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.

[A case of nontuberculous mycobacterium presenting as a mass and atelectasis with mediastinal and hilar lymph node enlargement].

With the development of testing technology, the diagnosis of nontuberculous mycobacterium (NTM) lung disease has gradually increased in recent years. Because the clinical characteristics of NTM are not typical, and its imaging manifestations are diverse and nonspecific, missed diagnosis and misdiagnosis are common. Etiological investigation is necessary for diagnosis. Conventional etiological investigations are very limited for the diagnosis of NTM. We reported a case of NTM lung disease presenting with a mass and atelectasis with mediastinal and hilar lymph node enlargement that resembled malignant tumors. The literature on this condition was reviewed to improve the clinician's understanding and broaden clinical thinking.

Non-tuberculous mycobacterial pulmonary infection presenting in a patient with unilateral pulmonary artery agenesis.

People who have structural or developmental lung disease are more likely to develop non-tuberculous mycobacterial infections. We present the case of a young man in his 30s who had unilateral pulmonary artery agenesis on the right side and presented with a 6-month history of productive cough and fever. His CT scan showed nodular and cavitating lesions on the right side, and sputum analysis confirmed infection with Mycobacterium chimaera He had to undergo modifications in his treatment, including a change from rifampicin to rifabutin due to drug interactions and his amikacin had to be stopped due to signs of vestibular toxicity. Using a multidisciplinary approach, we were able to formulate an appropriate drug regimen for him, and he is now under regular follow-up with infectious diseases and respiratory medicine.

Multiparameter immunoprofiling for the diagnosis and differentiation of progressive versus nonprogressive nontuberculous mycobacterial lung disease-A pilot study.

Clinical prediction of nontuberculous mycobacteria lung disease (NTM-LD) progression remains challenging. We aimed to evaluate antigen-specific immunoprofiling utilizing flow cytometry (FC) of activation-induced markers (AIM) and IFN-γ enzyme-linked immune absorbent spot assay (ELISpot) accurately identifies patients with NTM-LD, and differentiate those with progressive from nonprogressive NTM-LD. A Prospective, single-center, and laboratory technician-blinded pilot study was conducted to evaluate the FC and ELISpot based immunoprofiling in patients with NTM-LD (n = 18) and controls (n = 22). Among 18 NTM-LD patients, 10 NTM-LD patients were classified into nonprogressive, and 8 as progressive NTM-LD based on clinical and radiological features. Peripheral blood mononuclear cells were collected from patients with NTM-LD and control subjects with negative QuantiFERON results. After stimulation with purified protein derivative (PPD), mycobacteria-specific peptide pools (MTB300, RD1-peptides), and control antigens, we performed IFN-γ ELISpot and FC AIM assays to access their diagnostic accuracies by receiver operating curve (ROC) analysis across study groups. Patients with NTM-LD had significantly higher percentage of CD4+/CD8+ T-cells co-expressing CD25+CD134+ in response to PPD stimulation, differentiating between NTM-LD and controls. Among patients with NTM-LD, there was a significant difference in CD25+CD134+ co-expression in MTB300-stimulated CD8+ T-cells (p <0.05; AUC-ROC = 0.831; Sensitivity = 75% [95% CI: 34.9-96.8]; Specificity = 90% [95% CI: 55.5-99.7]) between progressors and nonprogressors. Significant differences in the ratios of antigen-specific IFN-γ ELISpot responses were also seen for RD1-nil/PPD-nil and RD1-nil/anti-CD3-nil between patients with nonprogressive vs. progressive NTM-LD. Our results suggest that multiparameter immunoprofiling can accurately identify patients with NTM-LD and may identify patients at risk of disease progression. A larger longitudinal study is needed to further evaluate this novel immunoprofiling approach.

Disseminated Mycobacterium abscessus with endocarditis.

We present an uncommon case of endocarditis caused by Mycobacterium abscessus in an immunocompetent patient following a caesarean section. We discuss her turbulent admission course leading to her diagnosis following persistent M. abscessus bacteraemia, medical and surgical management, including a splenectomy and valve resection and repair, and subsequent prolonged course of combination antimicrobials for 24 months post valve surgery. The patient is alive 9 months after completing her treatment and 36 months after her valve surgery. We emphasise the importance of a multidisciplinary team approach in the management of such a complex case.

Clinical course of nontuberculous mycobacterial pulmonary disease in patients with rheumatoid arthritis.

OBJECTIVES: The impact of rheumatoid arthritis (RA) on nontuberculous mycobacterial pulmonary disease (NTM-PD) has not been well established. In this study, we investigated the clinical course of NTM-PD in patients with RA and the impact of RA on the prognosis of NTM-PD. METHODS: We analyzed patients who developed NTM-PD after being diagnosed with RA from January 2004 to August 2023 at a tertiary referral hospital in South Korea. The patient's baseline characteristics, clinical course, and prognosis were evaluated. An optimal matching analysis was performed to measure the impact of RA on the risk of mortality. RESULTS: During the study period, 18 patients with RA [median age, 68 years; interquartile range (IQR) 59-73; female, 88.9%] developed NTM-PD. The median interval between RA diagnosis and subsequent NTM-PD development was 14.8 years (IQR, 8.6-19.5). At a median of 30 months (IQR, 27-105) after NTM-PD diagnosis, 10 of 18 (55.6%) patients received anti-mycobacterial treatment for NTM-PD and 5 (50.0%) patients achieved microbiological cure. When matched to patients with NTM-PD but without RA, patients with both RA and NTM-PD had a higher risk of mortality (adjusted hazard ratio, 8.14; 95% confidence interval, 2.43-27.2). CONCLUSION: NTM-PD occurring after RA is associated with a higher risk of mortality than NTM-PD in the absence of RA.

Neutralizing IFN-γ autoantibodies are rare and pathogenic in HLA-DRB1*15:02 or 16:02 individuals.

BACKGROUNDWeakly virulent environmental mycobacteria (EM) can cause severe disease in HLA-DRB1*15:02 or 16:02 adults harboring neutralizing anti-IFN-γ autoantibodies (nAIGAs). The overall prevalence of nAIGAs in the general population is unknown, as are the penetrance of nAIGAs in HLA-DRB1*15:02 or 16:02 individuals and the proportion of patients with unexplained, adult-onset EM infections carrying nAIGAs.METHODSThis study analyzed the detection and neutralization of anti-IFN-γ autoantibodies (auto-Abs) from 8,430 healthy individuals of the general population, 257 HLA-DRB1*15:02 or 16:02 carriers, 1,063 patients with autoimmune disease, and 497 patients with unexplained severe disease due to EM.RESULTSWe found that anti-IFN-γ auto-Abs detected in 4,148 of 8,430 healthy individuals (49.2%) from the general population of an unknown HLA-DRB1 genotype were not neutralizing. Moreover, we did not find nAIGAs in 257 individuals carrying HLA-DRB1* 15:02 or 16:02. Additionally, nAIGAs were absent in 1,063 patients with an autoimmune disease. Finally, 7 of 497 patients (1.4%) with unexplained severe disease due to EM harbored nAIGAs.CONCLUSIONThese findings suggest that nAIGAs are isolated and that their penetrance in HLA-DRB1*15:02 or 16:02 individuals is low, implying that they may be triggered by rare germline or somatic variants. In contrast, the risk of mycobacterial disease in patients with nAIGAs is high, confirming that these nAIGAs are the cause of EM disease.FUNDINGThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI095983 and U19AIN1625568), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), ANR-GENMSMD (ANR-16-CE17-0005-01), ANR-MAFMACRO (ANR-22-CE92-0008), ANRSECTZ170784, the French Foundation for Medical Research (FRM) (EQU201903007798), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AI2D (ANR-22-CE15-0046) projects, the ANR-RHU program (ANR-21-RHUS-08-COVIFERON), the European Union's Horizon 2020 research and innovation program under grant agreement no. 824110 (EASI-genomics), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the Battersea & Bowery Advisory Group, William E. Ford, General Atlantic's Chairman and Chief Executive Officer, Gabriel Caillaux, General Atlantic's Co-President, Managing Director, and Head of business in EMEA, and the General Atlantic Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM) and of Paris Cité University. JR was supported by the INSERM PhD program for doctors of pharmacy (poste d'accueil INSERM). JR and TLV were supported by the Bettencourt-Schueller Foundation and the MD-PhD program of the Imagine Institute. MO was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the New York Hideyo Noguchi Memorial Society (HNMS).

Microevolution, reinfection and highly complex genomic diversity in patients with sequential isolates of Mycobacterium abscessus.

Mycobacterium abscessus is an opportunistic, extensively drug-resistant non-tuberculous mycobacterium. Few genomic studies consider its diversity in persistent infections. Our aim was to characterize microevolution/reinfection events in persistent infections. Fifty-three sequential isolates from 14 patients were sequenced to determine SNV-based distances, assign resistance mutations and characterize plasmids. Genomic analysis revealed 12 persistent cases (0-13 differential SNVs), one reinfection (15,956 SNVs) and one very complex case (23 sequential isolates over 192 months), in which a first period of persistence (58 months) involving the same genotype 1 was followed by identification of a genotype 2 (76 SNVs) in 6 additional alternating isolates; additionally, ten transient genotypes (88-243 SNVs) were found. A macrolide resistance mutation was identified from the second isolate. Despite high diversity, the genotypes shared a common phylogenetic ancestor and some coexisted in the same specimens. Genomic analysis is required to access the true intra-patient complexity behind persistent infections involving M. abscessus.

Shower dehumidification to reduce nontuberculous mycobacteria aerosolization.

OBJECTIVE: Nontuberculous mycobacteria (NTM) are environmentally acquired opportunistic pathogens that can cause recalcitrant lung disease. Prior reports have demonstrated links between shower use and infections, yet the aerosolization of NTM from showerheads, as well as the humidity levels that may modulate NTM aerosolization from showerheads is less studied. The objective of the current study was to investigate the role of humidity in NTM aerosolization among showers in homes located in a geographic area with high lung disease incidence, Hawai'i, and test whether deployment of a dehumidifier in well-ventilated bathrooms reduce NTM exposure. RESULTS: Across two sampling events and five showers, existing NTM showerhead biofilms along with shower air were sampled at three points: pre-shower, post-shower, and post-dehumidification. In each of the sampling events, respiratory relevant NTM species were identified from shower biofilms, which were also detected in aerosolized shower air after showering events, but not after the shower was dehumidified and bathrooms vented. While sample size was small, these data suggest running a shower is a possible source of NTM aerosolization and using a commercial household dehumidifier in conjunction with opening bathroom doors and windows may be simple, cost-effective interventions to reduce environmental NTM exposures.

Non-Tuberculous Mycobacterial isolates from Panama: A retrospective 5-year analysis (2017-2021).

BACKGROUND: The genus Mycobacterium includes well-known bacteria such as M. tuberculosis causing tuberculosis and M. leprae causing leprosy. Additionally, various species collectively termed non-tuberculous mycobacteria (NTM) can cause infections in humans and animals, affecting individuals across all age groups and health conditions. However, information on NTM infection prevalence in Panama is limited. METHODS: This study conducted a retrospective analysis of clinical records from 2017 to 2021, specifically focusing on patients with NTM isolates. Data were categorized by variables like sex, age, HIV status, and sample source. RESULTS: Among the 4430 clinical records analyzed, 698 were linked to patients with NTM isolates. Of these patients, 397 were male, and 301 were female. Most female patients with NTM isolates (n = 190) were aged >45 to 85 years, while most male patients (n = 334) fell in the >25 to 75 years age group. A noteworthy proportion of male patients (n = 65) were aged 25-35 years. A significant age difference between male (median [min-max] = 53 years [3-90]) and female (median [61 years [6-94]) patients was observed (p < 0.001). Regarding HIV status, 77 positive individuals were male, and 19 were female (p < 0.001). Most samples (n = 566) were sputum samples, with additional pulmonary-associated samples such as broncho-alveolar lavage, tracheal secretions, and pleural fluid samples. Among extrapulmonary isolates (n = 48), sources included catheter secretions, intracellular fluids, peritoneal fluid, blood cultures, cerebrospinal fluid, bone marrow samples, and capillary transplant lesions. Specifically, the analysis identified the pathogenic microorganisms responsible for mycobacteriosis in Panama during the specific period 2017-2021, as M. fortuitum (34.4%), M. intracellulare (20.06%), and M. abscessus (13.75%), respectively. CONCLUSIONS: This study highlights the growing public health concern of NTM infections in Panama. The research provides valuable insights into the prevalence and distribution of NTM species in the country, offering a foundation for the development and implementation of effective prevention and control strategies for NTM infections in Panama.

Employing Multicolor Melting Curve Analysis to Rapidly Identify Non-Tuberculous Mycobacteria in Patients with Bronchiectasis: A Study from a Pulmonary Hospital in the Fuzhou District of China, 2018-2022.

Non-tuberculous mycobacteria (NTM) infection is common in bronchiectasis, with rising incidence globally. However, investigation into NTM in bronchiectasis patients in China remains relatively limited. This work aimed to identify and understand the features of NTM in bronchiectasis patient in Fuzhou district of China. The pulmonary samples were collected from 281 bronchiectasis patients with suspected NTM infection in Fuzhou, 2018-2022. MPB64 antigen detection was employed for the preliminary evaluation of NTM. Further NTM identification was realized using gene chip and gene sequencing. Among 281 patients, 172 (61.21%) patients were NTM-positive (58.72%) according to MPB64 antigen detection, with females (58.72%) outnumbering males (41.28%) and the highest prevalence in the age group of 46-65 years. In total, 47 NTM single infections and 3 mixed infections (1 Mycobacterium tuberculosis complex-M. intracellulare, 1 M. avium-M. intracellulare, and 1 M. abscessus-M. intracellulare) were identified through multicolor melting curve analysis (MMCA), which was compared with gene sequencing results. Both methods suggested Mycobacterium (M.) intracellulare, M. abscessus, and M. avium as the primary NTM species affecting bronchiectasis patients. M. intracellulare and M. abscessus were more frequent in females than males with the highest prevalence in the age group of 46-65 years according to MMCA. This research provides novel insights into the epidemiological and clinical features of NTM in bronchiectasis patients in Southeastern China. Significantly, M. intracellulare, M. abscessus, and M. avium were identified as the major NTM species, contributing to a better understanding and management of bronchiectasis accompanied by NTM infection.

Profile of non-tuberculous mycobacteria amongst tuberculosis presumptive people in Cameroon.

BACKGROUND: Cameroon is a tuberculosis (TB) burden country with a 12% positivity among TB presumptive cases. Of the presumptive cases with a negative TB test, some are infected with Non-tuberculous Mycobacteria (NTM). However, the diagnosis of NTM infections remains difficult due to the lack of tools in many laboratories, particularly in resource limited laboratories and remote setting. The present study was undertaken to determine NTM profile and associated comorbidities among TB presumptive people. METHODS: A retrospective study was conducted from December 2018 to December 2019 in the Tuberculosis-National Reference Laboratory (TB-NRL) for Bacteriological analysis of samples and Jamot Hospital of Yaounde (JHY) for clinical evaluation of confirmed NTM patients. We included in this study data of 5267 TB presumptive people previously diagnosed using three consecutive samples and having culture and SD Bioline results with or without Microscopy and reverse hybridization-based Line Probe Assay(LPA) results. The data on co-morbidities or history of people infected with NTM were then collected from the three participants with available clinical data. RESULTS: We collected data of 5267 presumptive TB people. Among them, 3436 (65.24%), have a positive culture with 3200 (60.75%) isolates belong to Mycobacterium tuberculosis Complex (MBTC) and 236 (4.48%) to NTM. Our results showed that, 123 (52.11%) NTM were isolated from people with negative microscopy and 113 (47.88%) from people with positive microscopy. Among the 236 NTM, 108 (45.8%) isolates were identified using LPA. M. fortuitum was the most represented species (32.41%) followed by M. intracellulare (19.44%). Sputum had the highest proportion of NTM (56%), followed by bronchial aspirations (31%). The extra-pulmonary samples presented lower proportions of isolates compared to pulmonary samples. Some patients affected with NTM presented comorbidities as HIV infection, Pulmonary tuberculosis, Type 2 diabetes, Chronic bronchitis and Alveolar pneumonia. CONCLUSIONS: Our study showed the presence of NTM strains among presumptive TB people with a predominance of M. fortuitum and M. intracellulare. It is important to implement a surveillance system of NTM in TB burden country and also to develop a point-of-care test for NTM identification in limited-resource settings.

[A case of silicosis complicated with non-tuberculous mycobacterium pulmonary disease].

Non-tuberculosis mycobacterium (NTM) refers to a general term for a large group of mycobacteria, excluding the mycobacterium tuberculosis and mycobacterium leprae, which is an opportunistic pathogen. NTM pulmonary disease and pulmonary tuberculosis have very similar clinical and imaging manifestations. Ordinary sputum tests can not distinguish between mycobacterium tuberculosis and NTM accurately, and it needs to be differentiated through detection methods such as mycobacterium culture medium, high-performance liquid chromatography, and molecular biology. During the diagnosis of occupational pneumoconiosis, a sandblasting and polishing worker's lung CT showed dynamic changes in infiltrating shadows and cavities in the right lung. A sputum drug sensitivity test showed NTM infection, but the patient refused treatment. After 20 months, the CT examination of the lung showed further enlargement of infiltrating shadows and cavities, and NTM bacterial identification showed intracellular mycobacterial infection. Amikacin, moxifloxacin, azithromycin, and ethambutol combined antibacterial treatment were given. Currently, the patient is still under treatment.

Prevalence and Clinical Implications of Nontuberculous Mycobacteria Isolation and Infection among Patients with Bronchiectasis in the Jerusalem Area.

BACKGROUND: Bronchiectasis is an obstructive chronic lung disease characterized by structural changes in large and small airways, namely permanent widening of bronchial lumen resulting in chronic inflammation and infection. Nontuberculous mycobacteria (NTM) are environmental mycobacteria that may cause human infection or colonization with over 150 species identified to date. Bronchiectasis with NTM colonization or infection is often encountered but with varying prevalence and unknown clinical or prognostic significance. OBJECTIVES: To find the prevalence of NTM among patients with bronchiectasis in the Jerusalem district. To assess whether there were clinical differences between patients with bronchiectasis who were isolated with NTM and those without. METHODS: In this retrospective observational research study, we reviewed all computerized medical charts of patients over 18 years of age, who were diagnosed with bronchiectasis at Hadassah Medical Centers in Jerusalem between 2012 and 2017. We assessed the prevalence of NTM pulmonary disease. To compare patients with and without NTM, we reviewed and analyzed clinical, radiological, and microbiological data of all NTM patients and a group of controls in a 4:1 ratio. RESULTS: Prevalence of NTM among bronchiectasis patients was 5.1%, slightly lower than previously reported in Israel. We did not find clinically or radiological significant differences in patients with NTM disease compared to controls. This result included a similar number of exacerbations, hospitalization rates, number of lobes involved, and pulmonary function tests. CONCLUSIONS: Bronchiectasis patients with isolation of Pseudomonas aeruginosa experienced more exacerbations than patients with other isolates, consistent with previous studies.

Bilateral Nontuberculous Mycobacterial Otitis Media: A Case Report.

Established treatment strategies for nontuberculous mycobacterial (NTM) infections are currently lacking, and whether surgical treatment should be applied in combination with antibiotic therapy remains debatable. Here, we report a case of bilateral otitis media caused by Mycobacterium abscessusa, a highly antibiotic-resistant bacterium. Many reported cases of NTM otitis media are unilateral, in which hearing of the contralateral ear is preserved. In the present case, strategies to improve hearing outcomes were considered, as both ears were affected. A 27-year-old woman presented with bilateral otorrhea that had lasted for the past 9 months. Bacterial culture showed M. abscessus in both ears. Based on drug sensitivity tests, clarithromycin, amikacin, and imipenem were administered. Three days after treatment initiation, diseased tissues were removed from the right middle ear, which had impaired hearing. On day 38, otorrhea stopped in both ears, and the hearing improved. Computed tomography revealed air in both middle ears. No apparent recurrence was detected. Under the same antibiotic therapy, resolution of diseased tissues and improvement in hearing were similar between the ears with and without surgery, suggesting that surgery is not always necessary. This finding may be incorporated into the treatment guidelines for NTM infections in the future.

Computational drug repositioning identifies niclosamide and tribromsalan as inhibitors of Mycobacterium tuberculosis and Mycobacterium abscessus.

Tuberculosis (TB) is still a major global health challenge, killing over 1.5 million people each year, and hence, there is a need to identify and develop novel treatments for Mycobacterium tuberculosis (M. tuberculosis). The prevalence of infections caused by nontuberculous mycobacteria (NTM) is also increasing and has overtaken TB cases in the United States and much of the developed world. Mycobacterium abscessus (M. abscessus) is one of the most frequently encountered NTM and is difficult to treat. We describe the use of drug-disease association using a semantic knowledge graph approach combined with machine learning models that has enabled the identification of several molecules for testing anti-mycobacterial activity. We established that niclosamide (M. tuberculosis IC90 2.95 µM; M. abscessus IC90 59.1 µM) and tribromsalan (M. tuberculosis IC90 76.92 µM; M. abscessus IC90 147.4 µM) inhibit M. tuberculosis and M. abscessus in vitro. To investigate the mode of action, we determined the transcriptional response of M. tuberculosis and M. abscessus to both compounds in axenic log phase, demonstrating a broad effect on gene expression that differed from known M. tuberculosis inhibitors. Both compounds elicited transcriptional responses indicative of respiratory pathway stress and the dysregulation of fatty acid metabolism.

Clinical phenotypes of nontuberculous mycobacterial disease by cluster analysis based on pulmonary function.

BACKGROUND: Nontuberculous mycobacterial pulmonary disease (NTM-PD) often exhibits pulmonary function impairment, such as obstructive or restrictive pattern, with variation among patients according to the damaged lesions in the lung. METHODS: Patients with NTM-PD were consecutively enrolled between September 2019 and December 2020 at the Respiratory Infection Clinic of our hospital. Patients' data were comprehensively collected through laboratory examinations, PFT, chest computed tomography, and questionnaires for the assessment of subjective symptoms and health-related quality of life (HRQOL). Hierarchical cluster analysis was performed using PFT parameters to compare the clinical findings among clusters. RESULTS: Data of 104 patients were analyzed and classified into four clusters. The restrictive pattern with decreased forced expiratory volume in 1 s (FEV1) group showed high serum C-reactive protein and low albumin levels, severe radiological findings, and low HRQOL. In the restrictive pattern with preserved FEV1 group, HRQOL was as low as that in the restrictive pattern with decreased FEV1 group, and bacterial exacerbation was observed relatively frequently. HRQOL in the obstructive impairment group was maintained in comparison with that in the normal group. CONCLUSION: NTM-PD phenotypes were identified using cluster analysis based on PFT. Two different severe phenotypes were also observed. In the early stages of NTM-PD, PFT may be useful in recognizing disease progression.

Efficacy of SPR720 in murine models of non-tuberculous mycobacterial pulmonary infection.

BACKGROUND: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing worldwide, with Mycobacterium avium complex (MAC) and Mycobacterium abscessus as the predominant pathogens. Current treatments are poorly tolerated and modestly effective, highlighting the need for new treatments. SPR719, the active moiety of the benzimidazole prodrug SPR720, inhibits the ATPase subunits of DNA gyrase B, a target not exploited by current antibiotics, and therefore, no cross-resistance is expected with standard-of-care (SOC) agents. OBJECTIVES: To evaluate the in vitro activity of SPR719 against MAC and M. abscessus clinical isolates, including those resistant to SOC agents, and in vivo efficacy of SPR720 in murine non-tuberculous mycobacteria (NTM) pulmonary infection models. METHODS: NTM isolates were tested for susceptibility to SPR719. Chronic C3HeB/FeJ and severe combined immunodeficient murine models of pulmonary infection were used to assess efficacy of SPR720 against MAC and M. abscessus, respectively. RESULTS: SPR719 was active against MAC (MIC90, 2 mg/L) and M. abscessus (MIC90, 4 mg/L) clinical isolates. Efficacy of SPR720 was demonstrated against MAC pulmonary infection, both as a monotherapy and in combination with SOC agents. SPR720 monotherapy exhibited dose-dependent reduction in bacterial burden, with the largest reduction observed when combined with clarithromycin and ethambutol. Efficacy of SPR720 was also demonstrated against M. abscessus pulmonary infection where monotherapy exhibited a dose-dependent reduction in bacterial burden with further reductions detected when combined with SOC agents. CONCLUSIONS: In vitro activity of SPR720 against common NTM pathogens and efficacy in murine infections warrant the continued clinical evaluation of SPR720 as a new oral option for the treatment of NTM-PD.