Management of Nontuberculous Mycobacterial Pulmonary Disease Refractory to Guideline-Based Therapy: A Systematic Review

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Akkerman , Timothy R Aksamit , Stefano Aliberti , Claire Andrejak , Charles L. Daley , Jakko van Ingen , Christoph Lange , Marc Lipman , Michael R Loebinger , Mateja Jankovic Makek , Kozo Morimoto , Rachel Thomson , Dirk Wagner , Kevin L Winthrop , Jae-Joon Yim , Raquel Duarte doi: https://doi.org/10.1101/2025.06.23.25330100 Diana Moreira-Sousa 1 Pulmonology Department, Local Health Unit Cova da Beira , Covilhã, Portugal Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Diana Moreira-Sousa Beatriz Martins 2 Pulmonology Department, Local Health Unit São João , Porto, Portugal Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ana Aguiar 3 EPIUnit ITR, Instituto de Saúde Pública da Universidade do Porto, Universidade do Porto, Rua das Taipas, n° 135, 4050-600 Porto , Portugal , Estudo das Populações - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marina Pinheiro 4 Public Health Unit, Local Health Unit Barcelos/Esposende , Barcelos, Portugal Find this author on Google Scholar Find this author on PubMed Search for this author on this site Onno W. Akkerman 5 Department of Pulmonary Disease and Tuberculosis, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands; Tuberculosis Centre Beatrixoord, University Medical Centre Groningen, University of Groningen , Groningen, Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site Timothy R Aksamit 6 Mayo Clinic, Pulmonary Disease and Critical Care Medicine , Rochester, MN, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stefano Aliberti 7 Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072, Pieve Emanuele, Milan, Italy, IRCCS Humanitas Research Hospital, Respiratory Unit , Via Manzoni 56, 20089, Rozzano, Milan, Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Claire Andrejak 8 Department of Respiratory Diseases, Amiens-Picardie University Hospital, Amiens, France UR 4294 AGIR, Picardie Jules Verne University , Amiens, France Find this author on Google Scholar Find this author on PubMed Search for this author on this site Charles L. Daley 9 Division of Mycobacterial and Respiratory Infections, Department of Medicine, National Jewish Health, Denver , Colorado, USA., Division of Infectious Diseases, Department of Medicine, University of Colorado, Aurora, Colorado, USA., Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jakko van Ingen 10 Radboudumc Community for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Centre , Nijmegen, The Netherlands Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christoph Lange 11 Division of Clinical Infectious Diseases, Research Centre Borstel, Borstel, Germany., German Centre for Infection Research (DZIF), Partner Site Borstel-Hamburg-Lübeck-Riems , Borstel, Germany ., Respiratory Medicine and International Health, University of Lübeck, Lübeck, Germany. Department of Pediatrics, Global and Immigrant Health, Global Tuberculosis Program, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Marc Lipman 12 Respiratory Medicine, Royal Free Hospital NHS Foundation Trust, London, & University College London , London UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael R Loebinger 13 Royal Brompton Hospital and NHLI, Imperial College London , London, UK Find this author on Google Scholar Find this author on PubMed Search for this author on this site Mateja Jankovic Makek 14 Clinic for Respiratory Diseases, University Hospital Centre Zagreb, Zagreb, Croatia. University of Zagreb, School of Medicine , Zagreb, Croatia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kozo Morimoto 15 Respiratory Disease Centre, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan. Department of Clinical Mycobacteriosis, Nagasaki University Graduate School of Biomedical Sciences , Japan ., Division of Clinical Research, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Japan Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rachel Thomson 16 Gallipoli Medical Research and Greenslopes Clinical Unit, The University of Queensland , Brisbane Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dirk Wagner 17 Division of Infectious Diseases, Department of Internal Medicine II, Freiburg University Medical Centre, Freiburg, Germany., Department of Epidemiology, Helmholtz Centre for Infection Research Braunschweig , Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kevin L Winthrop 18 Division of Infectious Diseases, Department of Medicine, Oregon Health & Science University , Portland, Oregon, USA ., Centre for Infectious Disease Studies, Oregon Health & Science University-Portland State University School of Public Health, Portland, Oregon, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jae-Joon Yim 19 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine , Seoul, Republic of Korea Find this author on Google Scholar Find this author on PubMed Search for this author on this site Raquel Duarte 20 EPIUnit ITR, Instituto de Saúde Pública da Universidade do Porto, Universidade do Porto, Rua das Taipas, n° 135, 4050-600 Porto , Portugal , Estudo das Populações - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal, Centro de Saúde Pública Doutor Gonçalves Ferreira – Instituto de Saúde Pública Doutor Ricardo Jorge, INSA Porto, Porto, Portugal Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: raquelafduarte{at}gmail.com Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF ABSTRACT Introduction Managing patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) unresponsive to guideline-based therapy presents a significant clinical challenge. Limited treatment options and the complex nature of disease progression make therapeutic decision-making difficult. This study systematically reviewed the existing literature on management strategies and emerging therapeutic approaches for refractory NTM-PD. Methods We systematically reviewed studies on NTM-PD treatment failure published from inception until 31 January 2024, examining associated factors, intensification strategies, and supportive measures. Twenty-five studies met the inclusion criteria, predominantly exhibiting retrospective observational methodology and focusing on pulmonary disease by Mycobacterium avium complex and Mycobacterium abscessus species. Findings were synthesised qualitatively due to the considerable heterogeneity in study design and outcomes. Results Before treatment intensification or de-escalation, the impact of antibiotic treatment on health-related quality of life and microbiological factors, such as acquired resistance and changes in the pathogenic NTM, should be assessed. The presence of severe radiological findings at the beginning of treatment and a history of multiple antibiotic regimen modifications were associated with a lower chance of treatment success. Evidence regarding supportive interventions for treatment-refractory NTM-PD, such as nutritional counselling, respiratory rehabilitation, and psychosocial support, remains limited. Intermittent administration of intravenous antibiotics may be an additional strategy for symptom management. Depending on the causative NTM species, some antibiotic options have been explored for treatment intensification, although most of these are based on observational studies. Surgical resection remains an option for localised disease, although the risk of recurrence remains substantial in the case of preoperative positive culture. Novel therapeutic approaches remain under investigation as potential alternatives. Discussion This systematic review underscores the complexity of managing refractory NTM-PD, highlighting the role of treatment intensification, symptom control, supportive measures and knowledge gaps. While no standardised approach exists, individualised strategies incorporating clinical, microbiological, and radiological factors remain essential for optimising patient outcomes. INTRODUCTION Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic infection with heterogeneous clinical and microbiological manifestations, associated with significant morbidity and mortality [ 1 – 4 ]. The rising incidence of NTM-PD is attributed to increased life expectancy, a higher prevalence of chronic diseases, widespread immunosuppressive therapy use, and growing awareness of these microorganisms [ 5 – 8 ]. As NTM-PD is diagnosed more frequently, the need for comprehensive and standardised approaches has become evident. Current guidelines were designed to provide therapeutic recommendations for NTM-PD cases based on evidence-based medicine [ 9 , 10 ]. As such, they cannot offer a structured approach for managing challenges such as treatment-related adverse events, drug intolerance, pathogen re-exposure, symptom management difficulties, and, in particular, treatment failure [ 9 , 10 ]. Treatment outcomes remain suboptimal, largely due to the complexity of the disease, patients’ frailty, the need for prolonged multidrug antibiotic regimens and ineffective therapies, drug toxicities with poor tolerance and antimicrobial resistance [ 11 , 12 ]. Despite the established association between NTM-PD and underlying risk factors, particularly bronchiectasis, current therapy recommendations do not include host-directed therapies [ 9 , 10 , 13 ]. Consequently, clinicians often rely on personal expertise and limited available evidence to guide treatment decisions. This study systematically reviews the available evidence on therapeutic options for patients with NTM-PD refractory to guideline-based therapy (GBT). Our goal was to evaluate alternative approaches and identify gaps in the literature, to further support the development of a structured framework to develop an expert consensus on the management of NTM-PD presenting treatment failure. MATERIALS AND METHODS Protocol and registration We performed a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered it in the PROSPERO database (PROSPERO 2024. CRD42024491009) [ 14 , 15 ]. Search strategy A comprehensive systematic literature search was performed using PubMed/Medline for studies, concerning human subjects, regarding NTM patients with treatment failure, from inception to 31 January 2024. The search expression was “nontuberculous mycobacteria AND treatment AND antibiotic ” (Supplementary Material 1 for full query). Eligibility and quality assessment We included case series, cross-sectional, case-control, cohort studies, and clinical trials reporting the management of NTM patients undergoing treatment failure, irrespective of the species. Case reports, conference abstracts, editorials and reviews, and animal or in-vitro studies were excluded. Works in languages other than English were excluded. Treatment failure was defined as persistent culture positivity after six months of GBT, incorporating definitions from Griffith et al. (2018) and the NTM-NET consensus statement (which considered culture positivity after ≥12 months of antimycobacterial therapy) [ 16 , 17 ]. To address the study’s objectives, we formulated the following research questions: What factors support treatment intensification with curative intent or de-escalation for symptom control in patients with NTM-PD treatment failure? What supportive measures, including non-pharmacological therapies, should be offered? What treatment strategies with curative intent are currently available for treatment intensification? “Treatment intensification” refers to the modification of the therapeutic regimen to achieve sustained culture conversion and, ultimately, cure, whereas “de-escalation” encompasses treatment halted, as defined by NTM-NET, and the reformulation of the therapeutic plan aiming for symptomatic control, without curative intent [ 17 ]. Data extraction and qualitative assessment The extracted library was reviewed using EndNote TM 20.2.1 tool (Clarivate, Berkeley, California, United States), by D.MS. and B.M., that were responsible for screening the studies by title and abstract (phase 1) with a third reviewer (A.A.) resolving any eligibility uncertainties in Phase 2 (full-text review). All studies that included data about treatment failure of pulmonary NTM in adult patients were included. Following this, a backward and forward citation assessment was performed. From each study, the following data was extracted: title, first author; year of publication, the country where the study was conducted; study design, population, and aim; sample size (number of patients included); information on NTM species investigated; treatment outcomes regarding culture sustained conversion rate and treatment period, rate of treatment failure (persistent positive culture), data on clinical improvement, rate of re-infection by other NTM pathogens, and presence of antibiotic resistance. Descriptive and qualitative analysis The authors systematically structured the extracted data from the selected studies to answer the research questions. Given the limited evidence on treatment failure, conducting a meta-analysis was not feasible. Instead, the data were summarised descriptively in tabular format outlining the evaluated interventions and their treatment outcomes. The information on the tables were supplemented with a narrative synthesis of the results and an in-depth discussion, organised by topic, to provide a detailed analysis of the findings and highlight gaps in the literature. RESULTS AND DISCUSSION A total of 5707 studies were retrieved, 135 full-text manuscripts were examined, and 21 studies were included. Additionally, 4 studies were retrieved from citation tracking, making a total of 25 studies included in the review. The flowchart in Figure 1 synthesises the study selection process. Download figure Open in new tab Figure 1 PRISMA flow-chart diagram of included studies. To assess the quality of the included articles, encompassing 24 non-randomized studies, the authors utilised the validated Mixed Methods Appraisal Tool (MMAT; Version 2018) (Supplementary Material 2) [ 18 ]. The majority of the studies did not meet the criteria for accounting for confounders in the analysis. With the available evidence, seven major topics were identified: Quality of Life and Symptom Management, Radiological Severity and Treatment Failure, Microbiological Factors and Resistance Patterns, Impact of Prolonged Antibiotic Regimens, Supportive Measures and Non-Pharmacological Approaches, Intermittent Antibiotic Therapy for Symptom Control and, Alternative Treatment Strategies After Guideline-Based Treatment Failure. From the 25 studies included ( Table 1 ), most were retrospective cohort studies (n=17). The research focused on Mycobacterium avium complex (MAC) (n=16) and/or Mycobacterium abscessus (MABS) pulmonary disease (n=17) [ 16 , 19 – 42 ]. The studies varied in design, patient populations, microbiological endpoint definitions, and treatment regimens, limiting direct comparability. While none specifically examined clinical decision-making following treatment failure, some identified factors linked to treatment response, which could have implications for patient management ( Table 1 ). View this table: View inline View popup Table 1. Characteristics of the selected articles. Quality of Life (QoL) and Symptom Management Kwak et al. (2020) assessed health-related QoL changes by applying the St. George’s Respiratory Questionnaire (SGRQ) in 114 NTM-PD patients, of whom 53 received antibiotic treatment and 24 achieved microbiological cure [ 19 ]. The study revealed that QoL improved within the first two years of treatment, even among those classified as treatment failures (n=29), with sustained improvements observed at three years. Whether these changes in QoL correlate with bacterial load or other disease parameters remains uncertain. However, these findings indicate that antibiotic treatment may be associated with symptomatic improvement, despite persistent positive cultures. Radiological Severity and Treatment Failure Radiological severity has been proposed as a potential predictor of treatment failure. Park et al. (2021) observed that a higher radiological disease burden at the initiation of antibiotic treatment was associated with an increased risk of treatment failure in MABS-PD [ 20 ]. However, short-term radiographic changes (after a median of 20 days) showed no association with treatment outcomes. Kim et al. (2024) recently reported findings from a cohort of MAC-PD patients, showing that post-treatment radiographic severity and its improvement from baseline after 12 months of treatment were associated to a reduction in all-cause mortality [ 43 ]. This association was observed regardless of culture conversion status, as the study found no significant correlation between achieving culture conversion and severity of radiographic findings. The utility of radiographic severity scores in guiding treatment adjustments after initial treatment failure remains uncertain. Additionally, radiological evaluation is challenging due to underlying lung structural disease and immunosuppression, where deterioration may be linked to co-infections or other pathogens [ 44 – 46 ]. Microbiological Factors and Resistance Patterns Macrolide and amikacin resistance in MAC and MABS-PD is associated with an increased likelihood of treatment failure, aligning with the current understanding of NTM-PD treatment challenges [ 9 , 10 , 16 , 34 , 47 ]. For antimicrobials other than macrolides and amikacin, the absence of clinically validated breakpoints complicates associating in vitro susceptibility and clinical response [ 48 ]. Park et al. (2021) found significant differences in microbiological outcomes only in subgroups of patients with cefoxitin and amikacin susceptibility in a cohort of . M. abscessus ssp. abscessus PD patients [ 21 ]. Similarly, Kwak et al. (2021) identified an association between negative sputum culture conversion and lower minimum inhibitory concentrations (MICs) for clofazimine in patients with MAC and MABS-PD, although standardised cutoff values have yet to be established [ 22 ]. Additionally, genotypic variation during treatment and at relapse has been previously described in works with MAC-PD cohorts [ 49 , 50 ]. A study with a cohort of patients M. abscessus ssp. abscessus PD under treatment for ≥ 12 months identified genotypic variation in 92% of the cases with persistently positive cultures during antibiotic treatment and in all microbiologic recurrences post-treatment [ 23 ]. Additionally, an in-vitro and in-animal recent study demonstrated that M. avium presents intrinsic heteroresistance to clarithromycin in vivo, which may justify inadequate treatment response in cases with susceptible antibiotic susceptibility test (AST) results [ 51 ]. The clinical implications of both genotyping variation and NTM strains’ intrinsic heteroresistance require further investigation. Impact of Prolonged Antibiotic Regimens One of the challenges in managing NTM infections is the prolonged course of antibiotics, which is often associated with adverse effects and difficulties in treatment adherence [ 52 ]. Tsai et al. (2022) reported an association of a threshold of more than five changes to antimicrobial regimens with an 81.3% increased risk of poor outcomes, including mortality, treatment discontinuation, or intolerance [ 24 ]. These findings suggest that frequent modifications to regimens, often justified by intolerance or failure to respond, are linked to worse clinical outcomes, although the causality of this relationship was only established in this study. Conversely, private insurance was associated with more favourable clinical outcomes, which was attributed by the authors to enhanced access to more treatment options, suggesting that the healthcare system may also have an impact on the outcome [ 24 ]. Another study of MABS-PD patients revealed that the administration of intravenous amikacin beyond 28 weeks did not result in the achievement of additional sustained negative cultures, thus demonstrating poor outcomes for patients receiving regimens with extended amikacin periods beyond the guideline 16-week recommendation [ 25 ]. These results underscore the need for careful treatment planning, balancing regimen modifications with patient tolerance, and the likelihood of successful outcomes. Further research is required to refine treatment strategies, optimise long-term management and define the optimal treatment duration for these patients. Given the challenges associated with prolonged antibiotic regimens, exploring supportive measures and non-pharmacological approaches becomes essential in improving patient outcomes and treatment tolerance. Supportive Measures and Non-Pharmacological Approaches The role of non-pharmacological interventions in NTM-PD treatment failure remains inadequately defined. Some studies have examined nutritional status, rehabilitation programmes, and the psychological burden of the disease, but the evidence on effective interventions continues to be limited [ 26 , 53 – 56 ]. Moon et al. (2020) found that malnutrition was not associated with culture conversion failure but was linked to higher mortality and increased treatment intolerance [ 26 ]. However, in this study, the influence of nutritional advice on clinical or microbiological outcomes was not assessed. The only cohort study on respiratory rehabilitation in NTM-PD focused on untreated patients and reported improvements in cough, sputum production, functional status, and radiological findings in some cases [ 55 ]. Chest physiotherapy combined with hypertonic saline inhalation has been investigated as a supportive measure, though the available data remains limited to one study [ 57 ]. Currently, non-pharmacological and symptomatic interventions are guided by expert opinion and extrapolation from other respiratory diseases, such as bronchiectasis [ 13 , 58 ]. Intermittent Antibiotic Therapy for Symptom Control Intermittent antibiotic regimens have been explored to reduce treatment burden in patients experiencing intolerance to long-term therapy. Im et al. (2023) reported that intermittent IV antibiotic courses provided symptom relief for a median duration of 22.8 months in MABS-PD patients [ 27 ]. Although it is important to highlight that there are no data on patient outcomes following the complete discontinuation of antibiotics, making it unclear which patients may benefit from this approach, these findings suggest that anticipated planning of antibiotic regimens that allow symptom-suppressive intermittent phases may be advantageous in cases of treatment-resistant microbiological conditions. Alternative Treatment Strategies After Guideline-Based Treatment Failure Alternative strategies for NTM-PD treatment failure include surgical interventions, modifications in antibiotic regimens, and experimental therapies [ 16 , 28 – 42 ]. Surgery has been evaluated in localised NTM-PD cases, particularly those with structural lung disease or haemoptysis. The frequency of reported culture conversion ranges between 71.7% and 94.0% [ 28 – 33 ]. However, the presence of residual bronchiectasis, contralateral nodules, and, most importantly, preoperative positive cultures is associated with higher postoperative recurrence rates, making surgery a less reliable option [ 32 ]. Studies on antibiotic-based treatment intensification have primarily focused on Amikacin Liposome Inhalation Suspension (ALIS), which has been shown to improve culture conversion rates in MAC-PD and was therefore incorporated into the GBT [ 9 ]. In fact, ALIS has been associated with a 29.0% culture conversion rate at 6 months in treatment-refractory MAC-PD, with a cumulative conversion of up to 33.3% after 12 months, and sustained culture conversion in 46.2% of the converter patients 12 months after treatment [ 16 , 34 , 35 ]. The effectiveness of ALIS in MABS-PD remains less well-established, though preliminary data suggest a potential microbiological benefit [ 36 ]. Additionally, limited data are available on the use of other agents, including clofazimine, bedaquiline, tigecycline, and omadacycline, highlighting the need for further research on their role in treatment optimisation. Regarding MAC-PD, clofazimine and bedaquiline lack robust evidence to incorporate treatment schemes in cases of treatment failure [ 37 – 39 ]. However, clofazimine has been frequently studied in treatment-naïve cohorts or as a component of alternative regimens, showing more promising results [ 59 – 63 ], and inclusion of bedaquiline in the treatment scheme for treatment-refractory MAC-PD is the subject of an ongoing clinical trial (ClinicalTrials.gov identifier NCT04630145 [ 64 ]). No substantial evidence supports other antibiotic options’ efficacy, including moxifloxacin, rifabutin, or linezolid [ 37 ]. For MABS-PD, antibiotic approaches studied for treatment failure are already included as first-line options in NTM guidelines, including clofazimine and 3rd-generation tetracyclines, as omadacycline and tigecycline [ 9 , 10 ]. Observational studies have demonstrated the potential efficacy of these antibiotics when utilised as additional components of treatment regimens or as alternative pharmacological options [ 38 – 41 , 65 , 66 ]. The current evidence does not allow for a definitive conclusion regarding which approach must be considered, as decisions were tailored case-by-case. Furthermore, ongoing investigations on novel antibiotics for refractory MABS-PD, including Delpazolid, may expand therapeutic options (ClinicalTrials.gov identifier NCT06004037 [ 67 ]). Phage therapy has been explored as a potential treatment option for refractory MABS-PD, with a preliminary case series suggesting microbiological and clinical improvements in some patients [ 42 ]. However, the long-term impact and optimal patient selection criteria remain unclear, and further results of clinical trials are required (ClinicalTrials.gov identifier NCT06262282 [ 68 ]). Additional studies have explored the potential role of host-directed therapies in modifying the immune response and underlying comorbidities, though further supporting data are needed [ 69 , 70 ]. Strengths and Limitations This systematic review possesses several strengths, including adherence to PRISMA guidelines and registration with PROSPERO, which ensures methodological rigour. A comprehensive search strategy minimised selection bias, and the focus on treatment failure in NTM-PD addresses a critical gap in the literature. Unlike previous reviews, this study assesses both treatment intensification and de-escalation, integrating pharmacological and non-pharmacological approaches in patients with refractory NTM-PD. Moreover, the incorporation of symptomatic control and quality of life (QoL) enhancement as treatment objectives provides an opportunity to reflect upon existing therapeutic approaches that focus on microbiological outcomes. However, this review also has limitations. The heterogeneity of study designs, populations, and treatment regimens precluded a statistical analysis. Most of the studies included were small retrospective cohorts, increasing the risk of bias. The lack of standardised endpoints complicated comparisons, and long-term outcomes remain largely underexplored. Non-pharmacological interventions were underrepresented, which limits insights into supportive care strategies. Potential publication bias may also have led to the overrepresentation of successful interventions. Summary of Findings This systematic review highlights significant gaps in the management of NTM-PD treatment failure, aiming to identify key areas requiring further evidence and to support the development of expert consensus. Several factors, including QoL score changes, radiological severity, resistance patterns, and treatment prolongation, were examined but none offered a clear decision-making framework. The role of non-pharmacological interventions, alternative therapies, and emerging treatments remains poorly defined, with limited evidence on long-term outcomes. Further research is needed to clarify the clinical utility of different approaches, particularly in guiding treatment adjustments after GBT failure. Establishing a standardised definition of treatment success and distinguishing between reinfection and treatment failure through genotypic identification of NTM species could enhance the evaluation of treatment regimens in the future. FUNDING This work was supported by Portuguese Funds through FCT - Foundation for Science and Technology, I.P., under the projects UIDB/04750/2020 (DOI identifier: https://doi.org/10.54499/UIDB/04750/2020 ) and LA/P/0064/2020 (DOI identifier: https://doi.org/10.54499/LA/P/0064/2020 ). Data Availability All data produced in the present work are contained in the manuscript Footnotes ↵ + Authors are ordered by alphabetical order (last name) diana.sof.sousa{at}gmail.com bea.almeidamartins{at}gmail.com ana.aguiar{at}ispup.up.pt marinabppinheiro{at}gmail.com onnoakkerman{at}gmail.com aksamit.timothy{at}mayo.edu stefano.aliberti{at}hunimed.eu clandrejak{at}gmail.com daleyc{at}njhealth.org jakko.vaningen{at}radboudumc.nl clange{at}fz-borstel.de marclipman{at}nhs.net m.loebinger{at}rbht.nhs.uk mateja.jankovic{at}gmail.com bxypb621{at}ybb.ne.jp r.thomson{at}uq.edu.au wagnerdirk{at}medizin.ukl.uni-freiburg.de winthrop{at}ohsu.edu yimjj{at}snu.ac.kr Conflict of interest D. Moreira-Sousa, B. Martins, A. Aguiar, M. Pinheiro, O. Akkerman, M. Jankovic Makek and R. Duarte have non conflicts of interest to declare. T. R. Aksamit has participated in clinical trial design and implementation with AstraZeneca, Insmed Incorporated, Johnson & Johnson, Redhill Biopharma, Spero Therapeutics, Verona, Boehringer Ingleheim, and Zambon; has worked with Hillrom and RespirTech. He did not receive any personal honoraria or research support. Support was provided to the Mayo Foundation for Medical Education and Research; serves as Medical Director of Bronchiectasis and NTM 360 for the COPD Foundation. S. Alberti reports grants from INSMED Incorporated, Chiesi, Fisher & Paykel and GSK, royalties or licences from McGraw Hill, consultancy fees from An2 Therapeutics; Astrazeneca; Boehringer Ingelheim; Chiesi Farmaceutici Spa; Gsk; Insmed Incorporated; Insmed Ireland Limited; Insmed Netherlands Bv; Insmed Germany; Moderna Italy; Moderna Tx; Pfizer Srl; Physioassist Sas; Verona Pharma Plc; Vertex Pharmaceutical Europe; Zambon; Sanofi, payment or honoraria for lectures, presentations, manuscript writing or educational events from GlaxoSmithKline Spa, Thermofisher Scientific, INSMED Italy, INSMED Ireland Ltd, Boehringer Ingelheim, Zambon, Vertex Pharmaceuticals and Fondazione Internazionale Menarini, and participation on a data safety monitoring board or advisory board with INSMED Incorporated, INSMED Italy, AstraZeneca UK Limited and MSD Italia S.r.l. C. Andrejak has been principal investigator for studies for Insmed, and worked with them. She did not receive any personal honoraria. C. L. Daley reports grant support from AN2 Therapeutics, Bugworks, Insmed, Paratek Pharmaceuticals, Juvabis, FDA, NIH, PCORI, Cystic Fibrosis Foundation, COPD Foundation, and Renovion; advisory board work with AN2 Therapeutics, AstraZeneca, Cepheid, Galapagos, Grifols, Insmed, Hyfe, MannKind, Matinas Biopharma, NobHill, Spero Therapeutics; data monitoring committee work with Otsuka and Bill & Melinda Gates Foundation. J. van Ingen has participated in advisory boards for Insmed, Paratek, Jansen, AN2, Spero Therapeutics, and MannKind. C. Lange reports honoraria from Astra Zeneca, Gilead, GSK, Insmed, MedUpdate and MedUpdate Europe for lectures at sponsored symposia and advisory board work for Insmed. M. Lipman is Chair and Trustee of NTM Network UK; and a Trustee of NTM Patient Care UK. He has participated in clinical trials supported by Insmed Inc. He receives no payment for these activities. M. Loebinger has received honoraria for advisory boards, consultancy or lecture fees from Insmed Inc, Mannkind, AN2 Therapeutics, Armata, 30T, Astra Zeneca, Parion, Chiesis, Zambon, Electromed, Boehringer Ingelheim, Recode and Ethris. K. Morimoto reports receiving fees as a consultant and advisory board member from Insmed, Boehringer Ingelheim, and Mannkind, outside the submitted work. R. M. Thomson has been a PI on clinical trials for INSMED, AN2 Therapeutics, MannKind, Savara, Beyond Air, and Zambon. She has previously participated in advisory boards for AN2, Beyond Air and Savara but receives no personal payment for these activities. D. Wagner participated in clinical trials supported by Insmed Inc. but otherwise has no conflict of interests to declare. K. L. Winthrop serves as a consultant, and as the PI in multiple clinical trials sponsored by Insmed, Paratek, AN2, Renovion, Spero, and Mannkind J.J. Yim participated or is participating as the overall PI or institutional PI in multiple clinical trials sponsored by Insmed Inc, AN2 Therapeutics, and LigaChem Biosciences Inc. REFERENCES 1. ↵ Cowman S , van Ingen J , Griffith DE , Loebinger MR . Non-tuberculous mycobacterial pulmonary disease . Eur Respir J . 2019 ; 54 ( 1 ). doi: 10.1183/13993003.00250-2019 . OpenUrl Abstract / FREE Full Text 2. Asakura T , Ishii M , Ishii K , et al. Health-related QOL of elderly patients with pulmonary M. avium complex disease in a university hospital . Int J Tuberc Lung Dis . 2018 ; 22 ( 6 ): 695 – 703 . doi: 10.5588/ijtld.17.0433 . OpenUrl CrossRef PubMed 3. Park HY , Jeong BH , Chon HR , et al. Lung Function Decline According to Clinical Course in Nontuberculous Mycobacterial Lung Disease . Chest . 2016 ; 150 ( 6 ): 1222 – 32 . doi: 10.1016/j.chest.2016.06.005 . OpenUrl CrossRef PubMed 4. ↵ Diel R , Lipman M , Hoefsloot W . High mortality in patients with Mycobacterium avium complex lung disease: a systematic review . BMC Infect Dis . 2018 ; 18 ( 1 ): 206 . doi: 10.1186/s12879-018-3113-x . OpenUrl CrossRef PubMed 5. ↵ Winthrop KL , Marras TK , Adjemian J , et al. Incidence and Prevalence of Nontuberculous Mycobacterial Lung Disease in a Large U.S. Managed Care Health Plan, 2008-2015 . Ann Am Thorac Soc . 2020 ; 17 ( 2 ): 178 – 85 . doi: 10.1513/AnnalsATS.201804-236OC . OpenUrl CrossRef 6. van Ingen J , Obradovic M , Hassan M , et al. Nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex - disease burden, unmet needs, and advances in treatment developments . Expert Review of Respiratory Medicine . 2021 ; 15 ( 11 ): 1387 – 401 . doi: 10.1080/17476348.2021.1987891 . OpenUrl CrossRef PubMed 7. Prevots DR , Marshall JE , Wagner D , Morimoto K . Global Epidemiology of Nontuberculous Mycobacterial Pulmonary Disease: A Review . Clin Chest Med . 2023 ; 44 ( 4 ): 675 – 721 . doi: 10.1016/j.ccm.2023.08.012 . OpenUrl CrossRef PubMed 8. ↵ Dahl VN , Mølhave M , Fløe A , et al. Global trends of pulmonary infections with nontuberculous mycobacteria: a systematic review . Int J Infect Dis . 2022 ; 125 : 120 – 31 . doi: 10.1016/j.ijid.2022.10.013 . OpenUrl CrossRef PubMed 9. ↵ Daley CL , Iaccarino JM , Lange C , et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline . Eur Respir J . 2020 ; 56 ( 1 ). doi: 10.1183/13993003.00535-2020 . OpenUrl Abstract / FREE Full Text 10. ↵ Haworth CS , Banks J , Capstick T , et al. British Thoracic Society guidelines for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD) . Thorax . 2017 ; 72 ( Suppl 2 ):ii1-ii64. doi: 10.1136/thoraxjnl-2017-210927 . OpenUrl FREE Full Text 11. ↵ Pasipanodya JG , Ogbonna D , Ferro BE , et al. Systematic Review and Meta-analyses of the Effect of Chemotherapy on Pulmonary Mycobacterium abscessus Outcomes and Disease Recurrence . Antimicrob Agents Chemother . 2017 ; 61 ( 11 ). doi: 10.1128/aac.01206-17 . OpenUrl CrossRef 12. ↵ Xu HB , Jiang RH , Li L . Treatment outcomes for Mycobacterium avium complex: a systematic review and meta-analysis . Eur J Clin Microbiol Infect Dis . 2014 ; 33 ( 3 ): 347 – 58 . doi: 10.1007/s10096-013-1962-1 . OpenUrl CrossRef PubMed 13. ↵ Van Braeckel E , Bosteels C . Growing from common ground: nontuberculous mycobacteria and bronchiectasis . Eur Respir Rev . 2024 ; 33 ( 173 ). doi: 10.1183/16000617.0058-2024 . OpenUrl Abstract / FREE Full Text 14. ↵ Page MJ , McKenzie JE , Bossuyt PM , et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews . Bmj . 2021 ; 372 : n71 . doi: 10.1136/bmj.n71 . OpenUrl FREE Full Text 15. ↵ Moreira-Sousa D , Martins B , Aguiar A , et al. Management of Nontuberculous Mycobacterial Pulmonary Disease Refractory to Guideline-Based Therapy : A Systematic Review. PROSPERO 2024 CRD42024491009 [Available from: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024491009 . 16. ↵ Griffith DE , Eagle G , Thomson R , et al. Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Mycobacterium avium Complex (CONVERT). A Prospective, Open-Label, Randomized Study . Am J Respir Crit Care Med . 2018 ; 198 ( 12 ): 1559 – 69 . doi: 10.1164/rccm.201807-1318OC . OpenUrl CrossRef PubMed 17. ↵ Ingen Jv , Aksamit T , Andrejak C , et al. Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement . European Respiratory Journal . 2018 ; 51 ( 3 ): 1800170 . doi: 10.1183/13993003.00170-2018 . OpenUrl Abstract / FREE Full Text 18. ↵ Hong QN , Fàbregues S , Bartlett G , et al. The Mixed Methods Appraisal Tool (MMAT) version 2018 for information professionals and researchers . Education for Information . 2018 ; 34 : 1 – 7 . doi: 10.3233/EFI-180221 . OpenUrl CrossRef 19. ↵ Kwak N , Kim SA , Choi SM , et al. Longitudinal changes in health-related quality of life according to clinical course among patients with non-tuberculous mycobacterial pulmonary disease: a prospective cohort study . BMC Pulm Med . 2020 ; 20 ( 1 ): 126 . doi: 10.1186/s12890-020-1165-3 . OpenUrl CrossRef PubMed 20. ↵ Park J , Yoon SH , Kim JY , et al. Radiographic severity and treatment outcome of Mycobacterium abscessus complex pulmonary disease . Respir Med . 2021 ; 187 : 106549 . doi: 10.1016/j.rmed.2021.106549 . OpenUrl CrossRef 21. ↵ Park Y , Park YE , Jhun BW , et al. Impact of Susceptibility to Injectable Antibiotics on the Treatment Outcomes of Mycobacterium abscessus Pulmonary Disease . Open Forum Infect Dis . 2021 ; 8 ( 6 ):ofab215. doi: 10.1093/ofid/ofab215 . OpenUrl CrossRef 22. ↵ Kwak N , Whang J , Yang JS , et al. Minimal Inhibitory Concentration of Clofazimine Among Clinical Isolates of Nontuberculous Mycobacteria and Its Impact on Treatment Outcome . Chest . 2021 ; 159 ( 2 ): 517 – 23 . doi: 10.1016/j.chest.2020.07.040 . OpenUrl CrossRef PubMed 23. ↵ Koh WJ , Jeong BH , Kim SY , et al. Mycobacterial Characteristics and Treatment Outcomes in Mycobacterium abscessus Lung Disease . Clin Infect Dis . 2017 ; 64 ( 3 ): 309 – 16 . doi: 10.1093/cid/ciw724 . OpenUrl CrossRef PubMed 24. ↵ Tsai YV , Derrick C , Yunusa I , et al. Epidemiology, Outcomes and Tolerability of Protracted Treatment of Nontuberculous Mycobacterial Infections at a Community Teaching Hospital in the Southeastern United States . Antibiotics (Basel ). 2022 ; 11 ( 12 ). doi: 10.3390/antibiotics11121720 . OpenUrl CrossRef 25. ↵ Park YE , Park SY , Jhun BW , et al. Treatment outcome of continuation of intravenous amikacin for Mycobacterium abscessus pulmonary disease with a persistent culture positivity after the treatment initiation . J Infect Chemother . 2022 ; 28 ( 8 ): 1098 – 104 . doi: 10.1016/j.jiac.2022.03.026 . OpenUrl CrossRef PubMed 26. ↵ Moon SW , Lee EH , Choi JS , et al. Impact of prognostic nutritional index on outcomes in patients with Mycobacterium avium complex pulmonary disease . PLoS One . 2020 ; 15 ( 5 ): e0232714 . doi: 10.1371/journal.pone.0232714 . OpenUrl CrossRef PubMed 27. ↵ Im Y , Kim SY , Kim DH , Jhun BW . Outcomes of Intermittent Multidrug IV Therapy for Refractory Mycobacterium abscessus Pulmonary Disease . Chest . 2023 . doi: 10.1016/j.chest.2023.08.025 . OpenUrl CrossRef 28. ↵ Pomerantz M , Denton JR , Huitt GA , et al. Resection of the right middle lobe and lingula for mycobacterial infection . Ann Thorac Surg . 1996 ; 62 ( 4 ): 990 – 3 . doi: 10.1016/0003-4975(96)00534-6 . OpenUrl CrossRef PubMed Web of Science 29. Shiraishi Y , Fukushima K , Komatsu H , Kurashima A . Early pulmonary resection for localized Mycobacterium avium complex disease . Ann Thorac Surg . 1998 ; 66 ( 1 ): 183 – 6 . doi: 10.1016/s0003-4975(98)00373-7 . OpenUrl CrossRef PubMed Web of Science 30. Lang-Lazdunski L , Offredo C , Le Pimpec-Barthes F , et al. Pulmonary resection for Mycobacterium xenopi pulmonary infection . Ann Thorac Surg . 2001 ; 72 ( 6 ): 1877 – 82 . doi: 10.1016/s0003-4975(01)03245-3 . OpenUrl CrossRef PubMed Web of Science 31. Shiraishi Y , Katsuragi N , Kita H , et al. Adjuvant surgical treatment of nontuberculous mycobacterial lung disease . Ann Thorac Surg . 2013 ; 96 ( 1 ): 287 – 91 . doi: 10.1016/j.athoracsur.2013.03.008 . OpenUrl CrossRef PubMed 32. ↵ Kang HK , Park HY , Kim D , et al. Treatment outcomes of adjuvant resectional surgery for nontuberculous mycobacterial lung disease . BMC Infect Dis . 2015 ; 15 : 76 . doi: 10.1186/s12879-015-0823-1 . OpenUrl CrossRef PubMed 33. ↵ Kim JY , Park S , Park IK , et al. Outcomes of adjunctive surgery for nontuberculous mycobacterial pulmonary disease . BMC Pulm Med . 2021 ; 21 ( 1 ): 312 . doi: 10.1186/s12890-021-01679-0 . OpenUrl CrossRef PubMed 34. ↵ Winthrop KL , Flume PA , Thomson R , et al. Amikacin Liposome Inhalation Suspension for Mycobacterium avium Complex Lung Disease: A 12-Month Open-Label Extension Clinical Trial . Ann Am Thorac Soc . 2021 ; 18 ( 7 ): 1147 – 57 . doi: 10.1513/AnnalsATS.202008-925OC . OpenUrl CrossRef PubMed 35. ↵ Griffith DE , Thomson R , Flume PA , et al. Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease: Sustainability and Durability of Culture Conversion and Safety of Long-term Exposure . Chest . 2021 ; 160 ( 3 ): 831 – 42 . doi: 10.1016/j.chest.2021.03.070 . OpenUrl CrossRef PubMed 36. ↵ Siegel SAR , Griffith DE , Philley JV , et al. Open-Label Trial of Amikacin Liposome Inhalation Suspension in Mycobacterium abscessus Lung Disease . Chest . 2023 ; 164 ( 4 ): 846 – 59 . doi: 10.1016/j.chest.2023.05.036 . OpenUrl CrossRef PubMed 37. ↵ Jo K-W , Kim S , Lee JY , et al. Treatment outcomes of refractory MAC pulmonary disease treated with drugs with unclear efficacy . Journal of Infection and Chemotherapy . 2014 ; 20 ( 10 ): 602 – 6 . doi: 10.1016/j.jiac.2014.05.010 . OpenUrl CrossRef PubMed 38. ↵ Philley JV , Wallace RJ , Jr. , Benwill JL , et al. Preliminary Results of Bedaquiline as Salvage Therapy for Patients With Nontuberculous Mycobacterial Lung Disease . Chest . 2015 ; 148 ( 2 ): 499 – 506 . doi: 10.1378/chest.14-2764 . OpenUrl CrossRef 39. ↵ Martiniano SL , Wagner BD , Levin A , et al. Safety and Effectiveness of Clofazimine for Primary and Refractory Nontuberculous Mycobacterial Infection . Chest . 2017 ; 152 ( 4 ): 800 – 9 . doi: 10.1016/j.chest.2017.04.175 . OpenUrl CrossRef 40. Wallace RJ , Jr , Dukart G , Brown-Elliott BA , et al. Clinical experience in 52 patients with tigecycline-containing regimens for salvage treatment of Mycobacterium abscessus and Mycobacterium chelonae infections . Journal of Antimicrobial Chemotherapy . 2014 ; 69 ( 7 ): 1945 – 53 . doi: 10.1093/jac/dku062 . OpenUrl CrossRef PubMed 41. ↵ Mingora CM , Bullington W , Faasuamalie PE , et al. Long-term Safety and Tolerability of Omadacycline for the Treatment of Mycobacterium abscessus Infections . Open Forum Infectious Diseases . 2023 ; 10 ( 7 ). doi: 10.1093/ofid/ofad335 . OpenUrl CrossRef PubMed 42. ↵ Dedrick RM , Smith BE , Cristinziano M , et al. Phage Therapy of Mycobacterium Infections: Compassionate Use of Phages in 20 Patients With Drug-Resistant Mycobacterial Disease . Clin Infect Dis . 2023 ; 76 ( 1 ): 103 – 12 . doi: 10.1093/cid/ciac453 . OpenUrl CrossRef PubMed 43. ↵ Kim JY , Lee S , Park H , et al. Post-treatment Radiographic Severity and Mortality in Mycobacterium avium Complex Pulmonary Disease . Ann Am Thorac Soc . 2024 ; 21 ( 2 ): 235 – 42 . doi: 10.1513/AnnalsATS.202305-407OC . OpenUrl CrossRef PubMed 44. ↵ Fayos M , Silva JT , López-Medrano F , Aguado JM . Non-Tuberculous Mycobacteria and Aspergillus Lung Co-Infection: Systematic Review . J Clin Med . 2022 ; 11 ( 19 ). doi: 10.3390/jcm11195619 . OpenUrl CrossRef 45. Kunst H , Wickremasinghe M , Wells A , Wilson R . Nontuberculous mycobacterial disease and Aspergillus-related lung disease in bronchiectasis . European Respiratory Journal . 28 ( 2 ): 352 – 7 . doi: 10.1183/09031936.06.00139005 . OpenUrl Abstract / FREE Full Text 46. ↵ Hsieh MH , Lin CY , Wang CY , et al. Impact of concomitant nontuberculous mycobacteria and Pseudomonas aeruginosa isolates in non-cystic fibrosis bronchiectasis . Infect Drug Resist . 2018 ; 11 : 1137 – 43 . doi: 10.2147/idr.S169789 . OpenUrl CrossRef PubMed 47. ↵ Park Y , Lee EH , Jung I , et al. Clinical characteristics and treatment outcomes of patients with macrolide-resistant Mycobacterium avium complex pulmonary disease: a systematic review and meta-analysis . Respir Res . 2019 ; 20 ( 1 ): 286 . doi: 10.1186/s12931-019-1258-9 . OpenUrl CrossRef PubMed 48. ↵ van Ingen J , Boeree MJ , van Soolingen D , Mouton JW . Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria . Drug Resist Updat . 2012 ; 15 ( 3 ): 149 – 61 . doi: 10.1016/j.drup.2012.04.001 . OpenUrl CrossRef PubMed 49. ↵ Wallace RJ , Jr ., Zhang Y , Brown BA , et al. Polyclonal Mycobacterium avium complex infections in patients with nodular bronchiectasis . Am J Respir Crit Care Med . 1998 ; 158 ( 4 ): 1235 – 44 . doi: 10.1164/ajrccm.158.4.9712098 . OpenUrl CrossRef PubMed Web of Science 50. ↵ Wallace RJ , Jr ., Zhang Y , Brown-Elliott BA , et al. Repeat positive cultures in Mycobacterium intracellulare lung disease after macrolide therapy represent new infections in patients with nodular bronchiectasis . J Infect Dis . 2002 ; 186 ( 2 ): 266 – 73 . doi: 10.1086/341207 . OpenUrl CrossRef PubMed Web of Science 51. ↵ Ito A , Nanjo Y , Kajiwara C , et al. Intrinsic clarithromycin heteroresistance in Mycobacterium avium . J Infect Chemother . 2024 ; 30 ( 8 ): 752 – 6 . doi: 10.1016/j.jiac.2024.02.016 . OpenUrl CrossRef PubMed 52. ↵ Ku JH , Henkle E , Aksamit TR , et al. Treatment of Nontuberculous Mycobacterial (NTM) Pulmonary Infection in the US Bronchiectasis and NTM Registry: Treatment Patterns, Adverse Events, and Adherence to American Thoracic Society/Infectious Disease Society of America Treatment Guidelines . Clin Infect Dis . 2023 ; 76 ( 2 ): 338 – 41 . doi: 10.1093/cid/ciac788 . OpenUrl CrossRef PubMed 53. ↵ Ikegame S , Maki S , Wakamatsu K , et al. Nutritional assessment in patients with pulmonary nontuberculous mycobacteriosis . Intern Med . 2011 ; 50 ( 21 ): 2541 – 6 . doi: 10.2169/internalmedicine.50.5853 . OpenUrl CrossRef PubMed 54. Takayama Y , Kitajima T , Honda N , et al. Nutritional status in female patients with nontuberculous mycobacterial lung disease and its association with disease severity . BMC Pulm Med . 2022 ; 22 ( 1 ): 315 . doi: 10.1186/s12890-022-02109-5 . OpenUrl CrossRef PubMed 55. ↵ Basavaraj A , Segal L , Samuels J , et al. Effects of Chest Physical Therapy in Patients with Non-Tuberculous Mycobacteria . Int J Respir Pulm Med . 2017 ; 4 ( 1 ). doi: 10.23937/2378-3516/1410065 . OpenUrl CrossRef 56. ↵ Jung HI , Kim SA , Kim HJ , et al. Anxiety and Depression in Patients With Nontuberculous Mycobacterial Pulmonary Disease: A Prospective Cohort Study in South Korea . Chest . 2022 ; 161 ( 4 ): 918 – 26 . doi: 10.1016/j.chest.2021.10.024 . OpenUrl CrossRef PubMed 57. ↵ Huiberts A , Zweijpfenning SMH , Pennings LJ , et al. Outcomes of hypertonic saline inhalation as a treatment modality in nontuberculous mycobacterial pulmonary disease . Eur Respir J . 2019 ; 54 ( 1 ). doi: 10.1183/13993003.02143-2018 . OpenUrl Abstract / FREE Full Text 58. ↵ Zanini A , Aiello M , Adamo D , et al. Effects of Pulmonary Rehabilitation in Patients with Non-Cystic Fibrosis Bronchiectasis: A Retrospective Analysis of Clinical and Functional Predictors of Efficacy . Respiration . 2015 ; 89 ( 6 ): 525 – 33 . doi: 10.1159/000380771 . OpenUrl CrossRef PubMed 59. ↵ Jarand J , Davis JP , Cowie RL , et al. Long-term Follow-up of Mycobacterium avium Complex Lung Disease in Patients Treated With Regimens Including Clofazimine and/or Rifampin . Chest . 2016 ; 149 ( 5 ): 1285 – 93 . doi: 10.1378/chest.15-0543 . OpenUrl CrossRef PubMed 60. Nasiri MJ , Calcagno T , Hosseini SS , et al. Role of Clofazimine in Treatment of Mycobacterium avium Complex . Frontiers in Medicine . 2021 ; 8 . doi: 10.3389/fmed.2021.638306 . OpenUrl CrossRef 61. Zweijpfenning SMH , Aarnoutse R , Boeree MJ , et al. Safety and Efficacy of Clofazimine as an Alternative for Rifampicin in Mycobacterium avium Complex Pulmonary Disease Treatment: Outcomes of a Randomized Trial . Chest . 2024 ; 165 ( 5 ): 1082 – 92 . doi: 10.1016/j.chest.2023.11.038 . OpenUrl CrossRef PubMed 62. Bao S , Chen S , Zheng J , et al. Efficacy of clofazimine-containing regimens for treatment of Mycobacterium avium complex-pulmonary disease in patients unsuitable for standard treatment regimen . Int J Antimicrob Agents . 2024 ; 63 ( 2 ): 107061 . doi: 10.1016/j.ijantimicag.2023.107061 . OpenUrl CrossRef PubMed 63. ↵ Lee I , Hwang EJ , Kim J-Y , et al. Treatment Outcomes of Clofazimine-Containing Regimens in Severe Mycobacterium avium Complex Pulmonary Disease . Open Forum Infectious Diseases . 2023 ; 11 ( 2 ). doi: 10.1093/ofid/ofad682 . OpenUrl CrossRef PubMed 64. ↵ Janssen Pharmaceutical KK. A Study of Bedaquiline Administered as Part of a Treatment Regimen With Clarithromycin and Ethambutol in Adult Patients With Treatment-refractory Mycobacterium Avium Complex-lung Disease (MAC-LD) . ClinicalTrials.gov identifier: NCT04630145 . Updated February 28, 2025 . Accessed March 20, 2025. [Available from: https://clinicaltrials.gov/study/NCT04630145?term=NCT00004689%20NCT04630145&rank=1#contacts-and-locations . 65. ↵ Yang B , Jhun BW , Moon SM , et al. Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease . Antimicrob Agents Chemother . 2017 ; 61 ( 6 ). doi: 10.1128/aac.02052-16 . OpenUrl CrossRef 66. ↵ Pearson JC , Dionne B , Richterman A , et al. Omadacycline for the Treatment of Mycobacterium abscessus Disease: A Case Series . Open Forum Infectious Diseases . 2020 ; 7 ( 10 ). doi: 10.1093/ofid/ofaa415 . OpenUrl CrossRef PubMed 67. ↵ Inc . LB. Study to Evaluate the Efficacy of Delpazolid As Add-on Therapy in Refractory Mycobacterium Abscessus Complex . ClinicalTrials.gov identifier : NCT06004037 . Updated January 23, 2025 . Accessed March 20, 2025. [Available from: https://clinicaltrials.gov/study/NCT06004037?term=nontuberculous%20mycobacteria%20AND%20Lung%20Diseases&sort=StudyFirstPostDate&page=2&rank=12 . 68. ↵ Health NJ. Mycobacteriophage Treatment of Non-tuberculosis Mycobacteria (POSTSTAMP) . ClinicalTrials.gov identifier: NCT06262282 . Updated February 16, 2024 . Accessed March 20, 2025. [Available from: https://clinicaltrials.gov/study/NCT06262282?term=nontuberculous%20mycobacteria%20AND%20Lung%20Diseases&sort=StudyFirstPostDate&rank=8 . 69. ↵ Wiesel V , Aviram M , Mei-Zahav M , et al. Eradication of Nontuberculous Mycobacteria in People with Cystic Fibrosis Treated with Elexacaftor/Tezacaftor/Ivacaftor: A Multicenter Cohort Study . J Cyst Fibros . 2024 ; 23 ( 1 ): 41 – 9 . doi: 10.1016/j.jcf.2023.05.003 . OpenUrl CrossRef PubMed 70. ↵ Anidi IU , Olivier KN . Host-Directed Therapy in Nontuberculous Mycobacterial Pulmonary Disease: Preclinical and Clinical Data Review . Clin Chest Med . 2023 ; 44 ( 4 ): 839 – 45 . doi: 10.1016/j.ccm.2023.07.004 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted June 23, 2025. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Management of Nontuberculous Mycobacterial Pulmonary Disease Refractory to Guideline-Based Therapy: A Systematic Review Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Management of Nontuberculous Mycobacterial Pulmonary Disease Refractory to Guideline-Based Therapy: A Systematic Review Diana Moreira-Sousa , Beatriz Martins , Ana Aguiar , Marina Pinheiro , Onno W. Akkerman , Timothy R Aksamit , Stefano Aliberti , Claire Andrejak , Charles L. Daley , Jakko van Ingen , Christoph Lange , Marc Lipman , Michael R Loebinger , Mateja Jankovic Makek , Kozo Morimoto , Rachel Thomson , Dirk Wagner , Kevin L Winthrop , Jae-Joon Yim , Raquel Duarte medRxiv 2025.06.23.25330100; doi: https://doi.org/10.1101/2025.06.23.25330100 Share This Article: Copy Citation Tools Management of Nontuberculous Mycobacterial Pulmonary Disease Refractory to Guideline-Based Therapy: A Systematic Review Diana Moreira-Sousa , Beatriz Martins , Ana Aguiar , Marina Pinheiro , Onno W. Akkerman , Timothy R Aksamit , Stefano Aliberti , Claire Andrejak , Charles L. Daley , Jakko van Ingen , Christoph Lange , Marc Lipman , Michael R Loebinger , Mateja Jankovic Makek , Kozo Morimoto , Rachel Thomson , Dirk Wagner , Kevin L Winthrop , Jae-Joon Yim , Raquel Duarte medRxiv 2025.06.23.25330100; doi: https://doi.org/10.1101/2025.06.23.25330100 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Respiratory Medicine Subject Areas All Articles Addiction Medicine (569) Allergy and Immunology (863) Anesthesia (300) Cardiovascular Medicine (4441) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1510) Epidemiology (15230) Forensic Medicine (30) Gastroenterology (1126) Genetic and Genomic Medicine (6608) Geriatric Medicine (668) Health Economics (998) Health Informatics (4542) Health Policy (1369) Health Systems and Quality Improvement (1613) Hematology (543) HIV/AIDS (1266) Infectious Diseases (except HIV/AIDS) (15923) Intensive Care and Critical Care Medicine (1103) Medical Education (623) Medical Ethics (147) Nephrology (668) Neurology (6607) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1146) Occupational and Environmental Health (957) Oncology (3335) Ophthalmology (974) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (663) Pediatrics (1693) Pharmacology and Therapeutics (692) Primary Care Research (711) Psychiatry and Clinical Psychology (5448) Public and Global Health (9237) Radiology and Imaging (2201) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1196) Rheumatology (596) Sexual and Reproductive Health (714) Sports Medicine (530) Surgery (712) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a0180fa2ec98df88',t:'MTc3OTc0OTAyOA=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();