Animal models of chronic and recurrent Pseudomonas aeruginosa lung infection: significance of macrolide treatment.

Animal models of human diseases are invaluable and inevitable elements in identifying and testing novel treatments for serious diseases, including severe infections. Planning and conducting investigator-initiated human trials are generally accepted as being enormously challenging. In contrast, it is often underestimated how much planning, including background and modifying experiments, is needed to establish a relevant infectious disease animal model. However, representative animal infectious models, well designed to test generated hypotheses, are useful to improve our understanding of pathogenesis, virulence factors and host response and to identify novel treatment candidates and therapeutic strategies. Such results can subsequently proceed to clinical testing if suitable. The present review aims at presenting all the pulmonary Pseudomonas aeruginosa infectious models we have knowledge of and the detailed descriptions of established animal models in our laboratory focusing on macrolide therapy are presented.

Effect of long-term clarithromycin therapy on prevention of pneumonia in older adults: A randomized, controlled trial.

AIM: Pneumonia in older adults is increasingly recognized as a healthcare issue in countries with an aging population. Long-term macrolide therapy reduces exacerbations of chronic respiratory diseases, but its effects on the prevention of pneumonia have not been determined. METHODS: We carried out a randomized, controlled trial to test the effect of long-term clarithromycin therapy on the prevention of pneumonia among older adults. People aged ≥65 years who had recovered from pneumonia within the previous 3 months were recruited and randomly allocated to a long-term, low-dose clarithromycin (CAM) therapy group (n = 13) or a control group (n = 15). RESULTS: Both groups were followed up until recurrence of pneumonia. The median follow-up period was 251 days (95% CI 171-330) in the CAM group and 132 days (95% CI 67-196) in the control group (P = 0.627). The recurrence rate of pneumonia was two out of 13 (15%) in the CAM group and five out of 15 (33%) in the control group (P = 0.268). The median time to recurrence of pneumonia was 315 days (95% CI 249-382) in the CAM group and 260 days (95% CI 184-335) in the control group (P = 0.260). None of the differences between groups were statistically significant. CONCLUSIONS: No statistically significant suppressive effects of long-term, low-dose macrolide therapy on the development of pneumonia among older people were found in this small sample. A large-scale, randomized, controlled study is required. Geriatr Gerontol Int 2019; 19: 1006-1009.

Insulinoma resembling a rapid eye movement sleep behavior disorder: a case report.

Some patients with insulinoma present with neuropsychiatric symptoms and are often misdiagnosed with psychiatric disease. We present the case of a 72-year-old Japanese female who exhibited violent behavior while asleep and received a diagnosis of suspected rapid eye movement sleep behavior disorder (RBD). She was admitted to the psychiatry ward after receiving levomepromazine 25 mg intramuscularly. The patient's blood glucose level was 27 mg/dL at the time of hospitalization, and a biochemical examination revealed that her insulin level was 9.1 µU/mL and C-peptide level was 2.16 ng/mL. A contrast-enhanced computed tomography revealed a mass 8 mm in diameter in the pancreatic head. The diagnosis was changed from RBD to insulinoma. The sleep behavior disorder disappeared after continuous glucose administration. After enucleation of the insulinoma, the administration of glucose was discontinued, and her blood glucose levels recovered. This case suggests that insulinoma should be considered by physicians and psychiatrists in the differential diagnosis of patients with symptoms presenting as RBD.

Successful Treatment of Acute Fulminant Eosinophilic Myocarditis in a Patient with Ulcerative Colitis Using Steroid Therapy and Percutaneous Cardiopulmonary Support.

A 47-year-old man with ulcerative colitis was transferred to our hospital due to progressive dyspnea. Electrocardiography on admission showed ST elevation in leads II, III, aVF, and V5-V6. Coronary angiography revealed no remarkable coronary stenosis, and left ventriculography showed a depressed left ventricular ejection fraction (EF) of 23%. Although the patient received percutaneous cardiopulmonary support, his EF progressively decreased (7-15%), and both ventricular tachycardia (VT) and high-degree atrial-ventricular block occurred. An endomyocardial biopsy showed eosinophilic infiltration in the myocardium. Steroid therapy improved the patient's EF. However, his severe inferior wall hypokinesis and non-sustained VT remained after the abovementioned treatment.

Sub-minimum inhibitory concentrations of ceftazidime inhibit Pseudomonas aeruginosa biofilm formation.

Pseudomonas aeruginosa exhibits the biofilm mode of growth and causes chronic as well as acute infections in humans. Several reports have shown that the treatments with sub-minimum inhibitory concentrations (sub-MICs) of antimicrobial agents influence biofilm formation by P. aeruginosa. The antibiotic ceftazidime (CAZ) is used to treat P. aeruginosa infections, but few studies have examined the effects of ß-lactams on biofilm formation by P. aeruginosa. In this study, we investigated the role of sub-MICs of CAZ in the formation of P. aeruginosa biofilms. 1/4 × MIC CAZ reduced the biofilm volume of P. aeruginosa PAO1, as quantified by crystal violet staining. The formation of P. aeruginosa PAO1 biofilms treated with 1/4 × MIC CAZ were observed by confocal laser scanning microscopy. They were more heterogeneous than the PAO1 biofilms without CAZ treatment. Furthermore, sub-MICs of CAZ inhibited the twitching motility, which played an important role in mature biofilm formation. 1/4 × MIC CAZ also reduced the gene expressions of lecA, lecB, pel and psl, which mediate the adhesion and polysaccharide matrix synthesis of P. aeruginosa. These effects suggest that sub-MICs of CAZ may affect a number of stages of biofilm formation. Investigating the effects of sub-MIC antibiotics on targeted bacterial biofilm may lead to the development of future antibiotic treatment modalities.

High-resolution Computed Tomography Findings in Patients with Pulmonary Nocardiosis.

RATIONALE AND OBJECTIVES: Nocardiosis is difficult to diagnose, and the diagnosis is thus frequently delayed. High-resolution computed tomography (HRCT) findings of patients with pulmonary nocardiosis have been documented in few reports. Our study objective was to assess HRCT findings of patients with pulmonary nocardiosis. MATERIALS AND METHODS: This was a retrospective study of 20 consecutive patients with pulmonary Nocardia infections who underwent HRCT of the chest at our institutions from January 2011 to August 2014. After the exclusion of two patients with concurrent infections, the study group comprised 18 patients (11 men, 7 women; age range, 39-83 years; mean, 67.9 years) with pulmonary Nocardia infections. Parenchymal abnormalities, enlarged lymph nodes, and pleural effusion were evaluated on HRCT. RESULTS: Underlying conditions included respiratory disease (n = 6, 33.3%), collagen diseases (n = 5, 27.8%), and diabetes mellitus (n = 4, 22.2%). All patients showed abnormal HRCT findings, including the presence of a nodule/mass (n = 17, 94.4%), ground-glass opacity (n = 14, 77.8%), interlobular septal thickening (n = 14, 77.8%), and cavitation (n = 12, 66.7%). Pleural effusion was seen in two patients. There were no cases of lymph node enlargement. CONCLUSIONS: Among the HRCT findings in patients with pneumonia, a nodule/mass with interlobular septal thickening and/or cavitation are suggestive of pulmonary nocardiosis.

Cloning of the lanosterol 14-α-demethylase ( ERG11 ) gene in Trichosporon asahii: a possible association between G453R amino acid substitution and azole resistance in T. asahii.

Lanosterol 14-α-demethylase ( Erg11 protein; Erg11p ), encoded by the ERG11 gene, is the primary target of azoles. Recently, a change in affinity of this enzyme for azoles has been reported as a resistance mechanism in several fungal species. Trichosporon asahii ( T. asahii) is susceptible to fluconazole (FLC). This report identified the ERG11 gene of T. asahii (NCBI accession; HQ176415). The Erg11p of T. asahii, presumed from the DNA sequence, was closely related to the Erg11p of Cryptococcus neoformans. Furthermore, a FLC-susceptible strain was cultured in medium containing FLC at concentrations from 4.0 to 16 µg mL(-1) in order to analyze the development of FLC resistance in T. asahii. The degree of resistance was related to the FLC concentration of the growth medium. One highly resistant strain that was cultured in the medium containing 16 µg mL(-1) FLC contained 1 point mutation (G1357C) that caused a single amino acid substitution at G453R. This amino acid is highly conserved among major fungal pathogens, and it is in a region very close to the heme-binding domain, which is characteristic of the cytochrome P450 superfamily, the primary target for the azole class of antifungal agents. This amino acid substitution may have caused the high resistance to azoles in T. asahii.

Clinical features of healthcare-associated pneumonia (HCAP) in a Japanese community hospital: comparisons among nursing home-acquired pneumonia (NHAP), HCAP other than NHAP, and community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: More than 100000 Japanese die of pneumonia every year. The number of people residing in nursing homes is increasing with the ageing of the population. In 2005, the American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) published important guidelines for the management of healthcare-associated pneumonia (HCAP). In Japan, however, the optimum strategy for management of HCAP is still unclear. The purpose of this study was to clarify the clinical features of patients with HCAP. METHODS: Patients (n = 202) who were consecutively admitted with a diagnosis of acute pneumonia between October 2007 and September 2009 were retrospectively evaluated. Using the ATS/IDSA guidelines, patients were divided into three groups: a community-acquired pneumonia (CAP) group (n = 123), a nursing home-acquired pneumonia (NHAP) group (n = 46) and a HCAP other than NHAP (O-HCAP) group (n = 33). These groups were then compared with respect to laboratory data, microbiological findings and mortality. RESULTS: Thirty-day mortality in the NHAP group (10.9%) tended to be higher than that in the CAP group (3.3%) or the O-HCAP group (0%). The pathogens most frequently identified were Streptococcus pneumoniae and Haemophilus influenzae in the CAP group, methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae in the NHAP group, and S. pneumoniae and K. pneumoniae in the O-HCAP group. CONCLUSIONS: The NHAP group was clinically different from the O-HCAP group, based on bacteriological examination and mortality rates. In order to accurately diagnose, and formulate optimum treatment strategies for Japanese patients, the categories of HCAP, as specified in the ATS/IDSA guidelines, should not be applied directly either to patients with NHAP or those with O-HCAP.

Clinical value of assessing the response to imatinib monitored by interphase FISH and RQ-PCR for BCR-ABL in peripheral blood for long-term survival of chronic phase CML patients: results of the Niigata CML-multi-institutional co-operative clinical study.

This retrospective analysis investigated the prognostic value of monitoring the response to imatinib using peripheral blood (PB) samples and the impact of the response on outcome in 133 patients with chronic myeloid leukemia (CML). We divided the response into 3 categories according to the results of neutrophil (N)-FISH and BCR-ABL transcript levels in PB; more than a 3-log reduction [major molecular response (MMR)], between a 2-log and 3-log reduction or negative with N-FISH [complete cytogenetic response equivalent (CCyRe)], N-FISH positive or less than a 2-log reduction (non-CCyRe). The median follow-up was 5.46 years. At 5 years, the overall survival (OS) rate and progression-free survival (PFS) rate were 94.4 and 92.0%, respectively. The estimated rate of the CCyRe and MMR were 81.7 and 67.1%, respectively. 106 patients achieving the CCyRe had significantly better OS and PFS than 27 patients without achieving the CCyRe. Patients with MMR had significantly better survival free from death, progression, imatinib withdrawal and a loss of the CCyRe, than patients whose response level remained in the CCyRe without achieving MMR until 18 months. Our observation suggests that the response level of the CCyRe on PB serve as a prognostic indicator, and achieving MMR provides stable long-term survival.

[Allergic bronchopulmonary mycosis induced by Schizophyllum commune--case report and review of the literature].

A 55-year-old man was admitted to our hospital because of pyrexia, cough and sputum. He suffered from bronchial asthma. Chest X-ray showed infiltrates in the left upper and right lower lung fields. Chest CT scans showed mucoid impaction and consolidation predominantly in the left upper lobe. Laboratory tests showed peripheral eosinophilia, elevated level of serum IgE, and the increased eosinophils in his sputum. Schizophyllum commune was isolated from the bronchoscopically-removed mucous plug. A diagnosis of allergic bronchopulmonary mycosis (ABPM) due to S. commune was made. Simultaneous daily administration of 400 mg itraconazole (ITCZ) and corticosteroid (prednisolone; 30 mg daily) provided sufficient improvement. However recurrence was recognized on chest CT scan findings one year later. There are not enough case reports concerning S. commune-induced ABPM to establish a therapeutic approach to the condition.

A Japanese family with multiple lung cysts and recurrent pneumothorax: a possibility of Birt-Hogg-Dubé syndrome.

We herein report a Japanese family lineage, possibly demonstrating Birt-Hogg-Dubé (BHD) syndrome. A 29-year-old nonsmoking woman was admitted to our hospital due to spontaneous pneumothorax. A chest CT showed multiple lung cysts, and breast cancer was simultaneously detected that needed priority surgical treatment. In the family history, the patient's father and half brother also experienced recurrent pneumothorax, and both had similar findings in their chest CT. In a genetic analysis of her half brother, the mutation of the BHD gene was identified. BHD syndrome is a rare autosomal and dominantly inherited disorder, which has three characteristics: multiple lung cysts that may be associated with pneumothorax, skin fibrofolliculomas, and renal neoplasm. For multiple-cystic disease of the lungs with an unknown etiology, or pneumothorax, as seen in a family history, it is necessary to consider the possibility of BHD syndrome.

[Sarcoidosis with epididymal and testicular lesions: case report and a review of the literature].

A 47-year-old man was admitted for further examination of uveitis. He had noticed scrotal swelling before his admission. A computed tomographic scan of the chest showed hilar and mediastinal lymphadenopathy, multiple micronodules and thickening of the interlobular septum, and these findings were consistent with sarcoidosis. Bronchoalveolar lavage fluid showed lymphocytosis. Gallium-67 scintigraphy revealed an abnormal accumulation in the hilar and mediastinal lymph nodes and in the bilateral scrotum. The resected and biopsied specimens of the epididymis and testis demonstrated numerous noncaseating epithelioid cell granulomas but no evidence of neoplasm. Therefore, systemic sarcoidosis was diagnosed. A review of the Japanese literature found most cases to be associated with a history of painless scrotal swelling with chest roentgenogram findings of stage I or II, while also indicating it was important to perform biopsy or surgically resect any epididymal and testicular lesion.

[Acute eosinophilic pneumonia caused by several drugs including ibuprofen].

A 41-year-old woman took an EVE-A tablet, which contained ibuprofen, because of pyrexia over 39 degrees C. Due to continued pyrexia, she visited a physician and received cefcapene and acetaminophen under a diagnosis of cold. However, next day, she was admitted to our hospital with severe hypoxemia and pulmonary infiltrates on chest radiograph. Analysis of bronchoalveolar lavage fluid disclosed an increased proportion of 66% eosinophils. All of the lymphocyte stimulation tests for EVE-A tablet, cefcapene and acetaminophen showed positive. After the cessation of these drugs, she was successfully treated with steroids. This case was diagnosed as eosinophilic pneumonia caused by several drugs, and to our knowledge, this is the first report in Japan of ibuprofen (EVE-A tablet)-induced pneumonia.

[A case of eosinophilic pneumonia due to Nicolase (serrapeptase) after recovery from acute eosinophilic pneumonia].

A case of eosinophilic pneumonia due to Nicolase (serrapeptase) after recovery from acute eosinophilic pneumonia is described. A 32-year-old woman was previously admitted to another hospital because of acute onset of dyspnea accompanied by cough and fever. Chest X-ray films revealed diffuse infiltration in both lungs two days after her symptoms occurred. Her bronchoalveolar lavage fluid showed 13% eosinophils and transbronchial lung biopsy specimen also showed many eosinophils infiltrating in the lesions of the bronchial submucosa and alveolar septa. No infectious causes or related drugs were found. Acute eosinophilic pneumonia was diagnosed, and her condition improved gradually without steroid treatment. Because she recovered clinically and radiologically, she was discharged from hospital. Half a month later she was treated with Nicolase because of pharyngitis. She was admitted to the hospital again because of dyspnea, cough and fever three days after commencing to take Nicolase. Chest X-ray films also revealed diffuse infiltration in both lungs with pleural effusion, and her bronchoalveolar lavage fluid showed 37% eosinophils. When the drug lymphocyte stimulation test was performed, it was positive for Nicolase. Therefore drug-induced eosinophilic pneumonia was diagnosed. This is a very rare case of Nicolase (serrapeptase)-induced eosinophilic pneumonia after recovering from acute eosinophilic pneumonia.

[A case of amyopathic dermatomyositis-associated interstitial pneumonia accompanied with massive hemothorax].

A 53-year-old man was admitted to our department because of interstitial pneumonia found on chest computed tomography when he was given a diagnosis of amyopathic dermatomyositis. Bronchoalveolar lavage (BAL) fluid showed an increased total cell count and lymphocytosis. An acute exacerbation of interstitial pneumonia occurred just after the BAL. Although the administration of corticosteroid and immunosuppressant for the progressive interstitial pneumonia produced temporary improvement, left hemothorax suddenly occurred soon after initiating treatment. The hemothorax was improved by thoracic drainage alone, but the patient died due to progressive worsening of interstitial pneumonia. In this case, we could not clarify the etiological mechanism of the hemothorax, however, there was a possible link with amyopathic dermatomyositis-associated interstitial pneumonia.

In vitro and in vivo potency of polymyxin B against IMP-type metallo-beta-lactamase-producing Pseudomonas aeruginosa.

Multidrug-resistant Pseudomonas aeruginosa, especially metallo-beta-lactamase (MBL)-producing P. aeruginosa, is an important pathogen in nosocomial infection and emergence of this pathogen has revived interest in polymyxin B (PMB) and colistin (COL). In this study, we evaluated the efficacies of PMB, COL and other antipseudomonal agents against IMP-type MBL-producing P. aeruginosa both in vitro and in vivo. A total of 75 isolates of bla(IMP)-positive P. aeruginosa obtained from clinical specimens (94.6% of isolates demonstrated resistance to beta-lactam, fluoroquinolone and aminoglycoside agents) were evaluated in the in vitro study. More than 90% of the examined isolates were susceptible to PMB (minimum inhibitory concentration for 50/90% of the isolates (MIC(50)/MIC(90)) 4/4 mg/L), although COL was less potent (MIC(50)/MIC(90) 8/16 mg/L). Cyclophosphamide-treated mice were intraperitoneally inoculated with bla(IMP)-positive P. aeruginosa. Treatment with PMB, but not COL, imipenem/cilastatin or aztreonam, significantly improved the survival rate and decreased the number of bacteria in the blood in a dose-dependent manner. Our results indicate that, among the agents studied, PMB is the most effective agent against bla(IMP)-positive P. aeruginosa.