Mycobacterium Avium Complex Pulmonary Disease Research Articles

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

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

Development of a rapid detection method for the macrolide resistance gene in Mycobacterium avium using the amplification refractory mutation system-loop-mediated isothermal amplification method.

Macrolide antibiotics such as clarithromycin (CLR) and azithromycin are the key drugs used in multidrug therapy for Mycobacterium avium complex (MAC) diseases. For these antibacterial drugs, drug susceptibility has been correlated with clinical response in MAC diseases. We have previously demonstrated the correlation between drug susceptibility and mutations in the 23S rRNA gene, which confers resistance to macrolides. Herein, we developed a rapid detection method using the amplification refractory mutation system (ARMS)-loop-mediated isothermal amplification (LAMP) technique to identify mutations in the 23S rRNA gene of M. avium. We examined the applicability of the ARMS-LAMP method to genomic DNA extracted from six genotypes of M. avium clinical isolates. The M. avium isolates were classified into 21 CLR-resistant and 9 CLR-susceptible strains based on the results of drug susceptibility tests; the 23S rRNA genes of these strains were sequenced and analyzed using the ARMS-LAMP method. Sequence analysis revealed that the 9 CLR-sensitive strains were wild-type strains, whereas the 21 CLR-resistant strains comprised 20 mutant-type strains and one wild-type strain. Using ARMS-LAMP, no amplification from genomic DNAs of the 10 wild-type strains was observed using the mutant-type mismatch primer sets (MTPSs); however, amplification from the 20 mutant-type strain DNAs was observed using the MTPSs. The rapid detection method developed by us integrates ARMS-LAMP with a real-time turbidimeter, which can help determine drug resistance in a few hours. In conclusion, ARMS-LAMP might be a new clinically beneficial technology for rapid detection of mutations.IMPORTANCEMultidrug therapy for pulmonary Mycobacterium avium complex disease is centered on the macrolide antibiotics clarithromycin and azithromycin, and resistance to macrolides is an important prognosticator for clinical aggravation. Therefore, it is important to develop a quick and easy method for detecting resistance to macrolides. Drug resistance is known to be correlated with mutations in macrolide resistance genes. We developed a rapid detection method using amplification refractory mutation system (ARMS)-loop-mediated isothermal amplification (LAMP) to identify a mutation in the 23S rRNA gene, which is a macrolide resistance gene. Furthermore, we examined the applicability of this method using M. avium clinical isolates. The rapid method developed by us for detection of the macrolide resistance gene by integrating ARMS-LAMP and a real-time turbidimeter can help in detection of drug resistance within a few hours. Since this method does not require expensive equipment or special techniques and shows high analytical speed, it would be very useful in clinical practice.

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

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

Serum Cell-Free DNA-based Detection of Mycobacterium avium Complex Infection.

Rationale: Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) pulmonary disease (PD), which exhibits increasing global incidence. Current microbiologic methods routinely used in clinical practice lack sensitivity and have long latencies, leading to delays in diagnosis and treatment initiation and evaluation. A clustered regularly interspaced short palindromic repeats (CRISPR)-based assay that measures MAC cell-free DNA (cfDNA) concentrations in serum could provide a rapid means to detect MAC infection and monitor response to antimicrobial treatment. Objectives: To develop and optimize a CRISPR MAC assay for MAC infection detection and to evaluate its diagnostic and prognostic performance in two MAC disease cohorts. Methods: MAC cfDNA serum concentrations were measured in individuals with diagnoses of MAC disease or who had bronchiectasis or chronic obstructive pulmonary disease diagnoses without histories of NTM PD or NTM-positive sputum cultures. Diagnostic performance was analyzed using pretreatment serum from two cohorts. Serum MAC cfDNA changes during MAC PD treatment were evaluated in a subset of patients with MAC PD who received macrolide-based multidrug regimens. Measurements and Main Results: The CRISPR MAC assay detected MAC cfDNA in MAC PD with 97.6% (91.6-99.7%) sensitivity and 97.6% (91.5-99.7%) specificity overall. Serum MAC cfDNA concentrations markedly decreased after MAC-directed treatment initiation in patients with MAC PD who demonstrated MAC culture conversion. Conclusions: This study provides preliminary evidence for the utility of a serum-based CRISPR MAC assay to rapidly detect MAC infection and monitor the response to treatment.

Change of erythrocyte sedimentation rate as prognostic biomarker for Mycobacterium avium complex pulmonary disease through anti-mycobacterial treatment.

It remains unclear whether erythrocyte sedimentation rate (ESR) accurately predicts prognosis during treatment and how ESR changes. We aimed to assess the predictive values of ESR as a prognostic factor of Mycobacterium avium complex pulmonary disease (MAC-PD) while on anti-mycobacterial treatment and its changes according to the treatment responses. This study is a retrospective cohort study. This study included patients aged 18 years or older who initiated anti-mycobacterial treatment for MAC-PD at Seoul National University Hospital between January 1, 2009 and March 31, 2022. ESR should be measured at least twice, with a minimum interval of 3 months, during the initial 12 months from the commencement of antibiotic treatment. A mixed linear regression and Cox proportional-hazards models were used to analyze repeated ESR data and the association with patient survival. Of a total of 825 patients who initiated antibiotic treatment for MAC-PD, 369 patients were included in the analysis. Increased levels of ESR during the treatment process were associated with a higher risk of mortality (adjusted hazard ratio 1.03; 95% confidence interval, 1.02-1.03) after adjusting age, sex, comorbidities, presence of cavity, acid-fast bacilli smear positivity, and culture conversion at 12 months. During the treatment, ESR at 12 months of treatment significantly decreased compared to baseline ESR in both the culture-converted and not-converted groups, which was categorized based on whether the culture conversion was achieved within the 12 months after treatment initiation. ESR predicted mortality during treatment and decreased over time, regardless of treatment outcomes. Our results underscore the importance of administering anti-mycobacterial treatment even in patients who did not achieve a microbiological cure.

Mycobacterium avium complex pulmonary disease patients with limited treatment options.

How to identify MAC-PD patients with limited treatment options: an expert consensus https://bit.ly/3QwLQ8T.

Treatment Outcomes of Clofazimine-Containing Regimens in Severe Mycobacterium avium Complex Pulmonary Disease.

Clofazimine is suggested as a promising drug for the treatment of nontuberculous mycobacterial pulmonary disease. However, the role of clofazimine in severe Mycobacterium avium complex pulmonary disease (MAC-PD) remains unclear. In this study, we investigated the treatment outcomes of patients with severe MAC-PD treated with regimens containing clofazimine. This study included patients diagnosed with severe MAC-PD at Seoul National University Hospital who underwent anti-mycobacterial treatment between 1 January 2011 and 31 December 2022. We assessed the rate of culture conversion within 6 months and microbiological cure in patients receiving clofazimine-containing regimens, considering the dose and duration of clofazimine administration. A total of 170 patients with severe MAC-PD, treated with regimens containing clofazimine, were included in the analysis. The median age of patients was 68 years (interquartile range, 59-75 years), with a female predominance (n = 114 [67.1%]). Cavities were identified in 121 patients (71.2%). Within 6 months, 77 patients (45.3%) achieved culture conversion, and 84 of 154 (54.6%) patients attained microbiological cure. The dose of clofazimine (100 mg vs 50 mg) was not associated with culture conversion (adjusted odds ratio [aOR], 0.64 [95% confidence interval {CI}, .29-1.42]) or microbiological cure (aOR, 1.21 [95% CI, .52-2.81]). The microbiological cure rate reached 71.0% when clofazimine was administered for 6-12 months, compared to 23.1% when administered for <6 months. Clofazimine demonstrated a relatively favorable efficacy in severe MAC-PD, regardless of the maintenance dose. This effect was more pronounced when administered for a duration exceeding 6 months.

Oral β-Lactam Pairs for the Treatment of Mycobacterium avium Complex Pulmonary Disease.

Cure rates for pulmonary disease caused by the Mycobacterium avium complex (MAC) are poor. While β-lactam are front line antibiotics against Mycobacterium abscessus pulmonary disease, they have not been used or recommended to treat MAC lung infections. Through a comprehensive screen of oral β-lactams, we have discovered that selected pairs combining either a penem/carbapenem or penicillin with a cephalosporin are strongly bactericidal at clinically achieved concentrations. These dual β-lactam combinations include tebipenem and sulopenem, both in phase 3, and Food and Drug Administration-approved amoxicillin and cefuroxime. They could therefore immediately enter clinical trials or clinical practice.

Efficacy of clofazimine-containing regimens for treatment of Mycobacterium avium complex–pulmonary disease in patients unsuitable for standard treatment regimen

ObjectivesPatients with Mycobacterium avium complex-pulmonary disease (MAC-PD) can exhibit contraindications in applying the recommended treatment regimens by the guidelines. Clofazimine (CFZ) is considered a promising drug for MAC-PD treatment and is frequently included in alternative regimens; however, its efficacy remains unclear. MethodsMAC-PD patients, unsuitable for standard regimens, were enrolled continuously in a prospective study at Beijing Chest Hospital. The treatment response of the CFZ-containing regimen was monitored. ResultsFifty patients were enrolled in the initial treatment, and 25 patients had a history of anti-TB treatment. Nodular bronchiectasis was observed in 34 patients, while 8 patients exhibited fibrocavitary changes. Additionally, eight patients displayed a combination of both patterns. In a multivariate analysis, MAC-PD patients with CFZ MIC < 0.25 mg/L were significantly associated with culture conversion [OR 8.415, 95% CI (1.983–35.705); P = 0.004]. Among patients who had previous TB treatment history, patients with CFZ MIC < 0.25 mg/L had a higher chance of acquiring culture conversion outcomes [(OR 7.737, 95% CI 1.032–57.989); P = 0.046]. In contrast, among patients with no previous TB treatment history, the RIF-containing regimen had a higher chance of acquiring culture conversion outcomes [(OR 11.038, 95%CI 1.008–120.888); P = 0.049]. ConclusionMAC-PD patients unsuitable for standard regimens could benefit from a CFZ-containing regimen, especially for patients with previous TB treatment history and baseline CFZ MIC values lower than 0.25 mg/L.

Tolerability Outcomes of American Thoracic Society/Infectious Diseases Society of America Guideline-Recommended Multidrug Antibiotic Treatment for Mycobacterium avium Complex Pulmonary Disease in US Medicare Beneficiaries With Bronchiectasis

Nontuberculous mycobacteria are environmental organisms that are increasingly causing chronic and debilitating pulmonary infections, of which Mycobacterium avium complex (MAC) is the most common pathogen. MAC pulmonary disease (MAC-PD) is often difficult to treat, often requiring long-term multidrug antibiotic therapy. Is there an association between various guideline-based three-drug therapy (GBT) regimens and (1) therapy-associated adverse events or (2) regimen change/discontinuation, within 12months of therapy initiation? In a retrospective cohort study, we examined tolerability outcomes of GBT regimens for MAC-PD in 4,626 US Medicare beneficiaries with bronchiectasis, who were prescribed a GBT as initial antibiotic treatment for presumed MAC-PD during 2006 to 2014. Using multivariable Cox proportional hazard regression, we estimated adjusted hazard ratios (aHRs) to compare the risk of adverse events and regimen change/discontinuations within 12months of therapy initiation in various GBT regimens. The cohort had a mean age ± SD of 77.9 ± 6.1 years at treatment start, were mostly female (77.7%), and were mostly non-Hispanic White (87.2%). The risk of regimen change/discontinuation within 12months of therapy was higher for clarithromycin-based regimens than azithromycin-based regimens (aHR, 1.12; 95%CI, 1.04-1.20 with rifampin; aHR, 1.11; 95%CI, 0.93-1.32 with rifabutin as the companion rifamycin), and for rifabutin-containing regimens than rifampin-containing regimens (aHR, 1.49; 95%CI, 1.33-1.68 with azithromycin; aHR, 1.47; 95%CI, 1.27-1.70 with clarithromycin as the companion macrolide). The aHR comparing regimen change/discontinuation with clarithromycin-ethambutol-rifabutin and azithromycin-ethambutol-rifampin was 1.64 (95%CI, 1.43-1.64). Overall, an azithromycin-based regimen was less likely to be changed or discontinued than a clarithromycin-based regimen, and a rifampin-containing regimen was less likely to be changed or discontinued than a rifabutin-containing regimen within 12months of therapy start. Our work provides a population-based assessment on the tolerability of multidrug antibiotic regimens used for the treatment of MAC-PD.

Ceftriaxone Efficacy for Mycobacterium avium Complex Lung Disease in the Hollow Fiber and Translation to Sustained Sputum Culture Conversion in Patients.

Only 35.6%-50.8% of patients with Mycobacterium avium complex (MAC) pulmonary disease achieve sustained sputum culture conversion (SSCC) on treatment with the azithromycin-ethambutol-rifabutin standard of care (SOC). We tested the efficacy of ceftriaxone, a β-lactam with a lung-to-serum penetration ratio of 12.18-fold. We mimicked lung concentration-time profiles of 7 ceftriaxone once-daily doses for 28 days in the hollow fiber system model of intracellular MAC (HFS-MAC). Monte Carlo experiments were used for dose selection. We also compared once-daily ceftriaxone monotherapy to 3-drug SOC against 5 MAC clinical isolates in HFS-MAC using γ (kill) slopes, and translated to SSCC rates. Ceftriaxone killed 1.02-3.82 log10 colony-forming units (CFU)/mL, at optimal dose of 2 g once-daily. Ceftriaxone killed all 5 strains below day 0 versus 2 of 5 for SOC. The median γ (95% confidence interval [CI]) was 0.49 (.47-.52) log10 CFU/mL/day for ceftriaxone and 0.38 (.34-.43) log10 CFU/mL/day for SOC. In patients, the SOC was predicted to achieve SSCC rates (CI) of 39.3% (36%-42%) at 6 months. The SOC SSCC was 50% at 8.18 (3.64-27.66) months versus 3.58 (2.20-7.23) months for ceftriaxone, shortening time to SSCC 2.35-fold. Ceftriaxone is a promising agent for creation of short-course chemotherapy.

Safety and Efficacy of Clofazimine as an Alternative for Rifampicin in Mycobacterium avium Complex Pulmonary Disease Treatment: Outcomes of a Randomized Trial

BackgroundRetrospective studies have suggested clofazimine as an alternative for rifampicin in MAC-PD treatment. Research questionIs a treatment regimen consisting of clofazimine-ethambutol-macrolide non inferior to the standard treatment regimen (rifampicin-ethambutol-macrolide) in the treatment of M.avium complex pulmonary disease? Study design and MethodsIn this single centre non-blinded clinical trial, we randomly assigned adult patients with MAC-PD in a 1:1 ratio to receive rifampicin or clofazimine as adjuncts to an ethambutol-macrolide backbone. The primary outcome was sputum culture conversion after six months of treatment. ResultsForty patients were assigned to receive either rifampicin (n=19) or clofazimine (n=21) ) next to ethambutol and a macrolide. After 6 months of treatment, both arms showed similar percentages of sputum culture conversion based on intention to treat analysis: 58% (11/19) for rifampicin; 62% (13/21) for clofazimine. Study discontinuation, mainly due to adverse events, was equal in both arms (26% vs 33%). Based on an on treatment analysis sputum culture conversion after 6 months of treatment was 79% in both groups.In the clofazimine arm, diarrhoea was more prevalent (76% vs 37%; p=0.012), while arthralgia was more frequent in the rifampicin arm (37% vs 5%; p=0.011). No difference in the frequency of QTc prolongation was seen between both groups. InterpretationA clofazimine-ethambutol-macrolide regimen showed similar results to the standard rifampicin-ethambutol-macrolide regimen and should be considered in the treatment of MAC-PD. The frequency of adverse events was similar in both arms, but their nature was different. Individual patients characteristics and possible drug-drug interactions should be taken into consideration when choosing an antibiotic regimen for MAC-PD.

Intracellular and in vivo activities of oxazolidinone drugs against Mycobacterium avium complex infection

The prevalence of Mycobacterium avium complex-pulmonary disease (MAC-PD) has become a growing concern worldwide, and current treatments involving macrolides (clarithromycin [CLR] or azithromycin), ethambutol, and rifampicin have limited success, highlighting the need for better therapeutic strategies. Recently, oxazolidinone drugs have been identified as novel anti-tuberculosis drugs effective against drug-resistant M. tuberculosis. However, the effects of these drugs against MAC are still controversial due to limited data. Here, we first evaluated the intracellular anti-MAC activities of two oxazolidinone drugs, linezolid (LZD) and delpazolid (DZD), against 10 macrolide-susceptible MAC strains and one macrolide-resistant M. avium strain in murine bone marrow-derived macrophages (BMDMs) and found that both drugs demonstrated similar potential. The synergistic efficacies with CLR were then determined in a chronic progressive MAC-PD murine model by initiating a 4-week treatment at 8 weeks post-infection. Upon assessment of bacterial burdens and inflamed lesions, oxazolidinone drugs exhibited no anti-MAC effect, and there was no significant difference in the synergistic effect of CLR between LZD and DZD. These findings suggest that oxazolidinone drugs inhibit intracellular bacterial growth, even against macrolide-resistant MAC, but their clinical application requires further consideration.

Spontaneous Cultural Conversion Rate of Mycobacterium avium Complex Pulmonary Disease Based on BACES Severity.

Only a few clinical factors can aid in predicting spontaneous culture conversion (SCC) in patients with Mycobacterium avium complex-pulmonary disease (MAC-PD). In this study, we aimed to evaluate whether the rate of SCC varies according to the severity of the disease in MAC-PD patients. We retrospectively classified 373 MAC-PD patients who had undergone watchful waiting without antibiotics based on the severity assessment using the 'body mass index (BMI), age, cavity, erythrocyte sedimentation rate (ESR), and sex (BACES)' criteria. We evaluated the rate of SCC in MAC-PD patients based on BACES severity and analyzed the relevant factors. Results: Of 373 patients, 153 (41%) achieved SCC without antibiotics during a median follow-up of 48.1 months. There was a trend toward a higher SCC rate in patients with lower BACES severity: 48% (87/183), 37% (58/157), and 24% (8/33) in the mild, moderate, and severe BACES groups, respectively. In addition, a favorable outcome, defined as maintaining SCC or having two consecutive negative sputum cultures until the last follow-up date, was also more common in patients with lower BACES severities of 53% (97/183), 34% (54/157), and 18% (6/33) in the mild, moderate, and severe BACES groups, respectively. In multivariate analysis, moderate BACES (hazard ratio [HR] = 0.63; 95% confidence interval [CI] 0.44-0.91; p = 0.013) and severe BACES (HR 0.37; 95% CI 0.16-0.90; p = 0.028) had a significantly negative impact on favorable outcomes compared to mild BACES. Lower BACES severity may be associated with SCC in MAC-PD patients.

Comparison of treatment outcomes between intermittent and daily regimens in non-cavitary nodular bronchiectatic-type Mycobacterium avium complex pulmonary disease in relation to sputum smear results: a retrospective cohort study.

This study retrospectively analyzed the treatment outcomes of 110 patients with non-cavitary nodular bronchiectatic-type Mycobacterium avium complex pulmonary disease who received intermittent or daily treatment with a three-drug oral antibiotic regimen (i.e., a macrolide, ethambutol, and rifampin) at a tertiary referral center in South Korea. Among these patients, 36 had sputum smear positivity. Of these 36 patients, intermittent treatment led to a lower culture conversion rate than daily treatment [50.0% (8/16) vs 85.0% (17/20), P = 0.034].

Sarecycline pharmacokinetics/pharmacodynamics in the hollow-fibre model of Mycobacterium avium complex: so near and yet so far.

Poor sustained sputum culture conversion rates with the standard-of-care therapy highlight the need for better drugs to treat Mycobacterium avium complex pulmonary disease (MAC-PD). To determine the pharmacokinetics/pharmacodynamics (PK/PD)-optimized exposure of sarecycline and its potential role in treating MAC-PD. We performed MIC studies with MAC ATCC 700898 and 19 clinical isolates and test-tube static concentration-response studies. A dynamic hollow-fibre system model of intracellular MAC (HFS-MAC) study was performed mimicking six human-equivalent sarecycline dose concentration-time profiles to identify the PK/PD optimal exposure of sarecycline for MAC kill. The inhibitory sigmoid maximal effect (Emax) model was used for PK/PD analysis. The sarecycline MIC of MAC ATCC 700898 was 1 mg/L, while the MIC for the 19 clinical strains ranged between 32 and >256 mg/L. The concentration mediating 50% of Emax (EC50) was similar between intracellular and extracellular MAC. In the HFS-MAC, all six sarecycline doses killed intracellular MAC, with an Emax of 1.0 log10 cfu/mL below Day 0 burden (stasis). The sarecycline EC80 (optimal) exposure was identified as AUC0-24/MIC = 139.46. Sarecycline demonstrated anti-MAC Emax in the HFS-MAC model better than ethambutol but worse than omadacycline (>5 log10 cfu/mL below stasis) in HFS-MAC. However, since currently approved highest oral sarecycline dose achieves an AUC0-24 of 48.2 mg·h/L and MAC MICs are >32 mg/L, the target AUC0-24/MIC of 139.46 is unlikely to be achieved in patients.

The role of rifampicin within the treatment of Mycobacterium avium pulmonary disease.

Rifampicin is recommended for the treatment of Mycobacterium avium complex pulmonary disease alongside azithromycin and ethambutol. We evaluated the azithromycin-ethambutol backbone with and without rifampicin in an intracellular hollow fiber model and performed RNA sequencing to study the differences in adaptation. In an in vitro hollow fiber experiment, we simulated epithelial lining fluid pharmacokinetic profiles of the recommended 3-drug (rifampicin, ethambutol, and azithromycin) or a 2-drug (ethambutol and azithromycin) treatment. THP-1 cells infected with M. avium ATCC700898 were exposed to these regimens for 21 days. We determined intra- and extra-cellular bacterial load- and THP-1 cell densities on days 0, 3, 7, 14, and 21, alongside RNA sequencing. The emergence of macrolide resistance was studied by inoculating intra- and extra-cellular fractions of azithromycin-containing Middlebrook 7H10 agar plates. Complete pharmacokinetic profiles were determined at days 0 and 21. Both therapies maintained stasis of both intra- and extra-cellular bacterial populations for 3 days, whilst regrowth coinciding with the emergence of a macrolide-resistant subpopulation was seen after 7 days. THP-1 cell density remained static. Similar transcriptional profiles were observed for both therapies that were minimally influenced by exposure duration. Transcriptional response was slightly larger during 2-drug treatment. Rifampicin did not add to the antimycobacterial effect to the 2-drug therapy or suppression of emergence resistance. RNA transcription was not greatly altered by the addition of rifampicin, which may be due to strong transcriptional influence of azithromycin and host cells. This questions the role of rifampicin in the currently recommended therapy. These findings should be confirmed in clinical trials.

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

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

Multiple bacterial culture positivity reflects the severity and prognosis as bronchiectasis in Mycobacterium avium complex pulmonary disease

BackgroundBacterial coinfections are observed in 19–66% of patients with Mycobacterium avium complex pulmonary disease (MAC-PD) during the entire duration of the disease. The impact of bacterial coinfection at diagnosis on the clinical course of MAC-PD has not been reported. MethodsAmong 558 patients diagnosed with MAC-PD between January 2016 and December 2020, 218 patients who underwent sputum culture tests twice or more within one year before and after diagnosis were included. We compared the patient characteristics and disease courses between the patients who had the same bacterial species detected twice or more (bacterial culture positive group: BCP group) and those who never had bacteria cultured (bacterial culture negative group: BCN group). ResultsWe included 70 patients in the BCP group and 74 in the BCN group. The radiological findings showed that BCP at diagnosis correlated with a high modified Reiff score. During the median follow-up period of 42 months, the patients in the BCP group were more likely to accomplish spontaneous sputum conversion of MAC. The treatment initiation rate for MAC-PD in the BCP group was lower than that in the BCN group (41.4% vs. 67.6%, P = 0.003). In contrast, the time to the first bronchiectasis exacerbation in the BCP group was shorter than that in the BCN group, and the frequency of bronchiectasis exacerbations was higher in the BCP group. ConclusionsPatients with BCP at diagnosis are less likely to initiate treatment for MAC-PD and more likely to develop bronchiectasis exacerbation.

Real-World Outcomes of Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Pulmonary Disease.

Real-World Outcomes of Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Pulmonary Disease.