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International Journal of Infectious... Mar 2022Precise subspeciation of Mycobacterium abscessus complex (MAB) is crucial for predicting antibiotic susceptibilities and patient outcomes. However, routine clinical...
PURPOSE
Precise subspeciation of Mycobacterium abscessus complex (MAB) is crucial for predicting antibiotic susceptibilities and patient outcomes. However, routine clinical microbiology laboratories have limited diagnostic tools for the differentiation of the subspecies. Thus, we investigated the predictors for MAB subspecies to actuate rapid differentiation and the optimal treatment plans.
METHODS
We retrospectively identified stored clinical isolates of MAB and reviewed patient medical records to compare clinical characteristics, sites of infection, and outcomes among patients infected with M. abscessus subsp. abscessus (M. abscessus) and M. abscessus subsp. massiliense (M. massiliense). MAB subspecies were characterised by multilocus sequence analysis with 3-locus sequence (hsp65, rpoB, and secA1) and pulsed-field gel electrophoresis.
RESULTS
After outbreak and duplicated cases were excluded, 56 and 36 patients with infection caused by M. abscessus and M. massiliense, respectively, were included in the analysis. Patients with either cardiovascular disease or risk factors for cardiovascular disease (male gender and age ≥55 years) were 4.5 times more likely to harbour M. abscessus (P = 0.002), whereas M. massiliense was 4.8 times more frequently recovered from cutaneous and surgical wounds (P = 0.04).
CONCLUSION
Distinct host and organ specificity were observed among patients infected with M. abscessus and those with M. massiliense. These differences may provide clinically significant clues to optimise treatment strategies.
Topics: Anti-Bacterial Agents; Cross-Sectional Studies; Humans; Male; Middle Aged; Multilocus Sequence Typing; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Organ Specificity; Retrospective Studies
PubMed: 34954310
DOI: 10.1016/j.ijid.2021.12.348 -
Frontiers in Immunology 2022Non-tuberculous mycobacteria (NTM) are a heterogeneous group of originally environmental organi3sms, increasingly recognized as pathogens with rising prevalence... (Review)
Review
Non-tuberculous mycobacteria (NTM) are a heterogeneous group of originally environmental organi3sms, increasingly recognized as pathogens with rising prevalence worldwide. Knowledge of NTM's mechanisms of virulence is lacking, as molecular research of these bacteria is challenging, sometimes more than that of M. tuberculosis (Mtb), and far less resources are allocated to their investigation. While some of the virulence mechanisms are common to several mycobacteria including Mtb, others NTM species-specific. Among NTMs, Mycobacterium abscessus (Mabs) causes some of the most severe and difficult to treat infections, especially chronic pulmonary infections. Mabs survives and proliferates intracellularly by circumventing host defenses, using multiple mechanisms, many of which remain poorly characterized. Some of these immune-evasion mechanisms are also found in Mtb, including phagosome pore formation, inhibition of phagosome maturation, cytokine response interference and apoptosis delay. While much is known of the role of Mtb-secreted effector molecules in mediating the manipulation of the host response, far less is known of the secreted effector molecules in Mabs. In this review, we briefly summarize the knowledge of secreted effectors in Mtb (such as ESX secretion, SecA2, TAT and others), and draw the parallel pathways in Mabs. We also describe pathways that are unique to Mabs, differentiating it from Mtb. This review will assist researchers interested in virulence-associated secretion in Mabs by providing the knowledge base and framework for their studies.
Topics: Mycobacterium abscessus; Mycobacterium tuberculosis; Nontuberculous Mycobacteria; Phagosomes; Virulence
PubMed: 35880173
DOI: 10.3389/fimmu.2022.938895 -
PLoS Pathogens Aug 2023Mycobacterium abscessus (Mabs) drives life-shortening mortality in cystic fibrosis (CF) patients, primarily because of its resistance to chemotherapeutic agents. To...
Mycobacterium abscessus (Mabs) drives life-shortening mortality in cystic fibrosis (CF) patients, primarily because of its resistance to chemotherapeutic agents. To date, our knowledge on the host and bacterial determinants driving Mabs pathology in CF patient lung remains rudimentary. Here, we used human airway organoids (AOs) microinjected with smooth (S) or rough (R-)Mabs to evaluate bacteria fitness, host responses to infection, and new treatment efficacy. We show that S Mabs formed biofilm, and R Mabs formed cord serpentines and displayed a higher virulence. While Mabs infection triggers enhanced oxidative stress, pharmacological activation of antioxidant pathways resulted in better control of Mabs growth and reduced virulence. Genetic and pharmacological inhibition of the CFTR is associated with better growth and higher virulence of S and R Mabs. Finally, pharmacological activation of antioxidant pathways inhibited Mabs growth, at least in part through the quinone oxidoreductase NQO1, and improved efficacy in combination with cefoxitin, a first line antibiotic. In conclusion, we have established AOs as a suitable human system to decipher mechanisms of CF-driven respiratory infection by Mabs and propose boosting of the NRF2-NQO1 axis as a potential host-directed strategy to improve Mabs infection control.
Topics: Humans; Cystic Fibrosis; Mycobacterium abscessus; Antioxidants; Oxidation-Reduction; Oxidative Stress
PubMed: 37619220
DOI: 10.1371/journal.ppat.1011559 -
International Journal of Molecular... Jul 2023, a species of nontuberculous mycobacteria (NTM), is an opportunistic pathogen that is readily cleared by healthy lungs but can cause pulmonary infections in people with...
, a species of nontuberculous mycobacteria (NTM), is an opportunistic pathogen that is readily cleared by healthy lungs but can cause pulmonary infections in people with chronic airway diseases. Although knowledge pertaining to molecular mechanisms of host defense against NTM is increasing, macrophage receptors that recognize remain poorly defined. Dectin-1, a C-type lectin receptor identified as a fungal receptor, has been shown to be a pathogen recognition receptor (PRR) for both and NTM. To better understand the role of Dectin-1 in host defense against , we tested whether blocking Dectin-1 impaired the uptake of by human macrophages, and we compared pulmonary infection in Dectin-1-deficient and wild-type mice. Blocking antibody for Dectin-1 did not reduce macrophage phagocytosis of , but did reduce the ingestion of the fungal antigen zymosan. Laminarin, a glucan that blocks Dectin-1 and other PRRs, caused decreased phagocytosis of both and zymosan. Dectin-1-/- mice exhibited no defects in the control of infection, and no differences were detected in immune cell populations between wild type and Dectin-1-/- mice. These data demonstrate that murine defense against pulmonary infection, as well as ingestion of by human macrophages, can occur independent of Dectin-1. Thus, additional PRR(s) recognized by laminarin participate in macrophage phagocytosis of
Topics: Humans; Animals; Mice; Mycobacterium abscessus; Zymosan; Macrophages; Phagocytosis; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous
PubMed: 37446240
DOI: 10.3390/ijms241311062 -
Microbiological Research Dec 2021Mycobacterium abscessus complex (MABC) infections cause significant morbidity and mortality among patients with chronic lung disease, like cystic fibrosis. MABC exists...
Mycobacterium abscessus complex (MABC) infections cause significant morbidity and mortality among patients with chronic lung disease, like cystic fibrosis. MABC exists in smooth (S) and rough (R) morphotypes, but triggers of morphotype switching and associated pathogenicity or antimicrobial susceptibility are poorly understood. We demonstrate that M. abscessus subspecies abscessus (Mab), massiliense (Mms), and bolletii (Mbl) cultured in Middlebrook (MB) broth exhibit S morphotype, whereas the bacteria grown in Luria Bertani (LB) broth adopt the R morphotype, characterized by low glycopeptidolipid (GPL) expression. The components of broth that mediate this selection are complex, with albumin supplementation promoting growth of S morphotype, but not sufficient for complete selection. Consistent with the findings of other groups, R forms of Mab, Mms and Mbl selected by LB broth were internalized in RAW 264.7 macrophages with higher efficiency than S. Intracellular survival of broth-selected organisms was variable and was higher for S Mab, but lower for S Mms and Mbl. It is proposed that growth in R morphotype is induced during stress conditions, such as nutrient poor environments or during inflammation. One key component of inflammation is release of nitric oxide. We demonstrated that a nitric oxide donor (DETA-NONOate) appears to induce growth in an R morphotype, as indicated by reduced GPL expression of Mab. Mab treated with DETA-NONOate also enhanced susceptibility to azithromycin at sub-MIC concentrations. In conclusion, morphotype and macrophage intracellular bacterial load of MABC subspecies can be manipulated by growing the bacteria in different culture conditions. Nitric oxide may also drive morphotype selection and enhanced azithromycin activity against Mab and macrophage killing.
Topics: Azithromycin; Culture Media, Conditioned; Drug Resistance, Bacterial; Humans; Inflammation; Mycobacterium abscessus; Nitric Oxide; Virulence
PubMed: 34628130
DOI: 10.1016/j.micres.2021.126887 -
Medicinal Research Reviews Jul 2021The Mycobacterium abscessus complex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successful M. abscessus pulmonary... (Review)
Review
The Mycobacterium abscessus complex is a group of emerging pathogens that are difficult to treat. There are no effective drugs for successful M. abscessus pulmonary infection therapy, and existing drug regimens recommended by the British or the American Thoracic Societies are associated with poor clinical outcomes. Therefore, novel antibacterial drugs are urgently needed to contain this global threat. The current anti-M. abscessus small-molecule drug development process can be enhanced by two parallel strategies-discovery of compounds from new chemical classes and commercial drug repurposing. This review focuses on recent advances in the finding of novel small-molecule agents, and more particularly focuses on the activity, mode of action and structure-activity relationship of promising inhibitors from five different chemical classes-benzimidazoles, indole-2-carboxamides, benzothiazoles, 4-piperidinoles, and oxazolidionones. We further discuss some other interesting small molecules, such as thiacetazone derivatives and benzoboroxoles, that are in the early stages of drug development, and summarize current knowledge about the efficacy of repurposable drugs, such as rifabutin, tedizolid, bedaquiline, and others. We finally review targets of therapeutic interest in M. abscessus that may be worthy of future drug and adjunct therapeutic development.
Topics: Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Mycobacterium Infections, Nontuberculous; Mycobacterium abscessus; Pharmaceutical Preparations; Rifabutin
PubMed: 33645845
DOI: 10.1002/med.21798 -
Microbiology Spectrum Aug 2023Nontuberculous mycobacterial infections are generally believed to be independently acquired from the environment. Although person-to-person transmission of...
Nontuberculous mycobacterial infections are generally believed to be independently acquired from the environment. Although person-to-person transmission of nontuberculous mycobacteria, especially Mycobacterium abscessus subsp. , is a serious concern among individuals with cystic fibrosis (CF), evidence of its spread among patients without CF has never been established. We unexpectedly found a number of M. abscessus subsp. cases among patients without CF in a hospital. This study aimed to define the mechanism of M. abscessus subsp. infection among patients who were ventilator dependent and without CF who had progressive neurodegenerative diseases in our long-term care wards from 2014 to 2018 during suspected nosocomial outbreaks. We conducted whole-genome sequencing of M. abscessus subsp. isolates from 52 patients and environmental samples. Potential opportunities for in-hospital transmission were analyzed using epidemiological data. M. abscessus subsp. was isolated from one air sample obtained near a patient without CF who was colonized with M. abscessus subsp. but not from other potential sources. Phylogenetic analysis of the strains from these patients and the environmental isolate revealed clonal expansion of near-identical M. abscessus subsp. isolates, with the isolates generally differing by fewer than 22 single nucleotide polymorphisms (SNPs). Approximately half of the isolates differed by fewer than nine SNPs, indicating interpatient transmission. Whole-genome sequencing revealed a potential nosocomial outbreak among patients who were ventilator dependent and without CF. The isolation of M. abscessus subsp. from the air, but not from environmental fluid samples, may suggest airborne transmission. This was the first report to demonstrate person-to-person transmission of M. abscessus subsp. , even among patients without CF. M. abscessus subsp. may spread among patients who are ventilator dependent without CF through direct or indirect in-hospital transmission. The current infection control measures should address potential transmission among patients without CF, particularly in facilities that treat patients who are ventilator dependent and patients with preexisting chronic pulmonary diseases, such as CF.
Topics: Humans; Mycobacterium abscessus; Mycobacterium Infections, Nontuberculous; Cystic Fibrosis; Phylogeny; Cross Infection; Nontuberculous Mycobacteria; Ventilators, Mechanical
PubMed: 37314340
DOI: 10.1128/spectrum.04908-22 -
Clinical Microbiology and Infection :... Jun 2024Mycobacterium abscessus (Mab) is considered as the most pathogenic rapid-growing mycobacteria in humans, causing pulmonary and extra-pulmonary diseases, especially in... (Review)
Review
BACKGROUND
Mycobacterium abscessus (Mab) is considered as the most pathogenic rapid-growing mycobacteria in humans, causing pulmonary and extra-pulmonary diseases, especially in patients with cystic fibrosis. Mab shows intrinsic and acquired resistance to many drugs, leaving limited treatment options that lead to a generally poor prognosis. The standard therapeutic regimen last for more than 6 months and consists of a drug cocktail that ideally includes a macrolide and amikacin. Yet, toxicity and efficacy are suboptimal due also to the high toxicity. There is a need to introduce innovative and out-of-the-box approaches to improve treatments.
OBJECTIVES
In this narrative review, we summarize the recent research on the alternative strategies proposed and discuss the importance of using appropriate experimental assays to assess their activity.
SOURCES
Included articles were identified by searching PubMed and MEDLINE until June 2023. The search terms were 'Mycobacterium abscessus', 'antimicrobial', and 'alternative therapies'. Additional relevant references were obtained from articles retrieved from the primary search.
CONTENT
Therapies against Mab including host directed therapies, repurposed drugs, phage therapy, anti-virulence strategies, essential oils, and inhalation therapies.
IMPLICATIONS
Alternative treatments may represent a valid tool to cope the burden of antimicrobial resistance in Mab-caused diseases.
Topics: Mycobacterium abscessus; Humans; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Complementary Therapies; Drug Repositioning; Phage Therapy
PubMed: 37820951
DOI: 10.1016/j.cmi.2023.10.001 -
International Journal of Antimicrobial... Oct 2023Mycobacterium abscessus is an emerging infection in people living with lung diseases, including cystic fibrosis (CF) and bronchiectasis, and it has limited treatment...
OBJECTIVES
Mycobacterium abscessus is an emerging infection in people living with lung diseases, including cystic fibrosis (CF) and bronchiectasis, and it has limited treatment options and low cure rates. The off-label use of novel antibiotics developed for other bacterial pathogens offers potential new therapeutic options. We aimed to describe the in vitro activity of imipenem, imipenem-relebactam and tedizolid against comparator antibiotics in M. abscessus isolates from Australian patients with and without CF.
METHODS
We performed susceptibility testing for imipenem-relebactam, tedizolid and comparator antibiotics by Clinical and Laboratory Standards Institute (CLSI) criteria against 102 clinical M. abscessus isolates, including 46 from people with CF.
RESULTS
In this study, the minimum inhibitory concentration (MICs) of imipenem-relebactam was one-fold dilution less than of imipenem alone. The MIC and MIC of imipenem-relebactam were 8 and 16 mg/L, respectively, whereas for imipenem they were 16 and 32 mg/L. Tedizolid had an MIC and MIC of 2 and 4 mg/L, respectively. Forty non-CF isolates had linezolid susceptibility performed, with MIC and MIC values of 16 and 32 mg/L, respectively, measured.
CONCLUSIONS
This study shows lower MICs for imipenem-relebactam and tedizolid compared to other more commonly used antibiotics and supports their consideration in clinical trials for M. abscessus treatment.
Topics: Humans; Mycobacterium abscessus; Australia; Anti-Bacterial Agents; Imipenem; Microbial Sensitivity Tests
PubMed: 37517624
DOI: 10.1016/j.ijantimicag.2023.106938 -
Microbiology Spectrum Jun 2023Mycobacterium abscessus (MABS) is the most pathogenic and drug-resistant rapidly growing mycobacteria. However, studies on MABS epidemiology, especially those focusing...
Mycobacterium abscessus (MABS) is the most pathogenic and drug-resistant rapidly growing mycobacteria. However, studies on MABS epidemiology, especially those focusing on subspecies level, are scarce. We aimed to determine MABS subspecies distribution and its correlation with phenotypic and genotypic antibiotic profiles. A retrospective multicenter study of 96 clinical MABS isolates in Madrid between 2016 to 2021 was conducted. Identification at the subspecies level and resistance to macrolides and aminoglycosides were performed by the GenoType NTM-DR assay. The MICs of 11 antimicrobials tested against MABS isolates were determined using the broth microdilution method (RAPMYCOI Sensititer titration plates). Clinical isolates included 50 (52.1%) MABS subsp. ; 33 (34.4%) MABS subsp. ; and 13 (13.5%) MABS subsp. . The lowest resistance rates corresponded to amikacin (2.1%), linezolid (6.3%), cefoxitin (7.3%), and imipenem (14.6%), and the highest to doxycycline (100.0%), ciprofloxacin (89.6%), moxifloxacin (82.3%), cotrimoxazole (82.3%), tobramycin (81.3%), and clarithromycin (50.0% at day 14 of incubation). Regarding tigecycline, although there are no susceptibility breakpoints, all strains but one showed MICs ≤ 1 μg/mL. Four isolates harbored mutations at positions 2058/9 of the gene, one strain harbored a mutation at position 1408 of the gene, and 18/50 harbored the T28C substitution at (41) gene. Agreement of the GenoType results with clarithromycin and amikacin susceptibility testing was 99.0% (95/96). The rate of MABS isolates showed an upward trend during the study period, being M. abscessus the most frequently isolated subspecies. Amikacin, cefoxitin, linezolid, and imipenem showed great activity. The GenoType NTM-DR assay provides a reliable and complementary tool to broth microdilution for drug resistance detection. Infections caused by Mycobacterium abscessus (MABS) are increasingly being reported worldwide. Identifying MABS subspecies and assessing their phenotypic resistance profiles are crucial for optimal management and better patient outcomes. subspecies differ in (41) gene functionality, which is a critical determinant of macrolide resistance. Additionally, resistance profiles of MABS and the subspecies distribution can vary geographically, highlighting the importance of understanding local epidemiology and resistance patterns. This study provides valuable insights into the epidemiology and resistance patterns of MABS and its subspecies in Madrid. Elevated resistance rates were observed for several recommended antimicrobials, emphasizing the need for cautious drug use. Furthermore, we assessed the GenoType NTM-DR assay, which examines principal mutations in macrolides and aminoglycosides resistance-related genes. We observed a high level of agreement between the GenoType NTM-DR assay and the microdilution method, indicating its usefulness as an initial tool for early initiation of appropriate therapy.
Topics: Humans; Anti-Bacterial Agents; Clarithromycin; Mycobacterium abscessus; Amikacin; Linezolid; Cefoxitin; Spain; Mycobacterium Infections, Nontuberculous; Macrolides; Drug Resistance, Bacterial; Imipenem; Aminoglycosides; Microbial Sensitivity Tests
PubMed: 37212700
DOI: 10.1128/spectrum.05041-22