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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 -
Clinical Microbiology and Infection :... Jun 2023For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their...
Towards clinical breakpoints for non-tuberculous mycobacteria - Determination of epidemiological cut off values for the Mycobacterium avium complex and Mycobacterium abscessus using broth microdilution.
OBJECTIVE
For non-tuberculous mycobacteria (NTM), minimum inhibitory concentration (MIC) distributions of wild-type isolates have not been systematically evaluated despite their importance for establishing antimicrobial susceptibility testing (AST) breakpoints.
METHODS
We gathered MIC distributions for drugs used against the Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) obtained by commercial broth microdilution (SLOMYCOI and RAPMYCOI) from 12 laboratories. Epidemiological cut-off values (ECOFFs) and tentative ECOFFs (TECOFFs) were determined by EUCAST methodology including quality control (QC) strains.
RESULTS
The clarithromycin ECOFF was 16 mg/L for M. avium (n = 1271) whereas TECOFFs were 8 mg/L for M. intracellulare (n = 415) and 1 mg/L for MAB (n = 1014) confirmed by analysing MAB subspecies without inducible macrolide resistance (n = 235). For amikacin, the ECOFFs were 64 mg/L for MAC and MAB. For moxifloxacin, the WT spanned >8 mg/L for both MAC and MAB. For linezolid, the ECOFF and TECOFF were 64 mg/L for M. avium and M. intracellulare, respectively. Current CLSI breakpoints for amikacin (16 mg/L), moxifloxacin (1 mg/L) and linezolid (8 mg/L) divided the corresponding WT distributions. For QC M. avium and M. peregrinum, ≥95% of MIC values were well within recommended QC ranges.
CONCLUSION
As a first step towards clinical breakpoints for NTM, (T)ECOFFs were defined for several antimicrobials against MAC and MAB. Broad wild-type MIC distributions indicate a need for further method refinement which is now under development within the EUCAST subcommittee for anti-mycobacterial drug susceptibility testing. In addition, we showed that several CLSI NTM breakpoints are not consistent in relation to the (T)ECOFFs.
Topics: Humans; Mycobacterium avium Complex; Anti-Bacterial Agents; Nontuberculous Mycobacteria; Amikacin; Mycobacterium abscessus; Moxifloxacin; Linezolid; Mycobacterium avium-intracellulare Infection; Microbial Sensitivity Tests; Drug Resistance, Bacterial; Macrolides; Mycobacterium tuberculosis; Mycobacterium Infections, Nontuberculous; Mycobacterium avium
PubMed: 36813087
DOI: 10.1016/j.cmi.2023.02.007 -
Radiologia 2023To describe the epidemiology and CT findings for nontuberculous mycobacterial lung infections and outcomes depending on the treatment.
OBJECTIVE
To describe the epidemiology and CT findings for nontuberculous mycobacterial lung infections and outcomes depending on the treatment.
MATERIAL AND METHODS
We retrospectively studied 131 consecutive patients with positive cultures for nontuberculous mycobacteria between 2005 and 2016. We selected those who met the criteria for nontuberculous mycobacterial lung infection. We analysed the epidemiologic data; clinical, microbiological, and radiological findings; treatment; and outcome according to treatment.
RESULTS
We included 34 patients (mean age, 55 y; 67.6% men); 50% were immunodepressed (58.8% of these were HIV+), 20.6% had COPD, 5.9% had known tumors, 5.9% had cystic fibrosis, and 29.4% had no comorbidities. We found that 20.6% had a history of tuberculosis and 20.6% were also infected with other microorganisms. Mycobacterium avium complex was the most frequently isolated germ (52.9%); 7 (20.6%) were also infected with other organisms. The most common CT findings were nodules (64.7%), tree-in-bud pattern (61.8%), centrilobular nodules (44.1 %), consolidations (41.2%), bronchiectasis (35.3%), and cavities (32.4%). We compared findings between men and women and between immunodepressed and immunocompetent patients. Treatment was antituberculosis drugs in 67.6% of patients (72% of whom showed improvement) and conventional antibiotics in 20.6% (all of whom showed radiologic improvement).
CONCLUSION
The diagnosis of nontuberculous mycobacterial lung infections is complex. The clinical and radiologic findings are nonspecific and a significant percentage of pateints can have other, concomitant infections.
Topics: Male; Humans; Female; Middle Aged; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Retrospective Studies; Cystic Fibrosis; Pneumonia; Antitubercular Agents; Lung
PubMed: 37758330
DOI: 10.1016/j.rxeng.2023.09.001 -
PloS One 2023The role of bacterial microbiota in the pathogenesis of nontuberculous mycobacterial pulmonary disease (NTM-PD) is unclear. We aimed to compare the bacterial microbiome...
BACKGROUND
The role of bacterial microbiota in the pathogenesis of nontuberculous mycobacterial pulmonary disease (NTM-PD) is unclear. We aimed to compare the bacterial microbiome of disease-invaded lesions and non-invaded lung tissue from NTM-PD patients.
METHODS
We analyzed lung tissues from 23 NTM-PD patients who underwent surgical lung resection. Lung tissues were collected in pairs from each patient, with one sample from a disease-involved site and the other from a non-involved site. Lung tissue microbiome libraries were constructed using 16S rRNA gene sequences (V3-V4 regions).
RESULTS
Sixteen (70%) patients had Mycobacterium avium complex (MAC)-PD, and the remaining seven (30%) had Mycobacterium abscessus-PD. Compared to non-involved sites, involved sites showed greater species richness (ACE, Chao1, and Jackknife analyses, all p = 0.001); greater diversity on the Shannon index (p = 0.007); and genus-level differences (Jensen-Shannon, PERMANOVA p = 0.001). Analysis of taxonomic biomarkers using linear discriminant analysis (LDA) effect sizes (LEfSe) demonstrated that several genera, including Limnohabitans, Rahnella, Lachnospira, Flavobacterium, Megamonas, Gaiella, Subdoligranulum, Rheinheimera, Dorea, Collinsella, and Phascolarctobacterium, had significantly greater abundance in involved sites (LDA >3.00, p <0.05, and q <0.05). In contrast, Acinetobacter had significantly greater abundance at non-involved sites (LDA = 4.27, p<0.001, and q = 0.002). Several genera were differentially distributed between lung tissues from MAC-PD (n = 16) and M. abscessus-PD (n = 7), and between nodular bronchiectatic form (n = 12) and fibrocavitary form (n = 11) patients. However, there was no genus with a significant q-value.
CONCLUSIONS
We identified differential microbial distributions between disease-invaded and normal lung tissues from NTM-PD patients, and microbial diversity was significantly higher in disease-invaded tissues.
TRIAL REGISTRATION
Clinical Trial registration number: NCT00970801.
Topics: Humans; RNA, Ribosomal, 16S; Mycobacterium Infections, Nontuberculous; Mycobacterium avium Complex; Lung Diseases; Lung; Microbiota; Nontuberculous Mycobacteria
PubMed: 37235629
DOI: 10.1371/journal.pone.0285143 -
Antimicrobial Agents and Chemotherapy Jun 2023Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and...
Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and has been confirmed to exhibit favorable activity against a well known pulmonary pathogen, Mycobacterium abscessus. However, according to ClinicalTrials.gov, in 2017, a clinical phase II study on the use of epetraborole to treat complicated urinary tract and intra-abdominal infections was terminated due to the rapid emergence of drug resistance during treatment. Nevertheless, epetraborole is in clinical development for nontuberculous mycobacteria (NTM) disease especially for Mycobacterium avium complex-related pulmonary disease (MAC-PD). DS86760016, an epetraborole analog, was further demonstrated to have an improved pharmacokinetic profile, lower plasma clearance, longer plasma half-life, and higher renal excretion than epetraborole in animal models. In this study, DS86760016 was found to be similarly active against M. abscessus , intracellularly, and in zebrafish infection models with a low mutation frequency. These results expand the diversity of druggable compounds as new benzoxaborole-based candidates for treating M. abscessus diseases.
Topics: Animals; Mycobacterium abscessus; Zebrafish; Mycobacterium Infections, Nontuberculous; Anti-Bacterial Agents; Amino Acyl-tRNA Synthetases; Nontuberculous Mycobacteria
PubMed: 37212672
DOI: 10.1128/aac.01567-22 -
Antimicrobial Agents and Chemotherapy Nov 2023Rifampicin is recommended for the treatment of complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with...
Rifampicin is recommended for the treatment of complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with and without rifampicin in an intracellular hollow fiber model and performed RNA sequencing to study the differences in adaptation. In an hollow fiber experiment, we simulated epithelial lining fluid pharmacokinetic profiles of the recommended 3-drug (rifampicin, ethambutol, and azithromycin) or a 2-drug (ethambutol and azithromycin) treatment. THP-1 cells infected with ATCC700898 were exposed to these regimens for 21 days. We determined intra- and extra-cellular bacterial load- and THP-1 cell densities on days 0, 3, 7, 14, and 21, alongside RNA sequencing. The emergence of macrolide resistance was studied by inoculating intra- and extra-cellular fractions of azithromycin-containing Middlebrook 7H10 agar plates. Complete pharmacokinetic profiles were determined at days 0 and 21. Both therapies maintained stasis of both intra- and extra-cellular bacterial populations for 3 days, whilst regrowth coinciding with the emergence of a macrolide-resistant subpopulation was seen after 7 days. THP-1 cell density remained static. Similar transcriptional profiles were observed for both therapies that were minimally influenced by exposure duration. Transcriptional response was slightly larger during 2-drug treatment. Rifampicin did not add to the antimycobacterial effect to the 2-drug therapy or suppression of emergence resistance. RNA transcription was not greatly altered by the addition of rifampicin, which may be due to strong transcriptional influence of azithromycin and host cells. This questions the role of rifampicin in the currently recommended therapy. These findings should be confirmed in clinical trials.
Topics: Humans; Rifampin; Mycobacterium avium; Anti-Bacterial Agents; Ethambutol; Azithromycin; Macrolides; Drug Resistance, Bacterial; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Lung Diseases
PubMed: 37877693
DOI: 10.1128/aac.00874-23 -
Frontiers in Cellular and Infection... 2023The incidence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) has increased in recent years. However, the clinical and immunologic characteristics of NTM-PD...
Clinical characteristics of patients with non-tuberculous mycobacterial pulmonary disease: a seven-year follow-up study conducted in a certain tertiary hospital in Beijing.
BACKGROUND
The incidence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) has increased in recent years. However, the clinical and immunologic characteristics of NTM-PD patients have received little attention.
METHODS
NTM strains, clinical symptoms, underlying diseases, lung CT findings, lymphocyte subsets, and drug susceptibility tests (DSTs) of NTM-PD patients were investigated. Then, the counts of immune cells of NTM-PD patients and their correlation were evaluated using principal component analysis (PCA) and correlation analysis.
RESULTS
135 NTM-PD patients and 30 healthy controls (HCs) were enrolled from 2015 to 2021 in a certain tertiary hospital in Beijing. The number of NTM-PD patients increased every year, and (), , , and were the major pathogens of NTM-PD. The main clinical symptoms of NTM-PD patients were cough and sputum production, and the primary lung CT findings were thin-walled cavity, bronchiectasis, and nodules. In addition, we identified 23 clinical isolates from 87 NTM-PD patients with strain records. The DST showed that almost all of and more than half of the and complex groups were resistant to anti-tuberculosis drugs tested in this study. was resistant to all aminoglycosides. was 100% resistant to kanamycin, capreomycin, amikacin, and para-aminosalicylic acid, and sensitive to streptomycin, ethambutol, levofloxacin, azithromycin, and rifamycin. Compared to other drugs, low resistance to rifabutin and azithromycin was observed among NTM-PD isolates. Furthermore, the absolute counts of innate and adaptive immune cells in NTM-PD patients were significantly lower than those in HCs. PCA and correlation analysis revealed that total T, CD4, and CD8 T lymphocytes played an essential role in the protective immunity of NTM-PD patients, and there was a robust positive correlation between them.
CONCLUSION
The incidence of NTM-PD increased annually in Beijing. Individuals with bronchiectasis and COPD have been shown to be highly susceptible to NTM-PD. NTM-PD patients is characterized by compromised immune function, non-specific clinical symptoms, high drug resistance, thin-walled cavity damage on imaging, as well as significantly reduced numbers of both innate and adaptive immune cells.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Follow-Up Studies; Tertiary Care Centers; Azithromycin; Lung Diseases; Antitubercular Agents; Bronchiectasis
PubMed: 37424783
DOI: 10.3389/fcimb.2023.1205225