Background:Vancomycin infusion reaction (VIR) is a common adverse reaction to vancomycin. We aimed to investigate the effects of infusion rate, age, infusion time, renal function and history of allergy on the incidence of VIR. Methods:We conducted a single-centre retrospective cohort study with 153 patients (aged 0-92.7 years) who received a single intravenous dose of vancomycin for perioperative prophylaxis. Patients treated for active infections were excluded. Medical records were retrospectively evaluated for VIR occurrence, defined as itching, flushing or rash documentation. Results:VIR incidence was 46.7% (7/15) in patients aged <10 years, 47.4% (9/19) in those aged 10-20 years and 44.4% (4/9) in those aged 20-30 years, versus 2.7% (2/74) in those aged ≥60 years. Multivariable logistic regression identified younger age [adjusted odds ratio (aOR) 0.95, 95% CI 0.93-0.97] and higher weight-adjusted infusion rate (aOR 1.22 per mg/kg/h increase, 95% CI 1.04-1.43) as independent risk factors for VIR. Receiver operating characteristic analysis of the infusion rate by age group showed that the optimal cut-off value for patients aged 30-60 years was 14.8 mg/kg/h, whereas for those aged <30 years, it was 14.0 mg/kg/h. No patients developed VIR when the infusion rate was <9.4 mg/kg/h. Conclusions:Age and higher weight-adjusted infusion rate were key risk factors for VIR. Tailoring infusion rate to age and weight may reduce VIR incidence without unnecessarily prolonging administration time.

Objectives The incidence of nontuberculous mycobacterial pulmonary disease (NTM-PD) is rising; however, only certain patients experience disease progression requiring therapy. Methods This retrospective cohort study enrolled 303 adults (age≥20 years) who were not receiving treatment at enrollment, including patients with a prior treatment history of Mycobacterium avium complex pulmonary disease (MAC-PD). Clinical, laboratory, microbiologic, physiological, and radiographic variables were extracted. The outcome was clinical progression, defined as treatment initiation. Results A point-wise linear neural network screened 63 features; the 22 most informative features yielded a parsimonious two-variable logistic model based on four routinely available inputs (age, treatment history, cavitation, and modified Reiff score). Overall, 124 patients experienced progression: these patients were younger, and frequently had cavitation, higher modified Reiff scores, and treatment history. The best model achieved an area under the curve (AUC) of 0.81. The Bayesian network indicated that age and treatment history influenced clinical progression through the radiographic disease burden. Conclusion For the first time, we demonstrated that the modified Reiff score is important for predicting clinical progression in MAC-PD using explainable AI models.

Accurate subspecies identification and determination of macrolide resistance status are crucial for the treatment of Mycobacterium abscessus complex (MABC) infections. In recent years, a kit that uses DNA chromatography to differentiate the three MABC subspecies and detect macrolide-induced resistance has become available in Japan. Using this kit, testing strains isolated from patients with MABC infection resulted in one false-positive and one false-negative result. A detailed analysis of these strains revealed that the discrepancies were due to the presence or absence of specific target genes included in the kit. Because MABC has a high level of genetic diversity, interpreting the test results obtained using this kit requires the consideration of such genetically exceptional strains.

Chronic kidney disease (CKD) is associated with an increased risk of severe urinary tract infections (UTIs), particularly those caused by antimicrobial-resistant bacteria. Although urinary microbiota and bacterial membrane vesicles (BMVs) are thought to contribute to UTI pathogenesis, their roles in CKD remain insufficiently understood. In this exploratory study, urine samples were collected from 10 male patients with CKD (eGFR <45 mL/min/1.73 m²) and 10 male non-CKD controls (eGFR ≥60 mL/min/1.73 m²). Urinary microbiota and BMV fractions were isolated and analyzed to compare microbial composition and antimicrobial resistance gene (ARG) profiles, and to evaluate their potential involvement in UTI development and the emergence of antimicrobial resistance in CKD. Both fractions were subjected to shotgun metagenomic sequencing; metagenomic analysis of BMVs was performed using pooled samples within each group. In addition, BMV fractions were characterized by transmission electron microscopy and 16S rRNA gene PCR. Urinary microbiota α-diversity was significantly lower in patients with CKD than in controls (ACE index, p = 0.04). Vesicle-like structures consistent with BMVs, with diameters of 20-200 nm, were detected in urine samples from both controls and patients with CKD. Principal coordinate analysis demonstrated that BMV fractions clustered within the corresponding urinary microbiota profiles. Furthermore, multiple antimicrobial resistance genes (ARGs), including ftsI and adeF, were identified in both urinary microbiota and BMV fractions. This study provides exploratory evidence of reduced urinary microbiota α-diversity in patients with CKD and the presence of ARGs in both urinary microbiota and BMV fractions from controls and patients with CKD. These findings suggest microbiological factors that may contribute to the high incidence of antimicrobial-resistant UTIs in this population. Future validation in larger cohorts with individual-level BMV profiling will be required to determine whether analyses focusing on urinary microbiota and BMVs can contribute to a better understanding of antimicrobial-resistant UTIs and to improved infection risk assessment in patients with CKD.

BACKGROUND:The association between acute-phase corticosteroid therapy and subsequent Long COVID symptoms remains uncertain. Therefore, we aimed to evaluate the association between systemic corticosteroid therapy during hospitalization and patient-reported Long COVID symptoms during follow-up. METHODS:In this prospective multicenter observational study, we enrolled adults hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection at 26 hospitals in Japan between January 2020 and February 2021. To account for evolving corticosteroid prescription practices, we used propensity score overlap weighting with calendar time adjustment relative to the RECOVERY trial announcement and fit overlap-weighted mixed-effects logistic regression models to estimate longitudinal associations across follow-up (3, 6, and 12 months). Additionally, symptom-specific outcomes were evaluated at 3 months. RESULTS:Among the 1044 participants, 373 received systemic corticosteroids and 671 did not. Corticosteroid therapy was associated with higher odds of any Long COVID symptom during follow-up (OR: 1.71; 95% CI: 1.12-2.63). In exploratory subgroup analyses stratified by oxygen requirement, no clear association was observed among patients who required oxygen therapy during hospitalization, whereas the association was more apparent among those who did not require oxygen therapy. At 3 months, corticosteroid therapy was associated with muscle weakness (OR: 2.43; 95% CI: 1.27-4.65). CONCLUSIONS:In this observational overlap-weighted analysis, acute-phase systemic corticosteroid therapy during COVID-19 hospitalization was associated with higher odds of patient-reported Long COVID symptoms during follow-up. However, these findings should not be interpreted as evidence against appropriately indicated corticosteroid therapy in patients with hypoxemic COVID-19 or respiratory failure.

We report a case of Mycobacterium riyadhense pulmonary disease in a patient who relocated from Saudi Arabia to Japan. Epidemiologic data and whole-genome analyses of the isolated strains suggested that the infection might have been acquired in Saudi Arabia and persisted, rather than a recent local acquisition in Japan.

Background Pulmonary non-tuberculous mycobacterial (NTM) disease is a respiratory infection with an increasing incidence worldwide, including Japan. Host factors may also be involved in the establishment of pulmonary NTM disease. Cystic fibrosis transmembrane conductance regulator (CFTR) variants are associated with pulmonary NTM disease and bronchiectasis. However, data on CFTR variants in the Japanese population remain limited.Objectives We aimed to determine the frequency of CFTR variants and the impact on the clinical features of pulmonary NTM disease and bronchiectasis in the Japanese population.Methods We analysed 458 patients with either pulmonary NTM disease, non-cystic fibrosis bronchiectasis or both at Keio University Hospital from February 2016 to March 2019. CFTR variants were identified using exome sequencing, Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). These variants were determined to be deleterious using CFTR2 and in silico tools. Clinical characteristics of patients with and without CFTR variants were compared in a 1:8 age-matched and sex-matched ratio. Additionally, exome sequencing was performed for the family of a patient with a family history of pulmonary NTM disease.Results Deleterious CFTR variants were identified in 16 patients (3.5%). One variant was identified by MLPA, and 15 by Sanger sequencing. All patients harboured a CFTR variant in one allele. Compared with matched controls, these patients had lower sputum culture conversion rates and higher rates of macrolide resistance. In one family cluster, members with pulmonary NTM disease were found to carry the same CFTR variant.Conclusions We defined the frequency and clinical characteristics of CFTR variants among the Japanese population with either pulmonary NTM disease, non-cystic fibrosis bronchiectasis or both and found that patients with CFTR variants may be refractory to pulmonary Mycobacterium avium complex disease. Further comprehensive research is needed to assess the impact of CFTR variants on pulmonary NTM disease and bronchiectasis in non-European populations.

Inappropriate antimicrobial therapy for surgical site infections (SSIs) can lead to poor outcomes and an increased risk of antibiotic resistance. A nationwide survey was conducted in Japan from 2021 to 2023 to investigate the antimicrobial susceptibility of pathogens isolated from SSIs. The data were compared with those obtained in the 2010, 2014-2015, and 2018-2019 surveillance studies. The rate of detection of extended-spectrum β-lactamase-producing strains of Enterobacterales was 4.4 % in 2010, 13.5 % in 2014-2015, and 6.6 % in 2018-2019; the incidence increased to 11.2 % in 2021-2023. A high rate of susceptibility to tazobactam/piperacillin was detected in the 2018-2019 survey, and this decreased to 71.8 % in the 2021-2023 survey. The geometric mean MICs for tazobactam/ceftolozane showed an increasing trend (0.397 in 2018-2019 and 0.778 in 2021-2023). The MRSA incidence rate decreased from 72 % in the first surveillance to 53 % in the second and third surveillance and to 39 % in the fourth surveillance. The susceptibility of E. coli and K. pneumoniae to sulbactam/ampicillin and cefazolin decreased. For Bacteroides species, low levels of susceptibility were observed for moxifloxacin (57 %), cefmetazole (54 %), and clindamycin (44 %). In conclusion, antimicrobial susceptibility changed mainly for Enterobacterales isolated from SSIs. Bacterial sensitivity to carbapenems was generally good, suggesting that the use of antimicrobial agents may have contributed to the observed reduction in MRSA incidence.

INTRODUCTION:Bronchiectasis, closely associated with nontuberculous mycobacterial pulmonary disease (NTM-PD), exhibits unevenly distributed lesions, yet their spatial features remain unclear. We hypothesized that upright CT, which may better depict distal airways due to gravity-induced lung expansion, might more accurately reflect disease severity and its relationship with pulmonary function tests (PFTs). METHODS:In this prospective study, twenty patients underwent low-dose inspiratory and expiratory CT scans in standing and supine positions. Airways were segmented with Vincent® software and classified as bronchiectatic or non-bronchiectatic. Generation-specific quantitative CT (QCT) parameters, including inspiratory airway total area (ITA), inspiratory airway lumen area (ILA), wall thickness, and wall area percentage (WA%), were measured and correlated with PFTs. RESULTS:Bronchiectatic lesions were primarily identified in the 8th-10th generation airways (anatomically the 7th-9th generations), the transition from distal bronchi to proximal bronchioles. Standing CT detected more distal airways than supine CT. Mixed-effect models revealed significantly larger ITA and higher WA% in bronchiectatic airways (8th-10th generations) on standing CT. In non-bronchiectatic airways (trachea to 6th generation), ITA and ILA were significantly larger in the standing position, except for the main bronchus ITA. ITA, ILA, and WA% were moderate to strongly correlated with %FVC, %FEV1, and FEF25-75%, reflecting airway obstruction, with stronger correlations in the standing position. ITA in bronchiectatic airways was moderately negatively correlated with diffusing capacity of the lungs for carbon monoxide, indicating potential alveolar disease. CONCLUSION:Upright CT offers useful structural biomarkers associated with airflow limitation and possible alveolar impairment in bronchiectasis with NTM-PD. REGISTRATION:University Hospital Medical Information Network (UMIN 000026587). URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000030456.

OBJECTIVE:Cefiderocol, a siderophore cephalosporin, has shown promise against carbapenem-resistant strains such as Pseudomonas aeruginosa and Stenotrophomonas maltophilia species complex. Despite its recent approval in Japan, susceptibility data remain limited. Therefore, this study evaluated the cefiderocol susceptibility of carbapenem-resistant P. aeruginosa and S. maltophilia species complex strains isolated from blood cultures to determine whether cefiderocol can be used as an empirical treatment option. METHODS:Carbapenem-resistant P. aeruginosa and S. maltophilia species complex strains isolated from blood cultures at a university hospital in Japan were included. Minimum inhibitory concentrations (MICs) and inhibition zone diameters were assessed using broth microdilution and disk diffusion methods, respectively. Whole-genome sequencing was conducted to elucidate the genetic backgrounds of the clinical isolates. RESULTS:The MIC50 and MIC90 values for cefiderocol in 65 carbapenem-resistant P. aeruginosa strains were 0.12 and 0.25 µg/mL, and 0.06 and 0.25 µg/mL for 51 S. maltophilia species complex strains, respectively. One S. maltophilia species complex strain exhibited non-susceptibility, with a MIC of 2 µg/mL in broth microdilution, while disk diffusion methods demonstrated susceptibility. A significant negative correlation was observed between MIC values and inhibition zone diameters. Whole-genome sequencing revealed that a limited number of P. aeruginosa strains possessed carbapenemase genes. CONCLUSIONS:The findings of this study support the efficacy of cefiderocol against carbapenem-resistant P. aeruginosa and S. maltophilia species complex, suggesting its potential as an empirical treatment option for bloodstream infection patients in Japan. Continued surveillance is advised to monitor resistance trends with increased cefiderocol use.

Patient risk factors related to coagulopathy and bleeding when using cefmetazole (CMZ) have not yet been identified, and no models exist to predict side effects during CMZ treatment. Moreover, reports that examine which patients should be careful when using CMZ to ensure safety are lacking. Our objective was to understand risk factors for elevated international normalized ratio (INR) in patients using CMZ and to develop a predictive model for INR elevation using a risk score to enable safe administration of CMZ. This multicenter, retrospective, and observational study was conducted in Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital using data from patients being treated with CMZ. Patients were classified into INR-elevated or non-INR-elevated groups. Univariate and multivariate analyses were performed to calculate the adjusted odds ratios (aOR) and 95% confidence intervals (CI). The actual probability of an elevated INR and probability of an elevated INR predicted by the regression β coefficients were calculated and classified into four categories according to the risk score. Binomial logistic regression analysis revealed that liver disorder (aOR, 5.65; 95% CI, 1.69–18.91; risk scores, 2), nutritional risk (aOR, 6.32; 95% CI, 3.14–12.74; risk scores, 2), no-diabetes mellitus (aOR, 4.53; 95% CI, 1.34–15.26; risk scores, 2), and warfarin use (aOR, 98.44; 95% CI, 7.05–1375.50; risk scores, 5) were significantly associated with INR elevation. The predicted incidence probabilities of INR elevation were < 5% (low risk), 5– < 30% (medium risk), 30– < 90% (high risk), and ≥ 90% (very high risk). The model validity showed a good fit (AUC, 0.79; 95% CI, 0.73–0.85, P < 0.001). We identified risk factors that contribute to INR elevation and constructed a model to predict INR elevation using the risk score. Using this predictive model enables the appropriate use of CMZ in a safe manner.

Objective: Mycobacterium abscessus pulmonary disease is a refractory infectious disease. Developing an effective treatment is urgent as the number of patients infected with M. abscessus species (MABS) is increasing worldwide. We previously reported that nacubactam, a diazabicyclooctane (DBO) β-lactamase inhibitor, could inhibit MABS β-lactamase. Few reports have indicated that dual β-lactams are effective with a DBO β-lactamase inhibitor against MABS. The objective of this study was to determine which dual β-lactams have high antibacterial activity against MABS in the presence and absence of nacubactam. Methods: Antimicrobial susceptibility tests were conducted through a checkerboard assay of 27 β-lactams using the broth microdilution method for three subspecies-type strains and 20 clinical isolates of MABS. The number of intracellular and extracellular bacteria was measured using human macrophages infected with M. abscessus treated with effective combinations confirmed in susceptibility tests. Results: In antimicrobial susceptibility tests, 91 combinations of dual β-lactams with nacubactam exhibited synergistic effects on M. abscessus JCM13569. Among them, the combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam exhibited highly synergistic effects, resulting in low MICs against MABS clinical isolates. Without nacubactam, the combination of imipenem and cefoxitin showed the lowest MIC. In experiments using human macrophages infected with M. abscessus, these dual β-lactam combinations reduced the number of intracellular and extracellular bacteria compared with those of single β-lactams. Conclusions: The combination of cefazolin, cefotiam, cefoxitin, or cefuroxime with imipenem and nacubactam was highly effective against MABS. Without nacubactam, the combination of cefoxitin and imipenem was effective.

BACKGROUND:This study reports the findings of the second antimicrobial susceptibility surveillance study of isolates recovered from odontogenic infections in Japan. METHODS:A total of 164 odontogenic infections samples including periodontitis (group 1, n = 33), pericoronitis (group 2, n = 7), jaw inflammation (group 3, n = 83), and phlegmon in the jawbone area (group 4, n = 42) from 21 facilities were included in the study. RESULTS:Antimicrobial susceptibility testing was performed on 515 isolates, consisting of 120, 115, 173, 38, and 69 Streptococcus spp., anaerobic gram-positive cocci, Prevotella spp., Porphyromonas spp., and Fusobacterium spp. isolates, respectively. The ratio of susceptible bacteria to causative agents of odontogenic infections was determined in accordance with the guidelines of the Clinical and Laboratory Standards Institute. The susceptibility rates of Streptococcus anginosus were as follows: ampicillin, 98.6 %; cefcapene, ceftriaxone, meropenem, and doripenem, 100 %; clarithromycin and azithromycin, 71.2 %; and clindamycin, 87.7 %. The MIC90 value for ampicillin for Prevotella spp. was 32 μg/mL, with a susceptibility rate of 65.3 %. The MIC90 value for sulbactam/ampicillin was 2 μg/mL, with a susceptibility rate of 100 %. CONCLUSIONS:The findings of the present study indicate that the resistance to the combination of penicillins and β-lactamase inhibitors, the first-line antimicrobial agents for odontogenic infections and oral infections caused by anaerobic flora, are low.

Rationale: Although nontuberculous mycobacteria (NTM) are widespread, only some individuals develop NTM pulmonary disease (NTM-PD), suggesting the involvement of host factors. Objectives: To identify the genomic structure of NTM-PD and determine whether a definitive association exists between NTM-PD and nine risk factors. Methods: We performed genome-wide association studies in two independent Korean cohorts involving 1,949 patients with NTM-PD and 2,955 healthy participants. Significantly associated genetic variants were validated in Japanese (1,137 cases, 1,546 controls) and European (243 cases, 570 controls) cohorts, respectively. Genes associated with lead variants were identified and their roles in NTM-PD were supported by single-cell transcriptome datasets. Genetic correlations and Mendelian randomization between NTM-PD and nine risk factors were examined. Measurements and Main Results: We identified two novel loci and replicated a locus associated with NTM-PD: rs60084385 (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.21-1.48; P = 6.97 × 10-9), rs1479595 (OR, 1.40; 95% CI, 1.27-1.55; P = 7.08 × 10-11), and rs194792 (OR, 1.70; 95% CI, 1.50-1.93; P = 1.39 × 10-16). These associations were replicated in the independent cohorts. The three loci were significantly associated with expression of IL1Rs, PDE8B (phosphodiesterase 8B), and PRKCB (protein kinase C β), respectively, whose involvement in the pathogenesis of NTM-PD was further validated. Among the risk factors, only body mass index demonstrated both a significant genetic correlation with NTM-PD (rg, -0.57; false discovery rate, 1.33 × 10-5) and a potential causal relationship (OR, 0.38; 95% CI, 0.24-0.59; false discovery rate, 8.55 × 10-5). Conclusions: Our study identified three genetic loci associated with NTM-PD and a negative association of body mass index with NTM-PD.

Vaccine immunogenicity is influenced by the vaccinee's genetic background. Here, we perform a genome-wide association study of vaccine-induced SARS-CoV-2-specific immunoglobulin G (IgG) antibody titers and T cell immune responses in 1,559 mRNA-1273 and 537 BNT162b2 vaccinees of Japanese ancestry. SARS-CoV-2-specific antibody titers are associated with the immunoglobulin heavy chain (IGH) and major histocompatibility complex (MHC) locus, and T cell responses are associated with MHC. The lead variants at IGH contain a population-specific missense variant (rs1043109-C; p.Leu192Val) in the immunoglobulin heavy constant gamma 1 gene (IGHG1), with a strong decreasing effect (β = -0.54). Antibody-titer-associated variants modulate circulating immune regulatory proteins (e.g., LILRB4 and FCRL6). Age-related hematopoietic expanded mosaic chromosomal alterations (mCAs) affecting MHC and IGH also impair antibody production. MHC-/IGH-affecting mCAs confer infectious and immune disease risk, including sepsis and Graves' disease. Impacts of expanded mosaic loss of chromosomes X/Y on these phenotypes were examined. Altogether, both germline and somatic mutations contribute to adaptive immunity functions.

Predictive models for determining coronavirus disease 2019 (COVID-19) severity have been established; however, the complexity of the interactions among factors limits the use of conventional statistical methods. This study aimed to establish a simple and accurate predictive model for COVID-19 severity using an explainable machine learning approach. A total of 3,301 patients ≥ 18 years diagnosed with COVID-19 between February 2020 and October 2022 were included. The discovery cohort comprised patients whose disease onset fell before October 1, 2020 (N = 1,023), and the validation cohort comprised the remaining patients (N = 2,278). Pointwise linear and logistic regression models were used to extract 41 features. Reinforcement learning was used to generate a simple model with high predictive accuracy. The primary evaluation was the area under the receiver operating characteristic curve (AUC). The predictive model achieved an AUC of ≥ 0.905 using four features: serum albumin levels, lactate dehydrogenase levels, age, and neutrophil count. The highest AUC value was 0.906 (sensitivity, 0.842; specificity, 0.811) in the discovery cohort and 0.861 (sensitivity, 0.804; specificity, 0.675) in the validation cohort. Simple and well-structured predictive models were established, which may aid in patient management and the selection of therapeutic interventions.

In the phase 3 CONVERT trial, amikacin liposome inhalation suspension (ALIS) plus guideline-based therapy (GBT) achieved greater culture conversion than GBT alone in the treatment of refractory Mycobacterium avium complex pulmonary disease (MAC-PD). In the original analysis of safety data in CONVERT, the rate of hypersensitivity pneumonitis, a prespecified group of adverse events of special interest, was higher in patients receiving ALIS plus GBT (3.1