhalation suspension (ALIS) improve culture conversion in patients with M abscessus pulmonary disease who are treatment naive or who have treatment-refractory disease?
STUDY DESIGN AND METHODS
In an open-label protocol, patients were given ALIS (590 mg) added to background multidrug therapy for 12 months. The primary outcome was sputum culture conversion defined as three consecutive monthly sputum cultures showing negative results. The secondary end point included development of amikacin resistance.
RESULTS
Of 33 patients (36 isolates) who started ALIS with a mean age of 64 years (range, 14-81 years), 24 patients (73%) were female, 10 patients (30%) had cystic fibrosis, and nine patients (27%) had cavitary disease. Three patients (9%) could not be evaluated for the microbiologic end point because of early withdrawal. All pretreatment isolates were amikacin susceptible and only six isolates (17%) were macrolide susceptible. Eleven patients (33%) were given parenteral antibiotics. Twelve patients (40%) received clofazimine with or without azithromycin as companion therapy. Fifteen patients (50%) with evaluable longitudinal microbiologic data demonstrated culture conversion, and 10 patients (67%) sustained conversion through month 12. Six of the 33 patients (18%) demonstrated mutational amikacin resistance. All were patients using clofazimine or clofazimine plus azithromycin as companion medication(s). Few serious adverse events occurred for ALIS users; however, reduction of dosing to three times weekly was common (52%).
INTERPRETATION
In a cohort of patients primarily with macrolide-resistant M abscessus, one-half of the patients using ALIS showed sputum culture conversion to negative findings. The emergence of mutational amikacin resistance was not uncommon and occurred with the use of clofazimine monotherapy.
TRIAL REGISTRY
ClinicalTrials.gov; No.: NCT03038178; URL: www.
CLINICALTRIALS
gov.
Topics: Humans; Female; Middle Aged; Male; Amikacin; Anti-Bacterial Agents; Mycobacterium abscessus; Liposomes; Clofazimine; Azithromycin; Macrolides; Drug Resistance, Bacterial; Leprostatic Agents; Cystic Fibrosis; Mycobacterium Infections, Nontuberculous; Microbial Sensitivity Tests
PubMed: 37419144
DOI: 10.1016/j.chest.2023.05.036 -
Ugeskrift For Laeger Apr 2024This review focuses on the treatment of nontuberculous pulmonary disease caused by Mycobacterium avium complex and M. abscessus. It covers treatment indications,... (Review)
Review
This review focuses on the treatment of nontuberculous pulmonary disease caused by Mycobacterium avium complex and M. abscessus. It covers treatment indications, antibiotic choice, resistance and side effects. Treatment of nontuberculous pulmonary disease is complex, lengthy, and fraught with side effects. Increased attention on this disease is needed in order to alleviate the severe consequences of this growing disease. Cooperation between pulmonologists and infectious disease specialists is needed to ensure uniform treatment, and to account for the heterogeneity seen in patients and mycobacteria alike.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Pneumonia; Anti-Bacterial Agents
PubMed: 38606709
DOI: 10.61409/V06230603 -
Infectious Disease Clinics of North... Sep 2023This review describes the epidemiology and risk factors of tuberculosis (TB) in solid organ transplant recipients. We discuss the pre-transplant screening for risk of TB... (Review)
Review
This review describes the epidemiology and risk factors of tuberculosis (TB) in solid organ transplant recipients. We discuss the pre-transplant screening for risk of TB and management of latent TB in this population. We also discuss the challenges of management of TB and other difficult to treat mycobacteria such as Mycobacterium abscessus and Mycobacterium avium complex. The drugs for the management of these infections include rifamycins which have significant drug interactions with immunosuppressants and must be monitored closely.
Topics: Humans; Mycobacterium; Tuberculosis; Mycobacterium Infections, Nontuberculous; Risk Factors; Transplant Recipients; Organ Transplantation; Mycobacterium tuberculosis
PubMed: 37268476
DOI: 10.1016/j.idc.2023.04.004 -
Cell Nov 2023Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with...
Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.
Topics: Humans; Male; Cell Cycle Proteins; Interferon-gamma; Interleukin-12; Interleukin-23; Janus Kinase 2; Mycobacterium; Mycobacterium Infections; Oncogene Proteins
PubMed: 37875108
DOI: 10.1016/j.cell.2023.09.024 -
Clinics in Chest Medicine Dec 2023Non-tuberculous mycobacteria (NTM) infection is a major cause of morbidity in people with cystic fibrosis (pwCF) with rates of infection increasing worldwide. Accurate... (Review)
Review
Non-tuberculous mycobacteria (NTM) infection is a major cause of morbidity in people with cystic fibrosis (pwCF) with rates of infection increasing worldwide. Accurate diagnosis and decisions surrounding best management remain challenging. Treatment guidelines have been developed to assist physicians in managing NTM in pwCF, but involve prolonged and complex mycobacterial regimens, often associated with significant toxicity. Fortunately, current management and outcomes of NTM in CF are likely to evolve due to improved understanding of disease acquisition, better diagnostics, emerging antimycobacterial therapies, and the widespread uptake of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies.
Topics: Humans; Cystic Fibrosis; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Anti-Bacterial Agents
PubMed: 37890921
DOI: 10.1016/j.ccm.2023.06.008 -
Frontiers in Immunology 2023Respiratory infections cause tremendous morbidity and mortality worldwide. Amongst these diseases, tuberculosis (TB), a bacterial illness caused by which often affects... (Review)
Review
Respiratory infections cause tremendous morbidity and mortality worldwide. Amongst these diseases, tuberculosis (TB), a bacterial illness caused by which often affects the lung, and coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), stand out as major drivers of epidemics of global concern. Despite their unrelated etiology and distinct pathology, these infections affect the same vital organ and share immunopathogenesis traits and an imperative demand to model the diseases at their various progression stages and localizations. Due to the clinical spectrum and heterogeneity of both diseases experimental infections were pursued in a variety of animal models. We summarize mammalian models employed in TB and COVID-19 experimental investigations, highlighting the diversity of rodent models and species peculiarities for each infection. We discuss the utility of non-human primates for translational research and emphasize on the benefits of non-conventional experimental models such as livestock. We epitomize advances facilitated by animal models with regard to understanding disease pathophysiology and immune responses. Finally, we highlight research areas necessitating optimized models and advocate that research of pulmonary infectious diseases could benefit from cross-fertilization between studies of apparently unrelated diseases, such as TB and COVID-19.
Topics: Animals; COVID-19; SARS-CoV-2; Tuberculosis; Respiratory Tract Infections; Models, Animal; Mammals
PubMed: 37638020
DOI: 10.3389/fimmu.2023.1223260 -
Chest Nov 2023Nontuberculous mycobacterial pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Nontuberculous mycobacterial pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression.
RESEARCH QUESTION
What are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis?
STUDY DESIGN AND METHODS
Electronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle-Ottawa Scale. Data analysis was conducted using the R-based "meta" package. Only studies that reported association outcomes for cases with NTM-PD compared with control participants (healthy populations or participants without NTM-PD) were considered for the meta-analysis.
RESULTS
Of the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95% CI, 5.90-77.82], history of TB [OR, 12.69; 95% CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95% CI, 2.65-15.37], COPD [OR, 6.63; 95% CI, 4.57-9.63], and asthma [OR, 4.15; 95% CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95% CI, 2.13-9.35), solid tumors (OR, 4.66; 95% CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95% CI, 2.72-11.26).
INTERPRETATION
The greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD to drive prompt testing and appropriate initiation of therapy.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Risk Factors; Bronchiectasis; Asthma; Respiratory Tract Diseases; Nontuberculous Mycobacteria; Lung Diseases; Retrospective Studies
PubMed: 37429481
DOI: 10.1016/j.chest.2023.06.014