In Vitro Synergistic Effects of Omadacycline with Other Antimicrobial Agents against Mycobacterium abscessus.

The clinical importance of Mycobacterium abscessus species (MABS) infections has been increasing. However, the standard treatment regimens recommended in the current guidelines often result in unfavorable outcomes. Therefore, we investigated the in vitro activity of omadacycline (OMC), a novel tetracycline, against MABS to explore its potential as a novel therapeutic option. The drug susceptibilities of 40 Mycobacterium abscessus subsp. abscessus (Mab) clinical strains obtained from the sputum of 40 patients from January 2005 to May 2014 were investigated. The MIC results for OMC, amikacin (AMK), clarithromycin (CLR), clofazimine (CLO), imipenem (IPM), rifabutin (RFB), and tedizolid (TZD) alone and their combined effects (with OMC) were examined using the checkerboard method. Additionally, we studied the differences in the effectiveness of the antibiotic combinations based on the colony morphotype of Mab. The MIC50 and MIC90 of OMC alone were 2 and 4 µg/mL, respectively. The combinations of OMC with AMK, CLR, CLO, IPM, RFB, and TZD showed synergy against 17.5%, 75.8%, 25.0%, 21.1%, 76.9%, and 34.4% of the strains, respectively. Additionally, OMC combined with CLO (47.1% versus 9.5%, P = 0.023) or TZD (60.0% versus 12.5%, P = 0.009) showed significantly higher synergy against strains with rough morphotypes than those with smooth morphotypes. In conclusion, the checkerboard analyses revealed that the synergistic effects of OMC were observed most frequently with RFB, followed by CLR, TZD, CLO, IPM, and AMK. Furthermore, OMC tended to be more effective against rough-morphotype Mab strains.

Characteristics of pleural effusion due to paradoxical response in patients with pulmonary tuberculosis.

BACKGROUND: Patients with pulmonary tuberculosis may present with deterioration of pleural effusion during anti-tuberculosis therapy, referred to as a paradoxical response (PR), with some patients requiring additional intervention. However, PR may be confused with other differential diagnoses, and the predictive factors for recommending additional therapies are unknown. Therefore, this study aimed to reveal useful information for the diagnosis and intervention of PR. METHODS: Data from human immunodeficiency virus-negative patients with tuberculous pleurisy (n = 210), including 184 patients with pre-existing pleural effusion and 26 patients with PR at Fukujuji Hospital, were retrospectively collected from January 2012 to December 2022 and compared. Furthermore, patients with PR were divided into the intervention group (n = 9) and the no intervention group (n = 17) and were compared. RESULTS: Patients in the PR group had lower pleural lactate dehydrogenase (LDH) (median 177 IU/L vs. 383 IU/L, p < 0.001) and higher pleural glucose (median 122 mg/dL vs. 93 mg/dL, p < 0.001) levels than those in the preexisting pleural effusion group. Other pleural fluid data were not significantly different. Patients in the intervention group had a shorter duration from the initiation of anti-tuberculosis therapy to the development of PR than patients in the no intervention group (median 19.0 days [interquartile range (IQR): 18.0-22.0] vs. median 37.0 days [IQR: 28.0-58.0], p = 0.012). CONCLUSION: This study demonstrates that, apart from lower pleural LDH and elevated pleural glucose levels, PR presents with similar features to preexisting pleural effusion and that patients who develop PR faster tend to require intervention.

Comparison of the thickness of the erector spinae muscles between aspiration pneumonia and bacterial pneumonia patients.

BACKGROUND AND AIMS: Aspiration pneumonia is generally associated with deterioration of skeletal muscle mass, which is usually evaluated by the erector spinae muscle cross-sectional area (ESMCSA); however, no report has assessed ESMCSA in patients with aspiration pneumonia. Furthermore, erector spinae muscle thickness (ESMT) was developed to be easier to measure than ESMCSA. Therefore, this study investigated the relationship between ESMT and ESMCSA in aspiration pneumonia patients compared to bacterial pneumonia patients. METHODS: We retrospectively collected data for 164 patients with aspiration pneumonia and 480 patients with bacterial pneumonia who were hospitalized at Fukujuji Hospital between September 2018 and May 2022. We assessed the correlations between ESMCSA and ESMT and compared the data between the two groups. RESULTS: ESMT had a strong, proportional relationship with ESMCSA in all patients (r = 0.908, p < 0.001) and those with aspiration pneumonia (r = 0.896, p < 0.001). ESMCSA (median 671.8 mm2 [range 164.0-1636.7] vs. median 1057.0 mm2 [range 161.3-2412.5], p < 0.001) and ESMT (median 17.1 mm [range 6.95-34.4] vs. median 23.8 mm [range 6.95-43.7], p < 0.001) were significantly lower in patients with aspiration pneumonia. A multivariate analysis of aspiration pneumonia diagnosis showed significant independent differences from bacterial pneumonia in ESMCSA (odds ratio 0.998 [95% CI: 0.996-0.999], p = 0.001) and ESMT (odds ratio 0.90 [95% CI: 0.84-0.96], p = 0.002). CONCLUSION: This study demonstrates a strong correlation between ESMCSA and ESMT. ESMT can be more easily used to evaluate skeletal muscle mass and can help in diagnosing aspiration pneumonia.

Pharmacokinetics and Adverse Effects of Clofazimine in the Treatment of Pulmonary Non-Tuberculous Mycobacterial Infection.

Clofazimine (CFZ) is used to treat pulmonary non-tuberculous mycobacterial (NTM) infection; however, its pharmacokinetics remain unexplored in patients with pulmonary NTM, and the relationship between CFZ serum concentration and adverse effects has not been investigated. The objectives of this study were to characterize the pharmacokinetics of CFZ in pulmonary NTM disease treatment and to investigate the relationship between the steady-state CFZ serum concentration and adverse effects. A prospective observational study was conducted on 45 patients with pulmonary NTM treated with CFZ (UMIN000041053). A maximum of five serum samples per patient were taken at the CFZ trough, and serum concentration was measured using high-performance liquid chromatography-mass spectrometry (HPLC-MS). The pharmacokinetics of CFZ were analyzed using a nonlinear mixed effect model. The relationships among steady-state CFZ serum concentration and adverse effects, pigmentation, and heart rate-corrected QT (QTc) interval were investigated. Twenty-six patients had M. avium or M. intracellulare infection and nineteen had M. abscessus infection. The primary CFZ dosage was 50 mg/day. The estimated apparent CFZ clearance, apparent volume of distribution, and half-life were 2.4 L/h, 2,960 L, and 36 days, respectively. The combined use of rifampicin and CFZ significantly reduced CFZ exposure by 22%. Although there was no relationship between CFZ serum concentration and pigmentation intensity, the QTc interval was significantly correlated with CFZ serum concentration. The estimation of accurate pharmacokinetics for CFZ required approximately 5 months of monitoring. The relationship between the serum concentration and specific adverse effects of CFZ confirmed that CFZ serum concentration was not associated with pigmentation but did affect the QTc interval.

Low-dosage ethambutol, less than 12.5 mg/kg/day, does not worsen the clinical outcomes of pulmonary Mycobacterium avium and Mycobacterium intracellulare disease: a retrospective cohort study.

OBJECTIVES: Multidrug chemotherapy is recommended for treating pulmonary Mycobacterium avium and Mycobacterium intracellulare disease. Although ethambutol has been demonstrated to inhibit macrolide resistance, the ethambutol dosage is sometimes decreased due to concerns about optic neuropathy. We aimed to assess whether lower ethambutol doses impact treatment outcomes. METHODS: Patients treated over 12 months between 2016 and 2020 were collected retrospectively. Clinical outcomes, including negative culture conversion, microbiological cure, adverse events, resistance to macrolides, and recurrence, were compared according to daily ethambutol dosage. RESULTS: Among 146 patients, 42 were treated with ethambutol dosages over 12.5 mg/kg/day, and 104 were treated with lower dosages. Negative culture conversion was achieved for 125 patients, and 90 patients achieved microbiological cure. Recurrence was identified in 16 patients who achieved microbiological cure. No macrolide resistance was observed, and no significant difference was observed in the percentage of negative culture conversion (P = 1.00) or microbiological cure (P = 0.67) between the high- and low-dosage ethambutol groups. Sputum smear positivity was associated with a lower adjusted odds ratio (aOR) of negative culture conversion (aOR: 0.48, 95% CI: 0.29-0.80). A lower aOR of microbiological cure was independently associated with sputum smear positivity (aOR: 0.52, 95% CI: 0.37-0.74) and with the use of an intermittent regimen (aOR: 0.60, 95% CI: 0.41-0.87). Daily ethambutol dosage was not identified as a prognostic factor for any of the outcomes. Optic neuropathy was observed in 7.1% of the high-dose ethambutol group and 1.0% of the low-dosage ethambutol group (P = 0.07). CONCLUSION: An ethambutol dosage of 12.5 mg/kg/day or less in guideline-based chemotherapy may reduce optic neuropathy without worsening clinical outcomes.

Usefulness of gastric aspirate for the diagnosis of smear-negative pulmonary tuberculosis.

INTRODUCTION: Gastric aspirate can be useful for the diagnosis of pulmonary tuberculosis (TB) in patients with smear-negative pulmonary TB or without sputum production. The gastric aspirate smear technique has low sensitivity, and a previous report demonstrated that no patient was diagnosed by only gastric aspirate analysis. However, some patients with TB have been negative on sputum examination but positive on gastric aspirate examination, and the incidence of such cases is uncertain. Therefore, this study investigated the usefulness of gastric aspirate in the diagnosis of pulmonary TB. METHODS: To analyze the diagnostic accuracy of gastric aspirate examination, the data of 513 patients with negative sputum smears or a lack of sputum production, including 203 patients with pulmonary TB (39.6%) and 93 patients with nontuberculous mycobacteriosis who underwent gastric aspiration at Fukujuji Hospital from January 2016 to March 2021, were collected retrospectively. RESULTS: The accuracy rates of gastric aspirate examination for the diagnosis of pulmonary TB were as follows: 21.2% sensitivity and 91.9% specificity for smear positivity, 55.8% sensitivity and 99.6% specificity for nucleic acid amplification test positivity, and 71.4% sensitivity and 100% specificity for culture positivity. Twenty-three patients (11.2%) were diagnosed by gastric aspirate examination alone. Among the 356 patients who underwent three repeated sputum examinations in addition to gastric aspirate examination, the cumulative diagnostic rate for the 3 mycobacterial examinations plus gastric aspirate examination was higher than that for only three sputum examinations. CONCLUSIONS: Gastric aspirate is useful for the diagnosis of TB in patients with smear-negative pulmonary TB or without sputum production.

Characteristics of pleural effusion with a high adenosine deaminase level: a case-control study.

BACKGROUND: Increased pleural fluid adenosine deaminase (ADA) is useful for diagnosing tuberculous pleurisy (TB), but high ADA levels are associated with other diseases. In this study, we compare various disease characteristics in patients with high-ADA pleural effusion. METHODS: We retrospectively collected data for 456 patients with pleural fluid ADA levels of ≥ 40 U/L from January 2012 to October 2021. Cases were classified as TB (n = 203), pleural infection (n = 112), malignant pleural effusion (n = 63), nontuberculous mycobacteria (n = 22), malignant lymphoma (ML) (n = 18), autoimmune diseases (n = 11), and other diseases (n = 27), and data were compared among those diseases. Predictive factors were identified by comparing data for a target disease to those for all other diseases. A diagnostic flowchart for TB was developed based on those factors. RESULTS: The most frequent disease was TB, though 60.0% of patients were diagnosed with other diseases. Median ADA levels in patients with TB were 83.1 U/L (interquartile range [IQR] 67.2-104.1), higher than those of patients with pleural infection (median 60.9 [IQR 45.3-108.0], p = 0.004), malignant pleural effusion (median 54.1 [IQR 44.8-66.7], p < 0.001), or autoimmune diseases (median 48.5 [IQR 45.9-58.2], p = 0.008), with no significant difference from NTM (p = 1.000) or ML (p = 1.000). Pleural fluid lactate dehydrogenase (LDH) levels of < 825 IU/L were beneficial for the diagnosis of TB. Neutrophil predominance or cell degeneration, white blood cell count of ≥ 9200/µL or C-reactive protein levels of ≥ 12 mg/dL helped in diagnosing pleural infection. Pleural fluid amylase levels of ≥ 75 U/L and a pleural fluid ADA/total protein (TP) ratio of < 14 helped in diagnosing malignant pleural effusion. High serum LDH and high serum/pleural fluid eosinophils helped in diagnosing ML and autoimmune diseases, respectively. The flowchart was comprised of the following three factors: pleural fluid LDH < 825 IU/L, pleural fluid ADA/TP of < 14, and neutrophil predominance or cell degeneration, which were decided by a decision tree. The diagnostic accuracy rate, sensitivity, and specificity for the diagnosis of TB were 80.9%, 78.8%, and 82.6%, respectively. CONCLUSION: Cases involving high pleural fluid ADA levels should be investigated using several factors to distinguish TB from other diseases.

Posttreatment Lymphopenia Is Associated With an Increased Risk of Redeveloping Nontuberculous Lung Disease in Patients With Mycobacterium avium Complex Lung Disease.

BACKGROUND: Lymphopenia has been reported as a risk factor for poor prognosis in various infectious diseases, including Mycobacterium avium complex lung disease (MAC-LD), and recurrence in several infectious diseases. However, the association between lymphopenia and the risk of redeveloping nontuberculous lung disease (NTM-LD) after completed treatment for MAC-LD is unknown. METHODS: We performed a retrospective cohort study with 147 patients with MAC-LD who successfully completed guideline-based therapy. Lymphopenia was defined as an absolute lymphocyte count (ALC) <1000 cells/µL based on commonly accepted reference values. RESULTS: During the median follow-up period of 41.9 months after treatment completion, 59 (40.1%) patients redeveloped NTM-LD. Patients with NTM-LD redevelopment had significantly lower posttreatment ALCs (median, 1260 vs 1420 cells/µL) than those without, and the univariate Cox proportional hazard analysis identified posttreatment ALC as a predictive factor for redevelopment (hazard ratio, .94 [95% confidence interval, .89-.99] for every increase of 100 cells/µL; P = .04). In the multivariate analysis, posttreatment ALC and the extent of bronchiectasis were independently associated with NTM-LD redevelopment. The cumulative rate of NTM-LD redevelopment was significantly higher in patients with posttreatment lymphopenia than in those without (P = .008). CONCLUSIONS: Posttreatment lymphopenia could predict an increased risk of NTM-LD redevelopment after completed treatment for MAC-LD.

Management of Drug Toxicity in Mycobacterium avium Complex Pulmonary Disease: An Expert Panel Survey.

Adverse events are frequent in nontuberculous mycobacteria pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus, and gastrointestinal upset. These opinions can provide assistance in individual patient management decisions.

Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease.

RATIONALE: Nontuberculous mycobacteria (NTM) are environmental mycobacteria that can cause a chronic progressive lung disease. Although epidemiological data indicate potential genetic predisposition, its nature remains unclear. OBJECTIVES: We aimed to identify host susceptibility loci for Mycobacterium avium complex (MAC), the most common NTM pathogen. METHODS: This genome-wide association study (GWAS) was conducted in Japanese patients with pulmonary MAC and healthy controls, followed by genotyping of candidate single-nucleotide polymorphisms (SNPs) in another Japanese cohort. For verification by Korean and European ancestry, we performed SNP genotyping. RESULTS: The GWAS discovery set included 475 pulmonary MAC cases and 417 controls. Both GWAS and replication analysis of 591 pulmonary MAC cases and 718 controls revealed the strongest association with chromosome 16p21, particularly with rs109592 (p=1.64×10-13, OR 0.54), which is in an intronic region of the calcineurin-like EF-hand protein 2 (CHP2). Expression quantitative trait loci analysis demonstrated an association with lung CHP2 expression. CHP2 was expressed in the lung tissue in pulmonary MAC disease. This SNP was associated with the nodular bronchiectasis subtype. Additionally, this SNP was significantly associated with the disease in patients of Korean (p=2.18×10-12, OR 0.54) and European (p=5.12×10-03, OR 0.63) ancestry. CONCLUSIONS: We identified rs109592 in the CHP2 locus as a susceptibility marker for pulmonary MAC disease.

Clinical risk factors related to treatment failure in Mycobacterium abscessus lung disease.

The clinical importance of Mycobacterium abscessus subsp. abscessus (M. abscessus) lung disease has been increasing, but few studies have assessed the clinical characteristics associated with the treatment outcome. We retrospectively analyzed 75 consecutive patients with M. abscessus lung disease diagnosed at a tertiary hospital from January 2004 to April 2018. Among 52 patients with sufficient clinical data, 19 patients (42.2%) achieved treatment success. Compared with 26 (57.8%) patients in the treatment failure group, body mass index (BMI) (19.8 vs 17.5 kg/m2, P = 0.022), previous nontuberculous mycobacterial (NTM) lung disease (26.3% vs 61.5%, P = 0.034), the presence of cavitary lesions (31.6% vs 69.2%, P = 0.017), and the bronchiectasis score (3.0 vs 5.0, P = 0.003) were significantly different in the treatment success group. Multivariate analysis showed that age (adjusted hazard ratio (aHR), 0.94; 95% confidence interval (CI), 0.90 to 0.99; P = 0.010), the presence of cavitary lesions (aHR, 0.34; 95% CI, 0.12 to 0.94; P = 0.039), and previous NTM lung disease (aHR, 0.28; 95% CI, 0.09 to 0.86; P = 0.026) were negatively associated with treatment success. This is the first study to show that previous NTM lung disease might be a clinically important factor related to unfavorable treatment outcomes in M. abscessus lung disease patients. To increase our understanding the characteristics of M. abscessus lung disease, this factor should be independently analyzed in future research.

Mycobacterium europaeum lung disease in an immunocompetent patient without underlying lung disease.

Mycobacterium europaeum (M. europaeum) was recently identified as a nontuberculous mycobacterium belonging to the Mycobacterium simiae complex. There have been only a few reported cases of M. europaeum lung disease, all of which occurred in patients with immunodeficiency or prior lung disease. We herein report a case of M. europaeum lung disease in an otherwise healthy Japanese individual. A 70-year-old woman who had no apparent immunodeficiency or medical history was diagnosed with M. europaeum lung disease by multiple positive sputum cultures. The patient was successfully treated with clarithromycin, rifampin, ethambutol, and amikacin. This report is the first case of M. europaeum lung disease occurring in an individual without predisposing risk factors.

Analysis of risk factors for the development of a post-bronchoscopy respiratory infection in lung cancer patients.

BACKGROUND: The development of pneumonia following bronchoscopy is a very important post-bronchoscopic complication, while lung abscesses after bronchoscopy are rare. However, bronchoscopic techniques have advanced, and recently, we have observed patients with lung abscess after bronchoscopy. Therefore, the risk factors might vary from those in past reports. This study was performed to identify the incidence of and risk factors for post-bronchoscopy respiratory infections. METHODS: We retrospectively studied adult patients diagnosed with lung cancer by bronchoscopy at Fukujuji Hospital from January 2017 to June 2019. The infection and noninfection groups were compared. The incidence of lung abscess was compared between recent periods and 2013, when endobronchial ultrasonography with a guide sheath (EBUS-GS) was not yet used in our hospital. RESULTS: We reviewed 327 patients, including 20 patients (6.1%) with infections. The risk factors for infection were necrosis and/or a cavity in the tumor (p < 0.001), a large tumor diameter (≥30 mm) (p = 0.010), and a low serum albumin level (<4.0 g/dL) (p = 0.010). We developed a predictive score with these risk factors, and the area under the curve was 0.737 (95% Cl: 0.610-0.864). No significant differences in age, current smoking status, or abnormal bronchoscopic findings were observed, although these were previously reported as risk factors. In total, 12 patients had lung abscesses (3.7%), which is a higher incidence than that in 2013 (0.8%). CONCLUSIONS: The risk factors for developing post-bronchoscopy respiratory infection in our study varied from those in past reports, possibly because of the advancements in bronchoscopic techniques, such as EBUS-GS.

Serum Procalcitonin Levels Predict Mortality Risk in Patients With Pulmonary Tuberculosis: A Single-Center Prospective Observational Study.

Globally, tuberculosis is the leading infectious cause of death; discovering biomarkers that predict a high mortality risk may improve treatment outcomes. We prospectively enrolled 252 pulmonary tuberculosis patients who were not coinfected with human immunodeficiency virus and initiated antituberculosis treatment, measured serum procalcitonin levels (PCT), and assessed mortality risk. PCT serum levels higher than 0.13 (day 0), 0.05 (day 7), 0.12 (day 14), or 0.06 (day 28) ng/mL predicted nonsurvivors with odds ratios of 7.9, 14.3, 20.0, and 7.3, respectively (P ≤ .005 for all), respectively. Therefore, serum PCT levels are a promising mortality risk indicator for patients with pulmonary tuberculosis. Main Point. For patients with pulmonary tuberculosis, a promising mortality risk indicator is the level of serum procalcitonin, which is weakly associated with sputum bacterial load and independent of radiographic findings.

Detection of Shunting Into Pulmonary Artery on Multidetector Row Computed Tomography Arteriography Before Bronchial Arterial Embolization: A Preliminary Study.

OBJECTIVE: The aim of this study was to investigate the diagnostic performance of detecting systemic arterial pulmonary circulation shunts on multidetector row computed tomography arteriography (MDCTA). METHODS: Thirty-five consecutive bronchial artery embolization sessions with preprocedural MDCTA were performed for 32 patients and 35 sessions. The MDCTA studies with computed tomography value of pulmonary trunk visually lower than that of ascending aorta were defined as "diagnostic MDCTA." Angiographic studies and "diagnostic MDCTA" were evaluated, respectively, for shunting into pulmonary artery. Based on the results of angiographic studies, diagnostic performance of "diagnostic MDCTA" was evaluated. RESULTS: The rate of diagnostic MDCTA was 63% (23 of 35). On "diagnostic MDCTA," sensitivity, specificity, and positive and negative predictive values for detecting shunts were 83% 100%, 100%, 94%, respectively. CONCLUSIONS: Systemic arterial pulmonary circulation shunts were detected on "diagnostic MDCTA" with high sensitivity and specificity.

Comorbidities associated with nontuberculous mycobacterial disease in Japanese adults: a claims-data analysis.

BACKGROUND: Nontuberculous mycobacterial (NTM) lung disease is one of a growing number of chronic health problems that is difficult to cure in aging societies. While it is important to be vigilant about associated comorbidities in order to provide better patient care, data on the prevalence of comorbidities stratified by country or region are scarce. We aimed to elucidate the comorbidities associated with NTM disease based on Japanese health insurance claims data. METHODS: Cross-sectional analyses were performed using the claims data for 2014 provided by the Japan Medical Data Center Co., Ltd. Patients aged 20-75 years with ≥3 claims associated with NTM disease were identified and matched to 10 sex-and-age-matched controls that had never made a claim for NTM disease. Thirty-one comorbidities previously suspected to be associated with NTM disease were selected, and the prevalence of these comorbidities compared between cases and controls. RESULT: Overall, 419 NTM patients (134 males and 285 females) and 4190 non-NTM controls were identified from the JMDC database. Aspergillosis, asthma, chronic heart failure, diffuse panbronchiolitis, gastroesophageal reflux, interstitial pneumonia, lung cancer, cancer other than breast, lung, ovary, or prostate cancer, and rheumatoid arthritis were associated with NTM disease in both males and females. Chronic obstructive pulmonary disease was associated with NTM in males while chronic kidney disease, osteoporosis, and Sjögren syndrome were associated with NTM in females. CONCLUSION: NTM disease was associated with multiple comorbidities that should be considered when providing medical care to individuals with NTM disease.

Efficacy and safety of intermittent maintenance therapy after successful treatment of Mycobacterium avium complex lung disease.

BACKGROUND: The optimal duration of antimicrobial therapy for Mycobacterium avium complex lung disease (MAC-LD) is unknown, and recurrence rates are high after treatment discontinuation. Intermittent therapy is recommended for the initial treatment of non-cavitary nodular/bronchiectatic MAC-LD. We hypothesized that intermittent maintenance therapy (IMT) could effectively prevent recurrence after successful treatment of MAC-LD. METHODS: Adult patients diagnosed with MAC-LD who received IMT after successful daily therapy (DT) between January 1, 2006 and December 31, 2016 were identified from clinical databases at three institutions in Japan. Treatment outcomes were evaluated for all patients. RESULTS: Of 38 patients (median age, 66 years; 29 women; nodular/bronchiectatic form, 29 patients) who received IMT after successful treatment, one was excluded due to death from an unknown cause, 1 month after IMT initiation. Finally, treatment outcomes were evaluated for 37 patients. Twenty-eight (76%) patients had sustained negative culture results over a median follow-up duration of 2.7 (interquartile range [IQR], 1.9-6.0) years, while six (16%) required switching to DT because of clinical deterioration over a median follow-up duration of 2.7 (IQR, 1.6-4.1) years. Favorable clinical outcomes were achieved for all patients who exhibited clinical deterioration. All patients tolerated the antimicrobials without discontinuation, and follow-up drug susceptibility testing showed negative results for clarithromycin-resistant MAC in the patients who experienced clinical deterioration. CONCLUSIONS: IMT after successful treatment may be a feasible option for patients with MAC-LD. Further studies should determine the population that would benefit from this strategy.

Antimicrobial susceptibility testing of Mycobacteroides (Mycobacterium) abscessus complex, Mycolicibacterium (Mycobacterium) fortuitum, and Mycobacteroides (Mycobacterium) chelonae.

The drug susceptibility of rapidly growing mycobacteria (RGM) varies among isolates. Treatment strategies similarly differ depending on the isolate, and for some, no clear strategy has been identified. This complicates clinical management of RGM. Following Clinical and Laboratory Standards Institute standard M24-A2, we assessed the susceptibility of 140 RGM isolates to 14 different antimicrobial drugs by measuring their minimal inhibitory concentrations (MICs). We also investigated the correlation of clarithromycin (CAM) MICs with the erm(41) and rrl gene mutations in the Mycobacteroides (Mycobacterium) abscessus complex, the rrl mutation in Mycobacteroides (Mycobacterium) chelonae, and the erm(39) mutation in Mycolicibacterium (Mycobacterium) fortuitum to determine the contribution of these mutations to CAM susceptibility. The five species and subspecies examined included 48 M. abscessus subsp. abscessus isolates (34.3%), 35 (25.0%) being M. abscessus subsp. massiliense, and two (1.4%) being M. abscessus subsp. bolletii. The M. abscessus complex accounted for 85 isolates (60.7%) in total, whereas 43 isolates (30.7%) were M. fortuitum, and 12 (8.6%) were M. chelonae. Our results demonstrated species-specific susceptibility to antimicrobials. In most cases, susceptibility to CAM could be predicted based on genetic pattern, but since one isolate did not fit that pattern, MIC values needed to be measured. Some isolates also exhibited rates of resistance to other drugs that differed from those previously reported in other locations, indicating that accurate identification of the bacterial isolate and use of the correct method for determining MIC are both important for the diagnosis of RGM.

Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Mycobacterium avium Complex (CONVERT). A Prospective, Open-Label, Randomized Study.

Rationale: Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives: To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods: Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions: Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

Primary ciliary dyskinesia in Japan: systematic review and meta-analysis.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder. Although the genetic tests and new diagnostic algorithms have recently been recommended, clinical signs and electron microscope (EM) findings have historically been the mainstays of diagnosis in Asia. To characterize PCD previously reported in Japan, we conducted a systematic review and meta-analysis. METHODS: A search using MEDLINE, EMBASE, and Japana Centra Revuo Medicina (in Japanese) databases was carried out to identify articles reporting PCD, Kartagener syndrome, or immotile cilia syndrome in Japanese patients and published between 1985 and 2015. RESULTS: After excluding duplication from 334 reports, we extracted 316 patients according to the criteria. Diagnosis was most frequently made in adulthood (148 patients [46.8%] ≥ 18 years old, 24 patients [7.6%] < 1 year old, 68 patients [21.5%] 1-17 years old and 76 patients [24.1%] lacking information). Of the 230 patients (72.8%) who received EM examination, there were patients with inner dynein arm (IDA) defects (n = 55; 23.9%), outer dynein arm (ODA) defects (14; 6.1%), both ODA and IDA defects (57; 24.8%), other structural abnormalities (25; 10.9%), no abnormalities (4; 1.7%), and no detailed conclusion or description (75; 32.6%). CONCLUSION: Delayed diagnosis of this congenital disease with high frequency of IDA defects and low frequency of ODA defects appear to be historical features of PCD reported in Japan, when EM was a main diagnostic tool. This review highlights problems experienced in this field, and provides basic information to establish a modernized PCD diagnosis and management system in the future.