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International Journal of... 2023Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium... (Review)
Review
Difficult-to-treat mycobacterial infections are increasing globally. There is an urgent need of new treatment alternatives for multidrug-resistant Mycobacterium tuberculosis (MTB), as well as nontuberculous mycobacteria such as the Mycobacterium abscessus complex (MABC) and Mycobacterium avium complex (MAC). Recently, new carbapenems and combinations of carbapenems with β-lactamase inhibitors have become available, but activity data in vitro against mycobacteria are so far scarce. Therefore, we performed a systematic review collating the minimum inhibitory concentrations (MICs) of carbapenems, with or without a β-lactamase inhibitors for MTB, MABC, and MAC. The databases PubMed and Web of Science were searched for the relevant articles in English up until September 21, 2022. Screening of studies was performed by two independent reviewers. MIC data by recommended methods with at least five individual MICs were included. Data were reported as MIC range, MIC, modal MIC, and/or histograms when individual MICs were available. The study protocol was registered at PROSPERO (CRD42021258537). After screening, a total of 75 studies with MIC data for carbapenems with or without β-lactamase inhibitors were included in the review. For MTB, the oral carbapenem tebipenem combined with the β-lactamase inhibitor clavulanic acid resulted in the most significant reduction of MICs. For MABC, the addition of avibactam to tebipenem resulted in a 64-fold reduction of modal MIC. Data were insufficient for the analysis of MAC. Carbapenems, and in particular the novel oral compound tebipenem, in combination with clavulanic acid for MTB and avibactam for MABC may be an untapped potential for difficult-to-treat mycobacterial infections.
Topics: Humans; beta-Lactamase Inhibitors; Mycobacterium abscessus; Mycobacterium avium Complex; Mycobacterium tuberculosis; Carbapenems; Penicillins; Clavulanic Acid; Microbial Sensitivity Tests; Anti-Bacterial Agents; Mycobacterium Infections, Nontuberculous
PubMed: 37721224
DOI: 10.4103/ijmy.ijmy_131_23 -
Frontiers in Immunology 2021Autophagy is critically involved in host defense pathways through targeting and elimination of numerous pathogens autophagic machinery. Nontuberculous mycobacteria... (Review)
Review
Autophagy is critically involved in host defense pathways through targeting and elimination of numerous pathogens autophagic machinery. Nontuberculous mycobacteria (NTMs) are ubiquitous microbes, have become increasingly prevalent, and are emerging as clinically important strains due to drug-resistant issues. Compared to (Mtb), the causal pathogen for human tuberculosis, the roles of autophagy remain largely uncharacterized in the context of a variety of NTM infections. Compelling evidence suggests that host autophagy activation plays an essential role in the enhancement of antimicrobial immune responses and controlling pathological inflammation against various NTM infections. As similar to Mtb, it is believed that NTM bacteria evolve multiple strategies to manipulate and hijack host autophagy pathways. Despite this, we are just beginning to understand the molecular mechanisms underlying the crosstalk between pathogen and the host autophagy system in a battle with NTM bacteria. In this review, we will explore the function of autophagy, which is involved in shaping host-pathogen interaction and disease outcomes during NTM infections. These efforts will lead to the development of autophagy-based host-directed therapeutics against NTM infection.
Topics: Animals; Anti-Bacterial Agents; Autophagy; Biological Evolution; Drug Resistance, Bacterial; Host-Pathogen Interactions; Humans; Immunity, Innate; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria
PubMed: 34552591
DOI: 10.3389/fimmu.2021.728742 -
Expert Review of Anti-infective Therapy 2023Nontuberculous mycobacteria infect patients who have structural lung disease or those who are immunocompromised. Nontuberculous mycobacterial pulmonary disease (NTM-PD)...
INTRODUCTION
Nontuberculous mycobacteria infect patients who have structural lung disease or those who are immunocompromised. Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in prevalence. Treatment guidelines for complex (MAC) pulmonary disease involve a three-drug regimen with azithromycin, ethambutol, and rifampin, and those of complex (MAB) pulmonary disease involve a combination of three or more antimicrobials including macrolides, amikacin, and a β-lactam or imipenem. However, these regimens are poorly tolerated and generally ineffective.
AREAS COVERED
SPR720 is a novel therapeutic agent that has demonstrated activity against a range of NTM species, including MAC and MAB. Encouraging and pre-clinical data demonstrate that SPR720 is active both alone and in combination with standard-of-care agents, with no evidence of cross-resistance to such agents. It is generally well tolerated with mainly gastrointestinal and headache adverse events of mild or moderate severity.
EXPERT OPINION
Management of NTM-PD is challenging for many reasons including length of therapy, poor efficacy, drug intolerance, recurrence, and resistance development. The current antimicrobial management options for NTM-PD are limited in number and there exists a large unmet need for new treatments. SPR720 has encouraging data that warrant further study in the context of a multidrug regimen.
Topics: Humans; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Mycobacterium avium Complex; Lung Diseases; Anti-Bacterial Agents
PubMed: 37862563
DOI: 10.1080/14787210.2023.2270158 -
Memorias Do Instituto Oswaldo Cruz 2022Non-tuberculous mycobacteria (NTMs) cause diseases known as mycobacteriosis and are an important cause of morbidity and mortality. The diagnosis of pulmonary disease...
BACKGROUND
Non-tuberculous mycobacteria (NTMs) cause diseases known as mycobacteriosis and are an important cause of morbidity and mortality. The diagnosis of pulmonary disease caused by NTM is hampered by its clinical similarity with tuberculosis (TB) and by the lack of an accurate and rapid laboratory diagnosis.
OBJECTIVES
Detect DNA from NTMs directly from lung samples using real-time polymerase chain reaction (qPCR) for amplification of 16S rRNA. Additionally, DNA sequencing (hsp65 and rpoB genes) was used to identify the species of MNTs.
METHODS
A total of 68 sputum samples (54 with suspected NTMs and 14 with TB) from patients treated at a referral hospital were used.
FINDINGS
Of these, 27/54 (50%) were qPCR positive for NTMs and 14/14 TB patients (controls) were qPCR negative with an almost perfect concordance (Kappa of 0.93) with the Mycobacterium spp. culture. Sequencing confirmed the presence of NTM in all positive samples. The most common species was Mycobacterium gordonae (33%), followed by Mycobacterium abscessus (26%), Mycobacterium fortuitum (22%), Mycobacterium avium (15%) and Mycobacterium peregrinum (4%).
MAIN CONCLUSIONS
The qPCR technique for detecting NTMs targeting 16S rRNA has the potential to detect NTMs and rapidly differentiate from Mycobacterium tuberculosis. However, it is necessary to identify the species to help in the differential diagnosis between disease and contamination, and to guide the choice of the therapeutic scheme.
Topics: Humans; Lung; Mycobacterium Infections, Nontuberculous; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; RNA, Ribosomal, 16S; Real-Time Polymerase Chain Reaction; Tuberculosis
PubMed: 35920498
DOI: 10.1590/0074-02760220031 -
Respiration; International Review of... 2022Nontuberculous mycobacteria (NTM) are increasingly identified in industrialized countries, and their role as pathogens is more frequently recognized. The relative...
BACKGROUND
Nontuberculous mycobacteria (NTM) are increasingly identified in industrialized countries, and their role as pathogens is more frequently recognized. The relative prevalence of NTM strains shows an important geographical variability. Thus, establishing the local relative prevalence of NTM strains is relevant and useful for clinicians.
METHODS
Retrospective analysis (2015-2020) of a comprehensive database was conducted including all results of cultures for mycobacteria in a University Hospital (Geneva, Switzerland), covering a population of approximately 500,000 inhabitants. All NTM culture-positive patients were included in the analyses. Patients' characteristics, NTM strains, and time to culture positivity were reported.
RESULTS
Among 38,065 samples analyzed during the study period, 411 were culture-positive for NTM, representing 236 strains, and 231 episodes of care which occurred in 222 patients. Patients in whom NTM were identified were predominantly female (55%), with a median age of 62 years, and a low BMI (median: 22.6 kg/m2). The Mycobacterium avium complex (MAC) was the most frequently identified group (37% of strains) followed by Mycobacterium gordonae (25%) and Mycobacterium xenopi (12%) among the slowly growing mycobacteria (SGM), while the Mycobacterium chelonae/abscessus group (11%) were the most frequently identified rapidly growing mycobacteria (RGM). Only 19% of all patients were treated, mostly for pulmonary infections: the MAC was the most frequently treated NTM (n = 19, 43% of cases in patients treated) followed by RGM (n = 15, 34%) and M. xenopi (n = 6, 14%). Among those treated, 23% were immunosuppressed, 12% had pulmonary comorbidities, and 5% systemic comorbidities. Cultures became positive after a median of 41 days (IQR: 23; 68) for SGM and 28 days (14; 35) for RGM.
CONCLUSIONS
In Western Switzerland, M. avium and M. gordonae were the most prevalent NTM identified. Positive cultures for NTM led to a specific treatment in 19% of subjects. Patients with a positive culture for NTM were mostly female, with a median age of 62 years, a low BMI, and a low prevalence of immunosuppression or associated severe comorbidities.
Topics: Female; Humans; Male; Middle Aged; Mycobacterium Infections, Nontuberculous; Mycobacterium avium Complex; Mycobacterium xenopi; Nontuberculous Mycobacteria; Retrospective Studies
PubMed: 34875659
DOI: 10.1159/000520033 -
American Journal of Respiratory Cell... Aug 2020The incidence and prevalence of nontuberculous mycobacteria (NTM) lung disease is rising worldwide and accounts for most clinical cases of NTM disease. NTM infections... (Review)
Review
The incidence and prevalence of nontuberculous mycobacteria (NTM) lung disease is rising worldwide and accounts for most clinical cases of NTM disease. NTM infections occur in both immunocompetent and immunocompromised hosts. Macrophages are the primary host cells that initiate an immune response to NTM. Defining the molecular events that govern the control of infection within macrophages is fundamental to understanding the pathogenesis of NTM disease. Here, we review key macrophage host signaling pathways that contribute to the host immune response to pulmonary NTM infections. In this review, we focus primarily on NTM that are known to cause lung disease, including , , and .
Topics: Animals; Humans; Lung Diseases; Macrophages; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Signal Transduction
PubMed: 32160017
DOI: 10.1165/rcmb.2019-0241TR -
Diseases of Aquatic Organisms Jul 2021Emerging infectious diseases in wild animals related to humans have received greater attention in recent years. Mycobacteriosis is a bacterial disease of animal and...
Emerging infectious diseases in wild animals related to humans have received greater attention in recent years. Mycobacteriosis is a bacterial disease of animal and human importance. Mycobacterium gordonae infects the skin and internal organs of free-ranging amphibians and is considered the least pathogenic member of the Mycobacteriaceae to humans. However, information about its infection and pathogenesis in wild amphibians is still lacking. A total of 1306 amphibian specimens belonging to 6 families, 12 genera, and 21 species were collected and dissected during a helminthological survey of 7 municipalities in southern Ceará state, Caatinga (eco)region, northeast Brazil. Of these, 17 specimens (0.76%), belonging to 2 families and 4 species (Leptodactylus macrosternum, n = 2; L. vastus, n = 10; Pseudopaludicola pocoto, n = 2; Rhinella jimi, n = 3), presented infections that consisted of calcification nodules in the coelomic cavity, kidney, liver, lung, gut, and pancreas. The nodules were examined by histopathology and PCR. The bacteria were identified as M. gordonae by molecular analyses. Infected animals presented with hepatocellular vacuolar degeneration, karyolysis, and karyorrhexis, hepatic portal congestion, hemorrhage, mononuclear cellular infiltration, melanomacrophage center hyperplasia, and granulomas in varying stages of development with intralesional acid-fast bacilli. This study is the first report of M. gordonae in these amphibian species, in which results of molecular analyses confirmed the presence of M. gordonae in natural environments and histopathology confirmed the typical lesion of mycobacteriosis in amphibians from northeastern Brazil.
Topics: Animals; Anura; Brazil; Liver; Lung; Nontuberculous Mycobacteria
PubMed: 34196283
DOI: 10.3354/dao03604 -
The Journal of Dermatology Nov 2022Nontuberculous mycobacteria cause a wide range of infections, including cutaneous infections, in both immunocompromised and immunocompetent patients. Although pulmonary... (Review)
Review
Nontuberculous mycobacteria cause a wide range of infections, including cutaneous infections, in both immunocompromised and immunocompetent patients. Although pulmonary nontuberculous mycobacterial infections have increased significantly in Japan in recent years, there is less evidence on clinical and microbiological characteristics of cutaneous nontuberculous mycobacterial infections in Japan. We reviewed 86 Japanese cases reported between July 2016 and November 2021 and analyzed them in conjunction with the eight patients from our institution who were diagnosed with cutaneous nontuberculous mycobacterial infections by culture between 2015 and 2021. In the aggregate series, the average patient age was 60 years, and the ratio of immunocompromised hosts was 53%, both of which were higher than those in previous reports from other countries. No female predominance was observed, unlike in pulmonary nontuberculous mycobacteria infections. Rapidly growing mycobacteria accounted for 58% of the cases (n = 54), whereas slowly growing mycobacteria for 43% (n = 40). Mycobacterium marinum (also known as Mycobacteroides marinum) (n = 20, 21%) was the most common cause, followed by Mycobacterium chelonae (n = 18, 19%), Mycobacterium abscessus (also known as Mycobacteroides abscessus) (n = 15, 16%), and Mycobacterium ulcerans (n = 11, 12%). While clinical appearance was variable, M ulcerans infections usually presented with ulcers, while nodules were common among infections caused by M chelonae and M marinum. Disseminated infections involving multiple organs were observed in 23 patients (24%). Thirty-two cases (30%) were preceded by exposure, including raising or handling fish, trauma, and invasive medical procedures. Most patients were treated with more than two antibiotics and responded to therapy.
Topics: Animals; Japan; Skin Diseases, Bacterial; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Mycobacterium abscessus
PubMed: 35906770
DOI: 10.1111/1346-8138.16531 -
Infection and Immunity Jul 2021Although nontuberculous mycobacteria (NTM) are considered opportunistic infections, incidence and prevalence of NTM infection are increasing worldwide becoming a major... (Review)
Review
Although nontuberculous mycobacteria (NTM) are considered opportunistic infections, incidence and prevalence of NTM infection are increasing worldwide becoming a major public health threat. Innate immunity plays an essential role in mediating the initial host response against these intracellular bacteria. Specifically, macrophages phagocytose and eliminate NTM and act as antigen-presenting cells, which trigger downstream activation of cellular and humoral adaptive immune responses. Identification of macrophage receptors, mycobacterial ligands, phagosome maturation, autophagy/necrosis, and escape mechanisms are important components of this immunity network. The role of the macrophage in mycobacterial disease has mainly been studied in tuberculosis (TB), but limited information exists on its role in NTM. In this review, we focus on NTM immunity, the role of macrophages, and host interaction in NTM infection.
Topics: Adaptive Immunity; Host-Pathogen Interactions; Humans; Immunity, Innate; Macrophages; Microbial Viability; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Phagocytosis
PubMed: 34097459
DOI: 10.1128/IAI.00812-20 -
International Journal of Molecular... Aug 2020Outside of and , nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections... (Review)
Review
Outside of and , nontuberculous mycobacteria (NTM) are environmental mycobacteria (>190 species) and are classified as slow- or rapid-growing mycobacteria. Infections caused by NTM show an increased incidence in immunocompromised patients and patients with underlying structural lung disease. The true global prevalence of NTM infections remains unknown because many countries do not require mandatory reporting of the infection. This is coupled with a challenging diagnosis and identification of the species. Current therapies for treatment of NTM infections require multidrug regimens for a minimum of 18 months and are associated with serious adverse reactions, infection relapse, and high reinfection rates, necessitating discovery of novel antimycobacterial agents. Robust drug discovery processes have discovered inhibitors targeting mycobacterial membrane protein large 3 (MmpL3), a protein responsible for translocating mycolic acids from the inner membrane to periplasm in the biosynthesis of the mycobacterial cell membrane. This review focuses on promising new chemical scaffolds that inhibit MmpL3 function and represent interesting and promising putative drug candidates for the treatment of NTM infections. Additionally, agents (FS-1, SMARt-420, C10) that promote reversion of drug resistance are also reviewed.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Biological Transport; Drug Discovery; Drug Resistance, Multiple, Bacterial; Gene Expression Regulation, Bacterial; Humans; Iodophors; Isoxazoles; Membrane Transport Proteins; Mycobacterium Infections, Nontuberculous; Mycolic Acids; Nontuberculous Mycobacteria; Polysaccharides; Spiro Compounds
PubMed: 32867307
DOI: 10.3390/ijms21176202