Published papers

症例は79歳女性.血液透析歴19年,関節リウマチに対して2年前からプレドニゾロン5mg/日を内服している.下腹部痛を主訴に入院後発熱が続き,膿尿と腹・骨盤部単純CTで残尿を認めた.尿路感染症を疑い,メロペネムで加療を開始した.尿培養でEscherichiaーcoli,血液培養でBacteroides thetaiotaomicronが検出,第3病日の造影CTで気泡を伴う膀胱周囲膿瘍を認めたため膀胱穿孔と診断した.手術は行わず,尿道カテーテルに加え,経皮的に膀胱周囲にドレーンを留置し,双方より持続ドレナージを開始した.穿刺液培養からPeptostreptococcus属が検出,クリンダマイシンを追加した.自覚症状・炎症反応は改善したが,膿瘍は残存しドレーン排液も遷延した.その後ドレナージ継続目的に転院した.本症例では,ステロイドの長期内服と慢性膀胱炎が膀胱穿孔の契機になった可能性が考えられた.また血液・尿培養での検出菌が異なったが,尿の嫌気性培養を行っておらず,病態を想定した適切な培養方法を実施する必要がある.(著者抄録)

医療従事者におけるCOVID-19の適切な感染対策を検討するため、血清抗体検査の陽性率から感染状況を推測した。さらに、血清抗体陽性者と陰性者の背景や臨床情報を比較し、感染者の特徴や感染危険因子を探索した。本大学医学部と大学病院に所属する医療従事者に対して2020年8月に実施した定期検査の際に、研究参加同意の得られた2341人を対象とした。COVID-19の既往歴のある21人を除外した2320人におけるIgG抗体陽性者は20人(0.862%)であった。年齢や職種では抗体陽性率に有意差はなかったが、性別は男性の方が有意に抗体陽性率が高かった。抗体陽性者は何らかの症状、特に嗅覚障害や味覚障害、発熱があった者で多かった。医療機関におけるCOVID-19の集団感染を防ぐために、医療従事者は適切な標準感染予防策と感染予防経路別予防策を実施し、発熱や嗅覚・味覚障害といった症状が出現した際は速やかに就業を中止すべきであると考えられた。

背景:薬剤耐性HIV調査ネットワークでは,新規診断者のHIV-1プロテアーゼ～逆転写酵素領域の塩基配列を用いて国内伝播クラスタ(dTC)を検索・同定しデータベース化する情報システム"SPHNCS"を開発した。本稿では,SPHNCSの解析結果に基づく2022年の本邦HIV-1流行動向を報告する。方法:2022年に報告のあった336件をSPHNCSに投入し,サブタイプBとCRF01_AEのdTCを同定した。その他のサブタイプについては過去の報告配列とともにBEASTによる時間系統樹を行ってdTCを特定した。結果:2022年は,サブタイプBのdTC所属例が65.3%であり,CRF139_02Bを含むCRF02_AG系列のdTC所属例が前年より高い割合(3.1%)で検出され,CRF01_AEのdTC所属例は4%に減少した。dTC所属例の検出数は,B-TC2が最大で,ついでB-TC21・B-TC3・B-TC77・B-TC33・B-TC230の順だった。B-TC2は九州地方で,B-TC21は関東地方で検出数が増加していた。2022年に検出されたB-TC77とB-TC98の報告例は,コロナ禍以前と遺伝的に近縁だった。B-TC33とB-TC230は九州地方で多く報告され,共通祖先の推定存在時間が古い報告例を多く含むdTCだった。2019～2021年にアウトブレイクしたAE-TC2は,7件と数を減らした。その他のサブタイプでは,CRF139_02Bの一系統である02-TC2と,北海道におけるCRF07_BCの増加が目立った。考察:2022年の本邦のHIV感染動向は,新たな亜型も含み,地域におけるdTC所属例の増加が注目される。コロナ禍が終息し始めた2022年のアウトブレイクや過去の感染の診断例の集積の観察は,リスク集団の行動変容や検査再開の影響かもしれない。地域ごとに異なる個別施策層への注意喚起が求められるだろう。(著者抄録)

© 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Some infectious diseases, such as infective endocarditis, osteomyelitis, and abscesses, require treatment with long-term intravenous antimicrobial treatment. Therefore, the patient is required to stay in the hospital to receive therapy, which lowers their quality of life. Establishing an outpatient parenteral antimicrobial therapy (OPAT) by continuous infusion pump is desired in Japan to overcome these issues. However, the 24-h stability of antimicrobial agents dissolved in infusion solutions is unclear. Thus, we investigated the stability of antimicrobial agents in five different infusion solutions in a clinical setting. Benzylpenicillin potassium (PCG) and ampicillin (ABPC) were dissolved separately in five different infusion solutions and kept at 25 or 31.1 °C for 24 h. The residual ratios were determined by high-performance liquid chromatography (HPLC). Dissolved PCG in acetate ringer solution remained stable for 24 h at temperatures of 25 and 31.1 °C (101.7 ± 1.4% and 92.9 ± 1.3%, respectively). In addition, the PCG solution did not adsorb onto the elastomeric infusion pump after 24 h at 31.1 °C. PCG dissolved in acetate ringer solution was also stable for 10 days after being kept in an elastomeric infusion pump at 4 °C (99.7 ± 0.5%). ABPC was unstable in all of the tested infusion solutions and temperatures. Based on our results, PCG in acetate ringer solution can be used in OPAT with continuous infusion pumps.

Mycobacterium avium complex refers to a group of environmental bacteria which inhabit water and soil. Although Mycobacterium avium complex is capable of causing refractory lung infections, the risk factors for Mycobacterium avium complex lung disease are still unclear. This study aimed to determine the associations between Mycobacterium avium complex lung disease and soil or water exposure. Using questionnaires along with clinical data, we compared soil exposure, along with bathtub bathing and showering habits between 172 women with Mycobacterium avium complex lung disease and 339 women without Mycobacterium avium complex infection as controls. Showering was found to be independently associated with the presence of Mycobacterium avium complex lung disease (adjusted odds ratio 5.72, 95%, confidence interval 1.99 to 16.46). Although the mean age of the groups was different, an age-matched sub-analysis yielded similar results. These results indicate that showering may be a risk factor for Mycobacterium avium complex lung disease.

Mechanisms underpinning the dysfunctional immune response in severe acute respiratory syndrome coronavirus 2 infection are elusive. We analyzed single-cell transcriptomes and T and B cell receptors (BCR) of >895,000 peripheral blood mononuclear cells from 73 coronavirus disease 2019 (COVID-19) patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell–cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19. Clonal expansions of BCR were evident in the plasmablasts of patients. Putative disease genes identified by COVID-19 genome-wide association study showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had context-specific and monocyte-specific expression quantitative trait loci effects. Our study highlights biological and host genetic involvement of innate immune cells in COVID-19 severity.

Background: Sitafloxacin (STFX) exhibits potent activity against Mycobacterium avium complex (MAC) in both in vitro and in vivo experiments. However, limited data are available for the clinical efficacy and adverse effects of STFX and the susceptibility of refractory MAC lung disease (MAC-LD) to the drug. Therefore, this study was aimed at evaluating the clinical efficacy and safety of an STFX-containing regimen for the treatment of refractory MAC-LD. Methods: We retrospectively evaluated treatment outcomes of 31 patients with refractory MAC-LD, who received an STFX-containing regimen for ≥4 weeks between January 2010 and July 2017. Refractory MAC-LD was defined as persistent positive sputum cultures for >6 months of macrolide-based standard therapy. Results: Clarithromycin resistance (minimum inhibitory concentration [MIC] ≥32 μg/mL) was identified in 15 patients (48%). Twelve months after receiving the STFX-containing regimen, 26% and 19% of patients showed symptomatic and radiological responses, respectively. Although STFX-associated adverse effects were noted in 9 patients, their severity was grade 1 (National Cancer Institute Common Terminology Criteria); only 1 patient discontinued STFX because of suspected gastrointestinal disturbance. Negative sputum culture conversion was achieved in 7 patients (23%). Both univariate and multivariate logistic regression analyses revealed that surgery, low STFX MIC (≤1 μg/mL), and macrolide resistance were significant predictors of negative sputum culture conversion. Conclusions: Our results demonstrate that STFX may be effective in one-fourth of patients with refractory MAC-LD. Prospective larger studies that include the analyses of MAC are needed to determine the clinical efficacy of STFX against refractory MAC-LD.

OBJECTIVES: The long-term stability of antimicrobials dissolved in infusion solution is necessary to establish and spread the outpatient parenteral antimicrobial therapy (OPAT). In this study, we evaluated the stability of antimicrobial agents dissolved in infusion solutions. METHODS: The antimicrobial agents were dissolved in infusion solutions and kept at 25 °C and 31.1 °C for 24 h or 4 °C for 10 days in a polypropylene tube or an elastomeric infusion pump. The stability was measured by high-performance liquid chromatography. RESULTS AND CONCLUSION: The residual ratio of cefazolin (CEZ), cefmetazole (CMZ), piperacillin (PIPC), and tazobactam (TAZ) at 31.1 °C for 24 h was as follows: 95.7 ± 3.0%, 94.8 ± 0.9%, 102.6 ± 1.8%, and 103.9 ± 3.6% in saline, respectively; 94.7 ± 3.0%, 94.3 ± 1.5%, 106.1 ± 3.0%, and 107.3 ± 2.4% in 5% dextrose solution, respectively. The residual ratio of these antimicrobials at 4 °C for 10 days was maintained above 90% in both saline and 5% dextrose solution. The residual ratio of all the above antimicrobials in an elastomeric infusion pump at 31.1 °C for 24 h was equivalent to that in the polypropylene tube. On the other hand, doripenem and meropenem were not stable in any infusion solution at 31.1 °C. CEZ, CMZ, and PIPC/TAZ dissolved in saline or 5% dextrose solution can be used in OPAT with continuous infusion pumps.

The tuberculosis (TB) notification rate in Japan is gradually decreasing but has not yet achieved "pre-elimination," defined by the World Health Organization. To effectively tackle, control, and eliminate TB, estimating and monitoring the annual risk of TB infection (ARI) using tuberculin skin testing (TST) to understand the dynamics of TB epidemiology are significantly important. However, studies estimating ARIs using TST are few considering that Bacillus Calmette-Guérin vaccination coverage is high in Japan. This was a single-center, cross-sectional study conducted between January 2011 and December 2018 in Tokyo area where interferon-gamma release assays (IGRAs) were performed in newly hired researchers of Keio University School of Medicine and healthcare workers of Keio University Hospital to determine TB infection. We estimated the prevalence of TB infection and ARI based on their IGRA results. Among the 3908 subjects, 83 (2.124%) had positive IGRA results. Multiple logistic regression analysis revealed that age was a significant risk factor for positive IGRA result (adjusted odds ratio, 1.046). The ARIs were 0.049%-0.156% between 1986 and 2004, midyears of TB infection, but have not significantly decreased over approximately two decades. To decrease the risk of TB infection, advanced strategies to control and eliminate TB in Tokyo area are significantly required.

Introduction. The incidence of Mycobacterium avium complex (MAC) pulmonary disease (MAC PD), a refractory chronic respiratory tract infection, is increasing worldwide. MAC has three predominant colony morphotypes: smooth opaque (SmO), smooth transparent (SmT) and rough (Rg).Aim. To determine whether colony morphotypes can predict the prognosis of MAC PD, we evaluated the virulence of SmO, SmT and Rg in mice and in human macrophages.Methodology. We compared the characteristics of mice and human macrophages infected with the SmO, SmT, or Rg morphotypes of M. avium subsp. hominissuis 104. C57BL/6 mice and human macrophages derived from peripheral mononuclear cells were used in these experiments.Results. In comparison to SmO- or SmT-infected mice, Rg-infected mice revealed severe pathologically confirmed pneumonia, increased lung weight and increased lung bacterial burden. Rg-infected macrophages revealed significant cytotoxicity, increased bacterial burden, secretion of proinflammatory cytokines (TNF-α and IL-6) and chemokines (CCL5 and CCL3), and formation of cell clusters. Rg formed larger bacterial aggregates than SmO and SmT. Cytotoxicity, bacterial burden and secretion of IL-6, CCL5 and CCL3 were induced strongly by Rg infection, and were decreased by disaggregation of the bacteria.Conclusion. M. avium Rg, which is associated with bacterial aggregation, has the highest virulence among the predominant colony morphotypes.

Background: Medical corporations, which are non-profit organizations that aim to operate hospitals, clinics, or long-term care facilities, account for more than half of all hospital beds and play a central role in the health care system in Japan. However, limited analysis of hospital integration has been performed. Examining the hospital integration trends of medical corporations can provide valuable insights for optimizing health care delivery and resource allocation in Japan. This study conducted a comprehensive analysis of trends in the hospital integration of medical corporations and market concentration in Japan using nationwide longitudinal data. Methods: This longitudinal study evaluated the hospital integration of medical corporations in Japan between 2017 and 2021 using medical corporation financial data provided by the Neostage Company. The target population was medical corporations that own hospitals in Japan. The primary outcomes were the horizontal and vertical integration of medical corporation hospitals. Horizontal integration was defined as the integration of two or more hospitals within the same corporation, while vertical integration was defined as the integration of a hospital with different types of health care facilities, such as clinics or long-term care facilities, within a single medical corporation. The Herfindahl–Hirschman Index (HHI) was calculated to measure hospital market concentration using hospital bed data for medical corporations in all prefectures. Results: The number of hospitals and hospital beds within medical corporations decreased from 5,670 to 848,174 in 2017 to 5,486 and 814,462 in 2021, respectively. Both horizontal and vertical integration among medical corporation facilities showed a gradual upward trend, increasing from 24.92% to 55.75% in 2017 to 26.92% and 59.42% in 2021, respectively. The mean (standard deviation [SD]) HHI increased slightly from 262.7 (178.6) in 2017 to 275.2 (187.9) in 2021, with rural areas being more concentrated than urban areas, although both remained unconcentrated. Conclusions: This longitudinal study revealed a gradual downward trend in the number of hospitals and hospital beds owned by medical corporations, while horizontal and vertical integration gradually progressed without any particular medical corporation dominating the market. These findings are expected to contribute to policymaking efforts aimed at providing optimal health care services in Japan.

OBJECTIVES: Universal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; i.e., the causative agent of coronavirus disease 2019 [COVID-19]) polymerase chain reaction (PCR) screening before admission has been adopted by several hospitals to prevent nosocomial SARS-CoV-2 transmission from asymptomatic and pre-symptomatic patients. However, screening usefulness remains unclear because it depends on the regional COVID-19 prevalence, and only a few large-scale studies have been reported. Here we describe the universal PCR screening performed in our hospital before admission of more than 12,000 patients and their attendants to evaluate the usefulness of the screening. METHODS: We retrospectively described the universal PCR screening results for asymptomatic patients and their attendants before planned admissions at a hospital in Tokyo, Japan, from August 3, 2020, through March 31, 2021. Nasopharyngeal swab samples were collected at an in-hospital PCR center. RESULTS: In total, 12,133 persons (11,859 asymptomatic patients and 274 attendants) underwent PCR screening; nine (0.07%) tested positive for SARS-CoV-2 RNA. CONCLUSIONS: Universal PCR screening may be useful for the advanced detection of SARS-CoV-2 infected patients with or without symptoms, which can be a potential source of nosocomial SARS-CoV-2 transmission.

Abstract Background Integrase strand transfer inhibitors (INSTIs) are recommended as first-line ART for people living with HIV (PLWH) in most guidelines. The INSTI-resistance-associated mutation E157Q, a highly prevalent (2%–5%) polymorphism of the HIV-1 (human immunodeficiency virus type 1) integrase gene, has limited data on optimal first-line ART regimens. We assessed the virological outcomes of various first-line ART regimens in PLWH with E157Q in real-world settings. Methods A multicentre retrospective observational study was conducted on PLWH who underwent integrase genotypic drug-resistance testing before ART initiation between 2008 and 2019 and were found to have E157Q. Viral suppression (<50 copies/mL) rate at 24 and 48 weeks, time to viral suppression and time to viral rebound (≥100 copies/mL) were compared among the first-line ART regimens. Results E157Q was detected in 167 (4.1%) of 4043 ART-naïve PLWH. Among them, 144 had available clinical data after ART initiation with a median follow-up of 1888 days. Forty-five started protease inhibitors + 2 NRTIs (PI group), 33 started first-generation INSTI (raltegravir or elvitegravir/cobicistat) + 2 NRTIs (INSTI-1 group), 58 started once-daily second-generation INSTI (dolutegravir or bictegravir) + 2 NRTIs (INSTI-2 group) and eight started other regimens. In the multivariate analysis, the INSTI-2 group showed similar or favourable outcomes compared with the PI group for viral suppression rates, time to viral suppression and time to viral rebound. Two cases in the INSTI-1 group experienced virological failure. Conclusions The general guideline recommendation of second-generation INSTI-based first-line ART for most PLWH is also applicable to PLWH harbouring E157Q.

BACKGROUND: SARS-CoV-2 vaccination has started worldwide, including Japan. Although high rates of vaccine response and adverse reactions of BNT162b2 vaccine have been reported, knowledge about the relationship between sex differences and antibody response is limited. Furthermore, it is uncertain whether adverse reactions are associated with the vaccine response. METHODS: This prospective observational study included 673 Japanese participants working in a medical school and its affiliated hospital in Tokyo, Japan (UMIN000043340). Serum samples were collected before the first dose and three weeks after the second dose of BNT162b2 vaccine, and antibody titers against the receptor-binding domain of the spike protein of SARS-CoV-2 were measured. Answers to questionnaires about background characteristics and adverse reactions were obtained at the time of sample collection, and the relationship between antibody titers was analyzed. RESULTS: After excluding participants who did not complete receiving two doses of vaccination or two series of serum sample collection, 646 participants were analyzed. Although all participants became sero-positive after vaccination, antibody titers were highly variable among individuals (260.9-57,399.7A U/mL), with a median titer of 13478.0AU/mL. Mean titer was higher in females than in males and higher in young (≤45 years old) participants than in aged (>45 years old) participants. Participants who experienced adverse reactions demonstrated a higher antibody titer after vaccination than those without adverse reactions. Multivariable analysis demonstrated that young age, female sex, and adverse reactions after the second dose were independently related to higher antibody titers after the second dose. DISCUSSION: A favorable antibody response was observed after two doses of BNT162b2 vaccination among mostly healthy Japanese participants, especially among female and young participants. Although further investigation is essential, our results imply that the systemic adverse reactions (i.e., fever and general fatigue) are associated with a higher antibody response that indicates the acquisition of humoral immunity.