Nationwide surveillance of bacterial respiratory pathogens conducted by the surveillance committee of the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology in 2019-2020: General view of the pathogens' antibacterial susceptibility.

The trends and prevalence of antimicrobial susceptibility of pathogens vary by country, region, and time. Long-term regular surveillance is required to investigate trends in the antimicrobial resistance of various isolated bacterial pathogens. We report the results of a nationwide surveillance on the antimicrobial susceptibility of bacterial respiratory pathogens in Japan conducted by the Japanese Society of Chemotherapy, the Japanese Association for Infectious Diseases, and the Japanese Society for Clinical Microbiology. The isolates were collected from clinical specimens obtained from adult patients who visited a collaborating medical facility between June 2019 and December 2020 and were diagnosed with respiratory tract infections by a physician. Antimicrobial susceptibility testing was performed in a centralized laboratory according to the methods recommended by the Clinical and Laboratory Standards Institute. Susceptibility testing was performed for 932 strains (201 Staphylococcus aureus, 158 Streptococcus pneumoniae, 6 S. pyogenes, 136 Haemophilus influenzae, 127 Moraxella catarrhalis, 141 Klebsiella pneumoniae, and 163 Pseudomonas aeruginosa) collected from 32 facilities in Japan. The proportions of methicillin-resistant S. aureus and penicillin-resistant S. pneumoniae were 35.3% and 0%, respectively. In H. influenzae, 16.2% and 16.9% were ß-lactamase-producing ampicillin resistant and ß-lactamase-negative ampicillin resistant, respectively. Extended-spectrum ß-lactamase-producing K. pneumoniae accounted for 5.0% of all K. pneumoniae infections. Carbapenemase-producing K. pneumoniae and multi-drug-resistant P. aeruginosa with metallo-ß-lactamase were not detected in this study. This surveillance will be a useful reference for treating respiratory infections in Japan and will provide evidence to enhance the appropriate use of antimicrobial agents.

TNFR1 Mediated Apoptosis Is Protective against Mycobacterium avium in Mice.

Mycobacterium avium is an intracellular proliferating pathogen that causes chronic refractory respiratory infection. Although apoptosis induced by M. avium has been reported in vitro, the role of apoptosis against M. avium infection in vivo remains unclear. Here, we investigated the role of apoptosis in mouse models of M. avium infection. Tumor necrosis factor receptor-1 knockout mice (TNFR1-KO) andTNFR2-KO micewere used. M. avium (1 × 107 cfu/body) was administered intratracheally to mice. Apoptosis in lungs was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling and lung histology as well as cell death detection kits using BAL fluids. TNFR1-KO mice were susceptible to M. avium infection compared with TNFR2-KO and wild type mice based on the bacterial number and lung histology. Higher numbers of apoptotic cells were detected in the lungs of TNFR2-KO and wild-type mice were compared with TNFR1-KO mice. The inhalation of Z-VAD-FMK deteriorated M. avium infection compared with vehicle-inhaled controls. Overexpression of Iκ-B alpha by adenovirus vector attenuated M. avium infection. Our study showed apoptosis had an important role in innate immunity against M. avium in mice. The induction of apoptosis in M. avium-infected cells might be a new strategy to control M. avium infection.

Efficacy and Safety of Sitafloxacin in Treating Low-risk Febrile Neutropenia in Patients with Lung Cancer.

Introduction: Febrile episodes in patients with cancer and chemotherapy-induced neutropenia can be life-threatening and generally require prompt administration of broad-spectrum antimicrobials. However, little evidence exists for treating patients with solid tumors and febrile neutropenia (FN) with oral antimicrobials. Methods: In this prospective study, we aimed to determine the efficacy and safety of sitafloxacin (STFX) for treating FN in lung cancer patients. In this prospective study, low-risk FN patients with lung cancer received STFX. The primary endpoint was response rate, defined as 5 sequential days of absence of fever without adverse events. The study was registered as UMIN000010911. Results: As a result, STFX was administered to 26 patients, all of whom survived during its administration. Of the 26, 14 completed primary endpoint (53.85%). The low response rate was attributed to occurrence of fevers of unknown cause rather than failure of FN treatment. Only two patients received antibacterial agents other than STFX. If response rate omitted absence of fever and been defined only as recovery from FN without changing microbial agents or serious complications, the response rate would have been 91.67%. Adverse events occurred in eight patients, none of which were serious. Conclusions: In conclusion, STFX might be used to treat low-risk FN in patients with lung cancer; however, a more detailed study will be required in future.

Feasibility, utility, and safety of transbronchial cryobiopsy for interstitial lung diseases in Japan.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a new technique that enables larger tissue collection than can be obtained by conventional transbronchial lung biopsy. TBLC is becoming popular worldwide and is performed for diffuse lung disease and lung cancer. However, only a few reports of TBLC have been published in Japan. This study was performed to evaluate the efficacy and safety of TBLC at our hospital and compare these findings with past reports. METHODS: From April 2018 to January 2020, 38 patients who underwent TBLC for diffuse lung disease at our hospital were evaluated with respect to age, sex, biopsy site, biopsy size, diagnostic disease, and complications. RESULTS: The patients who underwent TBLC were 20 men and 18 women with an average age of 63.7 years. The average sample size was 5.7 mm, and the diagnostic rate was 65.7% (25/38). Grade ≥2 complications included bleeding (15.8%), pneumothorax (2.6%), and atrial fibrillation (2.6%). CONCLUSIONS: TBLC was considered to be useful for the diagnosis of diffuse lung disease and could be safely performed.

Prevalence of viral infection in acute exacerbation of interstitial lung diseases in Japan.

BACKGROUND: Fatal acute exacerbation of interstitial lung diseases is often accompanied by indicators of infection such as fever, cough, and sputum. Although viral infection can contribute to acute exacerbation of interstitial lung diseases, few studies have identified a relationship between acute exacerbations and viral infections. The present study aimed to prospectively clarify the role of viral infection in patients showing acute exacerbation of interstitial lung disease in Japan. METHODS: Nasopharyngeal swab specimens were collected from patients with acute exacerbation of interstitial lung disease between May 2017 and February 2019. Respiratory viruses were detected by the Luminex xTAG Respiratory Viral Panel FAST v2 RUO kit and the BioFire FilmArray Respiratory Panel assay. RESULTS: Three of 29 patients demonstrated respiratory viral infection during acute exacerbation of interstitial lung diseases. The infectious agents were identified as respiratory syncytial virus, respiratory syncytial virus and influenza A virus, and influenza A virus and rhino/enterovirus in the three patients, respectively. CONCLUSIONS: These results suggest that viral infection did not frequently induce acute exacerbation of interstitial lung diseases in Japan.

Phase II Study on Biweekly Combination Therapy of Gemcitabine plus Carboplatin for the Treatment of Elderly Patients with Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: The biweekly GEM plus CBDCA dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC. The biweekly GEM plus CBDCA regimen could be considered an alternative to the 3-week regimen in NSCLC. BACKGROUND: The gemcitabine (GEM)-carboplatin (CBDCA) combination is widely used for non-small cell lung cancer (NSCLC) and has some efficacy in elderly patients; however, a high incidence of thrombocytopenia is observed, and the optimal dosage and administration schedules are unknown. This multicenter phase II trial evaluated the efficacy and tolerability of GEM-CBDCA for elderly patients with chemotherapy-naive NSCLC. METHODS: Patients with chemotherapy-naive performance status 0-1 and with stage IIIB/IV NSCLC were administered chemotherapy biweekly (GEM 1,000 mg/m2 with CBDCA area under the blood concentration-time curve (AUC) 3 on days 1 and 15 every 4 weeks). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty-eight patients were enrolled. Median age was 76 years (range, 70-83); 35 patients were men (73%), and 27 patients had adenocarcinoma (56%). The ORR was 29.2% (95% confidence interval [CI], 17.0-44.1). The median PFS, median OS, and 1-year survival was 5.9 months (95% CI, 4.1-6.6), 13.3 months (95% CI, 8.3-23.5), and 58%, respectively. Grade ≥3 hematological toxicities included neutropenia (29.2%), thrombocytopenia (4.2%), and anemia (20.8%). The incidence of grade ≥3 nonhematological toxicities was <5%. CONCLUSION: This GEM-CBDCA combination administered biweekly showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

Inhaled corticosteroids might not increase the risk of pneumonia in patients with chronic obstructive pulmonary disease in Japan.

BACKGROUND: The use of inhaled corticosteroid (ICS) in patients with chronic obstructive pulmonary disease (COPD) decreases the frequency of COPD exacerbations. Recently, pneumonia was reported as a complication of ICS in patients with COPD. However, there have been few reports concerning the relationship between ICS and pneumonia in Japan. Moreover, there is little information on the types of ICS. PATIENTS AND METHODS: To clarify these issues, we investigated the occurrence of pneumonia in Japanese patients with COPD. We retrospectively investigated the occurrence of pneumonia in patients with COPD in our hospital from January 2009 to August 2013. Morbidity and mortality, ICS use, age, sex, and COPD classification were investigated. A group of patients with COPD who received ICS and a group of patients with COPD who did not receive ICS were compared each other. RESULTS: Fifty-one patients developed pneumonia among 639 (7.98%) patients with COPD. Among 252 ICS-treated patients with COPD, 13 (5.16%) developed pneumonia, and among 387 ICS-untreated patients with COPD, 38 (9.82%) developed pneumonia. The mortality rate in ICS-treated patients with COPD was 7.7%, while that in ICS-untreated patients was 10.5% (P=0.767). Fluticasone/salmeterol use tended to show a higher risk of pneumonia than budesonide/formoterol use. The use of ICS did not increase the risk of pneumonia or mortality due to pneumonia in Japanese patients with COPD. CONCLUSION: ICS might not increase the risk of pneumonia in Japanese patients with COPD. In regard to pneumonia, ICS can be safely used in Japanese patients with COPD. Because there are apparent differences in lung diseases among races, appropriate treatment should be investigated in each country.

Study of the usefulness of small-bore aspiration catheters (Aspiration Kit®) for treating pneumothorax.

BACKGROUND: Small-bore aspiration catheters (Aspiration Kit®) cause less pain than conventional trocar catheters in patients. The objective of this study was to examine the usefulness of these less invasive small-bore aspiration catheters for drainage of pneumothorax. METHODS: Baseline characteristics and laboratory test data at admission of 70 patients who were admitted to and underwent drainage treatment for pneumothorax at our hospital between April 2011 and February 2017 were retrospectively reviewed based on their medical records. The primary endpoints were factors associated with drainage treatment failure, and baseline characteristics and laboratory test data were compared between those treated with a small-bore aspiration catheter and those treated with a trocar catheter. RESULTS: The numbers of patients with anticoagulant use (P < 0.0001), ischemic stroke (P = 0.0063), and atrial fibrillation (P = 0.0410) were significantly different between the two groups. No significant intergroup differences were noted with respect to the length of hospitalization, drainage duration, subcutaneous emphysema, and treatment failure. Logistic regression analyses of baseline characteristics showed that the severity of pneumothorax, localization of pneumothorax, and recurrent pneumothorax were significantly associated with drainage treatment failure, but the type of drainage catheter was not significantly associated with treatment failure. [Conclusions] The results suggest that small-bore aspiration catheters, which cause less pain in patients, are potentially useful for pneumothorax drainage.

The limited impact of psychiatric disease and psychotropic medication on the outcome of hospitalization for pneumonia.

Psychotropic medicine has been suggested to be a risk factor for the onset of pneumonia, especially aspiration pneumonia. However, the impact of coexisting psychiatric disease and psychotropic medication on the outcomes of pneumonia patients in the respiratory care unit setting is less well-known. We conducted a single-centre retrospective study of 209 consecutive patients who were hospitalized due to pneumonia. Using the patients' records, coexisting psychiatric diseases and the use of psychotropic medicines were reviewed to examine their association with the clinical course of inpatients with pneumonia. Psychotropic medicines, including agents for insomnia, were used in 73 (34.9%) patients, and there were 35 (16.9%) patients who had psychiatric disease. Among the 12 (5.7%) fatal cases, 4 patients were treated with psychotropic medicines, all of which were agents for insomnia. However, the rate of psychotropic medicine usage in the fatal cases (33.3%) was equivalent to that of the survivors (35%, p = 0.905), and the coexistence of psychiatric disease did not affect survival. The median duration of hospitalization was 15 days. The duration of hospitalization of the patients who received psychotropic medicines (median: 17 [range: 7-89] days) was also equivalent to that of the other patients (14 [2-55] days, p = 0.081). While the present study was a single-centre study and had a small population, coexisting psychiatric disease and psychotropic medicine use did not have a strong impact on the outcomes of pneumonia patients who were hospitalized in the respiratory unit of a university hospital. Further prospective studies targeting a larger cohort are needed.

Chronic Pseudomonas aeruginosa infection-induced chronic bronchitis and emphysematous changes in CCSP-deficient mice.

The club cell secretory protein (CCSP) is a regulator of lung inflammation following acute respiratory infection or lung injury. Recently, the relationship between CCSP and COPD has been reported. Since COPD results from an abnormal inflammatory response, we hypothesized that CCSP could have a protective role against chronic inflammation-induced lung damage. To address this issue, the pathophysiology of chronic lung inflammation induced by Pseudomonas aeruginosa in CCSP-deficient mice was determined. A tube of 5 mm in length was soaked in a fluid containing P. aeruginosa (PAO01 strain) for 1 week and inserted into the trachea of CCSP-deficient mice. One week later, P. aeruginosa was administered into the trachea. Five weeks after insertion of tube, the mice were sacrificed. Bronchoalveolar lavage fluids were collected to determine the bacterial growth, and the lung histology and physiology were also examined. P. aeruginosa was continuously detected in bronchoalveolar lavage fluids during the study. Neutrophils were increased in the bronchoalveolar lavage fluids from the CCSP-deficient mice in comparison to wild-type mice. A histological study demonstrated chronic inflammation around bronchus, serious bronchial stenosis, and alveolar enlargement in the CCSP-deficient mice. The lung physiology study demonstrated an increase in the lung compliance of the CCSP-deficient mice. Chronic P. aeruginosa inflammation resulted in chronic bronchitis and emphysematous changes in the CCSP-deficient mice. CCSP could play an important role in protecting the host from the chronic inflammation-induced lung damage.

Critical role of tumor necrosis factor receptor 1 in the pathogenesis of pulmonary emphysema in mice.

COPD is a major cause of chronic morbidity and mortality throughout the world. Although tumor necrosis factor-α (TNF-α) has a critical role in the development of COPD, the role of different TNF receptors (TNFRs) in pulmonary emphysema has not been resolved. We aimed to clarify the role of TNFRs in the development of pulmonary emphysema. TNF-α transgenic mice, a murine model of COPD in which the mice spontaneously develop emphysema with a large increase in lung volume and pulmonary hypertension, were crossed with either TNFR1-deficient mice or TNFR2-deficient mice. After 6 months, the gross appearance of the lung, lung histology, and pulmonary and cardiac physiology were determined. In addition, the relationship between apoptosis and emphysema was investigated. Pulmonary emphysema-like changes disappeared with deletion of TNFR1. However, slight improvements were attained with deletion of TNFR2. Apoptotic cells in the interstitium of the lung were observed in TNF-α transgenic mice. The apoptotic signals through TNFR1 appear critical for the pathogenesis of pulmonary emphysema. In contrast, the inflammatory process has a less important role for the development of emphysema.

Adenoid Cystic Carcinoma of the Lung with an EGFR Mutation.

An 80-year-old woman was referred to our hospital due to the presence of a mass that was identified on a chest X-ray. A further investigation demonstrated advanced adenoid cystic carcinoma of the lungs. Anti-cancer chemotherapy with docetaxel was carried out and the lesion remained as stable disease. Subsequently, pleural effusion was detected, and an investigation of the pleural effusion revealed the existence of malignant cells with an epidermal growth factor (EGFR) mutation. Gefitinib was administered and the pleural effusion resolved. This is the first case of a positive EGFR mutation of adenoid cystic carcinoma of the lung with a favorable response to an EGFR-tyrosine kinase inhibitor.

The efficacy and safety of cefepime or meropenem in the treatment of febrile neutropenia in patients with lung cancer. A randomized phase II study.

Febrile neutropenia frequently develops after chemotherapy. There is little evidence to indicate the type of antimicrobial agents that should be used in the treatment of febrile neutropenia in patients with solid tumors. The objective is to determine the efficacy and safety of cefepime (CFPM) and meropenem (MEPM) in the treatment of febrile neutropenia in lung cancer patients in a prospective randomized study. FN patients with lung cancer were randomly divided into CFPM or MEPM groups. The primary end-point was the response rate. The secondary end-points were the defervescence rates at 72 h, 7 days, 14 days and the incidence of adverse events. Twenty-one patients were treated with CFPM and 24 patients were treated with MEPM. One patient died of FN. The CFPM treatment completion rate was 17.65% (95% CI; 0.00-35.77%), while the MEPM treatment completion rate was 38.10% (95% CI; 17.33-58.87%). The defervescence rates at 72 h, 7 days, and 14 days were 70.59%, 86.67%, and 100.00%, respectively in the CFPM group; and 65.00%, 84.21%, and 92.31% in the MEPM group. Adverse events were observed in 33.33% of the CFPM group and 45.83% of the MEPM group. The response rate of the CFPM group was 94.12% (95% CI; 73.02-98.95%), while that of the MEPM group was 85.71% (95% CI; 65.36-95.02%). No differences were found in the efficacy or safety of CFPM and MEPM in the treatment of febrile neutropenia in patients with lung cancer.

[Pilot study of intermittent administration of liposomal amphotericin B for chronic pulmonary aspergillosis].

Treatment for chronic pulmonary aspergillosis is difficult and frequently is required for prolong period. In outpatients setting, only voriconazole and itraconazole could be used. Since liposomal amphotericin B (L-AMB) demonstrated prolonged half-time, we have investigated the feasibility of L-AMB in outpatient setting. Three cases of chronic pulmonary aspergillosis were treated with intermittent administration of 2.5 mg/kg of L-AMB twice weekly for one month in outpatient settings. Improve of symptoms was attained in 2 of 3 cases. Improvement of chest images were in 2 of 3, improvement of laboratory test were in 2 of 3. Adverse events were only fatigue and short period of fever. No recurrence of pulmonary aspergillosis has been found after treatment. Intermittent administration of L-AMB in outpatient settings could be an option for pulmonary aspergillosis.

[Measurement of sitafloxacin MIC for Mycobacterium avium complex and application for treatment of pulmonary nontuberculous mycobacteriosis].

Treatment for pulmonary nontuberculous mycobacteriosis is difficult. Since current treatment has limitation, new application is needed. Fluoroquinolone is one of candidates. We have investigated the feasibility of sitafloxacin (STFX). At first, the drug of MIC (minimum inhibitory concentration) was determined by the methods based on BrothMIC NTM. The MICs of STFX, moxifloxacin (MFLX), gatifloxacin (GFLX) were low. On contrast, the MICs of garenoxacin (GRNX) and tosufloxacin (TFLX) were high. Two cases of pulmonary Mycobacterium avium-intracellulare complex (MAC) disease were treated by STFX-contained regimen. In all cases of pulmonary MAC disease, improve of symptoms and chest CT images were attained. Adverse events were slight. These MIC studies and case reports suggest that STFX might have excellent in vitro and in vivo antimicrobial activities against MAC and is considered to be a candidate for the medication against pulmonary MAC disease.

Phase II study of concurrent thoracic radiotherapy in combination with weekly paclitaxel plus carboplatin in locally advanced non-small cell lung cancer: LOGIK0401.

OBJECTIVES: Concurrent chemoradiotherapy for regionally advanced stage III non-small cell lung cancer is the standard treatment method. However, the clinical implications of consolidation chemotherapy following chemoradiation have been unclear. Therefore, we conducted a phase II study of concurrent weekly carboplatin plus paclitaxel treatment in combination with radiotherapy followed by vinorelbine monotherapy. The primary endpoint was the 1-year survival rate. PATIENTS AND METHODS: Chemonaive PS 0-1 patients with stage IIIA/B NSCLC were enrolled. During the concurrent chemoradiation phase, patients were treated with weekly paclitaxel 40 mg/m(2) plus carboplatin AUC 2. The primary tumor and involved nodes received 60 Gy in 2-Gy fractions over 6 weeks. During the consolidation phase, vinorelbine 25 mg/m(2) on days 1 and 8 was repeated for three cycles. RESULTS: A total of 40 eligible patients (72.5 % male; median age, 63 years; range 29-74 years) were analyzed for efficacy. Squamous cell carcinoma was the most common histology (47.5 %), and more patients had clinical stage IIIB (55 %) cancer. The average radiation dose was 56.5 Gy, and the average number of carboplatin plus paclitaxel cycles was 4.93. Seventeen patients proceeded to the consolidation chemotherapy phase, and 14 completed three cycles of vinorelbine monotherapy. The objective response rate was 75.0 %, including 1 patient who achieved a complete response. Progression-free survival and overall survival (OS) were 46 weeks [95 % confidence interval (CI) 31-64 weeks] and 110 weeks (95 % CI 90-184 weeks), respectively. The OS rate at 1 and 2 years was 85.0 % (95 % CI 69.6-93.0 %) and 53.9 % (95 % CI 37.1-68.0 %), respectively. CONCLUSION: Concurrent chemoradiation with weekly carboplatin and paclitaxel followed by vinorelbine consolidation is effective for stage III non-small cell lung cancer and shows a generally mild toxicity profile.

[A case report of pulmonary aspergillosis in lung transplant recipient successfully treated with inhalation administration of liposomal amphotericin B].

We report a case of pulmonary aspergillosis in lung transplant recipient who was successfully treated with inhalation administration of anti-fungal agent. The case was 33-year-old female. Two years ago, she had received lung transplant because of lymphangioleiomyomatosis. One year ago, she had diagnosed of pulmonary aspergillosis and successfully treated with micafungin and itraconazole. Then she had been continuous administered with itraconazole. In June 20xx, she had nausea and vomiting and was diagnosed of viral enteritis. Although abdominal symptoms were relieved, ground glass opacity was discovered in her right lung. Bronchoscopic examination revealed ulceration of bronchus with white necrotic substance. Laboratory culture test demonstrated Aspergillus spp. Finally she was diagnosed of recurrent pulmonary aspergillosis. First, she was treated with intravascular administration of micafungin. Then, inhalation administration of liposomal amphotericin B was changed. Ground glass opacity and bronchial region of pulmonary aspergillosis was improved. Thereafter, inhalation of amphotericin B was continued and no recurrence of pulmonary aspergillosis has been found. Inhalation of anti-fungal agent could be an option for pulmonary aspergillosis.

Elevation of serum C-reactive protein predicts failure of the initial antimicrobial treatment for febrile neutropenia with lung cancer.

Febrile neutropenia frequently develops after chemotherapy, and the prompt administration of antimicrobial agents is required for treatment. In the present study, we searched for predictive factors for the failure of the initial antimicrobial agents used for febrile neutropenia (FN) in patients with lung cancer. Sixty FN patients treated in our ward from June 2005 to May 2011 were retrospectively analyzed. The definition of FN and the response to antimicrobial agents were determined by the Japanese guidelines. We divided the FN patients into two groups by their response to the initial antimicrobial agents. Next, the characteristics of the two groups were compared. The Multinational Association of Supportive Care in Cancer (MASCC) score did not differ between the two groups. The non-responder group demonstrated significant elevation of serum C-reactive protein (CRP) level. A multivariate analysis demonstrated that a CRP level higher than 10 mg/dl is an independent risk factor for the failure of initial antimicrobial agents for FN with lung cancer (OR 11.0, 95 % CI 1.635-74.5). When the CRP score was added to the MASCC score, the scoring system could more precisely predict the failure of initial antimicrobial agents in patients with lung cancer who developed febrile neutropenia.