Search

Background: Antibiotic therapy, including clarithromycin (CLR), has been widely used for the management of Mycobacterium avium complex (MAC) lung disease in clinical settings. When patients develop adverse events (AEs) during CLR-based treatment, the treatment regimen is modified or chemotherapy itself is discontinued. The need for alternative macrolide treatment strategies is emphasized due to the high rate of AEs possibly caused by CLR. Thus, the current study aimed to examine the efficacy and safety of azithromycin (AZM) in patients with MAC lung disease whose treatment was switched from CLR to AZM., Methods: We performed a retrospective study of patients with MAC lung disease. The inclusion criteria were as follows: (1) patients who experienced AEs during treatment with antibiotics, including CLR, between December 2012 and November 2017, and (2) those who had antimicrobial therapy that was switched from CLR to AZM. The efficacy and safety of AZM during the clinical course of the disease after switching the regimen from CLR to AZM were investigated., Results: Antibiotic therapy was switched in 31 patients who presented with AEs including drug-induced fever, rash, dysgeusia, liver dysfunction, and neutropenia during treatment with CLR-containing regimens. After switching to AZM, the median duration of treatment was 1286 (364-4615) days. During follow-up, 13 patients had a negative conversion of sputum culture., Conclusions: AZM may be safe and effective for patients with MAC lung disease who have difficulty tolerating CLR. In patients who experienced AEs possibly caused by CLR, switching from CLR to AZM might be an appropriate strategy., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Hemoptysis is a frequent and sometimes fatal complication of non-tuberculous mycobacterial (NTM) lung disease. The risk factors for hemoptysis are not well understood. In the current study, potential risk factors for hemoptysis were investigated in patients with Mycobacterium avium complex (MAC) lung disease, which is the most common NTM in Japan., Methods: Medical records from the Kinki-Chuo Chest Medical Center were reviewed. Consecutive patients with MAC lung disease diagnosed in 2014 and followed up for more than 1 year in the hospital were included in the study. Hemoptysis was confirmed between 2014 and 2016. The characteristics of patients with hemoptysis and non-hemoptysis at the time of the initial diagnosis of MAC lung disease were obtained from the medical records, and the two groups were compared. The radiological findings assessed included nodules, infiltration shadows, cavities, and bronchiectasis. Each was classified and scored individually in six lung fields, and these data were used to generate radiological scores., Results: The study included 82 patients with MAC lung disease, 18 with hemoptysis and 64 without. Higher total radiological severity score at the time of the initial diagnosis of MAC was associated with an increased risk of hemoptysis. Among the radiological scores, infiltration and cavities were marginally associated with the risk of hemoptysis., Conclusions: The radiological severity score at the time of initial diagnosis of MAC lung disease was associated with hemoptysis., Competing Interests: Conflict of interest The authors declare that there are no conflicts of interest., (Copyright © 2020 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Liming has been regarded as an effective measure to reduce the bioavailability and mobility of cadmium (Cd) in soil. However, its effect on Cd transport in colloid-associated form remains unclear. In this study, relative importance of dissolved and colloid-associated transport of Cd was explored in columns packed with moist soil aggregates (diameter <2 mm) under intermittent simulated rainfall of distilled water or 5 mmol L -1 CaCl 2 solution. The Cd 2+ /Ca 2+ exchange selectivity coefficient determined in column experiments displayed gradual decreases with decreasing ionic strength. It is proposed that the exchange selectivity coefficient determined by repeated batch extraction can be used to predict Cd discharge in dissolved form in column effluent. Colloid-associated Cd was the main Cd form in the first flushing effluent sample upon resuming infiltration of distilled water. Otherwise, Cd was transported mainly in dissolved form, accounting for 81-93 % and 54-72 % of total Cd discharge for unlimed soils and limed soils, respectively. Liming remarkably reduced dissolved Cd concentration but only slightly enhanced colloidal Cd transport. Cd was enriched on colloids, and the enrichment factor was enhanced by liming. Colloidal Cd transport through preferential pathways (e.g., macropores, shrinkage cracks, tile drains) should be paid due attention., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Mycolicibacter kumamotonensis (M. kumamotonensis), formerly Mycobacterium kumamotonense, is a nontuberculous mycobacteria species, which was first separated from Mycobacterium terrae complex in 2006. Reports about infections caused by M. kumamotonensis are extremely rare, with most of them being lung infection. Here, we report the case of a 68-year-old man with a hobby of gardening who developed swelling in his right middle finger. He underwent surgical debridement at a previous hospital and was diagnosed with nontuberculous mycobacteria infection based on positive findings of acid-fast staining of pus obtained from the surgical specimen. He was treated with rifampicin, ethambutol, and clarithromycin, but the swelling worsened. Therefore, he was referred to our hospital for further examination and treatment. We performed a second debridement and added isoniazid to the treatment regimen, but the swelling continued to worsen. We then administered levofloxacin, but his condition did not change. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing analysis confirmed M. kumamotonensis as the causative bacterium. Since the finger swelling did not improve, the patient underwent a third debridement and amikacin was added to the treatment regimen. Finally, the infection was controlled. He completed amikacin therapy and will continue treatment with the other five antibiotics for a total of 24 months. To the best of our knowledge, this is the first report of a patient with M. kumamotonensis soft tissue infection. We consider this case might provide important insights into the diagnosis and treatment of soft tissue infections caused by M. kumamotonensis., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Although fluoroquinolones are considered as alternative therapies of pulmonary Mycobacterium avium complex (MAC) disease, the association between fluoroquinolone resistance and MAC genotypes in clinical isolates from individuals not previously treated for MAC infection is not fully clear., Methods: Totals of 154 M. avium isolates and 35 Mycobacterium intracellulare isolates were obtained from treatment-naïve patients with pulmonary MAC disease at the diagnosis of MAC infection at 8 hospitals in Japan. Their susceptibilities of moxifloxacin were determined by broth microdilution methods. Moxifloxacin-resistant isolates were examined for mutations of gyrA and gyrB. Variable numbers of tandem repeats (VNTR) assay was performed using 15 M. avium VNTR loci and 16 M. intracellulare VNTR loci., Results: Moxifloxacin susceptibility was categorized as resistant and intermediate for 6.5% and 16.9%, respectively, of M. avium isolates and 8.6% and 17.1% of M. intracellulare isolates. Although the isolates of both species had amino acid substitutions of Thr 96 and Thr 522 at the sites corresponding to Ser 95 in the M. tuberculosis GyrA and Gly 520 in the M. tuberculosis GyrB, respectively, these substitutions were observed irrespective of susceptibility and did not confer resistance. The VNTR assays showed revealed three clusters among M. avium isolates and two clusters among M. intracellulare isolates. No significant differences in moxifloxacin resistance were observed among these clusters., Conclusions: Although resistance or intermediate resistance to moxifloxacin was observed in approximately one-fourth of M. avium and M. intracellulare isolates, this resistance was not associated with mutations in gyrA and gyrB or with VNTR genotypes., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Pulmonary non-tuberculous mycobacterial disease (PNTM) is a known risk factor for chronic pulmonary aspergillosis (CPA). However, few studies have focused on the prognosis of PNTM-associated CPA. In the present investigation, we aimed to elucidate the clinical course and prognostic factors of CPA in patients with PNTM., Methods: We retrospectively investigated the medical records of 62 patients with CPA and a history of PNTM who were admitted to Kinki-chuo Chest Medical Center between 2010 and 2015. Co-morbidities, causative microorganisms, radiological findings, and outcomes were evaluated., Results: The patients' median age was 69.5 years, and the median follow-up period was 4.2 years. The major underlying diseases, other than PNTM and CPA, were old pulmonary tuberculosis, chronic obstructive pulmonary disease, and interstitial pneumonia. The most common causative NTM species were Mycobacterium avium complex (MAC; 37 patients; 59.7%) and Mycobacterium kansasii (20 patients; 32.3%). Survival was 83% after 1 year and 61% after 5 years. Use of systemic corticosteroids (hazard ratio: 3.32, 95% confidence interval: 1.23-9.51; P=0.00177) and C-reactive protein levels ≥ 5.0 mg/dL (hazard ratio: 8.96, 95% confidence interval: 2.15-62.9; P=0.0014) at the time of CPA diagnosis were associated with increased over-all mortality., Conclusions: CPA frequently developed in patients with MAC and M. kansasii PNTM. The treatment course of PNTM was not associated with all-cause mortality. However, systemic corticosteroid use and high CRP levels were negative prognostic factors of CPA in patients with PNTM. Since the prognosis is poor, early diagnosis and treatment of CPA are important in patients with PNTM., (Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Humic substances (HS) in soil and sediments, and surface water influence the behavior of organic xenobiotics in the environment. However, our knowledge of the effects of specific HS fractions, i.e., humic acids (HAs), fulvic acids (FAs), and humin (HM), on the sorption of organic xenobiotics is limited. The neonicotinoid insecticide acetamiprid is thought to contribute to the collapse of honeybee colonies. To understand the role that soil organic matter plays in the fate of acetamiprid, interactions between acetamiprid and the above HS fractions were examined. Batch experiments were conducted using various combinations of a field soil sample and the above 3 HS fractions prepared from the same soil, and differences in isotherm values for acetamiprid sorption were investigated based on the structural differences among the HS fractions. The sorption of acetamiprid to soil minerals associated with HM (MHM) (Freundlich isotherm constant, K f : 6.100) was reduced when HAs or FAs were added (K f : 4.179 and 4.756, respectively). This can be attributed to hydrophobic interactions between HM and HAs or FAs in which their dissociated carboxyl and phenolic groups become oriented to face the soil solution. The amount of acetamiprid that was adsorbed to (MHM+HA) or (MHM+FA) increased when aluminum ions were added (K f : 6.933 and 10.48, respectively), or iron ions were added (K f : 7.303 and 11.29, respectively). Since acetamiprid has no affinity for inorganic components in soil, the formation of HS-metal complexes by cation bridging may have oriented the hydrophobic moieties in the HAs or FAs to face the soil solution and may also have resulted in the formation of dense structures, resulting in an increase in the amount of acetamiprid that becomes adsorbed to these structures. These results highlight the importance of interactions among soil components in the pedospheric diffusion of acetamiprid., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In Japan, nontuberculous mycobacterial lung disease is mostly attributable to Mycobacterium avium complex (MAC), i.e., M. avium or M. intracellulare. However, clinical features of the disease caused by these two pathogens have not been studied sufficiently yet., Methods: A post-marketing survey of clarithromycin was performed at 130 facilities across Japan. The data on patients with M. avium infection and patients with M. intracellulare infection were selected from this survey for comparison of background variables and clinical features of the two pathogens., Results: Among the patients analyzed (n = 368), 67.4% had M. avium infection and 32.6% had M. intracellulare infection. Stratified analysis revealed no significant differences between the ratio of the two pathogens based on gender, disease type, complication, past medical history, or smoking history. However, the percentage of patients with M. intracellulare infection was significantly higher among those with underlying lung disease than among those without lung disease (p = 0.0217). The percentage of patients with M. intracellulare infection rose significantly with age (p = 0.0296). This age-related change was more significant in women (p = 0.0018). When district-wise analysis was performed for Japan, the percentage of M. intracellulare infection was higher in the Chugoku/Shikoku and Kyushu districts whereas the percentage of M. avium infection was higher in the other districts., Conclusions: This survey revealed some differences in the clinical and epidemiologic features of M. avium and M. intracellulare infection. The significant predominance of M. avium infection among relatively young women is suggestive of an increase in the M. avium/M. intracellulare infection ratio among women in the future., (Copyright © 2017 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The revised 2007 American Thoracic Society/Infectious Diseases Society of America statement recommend clarithromycin-based combination therapy for treatment of Mycobacterium avium complex lung disease and stipulates approximately 1 year of continuous treatment after bacilli negative conversion. However, supporting data are insufficient. Our objective was to obtain data on the clinical outcome of clarithromycin-based daily regimens by conducting a nationwide retrospective post-marketing study of M. avium complex lung disease. In accordance with the Japanese guidelines, patients were enrolled in this survey according to their chest radiographic findings and microbiologic test results. They were treated with a multidrug regimen including clarithromycin, rifampicin, and ethambutol (clarithromycin-based regimen) until bacilli negative conversion, and the treatment was continued for approximately 1 year after the initial conversion. Data were collected before administration, at the time of bacilli negative conversion, at the end of treatment, and at 6 months after the end of treatment. Of the 466 subjects enrolled in the study, 271 patients who received clarithromycin at 800 mg/day underwent evaluation for M. avium complex disease. The final bacilli negative conversion rate in those patients was 94.7%. The bacteriological relapse rate was 5.0% (5/100 patients). Bacteriological relapse was noted in patients treated for less than 15 months after conversion. No life-threatening or serious adverse drug reactions were observed. This study demonstrated that a clarithromycin-based daily regimen can yield a high bacteriological conversion rate in M. avium complex disease. After conversion, treatment for less than 15 months might be insufficient to prevent bacteriological relapse., (Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Although nontuberculous mycobacteria (NTM) lung diseases can occur in association with lung cancer, no study has evaluated the effect of lung cancer treatment on NTM lung diseases. Therefore, the present study aimed to retrospectively examine the effect of lung cancer treatment on NTM lung diseases., Methods: Patients diagnosed with NTM lung diseases in combination with cytologically or histologically proven lung cancer between January 1, 2010 and October 31, 2014 were enroled. The clinical history of eligible patients was retrospectively reviewed., Results: Seven hundred twenty-eight patients were diagnosed with NTM lung diseases. Among these patients, 29 (3.9%) also had lung cancer. Of the 29 patients with NTM and lung cancer, 62% had Mycobacterium avium complex as the pathogenic organism. The most common lung cancer histology was adenocarcinoma (62.1%). Anti-cancer cytotoxic chemotherapy was administered to seven patients, and the two patients who did not receive NTM treatment showed worsening of their NTM lung disease., Conclusion: Whether NTM lung disease should be treated during anti-cancer chemotherapy has not been not clarified by this study. Induction of anti-NTM therapy should be made after careful consideration, because the duration of anti-NTM treatment is long and anti-mycobacterial drugs have extensive effects on anti-cancer drugs. However, we think that anti-NTM therapy should be introduced after consideration of the worsening of symptoms and radiological findings associated with NTM lung disease., (Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Background: Pulmonary nocardiosis is a rare but severe infection caused by Nocardia species. This study aimed at describing the clinical characteristics and prognosis of pulmonary nocardiosis., Methods: An observational, retrospective study was undertaken of patients diagnosed with pulmonary nocardiosis over a 13-year period at the Kinki-Chuo Chest Medical Center, Osaka, Japan., Results: Seven patients with airway nocardial colonization and 59 patients with pulmonary nocardiosis were identified, one of whom had disseminated nocardiosis. Patients with pulmonary nocardiosis were predominantly male patients (73%), with a mean age of 66 (range, 15-88) years. New-onset cough and dyspnea were the most common manifestations (76%). Although 52 (88%) patients had at least one underlying pulmonary disease, most patients did not appear to be systemically immunocompromised. The predominant abnormality on chest computed tomography in pulmonary nocardiosis was airspace consolidation (52%), sometimes associated with cavitation. Multivariate Cox proportional-hazards analysis revealed the following significant and independent risk factors for overall mortality: age >68 years (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.6-14; p=0.05), pulmonary aspergillosis (HR, 8.8; 95% CI, 2.4-33; p=0.01), and trimethoprim/sulfamethoxazole (TMP-SMZ) resistance (HR, 4.3; 95% CI, 1.6-11; p=0.04)., Conclusions: Clinicians should be aware that pulmonary nocardiosis can occur even in immunocompetent patients, especially those with an underlying pulmonary disease. In pulmonary nocardiosis, older age, pulmonary aspergillosis, and TMP-SMZ resistance are associated with increased risk of mortality., (© 2013 Published by The Japanese Respiratory Society on behalf of The Japanese Respiratory Society.)

We compared rifabutin susceptibility and rpoB mutations in 98 multi-drug-resistant strains of Mycobacterium tuberculosis (MDR-TB) by DNA sequencing and with a line probe assay using the commercially available INNO-LiPA Rif. TB kit (the LiPA). Our results indicated that rifabutin continues to remain active against MDR-TB strains harboring certain genetic alterations and also that the LiPA might be useful in identifying MDR-TB strains susceptible to rifabutin.

The ability to predict circulating human metabolites of a candidate drug before first-in-man studies are carried out would provide a clear advantage in drug development. A recent report demonstrated that while in vitro studies using human liver preparations reliably predict primary human metabolites in plasma, the predictability of secondary metabolites, formed by multiple reactions, was low, with total success rates of < or =65%. Here, we assess the use of chimeric mice with humanized liver as an animal model for the prediction of human metabolism in vivo. Metabolism studies with debrisoquine and (S)-warfarin demonstrated significantly higher concentrations of their primary human abundant metabolites in serum or plasma in chimeric mice than in control mice. Humanized chimeric mice were also capable of producing human-specific metabolites of several in-house compounds which were generated through more than one metabolism reaction. This model is closer to in vivo human physiology and therefore appears to have an advantage over in vitro systems in predicting complex metabolites in human plasma. However, prediction of human metabolites failed for other compounds which were highly metabolized in mice. Although requiring careful consideration of compound suitability, this model represents a potential tool for predicting human metabolites in combination with conventional in vitro systems.

The new non-reversed transcriptase inhibitor (NRTI) drugs for treatment of acquired immunodeficiency syndrome (AIDS) are reported. An improvement in the sensitivity and selectivity of high-performance liquid chromatography was obtained by diamond electrode-electrochemical detector and fluorescence detector owing to different structural information. The four anti-retroviral NRTI drugs (abacavir, didanosine, lamivudine and zidovudine) were separated on a CapcellPak C18 UG120 column (250 mm x 4.6 mm I.D., 5 microm) with an acetonitrile-25 mM potassium dihydrogenphosphate buffer (pH 8.0; 1:9, v/v) as the mobile phase. We applied dual detection (electrochemical detection and florescence detection) for improving the peak identification and also for improved selectivity, which assisted monitoring by trace-volume samples (e.g., plasma). The electrochemical detector, equipped with a diamond electrode, was set at 2000 mV (applied voltage) and the fluorescence detector was set at excitation wavelength 275 nm and emission wavelength 315 nm. The detection limits of the four NRTIs in spiked plasma were 1-100 ng/ml by electrochemical detection and 5-10 pg/ml by fluorescence detection. The calibration graphs were linear up to 20 microg/ml by electrochemical detection and 10 microg/ml by fluorescence detection. This is the first report of LC analysis of NRTIs by electrochemical detection, also combined with fluorescence detection. The detection limits of didanosine, lamivudine and zidovudine were improved 20-fold by electrochemical detection and 500-fold by fluorescence detection compared to previous reports on UV detection. The selectivity was also improved by dual detection. The proposed method was applied to the preliminary monitoring of NRTIs in plasma.

Background: The mechanism of cutaneous allergic vasculitis still remains unclear, and to the best of our knowledge, no case has been reported in the literature in which the number of mast cells was examined., Methods: A 33-year-old woman, with a past history of allergic rhinitis due to Japanese cedar and Phleum pratense (timothy), presented with a chief complaint of palpable papules on both lower legs in December 2002. On blood examination, peripheral blood eosinophilia was present, but all other examinations for immunologic diseases were negative, including specific IgE. We suspected cutaneous allergic vasculitis and performed skin biopsy., Results: In December 2002, histological examination of biopsy specimens of the skin lesions showed leukocytoclastic vasculitis. The diagnosis of cutaneous allergic vasculitis was made based on the clinical symptoms and the pathological findings of biopsy specimens. Immunohistochemical staining for human mast cell tryptase using monoclonal antibody against human mast cell tryptase showed an accumulation of mast cells. Treatment with oral corticosteroid resulted in the disappearance of clinical symptoms, and the steroid tapered. A second skin biopsy was performed in June 2005 after informed consent was obtained. Histological examination showed no findings of leukocytoclastic vasculitis, and the number of mast cells had decreased. She has been well without treatment., Conclusions: Mast cells may increase in the skin lesion of cutaneous allergic vasculitis.

Mycobacterium abscessus accounts for 80% of rapidly growing mycobacterial pulmonary infections and can be lethal. Treatment is difficult because of the paucity of effective drugs. We describe a patient with pulmonary M. abscessus infection who was treated with a regimen that included faropenem, a novel oral penem, and clarithromycin. He showed favorable responses to the treatment for more than 12 months. In vitro, faropenem had considerable inhibitory activities against 56 strains of rapidly growing mycobacteria, including M. peregrinum, M. chelonae, M. fortuitum, and M. abscessus (stated in order of increasing minimal inhibitory concentrations). Thus, faropenem has the potential to be used as an adjunctive drug with clarithromycin for the treatment of infection with rapidly growing mycobacteria, including M. abscessus.