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Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in incidence globally and challenging to manage. The 2020 multisociety treatment guideline and the 2022 consensus recommendations provide comprehensive evidence-based guides to manage pulmonary diseases caused by the most common NTM. However, with >190 different NTM species that may require different multidrug regimens for treatment, the breadth and complexity of NTM-PD remain daunting for both patients and clinicians. In this narrative review, we aim to distill this broad, complex field into principles applicable to most NTM species and highlight important nuances, specifically elaborating on the presentation, diagnosis, principles of patient-centered care, principles of pathogen-directed therapy, and prospects of NTM-PD., Competing Interests: Potential conflicts of interest . S. H. K. reports consulting with AN2 Therapeutics, Insmed, and Paratek Pharmaceuticals; investigator work with Insmed; and speaker work with AN2 Therapeutics, Insmed, and Paratek Pharmaceuticals. J. D. M. reports consulting with Intuitive Surgical. D. E. G. reports advisory board work with Insmed and consulting with AN2 Therapeutics, Insmed, and Paratek Pharmaceuticals. C. L. D. reports grant support from AN2 Therapeutics, Bugworks, Insmed, Juvabis, and Paratek Pharmaceuticals; advisory board work with AN2 Therapeutics, AstraZeneca, Cepheid, Hyfe, Insmed, MannKind, Matinas Biopharma, NobHill, Spero Therapeutics, and Zambon; consulting with Genentech and Pfizer; and data monitoring committee work with Otsuka Pharmaceutical and the Gates Foundation. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Mycobacterium abscessus is a highly drug-resistant nontuberculous mycobacterium (NTM). Efforts to discover new treatments for M. abscessus infections are accelerating, with a focus on cell wall synthesis proteins ( M. abscessus l,d-transpeptidases 1 to 5 [Ldt Mab1 to Ldt Mab5 ] and d,d-carboxypeptidase) that are targeted by β-lactam antibiotics. A challenge to this approach is the presence of chromosomally encoded β-lactamase (Bla Mab ). Using a mechanism-based approach, we found that a novel ceftaroline-imipenem combination effectively lowered the MICs of M. abscessus isolates (MIC 50 ≤ 0.25 μg/ml; MIC 90 ≤ 0.5 μg/ml). Combining ceftaroline and imipenem with a β-lactamase inhibitor, i.e., relebactam or avibactam, demonstrated only a modest effect on susceptibility compared to each of the β-lactams alone. In steady-state kinetic assays, Bla Mab exhibited a lower K i  app (0.30 ± 0.03 μM for avibactam and 136 ± 14 μM for relebactam) and a higher acylation rate for avibactam ( k 2 / K  = 3.4 × 10 5 ± 0.4 × 10 5 M -1 s -1 for avibactam and 6 × 10 2 ± 0.6 × 10 2 M -1 s -1 for relebactam). The k cat / K m was nearly 10-fold lower for ceftaroline fosamil (0.007 ± 0.001 μM -1 s -1 ) than for imipenem (0.056 ± 0.006 μM -1 s -1 ). Timed mass spectrometry captured complexes of avibactam and Bla Mab , Ldt Mab1 , Ldt Mab2 , Ldt Mab4 , and d,d-carboxypeptidase, whereas relebactam bound only Bla Mab , Ldt Mab1 , and Ldt Mab2 Interestingly, Ldt Mab1 , Ldt Mab2 , Ldt Mab4 , Ldt Mab5 , and d,d-carboxypeptidase bound only to imipenem when incubated with imipenem and ceftaroline fosamil. We next determined the binding constants of imipenem and ceftaroline fosamil for Ldt Mab1 , Ldt Mab2 , Ldt Mab4 , and Ldt Mab5 and showed that imipenem bound >100-fold more avidly than ceftaroline fosamil to Ldt Mab1 and Ldt Mab2 (e.g., K i  app or K m of Ldt Mab1  = 0.01 ± 0.01 μM for imipenem versus 0.73 ± 0.08 μM for ceftaroline fosamil). Molecular modeling indicates that Ldt Mab2 readily accommodates imipenem, but the active site must widen to ≥8 Å for ceftaroline to enter. Our analysis demonstrates that ceftaroline and imipenem binding to multiple targets (l,d-transpeptidases and d,d-carboxypeptidase) and provides a mechanistic rationale for the effectiveness of this dual β-lactam combination in M. abscessus infections., (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)

This review summarizes the discussion of a session held during the 2018 North American Cystic Fibrosis (CF) Conference titled "Challenging Cases in Nontuberculous Mycobacterial (NTM) Management." In this session, a multidisciplinary panel of NTM experts discussed clinical challenges related to the management of NTM infection in people with CF in which decision-making falls outside of the Cystic Fibrosis Foundation/European Cystic Fibrosis Society NTM guidelines. Topics discussed included managing newly acquired NTM infection, selecting and monitoring treatment regimens, determining treatment endpoints, and caring for patients after NTM treatment., (© 2019 Wiley Periodicals, Inc.)

Purpose: Mycobacterium abscessus disease is one of the most difficult mycobacterial infections to cure, as the bacterium is highly resistant to conventional antibiotics. The purpose of this study was to evaluate the efficacy and safety of tigecycline treatment of M. abscessus disease., Procedure: We performed retrospective chart reviews of patients with M. abscessus disease receiving tigecycline-containing regimens at National Jewish Health from January 2009 to December 2017., Main Findings: Among the 35 patients, pulmonary disease was the most common presentation of M. abscessus disease (n = 29, 82.9%). Of those receiving tigecycline treatment, 17.4% (4/23) showed microbiological improvement (≥2 consecutive negative sputum cultures), while 86.2% (25/29) and 59.3% (16/27) showed symptomatic and radiological improvements, respectively. The rate of dose reduction or discontinuation of tigecycline owing to adverse drug reactions was 57.1% (20/35) at a median of 56.5 days (IQR 10.8-122.3). The most common adverse drug reactions were gastrointestinal side effects, including nausea, vomiting, and diarrhea., Conclusions: Tigecycline-containing regimens for M. abscessus disease have a high rate of symptomatic and radiological improvement. However, considering the poor microbiological response and the common adverse effects, selection of patients for tigecycline treatment and monitoring for adverse drug reactions should be performed carefully., (Copyright © 2019. Published by Elsevier Ltd.)

Nontuberculous mycobacteria represent an uncommon but important cause of infection of the musculoskeletal system. Such infections require aggressive medical and surgical treatment, and cases are often complicated by delayed diagnosis. We retrospectively reviewed all 14 nonspinal cases of nontuberculous mycobacterial musculoskeletal infections treated over 6 years by orthopedic surgeons at a university-affiliated tertiary referral center. All patients required multiple antimicrobial agents along with aggressive surgical treatment; 13 of 14 patients ultimately achieved cure. Four patients required amputation to control the infection. Half these patients were immunosuppressed by medications or other medical illness when they sought care at the referral center. Six cases involved joint prostheses; all ultimately required hardware removal and placement of an antimicrobial spacer for eradication of infection. Our findings highlight the importance of vigilance for nontuberculous mycobacterial musculoskeletal infection, particularly in patients who are immunosuppressed or have a history of musculoskeletal surgery.

The understanding of species distribution and inducible macrolide resistance in the Mycobacterium fortuitum complex (MFC) is limited. Of 90 mostly respiratory MFC clinical isolates, half were M. fortuitum , followed by M. peregrinum , M. porcinum , M. septicum , and M. conceptionense Most M. fortuitum , M. por cinum , and M. septicum isolates were inducibly resistant to clarithromycin, whereas two-thirds of the M. peregrinum isolates were clarithromycin susceptible. Clarithromycin-resistant M. fortuitum isolates exhibited common mutations of erm (39), potentially involved in clarithromycin resistance., (Copyright © 2019 American Society for Microbiology.)

We are in the midst of a global outbreak of Mycobacterium chimaera infections related to a point source contamination of a widely used surgical device, the 3T heater-cooler unit. More than 250000 heart bypass procedures using heater-cooler devices are performed in the United States every year. It is estimated that 60% of these operations use the device associated with this outbreak. Most of the reported cases present with a disseminated infection that is striking in both the latency of presentation and the high mortality. The diagnosis can be elusive due to intermittent bacteremia and normal echocardiography. Therapy includes several months of antibiotics, and surgical intervention appears to be critical for successful outcomes. Here, we review diagnostic methods and treatment options to guide clinicians in the management of this complicated infection., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

This article reviews the current epidemiology of nontuberculous mycobacterial pulmonary disease and the impact on thoracic disease. The prevalence of nontuberculous pulmonary disease in the United States is much higher than that of Mycobacterium tuberculosis. Estimates support an annual increase in incidence of 8% per year. Nontuberculous mycobacteria are distinguished by 2 group designations, slowly growing mycobacteria, such as Mycobacterium avium complex, and rapidly growing mycobacteria, which includes Mycobacterium abscessus. Most pulmonary infections in humans are caused by species belonging to M avium complex. This article also reviews risk factors for disease acquisition, including host and environmental risk factors., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Rapidly growing mycobacteria (RGM) include a diverse group of species. We address the treatment of the most commonly isolated RGM-M abscessus complex, M fortuitum, and M chelonae. The M abscessus complex is composed of 3 closely related species: M abscessus senso stricto (hereafter M abscessus), M massiliense, and M bolletii. Most studies address treatment of M abscessus complex, which accounts for 80% of lung disease caused by RGM and is the second most common RGM to cause extrapulmonary disease (after M fortuitum). The M abscessus complex represent the most drug-resistant nontuberculous mycobacteria and are the most difficult to treat., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) can be difficult. A previous study from Japan reported the usefulness of a serodiagnostic test for MAC-PD. The objective of this study was to evaluate the usefulness of the test in similar patients in the USA. 100 patients with known or suspected MAC-PD and 52 healthy volunteers were enrolled into the study at National Jewish Health, Denver, CO, USA. Serum glycopeptidolipid core immunoglobulin A antibody levels were measured with an enzyme immunoassay (EIA) kit and routine clinical evaluations were performed. The patients were divided into two groups based on clinical evaluation: 87 patients with MAC-PD that met American Thoracic Society criteria, and 13 who did not meet the criteria. The sensitivity and specificity (cut-off point 0.3 U·mL(-1)) of the serodiagnostic test for diagnosing MAC-PD were 70.1% and 93.9%, respectively. Among the 44 patients in the MAC-PD group with two or more positive sputum cultures within the previous 6 months, sensitivity was 81.8%. The EIA kit demonstrated good sensitivity and specificity for the identification of MAC-PD, particularly in patients with two or more positive cultures, and may be useful for rapid MAC-PD diagnosis.

MYCOBACTERIUM AVIUM complex (MAC) consists of nontuberculous mycobacteria that cause disease in immunocompromised and immunocompetent hosts. The organisms are ubiquitous in the environment, and acquisition occurs through ingestion or inhalation of aerosols from soil, water, or biofilms. Disease may manifest as disseminated infection, soft tissue infection, chronic pneumonia, or hypersensitivity pneumonitis. Nontuberculous mycobacteria are increasingly associated with pulmonary disease, with MAC being the most common nontuberculous mycobacteria to cause pulmonary disease in the United States. Pulmonary symptoms, nodular or cavitary opacities on a chest radiograph or high-resolution computed tomographic scan with multifocal bronchiectasis and multiple small nodules, plus positive culture results from two sputum specimens or one bronchoscopic specimen are consistent with MAC pulmonary disease. Treatment consists of a macrolide, rifamycin, and ethambutol given three times weekly for noncavitary disease and daily with or without an aminoglycoside for cavitary disease.