Clinical application value of metagenome next-generation sequencing in pulmonary diffuse exudative lesions: a retrospective study.

Objective: This study aims to investigate the clinical application value of Metagenome Next-Generation Sequencing (mNGS) for pulmonary diffuse exudative lesions. Methods: From January 1, 2014, to November 31, 2021, 136 cases with chest radiologic presentations of pulmonary diffuse exudative lesions admitted to Fujian Provincial Hospital were included in the study; of those, 77 patients underwent mNGS pathogen detection. Based on the pathogen detection outcomes and clinical diagnoses, patients were categorized into an infection group (IG) and a non-infection group (NIG). A comparison was made between the diagnostic efficacy of the mNGS technique and traditional culture methods. Meanwhile, 59 patients clinically identified as having infectious pulmonary diffuse exudative lesions but who did not receive mNGS testing were designated as the non-NGS infection group (non-IG). A retrospective cohort study was conducted on patients in both the IG and non-IG, with a 30-day all-cause mortality endpoint used for follow-up. Outcomes: When compared to conventional culture methods, mNGS demonstrated an approximate 35% increase in sensitivity (80.0% vs 45.5%, P<0.001), without significant disparity in specificity (77.3% vs 95.5%, P=0.185). Under antibiotic exposure, the positivity rate detected by mNGS was notably higher than that by traditional culture methods, indicating that mNGS is less affected by exposure to antibiotics (P<0.05). Within 30 days, the all-cause mortality rate for patients in the IG versus the non-IG was 14.55% and 37.29%, respectively (P<0.05). Following a COX regression analysis to adjust for confounding factors, the analysis revealed that a CURB-65 score ≥3 points (HR=3.348, P=0.001) and existing cardiovascular disease (HR=2.473, P=0.026) were independent risk factors for these patients. Conversely, mNGS testing (HR=0.368, P=0.017) proved to be an independent protective factor. Conclusion: mNGS technology makes it easier to pinpoint the cause of pulmonary diffuse infectious exudative lesions without much interference from antibiotics, helping doctors spot and diagnose these issues early on, thereby playing a key role in helping them decide the best treatment approach for patients. Such conclusions may have a bias, as the performance of traditional methods might be underestimated due to the absence of complete results from other conventional diagnostic techniques like serological testing and PCR.

Comparison of the sputum microbiome between patients with stable nontuberculous mycobacterial pulmonary disease and patients requiring treatment.

BACKGROUND: We evaluated whether the sputum bacterial microbiome differs between nontuberculous mycobacteria pulmonary disease (NTM-PD) patients with stable disease not requiring antibiotic treatment and those requiring antibiotics. METHODS: We collected sputum samples from 21 clinically stable NTM-PD patients (stable group) and 14 NTM-PD patients needing antibiotic treatment (treatment group). We also obtained 13 follow-up samples from the stable group. We analyzed the 48 samples using 16S rRNA gene sequencing (V3-V4 region) and compared the groups. RESULTS: In the linear discriminant analysis effect size (LEfSe) analysis, the species Porphyromonas pasteri, Haemophilus parahaemolyticus, Prevotella nanceiensis, and Gemella haemolysans were significantly more prevalent in the sputum of the stable group compared to the treatment group. No taxa showed significant differences in alpha-/beta-diversity or LEfSe between the 21 baseline and 13 follow-up sputum samples in the stable group. In the stable group, the genus Bergeyella and species Prevotella oris were less common in patients who achieved spontaneous culture conversion (n = 9) compared to those with persistent NTM positivity (n = 12) (effect size 3.04, p = 0.039 for Bergeyella; effect size 3.64, p = 0.033 for P. oris). In the treatment group, H. parainfluenzae was more common in patients with treatment success (n = 7) than in treatment-refractory patients (n = 7) (effect size 4.74, p = 0.013). CONCLUSIONS: Our study identified distinct bacterial taxa in the sputum of NTM-PD patients based on disease status. These results suggest the presence of a microbial environment that helps maintain disease stability.

Chlamydia muridarum Associated Pulmonary and Urogenital Disease and Pathology in a Colony of Enzootically Infected Il12rb2 Deficient and Stat1 Knockout Mice.

Chlamydia muridarum (Cm), an intracellular bacterium of historical importance, was recently rediscovered as moderately prevalent in research mouse colonies. Cm was first reported as a causative agent of severe pneumonia in mice about 80 y ago, and while it has been used experimentally to model Chlamydia trachomatis infection of humans, there have been no further reports of clinical disease associated with natural infection. We observed clinical disease and pathology in 2 genetically engi- neered mouse (GEM) strains, Il12rb2 KO and STAT1 KO, with impaired interferon-γ signaling and Th1 CD4+ T cell responses in a colony of various GEM strains known to be colonized with and shedding Cm. Clinical signs included poor condition, hunched posture, and poor fecundity. Histopathology revealed disseminated Cm with lesions in pulmonary, gastrointestinal, and urogenital tissues. The presence of Cm was confirmed using both immunohistochemistry for Cm major outer membrane protein-1 antigen and in situ hybridization using a target probe directed against select regions of Cm strain Nigg. Cm was also found in association with a urothelial papilloma in one mouse. These cases provide additional support for excluding Cm from research mouse colonies.

Pulmonary infections with nontuberculous mycobacteria.

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.

Bigger problems from smaller colonies: emergence of antibiotic-tolerant small colony variants of Mycobacterium avium complex in MAC-pulmonary disease patients.

BACKGROUND: Mycobacterium avium complex (MAC) is a group of slow-growing mycobacteria that includes Mycobacterium avium and Mycobacterium intracellulare. MAC pulmonary disease (MAC-PD) poses a threat to immunocompromised individuals and those with structural pulmonary diseases worldwide. The standard treatment regimen for MAC-PD includes a macrolide in combination with rifampicin and ethambutol. However, the treatment failure and disease recurrence rates after successful treatment remain high. RESULTS: In the present study, we investigated the unique characteristics of small colony variants (SCVs) isolated from patients with MAC-PD. Furthermore, revertant (RVT) phenotype, emerged from the SCVs after prolonged incubation on 7H10 agar. We observed that SCVs exhibited slower growth rates than wild-type (WT) strains but had higher minimum inhibitory concentrations (MICs) against multiple antibiotics. However, some antibiotics showed low MICs for the WT, SCVs, and RVT phenotypes. Additionally, the genotypes were identical among SCVs, WT, and RVT. Based on the MIC data, we conducted time-kill kinetic experiments using various antibiotic combinations. The response to antibiotics varied among the phenotypes, with RVT being the most susceptible, WT showing intermediate susceptibility, and SCVs displaying the lowest susceptibility. CONCLUSIONS: In conclusion, the emergence of the SCVs phenotype represents a survival strategy adopted by MAC to adapt to hostile environments and persist during infection within the host. Additionally, combining the current drugs in the treatment regimen with additional drugs that promote the conversion of SCVs to RVT may offer a promising strategy to improve the clinical outcomes of patients with refractory MAC-PD.

Pathological analysis and etiological assessment of pulmonary lesions and its association with pleurisy in slaughtered pigs.

The intensification of pig farming has posed significant challenges in managing and preventing sanitary problems, particularly diseases of the respiratory complex. Monitoring at slaughter is an important control tool and cannot be overstated. Hence, this study aimed at characterizing both macroscopical and microscopical lesions and identifying the Actinobacillus pleuropneumoniae (APP), Mycoplasma hyopneumoniae (Mhyo), and Pasteurella multocida (PM) associated with pleurisy in swine. For this, a selected slaughterhouse in São Paulo State underwent a thorough examination of carcasses on the slaughter line, followed by lung sampling. The carcasses and lungs underwent macroscopical examination and were classified according to the score of pleurisy and lung samples were allocated into five groups, being: G0: score 0 - no lesions; G1: score 1; G2: score 2; G3: score 3; and G4: score 4. In total, 217 lung fragments were collected, for the histopathological evaluation and detection of the following respiratory pathogens: APP, Mhyo, and PM by qPCR. The results demonstrated that Mhyo and APP were the most prevalent etiological agents (single and co-identification) in lung samples, in different scores of pleurisies, while bronchopneumonia and bronchus-associated lymphoid tissue (BALT) hyperplasia lesions were the most frequent histopathological findings. Positive correlations were found between the quantification of APP DNA with 1) the score of pleurisy (R=0.254); 2) with the score of lung consolidation in all lung lobes (R=0.181 to R=0.329); and 3) with the score of lung consolidation in the entire lung (R=0.389). The study brings relevant information regarding the main bacterial pathogens associated with pleurisy in pigs and helps with understanding the relationship between the abovementioned pathogens and their impact on the respiratory health of pigs.

Advances in diagnosis and treatment of non-tuberculous mycobacterial lung disease.

The prevalence of Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) is increasing worldwide. The advancement in molecular diagnostic technology has greatly promoted the rapid diagnosis of NTM-PD clinically, and the pathogenic strains can be identified to the species level through molecular typing, which provides a reliable basis for treatment. In addition to the well-known PCR and mNGS methods, there are numerous alternative methods to identify NTM to the species level. The treatment of NTM-PD remains a challenging problem. Although clinical guidelines outline several treatment options for common NTM species infections, in most cases, the therapeutic outcomes of these drugs for NTM-PD often fall short of expectations. At present, the focus of research is to find more effective and more tolerable NTM-PD therapeutic drugs and regimens. In this paper, the latest diagnostic techniques, therapeutic drugs and methods, and prevention of NTM-PD are reviewed.

Therapeutic developments for tuberculosis and nontuberculous mycobacterial lung disease.

Tuberculosis (TB) drug discovery and development has undergone nothing short of a revolution over the past 20 years. Successful public-private partnerships and sustained funding have delivered a much-improved understanding of mycobacterial disease biology and pharmacology and a healthy pipeline that can tolerate inevitable attrition. Preclinical and clinical development has evolved from decade-old concepts to adaptive designs that permit rapid evaluation of regimens that might greatly shorten treatment duration over the next decade. But the past 20 years also saw the rise of a fatal and difficult-to-cure lung disease caused by nontuberculous mycobacteria (NTM), for which the drug development pipeline is nearly empty. Here, we discuss the similarities and differences between TB and NTM lung diseases, compare the preclinical and clinical advances, and identify major knowledge gaps and areas of cross-fertilization. We argue that applying paradigms and networks that have proved successful for TB, from basic research to clinical trials, will help to populate the pipeline and accelerate curative regimen development for NTM disease.

The timing of intravenous antibiotics and clinical outcomes of Mycobacterium abscessus complex lung diseases.

BACKGROUND: The importance of early intravenous (IV) antibiotic use for Mycobacterium abscessus complex lung diseases (MABC-LD) treatment remains unknown. METHODS: A retrospective multi-centre observational study was conducted in Taiwan. Patients who were diagnosed with and received treatment for MABC-LD from January 2007 to April 2021 were included. Treatment outcome was defined as modified microbiological cure of MABC-LD.RESULTS: Of the 89 enrolled patients, 34 (38.2%) received IV antibiotics as part of the treatment regimen. The median time to IV initiation was 1 day (IQR 1???49); 24 (70.6%) of these patients received IV agents within 4 weeks, defined as early-use. Forty-two (47.2%) patients achieved modified microbiological cure. In the multivariable logistic analysis, early IV antibiotic use was an independent factor associated with modified microbiological cure (aOR 5.32, 95% CI 1.66???17.00), whereas high radiological score (aOR 0.86, 95% CI 0.73???1.00) demonstrated negative association.CONCLUSIONS: In the present study, early use of effective IV antibiotic was prescribed in a low percentage (27%) for MABC-LD. By contrast, early IV antibiotic use was correlated with higher microbiological cure than were late or non-use. Future larger and prospective studies are needed to validate the association.

Effect of multidrug therapy on the prognosis of Mycobacterium avium complex pulmonary disease.

Multidrug therapy for Mycobacterium avium complex pulmonary disease (MAC-PD) results in negative sputum cultures. However, the prognostic value of this treatment approach remains unclear. This study aimed to clarify whether multidrug therapy reduces the incidence of events related to MAC-PD and improves the mortality rate. Patients who met the diagnostic criteria for MAC-PD at our hospital between 2003 and 2019 were retrospectively evaluated using medical records. Events related to MAC-PD were defined as hospitalisation for haemoptysis or respiratory infection and the development of chronic respiratory failure. There were 90 and 108 patients in the multidrug and observation groups, respectively. The median observation period was 86 months. Intergroup differences in body mass index, proportion of patients with cavities, and erythrocyte sedimentation rate were not significant. However, the observation group was older with a higher mean age (multidrug group: 62 years, observation group: 69 years; P < 0.001) and had a higher proportion of male patients (multidrug group: 13/90 [14.4%], observation group: 35/108 [32.4%]; P < 0.01). Furthermore, intergroup differences in the incidence of events related to MAC-PD (multidrug group: 26.69/1000 person-years, observation group: 25.49/1000 person-years), MAC-PD-associated mortality rate (multidrug group: 12.13/1000 person-years, observation group: 12.74/1000 person-years), and total mortality (multidrug group: 24.26/1000 person-years, observation group: 29.50/1000 person-years) were not significant. Many patients relapse even after multidrug therapy, and our findings suggest that multidrug therapy has no effect in preventing the onset of respiratory events or prolonging life expectancy.

Clofazimine as a substitute for rifampicin improves efficacy of Mycobacterium avium pulmonary disease treatment in the hollow-fiber model.

Mycobacterium avium complex pulmonary disease is treated with an azithromycin, ethambutol, and rifampicin regimen, with limited efficacy. The role of rifampicin is controversial due to inactivity, adverse effects, and drug interactions. Here, we evaluated the efficacy of clofazimine as a substitute for rifampicin in an intracellular hollow-fiber infection model. THP-1 cells, which are monocytes isolated from peripheral blood from an acute monocytic leukemia patient, were infected with M. avium ATCC 700898 and exposed to a regimen of azithromycin and ethambutol with either rifampicin or clofazimine. Intrapulmonary pharmacokinetic profiles of azithromycin, ethambutol, and rifampicin were simulated. For clofazimine, a steady-state average concentration was targeted. Drug concentrations and bacterial densities were monitored over 21 days. Exposures to azithromycin and ethambutol were 20%-40% lower than targeted but within clinically observed ranges. Clofazimine exposures were 1.7 times higher than targeted. Until day 7, both regimens were able to maintain stasis. Thereafter, regrowth was observed for the rifampicin-containing regimen, while the clofazimine-containing regimen yielded a 2 Log10 colony forming unit (CFU) per mL decrease in bacterial load. The clofazimine regimen also successfully suppressed the emergence of macrolide tolerance. In summary, substitution of rifampicin with clofazimine in the hollow-fiber model improved the antimycobacterial activity of the regimen. Clofazimine-containing regimens merit investigation in clinical trials.

Microbiological persistence in patients with Mycobacterium abscessus complex lung disease: The prevalence, predictors, and the impact on progression.

OBJECTIVES: Persistent growth of Mycobacterium abscessus complex (MABC) in the respiratory system is not uncommon and may indicate continuous infection of MABC lung disease (MABC-LD), but its prevalence, risk factors, and clinical impact have not been investigated. METHODS: The present study was conducted in two medical centers in northern Taiwan. We enrolled patients with MABC-LD and investigated the prevalence and predictors of persistent culture positivity (MABC-PP). Furthermore, we analyzed the association between MABC-PP and radiographic or clinical progression. RESULTS: Among 189 patients with MABC-LD, 58 were in the MABC-PP group. Independent predictors for MABC-PP included an increasing radiographic score and highest acid-fast stain (AFS) of strong positivity (3-4+) at initial diagnosis (compared with negative AFS). MABC-PP and highest AFS were independently associated with MABC-LD progression by the multivariable analysis model. The adjusted hazard ratio increased to 3.56 when the two independent factors existed. CONCLUSIONS: MABC-PP accounted for 30.7% and was predicted by initial AFS grade and radiographic score. Patients with MABC-PP, and highest AFS grade might have disease progression.

Post-treatment Radiographic Severity and Mortality in Mycobacterium avium Complex Pulmonary Disease.

Rationale: Imaging studies are widely performed when treating Mycobacterium avium complex pulmonary disease (MAC-PD); however, the clinical significance of post-treatment radiographic change is unknown. Objectives: To determine whether a deep neural network trained with pulmonary tuberculosis could adequately score the radiographic severity of MAC-PD and then to examine relationships between post-treatment radiographic severity and its change from baseline and long-term prognosis. Methods: We retrospectively collected chest radiographs of adult patients with MAC-PD treated for ⩾6 months at baseline and at 3, 6, 9, and 12 months of treatment. We correlated the radiographic severity score generated by a deep neural network with visual and clinical severity as determined by radiologists and mycobacterial culture status, respectively. The associations between the score, improvement from baseline, and mortality were analyzed using Cox proportional hazards regression. Results: In total, 342 and 120 patients were included in the derivation and validation cohorts, respectively. The network's severity score correlated with radiologists' grading (Spearman coefficient, 0.40) and mycobacterial culture results (odds ratio, 1.02; 95% confidence interval [CI], 1.0-1.05). A significant decreasing trend in the severity score was observed over time (P < 0.001). A higher score at 12 months of treatment was independently associated with higher mortality (adjusted hazard ratio, 1.07; 95% CI, 1.03-1.10). Improvements in radiographic scores from baseline were associated with reduced mortality, regardless of culture conversion (adjusted hazard ratio, 0.42; 95% CI, 0.22-0.80). These findings were replicated in the validation cohort. Conclusions: Post-treatment radiographic severity and improvement from baseline in patients with MAC-PD were associated with long-term survival.

Comparing minimum inhibitory concentrations of amikacin for pulmonary Mycobacterium avium complex disease: An analysis of culture media differences.

Mycobacterium avium complex (MAC) is considered a paramount microbe, especially in East Asia, including Japan. The commonly used commercial Minimum Inhibitory Concentrations (MIC) assay using Middlebrook 7H9 (7H9) medium deviates from the latest Clinical and Laboratory Standards Institute (CLSI) guidelines. Alternatively, measurement with cation-adjusted Mueller-Hinton broth (CAMHB) that conforms to CLSI standards is not yet widely available. Following the approval and commercialization of amikacin liposome inhalation suspension (ALIS) in 2021, a more precise evaluation of amikacin (AMK) susceptibility in MAC is necessary for treatment decisions. In the present study, 33 sputum samples were extracted from 27 patients, and MICs of AMK were compared between the frequently used 7H9 and the recommended CAMHB of the isolated MAC strains. The history of exposure to aminoglycosides for each sample was also added as clinical information. The findings indicated that there was only an 18% concordance rate in MIC between the two media, with 19 samples (58%) indicating lower MICs in 7H9 relative to CAMHB. The 17 samples had a history of exposure to aminoglycosides for periods ranging from 1.5 to 28 months. Specifically, 10 samples were exposed to amikacin by inhalation and intravenous injection, and the remaining seven samples had a history of ALIS inhalation. Samples with a prior utilization of aminoglycosides were significantly predisposed to developing resistance to ALIS compared to those without such a history (P = 0.046). Physicians are encouraged to scrutinize the findings of susceptibility testing utilizing CLSI-endorsed MIC assay using CAMHB medium to ascertain the optimal therapeutic approach.

External Validation of the BACES Score in Canadian Patients With Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: The clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) can be variable and difficult to predict. Recently, the BACES score was developed as a tool to predict all-cause mortality in patients with NTM-PD. This score is calculated based on five patient characteristics (BMI, age, cavity, erythrocyte sedimentation rate, and sex), and higher scores portend worse prognosis. Although the BACES score has been validated in a cohort of South Korean patients, it has not yet been validated in other settings or ethnic groups. RESEARCH QUESTION: How well does the BACES mortality score perform in a cohort of Canadian patients with NTM-PD? STUDY DESIGN AND METHODS: We performed a single-center retrospective chart review. Patients who were seen between July 2003 and June 2021 were eligible for inclusion if they met guideline-based diagnostic criteria for NTM-PD and were excluded if any component of the BACES score was missing. To assess the model's discriminatory performance, we compared Kaplan-Meier curves between risk groups and calculated Harrell's C index. To assess calibration, we used a graphical calibration curve. RESULTS: The cohort included 435 patients with a median follow-up of 5.8 years. The median age was 64 years and 74% were female. Based on the BACES scores, patients were classified into three risk groups: low, moderate, or high. Survival curves showed clear separation of the risk groups. Harrell's C index was 0.733 in the study cohort, indicating moderate to good discriminatory performance, although this was lower than the value reported in the derivation cohort (0.812). The graphical calibration curve showed a tendency of the BACES model to underpredict mortality. INTERPRETATION: The BACES model was evaluated in a multicultural cohort of Canadian patients and demonstrated good discriminatory performance but suboptimal calibration, which may be due to population differences, the use of dichotomized variables in model construction, or both.

Effectiveness and safety of regimens containing linezolid for treatment of Mycobacterium abscessus pulmonary Disease.

OBJECTIVE: To evaluate the effectiveness and safety of linezolid-containing regimens for treatment of M. abscessus pulmonary disease. METHODS: The records of 336 patients with M. abscessus pulmonary disease who were admitted to Shanghai Pulmonary Hospital from January 2018 to December 2020 were retrospectively analyzed. A total of 164 patients received a linezolid-containing regimen and 172 controls did not. The effectiveness, safety, antibiotic susceptibility profiles, outcomes, culture conversion, cavity closure, and adverse reactions were compared in these two groups. RESULTS: The two groups had similar treatment success (56.1% vs. 48.8%; P > 0.05), but treatment duration was shorter in the linezolid group (16.0 months [inter-quartile ranges, IQR: 15.0-17.0] vs. 18.0 months [IQR: 16.0-18.0]; P < 0.01). The rates of sputum culture conversion were similar (53.7% vs. 46.5%, P > 0.05), but time to conversion was shorter in the linezolid group (3.5 months [IQR: 2.5-4.4] vs. 5.5 months [IQR: 4.0-6.8]; P < 0.01). The linezolid group had a higher rate of cavity closure (55.2% vs. 28.6%, P < 0.05) and a shorter time to cavity closure (3.5 months [IQR: 2.5-4.4] vs. 5.5 months [IQR: 4.0-6.8]; P < 0.01). Anemia and peripheral neuropathy were more common in the linezolid group (17.7% vs. 1.7%, P < 0.01; 12.8% vs. 0.6%, P < 0.01). CONCLUSIONS: The linezolid and control groups had similar treatment success rates. The linezolid group had a shorter treatment duration, shorter time to sputum culture conversion, and higher rate and shorter time to lung cavity closure. More patients receiving linezolid developed anemia and peripheral neuropathy.

Changes in sputum microbiota during treatment for nontuberculous mycobacterial pulmonary disease.

Limited data exist on longitudinal changes in the sputum bacterial microbiome during treatment in nontuberculous mycobacterial pulmonary disease (NTM-PD) patients. We prospectively collected serial sputum samples from 14 NTM-PD patients during treatment, at the start (n = 14) and at 1 (n = 10), 3 (n = 10), 6 (n = 12), and 12 (n = 7) months. The bacterial microbiome changes were analyzed using 16S rRNA sequences (V3-V4 regions). Subgroup analysis included culture conversion (n = 9) and treatment refractory (n = 5) groups. In all patients, sputum alpha-diversity (ACE, Chao1, and Jackknife) significantly decreased during antibiotic treatment at 1, 3, 6, and 12 months compared to treatment initiation levels. Within the culture conversion group, genus/species-level beta-diversity showed differences at 1, 3, 6, and 12 months compared to treatment initiation (all p < 0.05). However, in the refractory group, there were no differences in beta-diversity at the genus/species levels in the sputum at any time point. In the linear discriminant analysis (LDA) effect sizes (LEfSe) analysis, the culture conversion group exhibited decreasing taxa at various levels (phylum/genus/species), but no significant increase in taxa was observed. LEfSe analysis of the refractory patient group revealed multiple taxa decreased during treatment. However, proportions of Veillonella dispar (LDA = 4.78), Fusobacterium periodonticum (LDA = 4.35), and Pseudomonas aeruginosa (LDA = 2.92) increased as the treatment period progressed in the refractory group. Sputum microbiota diversity decreases during NTM-PD treatment. In the culture conversion group, most taxa decrease, while some increase in the refractory group. These findings suggest that a distinct respiratory microbial community may exist in refractory NTM-PD patients compared to responsive antibiotic-treated patients.

Non-tuberculous mycobacterial disease: progress and advances in the development of novel candidate and repurposed drugs.

Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved organ, with NTM pulmonary diseases causing serious health issues in patients with underlying lung disease. Moreover, NTM infections have been steadily increasing worldwide in recent years. NTM are also naturally resistant to many antibiotics, specifically anti-tuberculosis (anti-TB) drugs. The lack of drugs targeting NTM infections and the increasing drug resistance of NTM have further made treating these mycobacterial diseases extremely difficult. The currently recommended NTM treatments rely on the extended indications of existing drugs, which underlines the difficulties of new antibiotic discovery against NTM. Another challenge is determining which drug combinations are most effective against NTM infection. To a certain extent, anti-NTM drug development depends on using already available antibiotics and compounds. Here, we aimed to review new antibiotics or compounds with good antibacterial activity against NTM, focusing on their mechanisms of action, in vitro and in vivo antibacterial activities.