MAC Lung Disease Research Articles

2556. A Phase 1, Open-Label, Single Dose Study to Evaluate the Pharmacokinetics (PK), Safety, and Tolerability of Epetraborole Tablets and the Impact of Alcohol Dehydrogenase (ADH) Genotype on the PK of Epetraborole and Metabolite M3 in Healthy Japanese Adult Subjects

Abstract Background Epetraborole (EBO), an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria, is under clinical development for treatment-refractory MAC lung disease. Nonclinical studies suggest that metabolism of EBO to metabolite M3 may involve oxidation by ADH. The goal of this study was to evaluate the impact of ADH genotype on the PK of EBO and M3 in healthy Japanese subjects. Methods In this open-label trial, a single 500 mg EBO dose was administered to subjects in 3 cohorts defined by ADH1B genotype (*1/*1, *1/*2, or *2/*2). EBO and M3 plasma concentrations were measured by a validated LC-MS/MS method, and plasma EBO and M3 PK were determined using non-compartmental methods. Standard clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Results 18 subjects were enrolled (6/cohort). EBO was rapidly absorbed, with M3 subsequently appearing in plasma. After reaching Cmax, EBO and M3 concentrations declined with a geometric mean t1/2 of 10.7 to 11.4 h and 26.7 to 33.1 h, respectively. EBO exposures (Cmax and AUC) were similar between Cohort 1 and Cohort 2, while exposures were 1.2- to 1.4-fold higher in Cohort 3 (Table); however, exposure of M3 was similar across all cohorts. Compared to Cohort 1, M3:EBO ratios for Cohort 3 were generally similar for Cmax and were approximately 26% lower for AUC. No apparent differences in t1/2 were observed across cohorts for either EBO or M3. No TEAEs or clinically significant changes in clinical laboratory parameters, vital signs, physical examinations, or ECGs were reported in this study. Conclusion Administration of EBO in Japanese subjects with varying ADH1B genotypes had no meaningful effect on EBO or M3 plasma exposure. The slightly increased EBO exposures associated with the 500 mg dosage in subjects with ADH1B *2/*2 genotype were within the range of tolerable exposures. Oral EBO was well tolerated in this study; no TEAEs were reported. This Phase 1 study did not identify any risk that would preclude evaluation of oral EBO administered 500 mg daily in patients with different ADH1B genotypes, including Japanese patients. Disclosures All Authors: No reported disclosures

593. Population Pharmacokinetic Model Development for Epetraborole and Mycobacterium avium Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

593. Population Pharmacokinetic Model Development for Epetraborole and <i>Mycobacterium avium</i> Complex (MAC) Lung Disease Patients Using Data from Phase 1 and 2 Studies

1727. Phase 1b Dose-ranging Study Demonstrates Tolerability and Pharmacokinetics (PK) of Oral Epetraborole at the Predicted Therapeutic Dosage for Mycobacterium avium Complex (MAC) Lung Disease

Abstract Background Epetraborole (EBO) — an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria — is under clinical development for treatment of MAC lung disease. We conducted a Phase 1b dose-ranging study of EBO tablets in healthy adult volunteers, to inform dose selection in the treatment of MAC lung disease. Methods In this double-blind, placebo-controlled trial, EBO or placebo tablets were administered (n=8/cohort, 3:1 randomization) at dosages of 250-1000 mg q24h or 500 mg or 1000 mg q48h for up to 28 days. Standard Ph1 clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Based on prior human studies using significantly higher EBO daily doses, gastrointestinal (GI) events and anemia were predetermined AEs of special interest (AESIs). Plasma concentrations of EBO were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods. Results A total of 43 subjects were enrolled; the 1000 mg q24h cohort was terminated early due to local COVID restrictions. Overall, 80.6% EBO subjects and 83.3% placebo subjects experienced ≥1 TEAE, none of which was serious or severe (Table). Most TEAEs were mild in severity (90%), and the remainder were moderate (10%). No TEAE leading to withdrawal from study was reported. The most frequent types of TEAEs were GI events (48.4% EBO, 41.7% placebo subjects), the most common being mild nausea. Two subjects had premature discontinuation of EBO due to a TEAE (asymptomatic liver enzyme elevations in a 250 mg q24h subject and mild nausea in a 1000 mg q48h subject). One 1000mg q24h subject had a TEAE of anemia. No clinically significant findings or TEAEs were observed for physical examinations, ECGs, or urine laboratory tests. Plasma Cmax and AUC0-∞ of EBO increased in a linear, dose-proportional manner across cohorts. Tmax was observed at ∼1 h post dose; mean t1/2 ranged from 7.63 to 11.1 h. Conclusion Oral EBO administered for 28-day dosing was generally well tolerated at the predicted therapeutic dose (500mg q24h) Predictable PK characteristics facilitate its use in MAC lung disease Further evaluation in a Phase 2/3 treatment-refractory MAC lung disease study is planned Disclosures Paul B. Eckburg, MD, Paratek Pharmaceuticals, Inc.: Safety Review Board|Spero Therapeutics, Inc.: Advisor/Consultant Sanjay Chanda, PhD, AN2 Therapeutics: Stocks/Bonds George Talbot, MD, AN2 Therapeutics, Inc.: Advisor/Consultant|AN2 Therapeutics, Inc.: Co-founder Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support.

619. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Epetraborole Dose Selection for the Treatment of Patients with Mycobacterium avium Complex (MAC) Lung Disease

619. Pharmacokinetic-Pharmacodynamic (PK-PD) Target Attainment Analyses to Support Epetraborole Dose Selection for the Treatment of Patients with <i>Mycobacterium avium</i> Complex (MAC) Lung Disease

Prognostic significance of radiological pleuroparenchymal fibroelastosis in Mycobacterium avium complex lung disease: a multicentre retrospective cohort study

BackgroundMycobacterium avium complex (MAC) causes chronic respiratory infectious diseases with diverse clinical features and prognoses. Pleuroparenchymal fibroelastosis (PPFE) is a rare disease characterised by pleural fibrosis with subjacent intra-alveolar fibrosis...

Novel Screening System of Virulent Strains for the Establishment of a Mycobacterium avium Complex Lung Disease Mouse Model Using Whole-Genome Sequencing.

ABSTRACTThe establishment of animal models reflecting human Mycobacterium avium complex (MAC) lung disease (LD) pathology has the potential to expand our understanding of the disease pathophysiology. However, inducing sustained infection in immunocompetent mice is difficult since MAC generally shows less virulence and higher genetic variability than M. tuberculosis. To overcome this hurdle, we developed a screening system for identifying virulent MAC strains using whole-genome sequencing (WGS). We obtained nine clinical strains from Mycobacterium avium complex lung disease (MAC-LD) patients and divided them into two groups to make the mixed strain inocula for infection. Intranasal infection with the strain mixture of both groups in BALB/c mice resulted in progressive infection and extensive granuloma formation in the lungs, suggesting the existence of highly pathogenic strains in each group. We hypothesized that the change in the abundance of strain-specific single-nucleotide variants (SNVs) reflects the change in bacterial number of each strain in infected lungs. Based on this hypothesis, we quantified individual strain-specific SNVs in bacterial DNA from infected lungs. Specific SNVs for four strains were detected, suggesting the pathogenicity of these four strains. Consistent with these results, individual infection with these four strains induced a high lung bacterial burden, forming extensive peribronchial granuloma, while the other strains showed a decreased lung bacterial burden. The current method combining mixed infection and WGS accurately identified virulent strains that induced sustained infection in mice. This method will contribute to the establishment of mouse models that reflect human MAC-LD and lead to antimycobacterial drug testing.IMPORTANCE To promote research on Mycobacterium avium complex (MAC) pathogenicity, animal models reflecting human progressive MAC lung disease (MAC-LD) are needed. Because there is high genetic and virulence diversity among clinical MAC strains, choosing a suitable strain is an important process for developing a mouse model. In this study, we developed a screening system for virulent strains in mice by combining mixed infection and whole-genome sequencing analysis. This approach is designed on the hypothesis that in vivo virulence of MAC strains can be examined simultaneously by comparing changes in the abundance of strain-specific single-nucleotide variants in the mouse lungs after infection with mixed strains. The identified strains were shown to induce high bacterial burdens and cause extensive peribronchial granuloma resembling the pulmonary pathology of human MAC-LD. The current method will help researchers develop mouse models that reflect human MAC-LD and will lead to further investigation of MAC pathogenicity.

Amikacin liposome inhalation suspension as a treatment for patients with refractory mycobacterium avium complex lung infection

ABSTRACT Introduction: Amikacin liposome inhalation suspension (ALIS) contains amikacin sulfate, an aminoglycoside antibacterial drug. It has been approved in the US as a combined antibiotic treatment for refractory MAC lung disease patients. ALIS, as an inhaled antibiotic, can deliver amikacin to the infected site effectively and reduce systemic toxicity. Areas covered: This article gives a summated review of the pharmacodynamics, pharmacokinetics, therapeutic efficacy, post-marketing surveillance, and regulatory affairs of ALIS as an add-on therapy for MAC lung disease in adults by analyzing data from preclinical studies, clinical trials and original studies. We systematically searched Medline/PubMed through October 2020. Expert opinion: Studies demonstrate that ALIS as an add-on treatment significantly improve the rate of sputum culture conversion in MAC lung disease patients compare to guideline-recommended therapy only. The ALIS treatment showed a similar risk of serious adverse events and a low chance of renal adverse events. However, ALIS was associated with more respiratory adverse events than guideline-recommended therapy only. There was not sufficient data to conclude that ALIS treatment can improve clinical outcomes; however, with the significant improvement in the microbiology outcome in MAC lung disease patients, ALIS showed its potential use as an adjunct treatment for treating MAC lung disease.

Association of serum antibodies against the Mycobacterium avium complex and hemoptysis: a cross-sectional study

BackgroundHemoptysis is very common and can be life threatening in clinical practice for nontuberculous mycobacteria. The serum antibody against the Mycobacterium avium complex (MAC-Ab), the majority of nontuberculous mycobacteria species, is well known to reflect the activity of MAC lung disease; however, there is no study investigating the association between the MAC-Ab and hemoptysis in MAC patients. Therefore, we assessed whether the MAC-Ab is a good biomarker for hemoptysis among subjects with MAC lung disease.MethodsThis study was conducted as a five-year retrospective survey at the National Hospital Organization Fukuoka National Hospital. A total of 155 patients aged ≥20 years with MAC lung disease were enrolled and separated into seropositive and seronegative groups using the cutoff for MAC-Ab levels of 0.7 U/ml. The prevalence of hemoptysis and odds ratios for the presence of hemoptysis were estimated and compared between the groups. To investigate the linear trends in the relationship between MAC-Ab levels and hemoptysis, the subjects were classified into three groups using the tertile distribution of the MAC-Ab.ResultsThe prevalence of hemoptysis was twice as high in the seropositive group than in the seronegative group (42.2 and 21.7%, respectively, P = 0.02). The multivariable-adjusted risk of hemoptysis was elevated in the seropositive group as compared with the seronegative group (odds ratio = 2.79 (95% confidence interval 1.15–7.44)). Likewise, when categorizing the subjects into three groups, the risk of hemoptysis increased with increasing MAC-Ab levels (P = 0.03 for trend).ConclusionsA positive MAC-Ab level was a significant risk factor for hemoptysis among patients with MAC lung disease. There were also positive trends in the association between the MAC-Ab titer and the likelihood of hemoptysis. Measuring the MAC-Ab may contribute not only to early detection of the risk of hemoptysis but also to early intervention with anti-NTM therapy and, as a result, to the prevention of hemoptysis in MAC patients.

Subtle immunodeficiencies in nodular-bronchiectatic Mycobacterium avium complex lung disease.

Patients with nodular–bronchiectatic MAC lung disease have dysregulated adaptive immunity with defective IL-17 and IFN-γ production, and IL-10 overproduction. This suggests a role for adjunctive immunomodulatory treatments. https://bit.ly/33AALwx

Effective treatment for clarithromycin-resistant Mycobacterium avium complex lung disease

Clinical management of macrolide-resistant Mycobacterium avium complex (MR-MAC) lung disease is difficult. To date, there only exist a limited number of reports on the treatment of clarithromycin-resistant MAC (CR-MAC) lung disease. This study aimed to evaluate prognostic factors and identify effective treatments in CR-MAC lung disease. We retrospectively collected clinical data of patients newly diagnosed with CR-MAC lung disease at the Kinki-Chuo Chest Medical Center between August 2010 and June 2018. Altogether, 37 patients with CR-MAC lung disease were enrolled. The median age was 69 years; 30, 22, and 21 patients received clarithromycin, ethambutol, and rifampicin, respectively, on their own or in drug combination. The observed sputum culture conversion rate was 29.7% (11/37 patients). In univariate analysis, ethambutol significantly increased the rate of sputum culture conversion (p = 0.027, odds ratio (OR) 10; 95% confidence interval (CI) 1.11–89.77). Multivariate analysis confirmed that ethambutol increased sputum culture conversion rate (p = 0.026; OR 21.8; 95% CI 1.45–329) while the existence of lung cavities decreased it (p = 0.04; OR 0.088; 95% CI 0.009–0.887). The combined use of ethambutol with other drugs may improve sputum culture conversion rate in CR-MAC lung disease.

AN OPEN-LABEL EXTENSION STUDY OF AMIKACIN LIPOSOME INHALATION SUSPENSION (ALIS) FOR TREATMENT-REFRACTORY LUNG DISEASE CAUSED BY MYCOBACTERIUM AVIUM COMPLEX (MAC)

SESSION TITLE: Controversies in Nontuberculous Mycobacteria Treatment SESSION TYPE: Original Investigations PRESENTED ON: 10/21/2019 1:30 PM - 2:30 PM PURPOSE: MAC lung disease is challenging to treat, particularly for patients who are refractory to previous antimicrobial therapy. ALIS is an inhaled liposomal formulation of amikacin. In the CONVERT study (Griffith, AJRCCM 2018), ALIS + guideline-based therapy (GBT) achieved a significantly higher rate of sputum culture conversion vs GBT alone by month 6 (29.0% vs. 8.9%; P<.0001). The present study, INS-312 (NCT02628600), is an open-label extension of CONVERT that evaluated the long-term safety, tolerability, and efficacy of ALIS+GBT in patients who did not meet the strict definition of culture conversion by month 6 in CONVERT. METHODS: Patients were adults with refractory, radiographically confirmed MAC lung disease enrolled in the CONVERT study. Patients who did not achieve culture conversion by month 6 in CONVERT exited the study at month 8 and had the option to enroll directly into INS-312 to either continue ALIS+GBT (prior ALIS+GBT arm) or add ALIS to GBT (prior GBT-alone arm) for an additional 12 months. Once-daily ALIS 590 mg was administered using an investigational eFlow® nebulizer. Sputum was collected monthly; culture conversion was defined as 3 consecutive monthly MAC-negative cultures. RESULTS: Enrolled patients (prior GBT-alone, n=90; prior ALIS+GBT, n=73) were a median 64.8 years old and 64.4% female. By month 6 in INS-312, culture conversion criteria were met in 24/90 patients (26.7%) in the prior GBT-alone arm, and 7/73 (9.6%) in the prior ALIS+GBT arm. By 12 months, conversion occurred in 30/90 patients (33.3%) and 10/73 (13.7%), respectively. Across both arms, 96.9% of patients had ≥1 treatment-emergent adverse event (TEAE). The most common TEAEs were respiratory, reported in 83.3% (n=75/90) of patients initiating ALIS, and 46.6% (n=34/73) of patients continuing ALIS+GBT. Serious TEAEs (35.6%, n=32/90; 27.4%, n=20/73), and TEAEs leading to ALIS withdrawal (24.4%, n=22/90; 8.2%, n=6/73), were higher in patients adding ALIS to GBT versus those continuing ALIS+GBT from CONVERT, respectively. TEAEs leading to death occurred in 4.4% (n=4/90, prior GBT-alone) and 2.7% (n=2/73, prior ALIS+GBT). CONCLUSIONS: In the INS-312 extension study, 26.7% and 33.3% of patients initiating ALIS achieved culture conversion by months 6 and 12, respectively. By indirect comparison, similar proportions of patients achieved culture conversion by month 6 in the prior GBT-alone arm (initiated ALIS in INS-312) and the ALIS+GBT arm in CONVERT (26.7% versus 29.0%, respectively). Approximately 14% of patients who received ALIS+GBT but did not achieve culture conversion by month 6 of CONVERT achieved conversion by month 12 with continued administration of ALIS+GBT in INS-312. The safety profile was consistent with results from CONVERT. CLINICAL IMPLICATIONS: These results support the long-term safety of ALIS+GBT and suggest that additional patients may achieve culture conversion with ALIS+GBT continued beyond 6 months. DISCLOSURES: No relevant relationships by Paola Francesca Castellotti, source=Web Response No relevant relationships by Christopher Coulter, source=Admin input Grant recipient relationship with Insmed Corporation Please note: >$100000 Added 03/22/2019 by David Griffith, source=Admin input, value=Grant/Research Support Employee relationship with Insmed Please note: >$100000 Added 03/11/2019 by Kevin Mange, source=Web Response, value=Salary No relevant relationships by KOZO MORIMOTO, source=Web Response Employee relationship with Insmed Corporation Please note: >$100000 Added 03/12/2019 by James Nezamis, source=Web Response, value=Salary Advisory Committee Member relationship with Insmed, Inc. Please note: $1001 - $5000 Added 03/11/2019 by Stephen Ruoss, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Insmed Please note: $1001 - $5000 Added 03/12/2019 by Jakko van Ingen, source=Web Response, value=Consulting fee No relevant relationships by Kevin Winthrop, source=Web Response No relevant relationships by Jae-Joon Yim, source=Admin input

805. Amikacin Liposome Inhalation Suspension (ALIS) Add-on Therapy for Refractory Mycobacterium avium Complex (MAC) Lung Disease: Effect of In Vitro Amikacin Susceptibility on Sputum Culture Conversion

BackgroundALIS (590 mg amikacin base) is liposome-encapsulated amikacin for inhalation, which delivers amikacin directly to the lung and limits systemic exposure. In the CONVERT phase 3 trial, significantly more adults with treatment-refractory MAC lung disease receiving ALIS plus guideline-based therapy (GBT) vs. GBT alone achieved sputum culture conversion by month 6 (29.0% vs. 8.9%, P < 0.0001). Amikacin treatment failure has previously been reported in patients with amikacin minimum inhibitory concentrations (MIC) >64 µg/mL. We analyzed the impact of amikacin MIC on culture conversion during treatment with add-on ALIS.MethodsIn CONVERT, patients were randomly assigned (2:1) to receive once daily ALIS+GBT (n = 224) or GBT alone (n = 112). Patients with amikacin-resistant MAC isolates (MICs >64 μg/mL by broth microdilution) were excluded prior to randomization. The primary endpoint was culture conversion, defined as 3 consecutive monthly MAC-negative sputum cultures by month 6. Amikacin MICs were correlated with culture conversion rates.ResultsAmikacin MIC distributions at baseline (day 1) were similar in both groups (Figure 1). Conversion rates in the ALIS+GBT arm were 28.6–34.5% for MAC with amikacin MICs of 8–64 µg/mL (Figure 2). Overall, 28 patients developed post-screening amikacin MIC >64 µg/mL, 4/112 in the GBT alone arm (post-baseline), and 24/224 in the ALIS+GBT arm (1 at baseline and 23 post-baseline after adding ALIS). Most of these (18/24) had MAC isolates with persistent amikacin MIC >64 µg/mL. Only 1/24 patients in the ALIS+GBT arm with amikacin MIC >64 µg/mL achieved culture conversion. No patient with both macrolide resistance and persistent amikacin MIC >64 µg/mL (8/24) converted.ConclusionIn the ALIS+GBT arm of CONVERT, culture conversion rates were similar for amikacin MICs ranging from 8–64 µg/mL at baseline. Amikacin MIC >64 µg/mL emerged in 10.3% of patients after initiation of add-on ALIS treatment, and 3.6% in the GBT alone arm. Emergent amikacin MIC >64 µg/mL was associated with failure to convert, particularly with concurrent macrolide resistance. Determining amikacin susceptibility at both treatment initiation and during treatment may have utility for guiding treatment decisions. Disclosures B. A. Brown-Elliott, Insmed: Investigator, Research support. G. Eagle, Insmed Incorporated: Employee, Salary. R. J. Wallace, Insmed: Investigator, Research support. J. Van Ingen, Insmed: Investigator, Research support. L. J. Pennings, Insmed: Investigator, Research support. B. Berry, Insmed: Investigator, Research support. S. Pandey, Insmed: Investigator, Research support. C. Coulter, Insmed: Investigator, Research support. M. Syrmis, Insmed: Investigator, Research support. K. L. Winthrop, Insmed Incorporated: Consultant and Scientific Advisor, Consulting fee and Research grant. D. E. Griffith, Aradigm Corporation: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Bayer Healthcare Pharmaceuticals: Advisor/consultant, Consulting fee. Grifols: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Insmed Incorporated: Advisor/consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium.

RELATIONSHIP BETWEEN IN VITRO CLARITHROMYCIN SUSCEPTIBILITY AND SPUTUM CULTURE CONVERSION WITH ADD-ON AMIKACIN LIPOSOME INHALATION SUSPENSION (ALIS) FOR TREATMENT OF REFRACTORY MYCOBACTERIUM AVIUM COMPLEX (MAC) LUNG DISEASE

RELATIONSHIP BETWEEN IN VITRO CLARITHROMYCIN SUSCEPTIBILITY AND SPUTUM CULTURE CONVERSION WITH ADD-ON AMIKACIN LIPOSOME INHALATION SUSPENSION (ALIS) FOR TREATMENT OF REFRACTORY MYCOBACTERIUM AVIUM COMPLEX (MAC) LUNG DISEASE

Treatment of Mycobacterium avium Complex (MAC).

Mycobacterium avium complex (MAC) is the most commonly isolated nontuberculous mycobacterial respiratory pathogen worldwide. MAC lung disease is manifested either by fibrocavitary radiographic changes similar to pulmonary tuberculosis or by bronchiectasis with nodular and reticulonodular radiographic changes. This latter form of MAC lung disease, termed "nodular bronchiectatic (NB) MAC lung disease" is the most common form of MAC lung disease in the United States. Treatment at the time of diagnosis is always indicated for fibrocavitary MAC lung disease because it is always progressive and associated with increased morbidity and mortality compared with NB MAC lung disease. In contrast, the NB form of MAC lung disease is more indolent and frequently does not require antimycobacterial therapy. For patients with NB MAC lung disease, the priorities are typically to treat the underlying bronchiectasis and determine the course and impact of the MAC infection over time. Guidelines-based MAC therapy with multidrug regimens including macrolides is usually effective, but far from as predictably effective and durable as therapy for tuberculosis. It is imperative that clinicians are familiar with MAC drug resistance mechanisms and the pitfalls of inappropriate dependence on in vitro drug susceptibility testing which can predispose patients to the development of macrolide resistance with its attendant high mortality. It is now more than 20 years since the emergence of macrolides for MAC therapy with no new comparably effective agents introduced in that time, although one new inhaled amikacin therapy under study offers promise.

Interleukin 23/interleukin 17 axis activated by Mycobacterium avium complex (MAC) is attenuated in patients with MAC-lung disease

BackgroundMycobacterium avium complex (MAC)-lung disease (LD) is increasing in patients without human immunodeficiency virus infection. However, data on host vulnerability to MAC-related immune responses, and in particular the interleukin (IL)-23/IL-17 axis, are lacking. MethodsWe enrolled 50 patients with MAC-LD, 25 age-matched patients with tuberculosis (TB) and 25 controls. We measured levels of plasma cytokines, and studied IL-12/IL-17 responses in macrophage and lymphocyte activation to MAC. ResultsThe plasma level of IL-17 in the MAC group was higher than in the TB and control groups. In in-vitro macrophage stimulation, the expression of IL-23 in macrophages was similar in the patients with MAC-LD and controls, although the expression of IL-12 p40 was lower in the patients with MAC-LD. In assays of lymphocyte activation, IL-17 was induced by MAC-primed macrophages, but its level was lower in the patients with MAC-LD and TB than in the controls. The expression of programmed death (PD)-1 receptor was higher in CD4+IL17A+ lymphocytes in the patients with MAC-LD, and the production of IL-17 was significantly increased by blockade of PD-1 and PD-ligand 1. ConclusionsMAC induced a similar expression of IL-23 from macrophages in the patients with MAC-LD compared to the controls, but a lower expression of IL-17 from lymphocytes, which may be through an increased expression of PD-1. The macrophage response of IL-12 p40 was stronger than that of IL-12 p70, and higher in the controls during MAC disease, which may suggest another kind of MAC-related immune evasion.

生物学的製剤を使用中の関節リウマチ患者に器質化肺炎と肺MAC 症を合併した1 例

生物学的製剤を使用中の関節リウマチ患者に器質化肺炎と肺MAC 症を合併した1 例

Retrospective study of the predictors of mortality and radiographic deterioration in 782 patients with nodular/bronchiectatic Mycobacterium avium complex lung disease

ObjectivesSome patients with nodular/bronchiectatic Mycobacterium avium complex lung disease (NB MAC-LD) deteriorate and die. The main aim of the study is to evaluate the prognostic factors and radiographic outcomes in...

Risk factors for recurrence after successful treatment of Mycobacterium avium complex lung disease.

This study analyzed the recurrence rate and risk factors for recurrence of Mycobacterium avium complex (MAC) lung disease in patients successfully treated for this disease. The medical records of 158 patients successfully treated for MAC lung disease at a tertiary referral center in South Korea between March 2000 and December 2009 were retrospectively analyzed. Recurrence was recorded, and factors associated with recurrence were analyzed. The mean age of the 158 patients was 60.7 ± 11.1 years. The etiologic agent was Mycobacterium avium in 77 patients (48.7%) and Mycobacterium intracellulare in 81 patients (51.3%). Radiographic features included nodular bronchiectatic disease in 95 (60.1%), fibrocavitary disease in 49 (31.0%), and an unclassifiable form in 14 (8.9%) patients. Almost all (98.7%, 156/158) patients had been previously treated with a macrolide-containing regimen, and 68 (43.0%) patients had received treatment with an aminoglycoside. During a median follow-up of 43.8 months after completion of therapy, 50 patients (31.6%) experienced recurrence, at a median of 11.9 months after treatment completion. Multivariate analysis showed that only the nodular bronchiectatic form of the disease (hazard ratio, 2.39; 95% confidence interval, 1.19 to 4.81) was independently associated with an increased risk of recurrence. Recurrence after successful treatment is frequent in patients with MAC lung disease. The recurrence rate was significantly higher in patients with the nodular bronchiectatic form than in those with the fibrocavitary form or an unclassifiable form of the disease.

Patients with MAC Lung Disease Have a Low Visceral Fat Area and Low Nutrient Intake.

Objective. This study aimed to examine the nutritional status and nutrient intake of patients with MAC lung disease with a focus on visceral fat area. Patients and Methods. Among 116 patients of our hospital with nontuberculous mycobacteriosis who were registered between May 2010 and August 2011, 103 patients with MAC lung disease were included in this study. In all patients, nutritional status and nutrient intake were prospectively examined. Results. Patients were 23 men and 80 women (mean age, 72.3 ± 10.9 years). BMI (kg/m2) at the time of registration was 20.4 ± 2.7 in men and 19.2 ± 2.9 in women. Visceral fat area (cm2) was significantly lower in women (35.7 ± 26.6) than in men (57.5 ± 47.4) (p = 0.0111). The comparison with general healthy adults according to age revealed a markedly reduced visceral fat area among patients with MAC lung disease. With respect to nutrient intake, energy adequacy (86.1 ± 15.7%), protein adequacy (82.4 ± 18.2%), lipid adequacy (78.1 ± 21.8%), and carbohydrate adequacy (89.6 ± 19.2%) ratios were all low at the time of registration. BMI was significantly correlated with protein adequacy (p = 0.0397) and lipid adequacy (p = 0.0214) ratios, while no association was found between visceral fat area and nutrient intake. Conclusion. Patients with MAC lung disease had a low visceral fat area and low nutrient intake.

Treatment of Refractory Mycobacterium avium Complex Lung Disease with a Moxifloxacin-Containing Regimen

Moxifloxacin (MXF) has in vitro and in vivo activity against Mycobacterium avium complex (MAC) in experimental models. However, no data are available concerning its treatment effect in patients with MAC lung disease. The aim of this study was to evaluate the clinical efficacy of an MXF-containing regimen for the treatment of refractory MAC lung disease. Patients with MAC lung disease who were diagnosed between January 2002 and December 2011 were identified from our hospital database. We identified 41 patients who received MXF for ≥ 4 weeks for the treatment of refractory MAC lung disease. A total of 41 patients were treated with an MXF-containing regimen because of a persistent positive culture after at least 6 months of clarithromycin-based standardized antibiotic therapy. The median duration of antibiotic therapy before MXF administration was 410 days (interquartile range [IQR], 324 to 683 days). All patients had culture-positive sputum when MXF treatment was initiated. The median duration of MXF administration was 332 days (IQR, 146 to 547 days). The overall treatment success rate was 29% (12/41), and the median time to sputum conversion was 91 days (IQR, 45 to 190 days). A positive sputum acid-fast-bacillus smear at the start of treatment with MXF-containing regimens was an independent predictor of an unfavorable microbiological response. Our results indicate that MXF may improve treatment outcomes in about one-third of patients with persistently culture-positive MAC lung disease who fail to respond to clarithromycin-based standardized antibiotic treatment. Prospective studies are required to assess the clinical efficacy of MXF treatment for refractory MAC lung disease.