Probiotics-related Clostridium butyricum bacteraemia after COVID-19, confirmed by whole-genome sequencing.

A man in his 70s was admitted to an intensive care unit with severe COVID-19 and treated with dexamethasone and tocilizumab. After recovery from COVID-19, he developed Clostridium butyricum bacteraemia and non-occlusive mesenteric ischaemia, with fatal outcome. He had been prescribed C. butyricum MIYAIRI 588 fine granules as probiotics for a month. The genome sequences of the C. butyricum isolate from the blood culture and C. butyricum MIYAIRI 588 fine granules were identical by single nucleotide polymorphism analysis. This is the first case of definitive probiotics-related C. butyricum bacteraemia after treatment of severe COVID-19.

ZFP36 family expression is suppressed by Th2 cells in asthma, leading to enhanced synthesis of inflammatory cytokines and cell surface molecules.

Asthma is a chronic inflammatory airway disease, in which inflammatory cytokines play a pivotal role. The zinc finger binding protein 36 (ZFP36) family includes ZFP36, ZFP36L1, and ZFP36L2 and is among the RNA-binding proteins (RBPs) reported to cause inflammation. The present study aimed to clarify the roles of the ZFP36 family in asthma, particularly highlighting the relationship between the ZFP36 family and Th2 cells, which are key players in type 2 inflammation in asthma. Real-time PCR analysis revealed the preferential expression of ZFP36 family mRNAs in human white blood cells. Gene expression analysis using public datasets from the GEO database (https://www.ncbi.nlm.nih.gov/gds) showed significantly suppressed expression of ZFP36 family mRNAs in patients with asthma compared to that in healthy controls. Using multiple cytokine assays, Th2 cell transfection with ZFP36 family siRNAs enhanced the expression of inflammatory cytokines IL-8, IFN-γ, CCL3/MIP-1α, CCL4/MIP-1ß, and TNF-α and cell surface molecules CCR4 (CD194) and PSGL-1 (CD162). Treatment with IL-2, 4, and 15 significantly suppressed, and corticosteroid significantly enhanced the expressions of ZFP36 family mRNAs by Th2 cells. In conclusion, the ZFP36 family expressed by Th2 cells was suppressed in patients with asthma, leading to the enhanced expression of cytokines and cell surface molecules. Suppressed ZFP36 expression in asthma may be involved in the enhancement of airway inflammation, and the ZFP36 family may be a therapeutic target for inflammatory diseases, including asthma.

Recurrent Bacillus subtilis Var. Natto Bacteremia and Review of the Literature on Bacillus subtilis: The First Case Report.

BACKGROUND Fermented foods, such as yogurt, are often considered healthy; however, there have been numerous reported cases of bacteremia associated with their consumption. In this report, we present a case of Bacillus subtilis var. natto (B. subtilis var. natto) bacteremia related to the consumption of natto, a traditional Japanese food made from fermented soybeans. We also conducted a literature review on B. subtilis bacteremia. CASE REPORT We report the case of a 41-year-old woman who presented with fever, had a medical history of congenital liver fibrosis, and experienced recurrent B. subtilis var. natto bacteremia along with acute cholangitis. Although she discontinued eating natto, she developed pyogenic thrombophlebitis due to B. subtilis var. natto. We successfully treated her with meropenem and an anti-coagulant. To investigate the management and prognosis of B. subtilis var. natto bacteremia, we conducted a literature review of B. subtilis intra-abdominal infection. We identified 17 papers describing 30 cases of B. subtilis intra-abdominal infection, 4 cases of which were caused by B. subtilis var. natto; the median age of the patients was 71 years (range, 15-96 years), 14 patients (47%) were female, and 3 patients (10%) died. From our findings, our case was the only one of recurrent B. subtilis var. natto infection. Even after patients discontinue eating natto, they should be carefully monitored. CONCLUSIONS Due to advancements in PCR identification techniques, case reports of infections caused by B. subtilis var. natto are increasing.

The impact of carbapenem shortage and stewardship countermeasures on antimicrobial practice at a tertiary care center.

We evaluated the impact of carbapenem shortage on antimicrobial practice and patient outcome at a tertiary care center. During the shortage, hospital antimicrobial practice could be safely managed through additional antimicrobial stewardship measures including treatment guidance and mandatory preauthorization. Antimicrobial shortage may present a unique opportunity for promoting antimicrobial stewardship.

Immune escape and waning immunity of COVID-19 monovalent mRNA vaccines against symptomatic infection with BA.1/BA.2 and BA.5 in Japan.

BACKGROUND: Repeated emergence of variants with immune escape capacity and waning immunity from vaccination are major concerns for COVID-19. We examined whether the surge in Omicron subvariant BA.5 cases was due to immune escape or waning immunity through vaccine effectiveness (VE) evaluation. METHODS: A test-negative case-control study was conducted in 16 clinics/hospitals during the BA.1/BA.2-dominant and BA.5-dominant periods. VE against symptomatic infection was estimated after adjusting for age, sex, comorbidity, occupation, testing frequency, prior infection, close contact history, clinic/hospital, week, and preventive measures. Absolute VE (aVE) was calculated for 2/3/4 doses, compared to the unvaccinated. Relative VE (rVE) was calculated, comparing 3 vs 2 and 4 vs 3 doses. RESULTS: 13,025 individuals were tested during the BA.1/BA.2-dominant and BA.5-dominant periods with similar baseline characteristics. For BA.1/BA.2, aVE was 52 % (95 %CI:34-66) 14 days-3 months post-dose 2, 42 % (29-52) > 6 months post-dose 2, 71 % (64-77) 14 days-3 months post-dose 3, and 68 % (52-79) 3-6 months post-dose 3. rVE was 49 % (38-57) 14 days-3 months post-dose 3 and 45 % (18-63) 3-6 months post-dose 3. For BA.5, aVE was 56 % (27-73) 3-6 months post-dose 2, 32 % (12-47) > 6 months post-dose 2, 70 % (61-78) 14 days-3 months post-dose 3, 59 % (48-68) 3-6 months post-dose 3, 50 % (29-64) > 6 months post-dose 3, and 74 % (61-83) ≥ 14 days post-dose 4. rVE was 56 % (45-65) 14 days-3 months post-dose 3, 39 % (27-48) 3-6 months post-dose 3, 25 % (-2-45) > 6 months post-dose 3, and 30 % (-6-54) ≥ 14 days post-dose 4. CONCLUSIONS: Booster doses initially provided high protection against BA.5 at a level similar to that against BA.1/BA.2. However, the protection seemed shorter-lasting against BA.5, which likely contributed to the surge. Furthermore, rVE post-dose 4 was low even among recent vaccinees. These results support the introduction of variant-containing vaccines and emphasize the need for vaccines with longer duration of protection.

A Systemic Lupus Erythematosus Patient with Cutaneous Mycobacterium haemophilum Infection under Belimumab Treatment: A Case Report.

A 38-year-old female with systemic lupus erythematosus (SLE) initiated belimumab treatment. One month later, she presented with a reddish painful swelling on her right lower leg. She was treated with ceftriaxone and vancomycin. However, novel erythematous papules and indurated nodules appeared on both her lower legs. Skin biopsy revealed microabscess formation with mixed cell granuloma surrounded by inflammatory cell infiltration within the dermis with subcutaneous fat tissue. A large number of acid-fast bacilli were observed with Ziehl-Neelsen staining. DNA sequencing of both the hsp65 and the 16S rRNA sequences showed a 100% match with the corresponding region of Mycobacterium haemophilum. Mycobacterial culture revealed satellite growth enhancement on Middlebrook 7H11 agar plates around a paper strip containing hemin. She was treated with levofloxacin, rifabutin, and ethambutol. Within 13 months, her cutaneous lesions improved markedly without any side effects. The B cell-targeted biologic belimumab, a fully humanized IgG1γ monoclonal antibody that inactivates B lymphocyte stimulator, has been considered to be beneficial for active SLE. However, this therapy could increase the risk for the development of biologic therapy-associated mycobacterial infections, both tuberculosis and nontuberculous mycobacteria infections.

Probiotic-related Clostridium butyricum bacteremia: a case report and literature review.

We report three cases of Clostridium butyricum bacteremia associated with taking C. butyricum-related probiotics. We performed a literature review and found 11 cases of C. butyricum bacteremia including our cases. Nine cases related to probiotics. We should consider that probiotics may infect clinically unstable patients.

Resurgence of human coronavirus OC43 at a long-term care facility during the coronavirus disease 2019 (COVID-19) pandemic: Outbreak investigation.

The incidence of seasonal infections due to respiratory viruses other than severe acute respiratory coronavirus virus 2 (SARS-CoV-2) has declined due to heightened public infection prevention measures against coronavirus disease 2019 (COVID-19). We describe an outbreak of human coronavirus OC43 infection that occurred at a long-term care facility and whose clinical features were indistinguishable from COVID-19.

Effectiveness of BA.1- and BA.4/BA. 5-Containing Bivalent COVID-19 mRNA Vaccines Against Symptomatic SARS-CoV-2 Infection During the BA.5-Dominant Period in Japan.

In this multicenter, prospective, test-negative, case-control study in Japan, the effectiveness of both BA.1-containing and BA.4/BA.5-containing bivalent coronavirus disease 2019 mRNA vaccines against symptomatic infection during the BA.5-dominant period was high compared with no vaccination (65% and 76%) and moderate compared with monovalent vaccines administered over half a year earlier (46% combined).

Emergence of community-associated methicillin-resistant Staphylococcus aureus ΨUSA300 among Japanese people with HIV, resulted from stepwise mutations in 2010s.

Although infection with the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 is extremely rare in Japan, the uniquely evolved clone ΨUSA300 has been reported in Japan. An outbreak of a distinct USA300 clone was recently reported in an HIV/AIDS referral hospital in Tokyo. The present study investigated the evolutionary origin and genetic diversity of USA300-related clones causing regional outbreaks among people living with HIV (PLWHIV) in Tokyo. MRSA isolates collected from PLWHIV in an HIV/AIDS referral center in Tokyo were subjected to whole-genome sequencing and their genetic features were compared with those of previously described USA300 MRSA genomes. Of the 28 MRSAs isolated in 2016-2019, 23 (82.1%) were identified as USA300, with 22 (95.6%) of the latter identified as ΨUSA300. Although the genomic structure of ΨUSA300 was identical to the structures of reference USA300 strains, one clade (cluster A) was found to have acquired 29 previously identified lineage-specific mutations in a stepwise manner. The estimated divergence dates of ΨUSA300 and Cluster A were 2009 and 2012, respectively. These findings suggested that the ΨUSA300 clone had spread among PLWHIVs in Tokyo in the early 2010s, with stepwise acquisition of lineage-specific nonsynonymous mutations.

A Fatal Case of Disseminated Infection Caused by Community-Associated Methicillin-Resistant Staphylococcus aureus USA300 Clone.

Methicillin-resistant Staphylococcus aureus (MRSA) USA300 is a representative community-associated MRSA (CA-MRSA) clone worldwide. Herein, we report the case of a patient with USA300 clone infection who could not be salvaged. A 25-year-old man who had sex with men presented with symptoms including fever persisting for one week and skin lesions located on the buttocks. Computed tomography imaging showed multiple nodules and consolidations, especially in the peripheral lung fields, right iliac vein thrombosis, and pyogenic myositis of medial thighs bilaterally. Blood cultures revealed MRSA bacteremia. The patient's condition deteriorated rapidly, complicated by acute respiratory distress syndrome and infective endocarditis. Despite the intubation on the 6th hospital day, he died on the 9th day. Multilocus sequence typing of this patient's MRSA strain revealed sequence type 8 with a staphylococcal cassette chromosome of mec type IVa, Panton-Valentine leukocidin gene, and the arginine catabolic mobile element, indicating presence of the USA300 clone. Patients with CA-MRSA skin lesions presenting with furuncles or carbuncles on the lower body are at a higher risk of severe disease. The patient's background, appearance, and location of skin lesions are critical for the early diagnosis of severe CA-MRSA infection.

Promotion of antimicrobial stewardship following issuance of the antimicrobial resistance national action plan in Japan: A systematic review of 2016-2020.

BACKGROUND: Antimicrobial resistance (AMR) represents a global threat with the potential to cause a significant healthcare burden. In 2016, the Japanese Government issued the national action plan (NAP) for AMR. Since issuance of this plan, several studies on antimicrobial stewardship programmes (ASPs) have been published in Japan. This systematic review was undertaken to elucidate the current state of ASPs and the impact of the NAP. METHODS: Medline (PubMed) and EMBASE were searched for studies published between January 2016 and the end of September 2021. The Risk of Bias in Non-Randomized Studies of Intervention tool was used to assess the risk of bias in interventional studies, and the Newcastle-Ottawa Scale was used to assess the quality of cohort, case-control and cross-sectional studies. RESULTS: Eighty studies, including 30 (37.5%) interventional studies, 15 (18.8%) database-oriented studies and nine (11.3%) analytical studies (one case-control study, six cohort studies and two cross-sectional studies), were included. All of the interventional studies were before-after trials, and interrupted time series analysis was commonly used to assess changes in antimicrobial consumption per intervention. Five database-related studies demonstrated decreasing antimicrobial consumption after issuance of the NAP. CONCLUSION: Several ASP studies were published after issuance of the NAP, suggesting that the latter promoted research into ASPs. A few database-related studies showed a positive impact of the NAP on antimicrobial consumption. However, more high-quality studies, especially interventional studies using an appropriate methodology and standardized data collection, are needed.

Discontinuation of admission screening for coronavirus disease 2019 (COVID-19) and the impact on in-hospital clusters of COVID-19: Experience at a tertiary-care center.

We evaluated the impact of discontinuing universal preadmission screening for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) on the occurrence of nosocomial clusters of coronavirus disease 2019 (COVID-19) during the SARS-CoV-2 o (omicron) variant period. No increasing trend in nosocomial clusters was observed during community-based surges before and after discontinuation. This finding supports the safety of the practice change.

T-Cell Response and Antibody Production Induced by the COVID-19 Booster Vaccine in Japanese Chronic Kidney Disease Patients Treated with Hemodialysis.

Humoral and cellular responses are critical in understanding immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Here, we evaluated these responses in hemodialysis (HD) patients after the booster vaccination. SARS-CoV-2 immunoglobulin (IgG) levels, neutralizing antibody titers, and the T-SPOT®.COVID test (T-SPOT) were measured prior to, three weeks after, and three months after the booster administration. The HD group had significantly higher SARS-CoV-2 IgG levels and neutralizing antibody titers against the original strain at three weeks and three months after the booster vaccination compared to the control group, albeit the HD group had lower SARS-CoV-2 IgG levels and neutralizing antibody titers before the booster administration. Moreover, the HD group had significantly higher T-SPOT levels at all three time points compared to the control group. The HD group also had significantly higher local and systemic adverse reaction rates than the control group. By booster vaccination, HD patients could acquire more effective SARS-CoV-2-specific humoral and cellular immunity than the control group.

Coronavirus Disease 19 (COVID-19) Vaccine Effectiveness Against Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection During Delta-Dominant and Omicron-Dominant Periods in Japan: A Multicenter Prospective Case-control Study (Factors Associated with SARS-CoV-2 Infection and the Effectiveness of COVID-19 Vaccines Study).

BACKGROUND: Although several coronavirus disease 2019 (COVID-19) vaccines initially showed high efficacy, there have been concerns because of waning immunity and the emergence of variants with immune escape capacity. METHODS: A test-negative design case-control study was conducted in 16 healthcare facilities in Japan during the Delta-dominant period (August-September 2021) and the Omicron-dominant period (January-March 2022). Vaccine effectiveness (VE) against symptomatic severe acute respiratory syndrome coronavirus 2 infection was calculated for 2 doses for the Delta-dominant period and 2 or 3 doses for the Omicron-dominant period compared with unvaccinated individuals. RESULTS: The analysis included 5795 individuals with 2595 (44.8%) cases. Among vaccinees, 2242 (55.8%) received BNT162b2 and 1624 (40.4%) received messenger RNA (mRNA)-1273 at manufacturer-recommended intervals. During the Delta-dominant period, VE was 88% (95% confidence interval [CI], 82-93) 14 days to 3 months after dose 2 and 87% (95% CI, 38-97) 3 to 6 months after dose 2. During the Omicron-dominant period, VE was 56% (95% CI, 37-70) 14 days to 3 months since dose 2, 52% (95% CI, 40-62) 3 to 6 months after dose 2, 49% (95% CI, 34-61) 6+ months after dose 2, and 74% (95% CI, 62-83) 14+ days after dose 3. Restricting to individuals at high risk of severe COVID-19 and additional adjustment for preventive measures (ie, mask wearing/high-risk behaviors) yielded similar estimates, respectively. CONCLUSIONS: In Japan, where most are infection-naïve, and strict prevention measures are maintained regardless of vaccination status, 2-dose mRNA vaccines provided high protection against symptomatic infection during the Delta-dominant period and moderate protection during the Omicron-dominant period. Among individuals who received an mRNA booster dose, VE recovered to a high level.

Diagnostic test property of transcription-reverse transcription concerted reaction reagent TRCReady® SARS-CoV-2 i using nasopharyngeal swab samples.

TRCReady® SARS-CoV-2 i is a reagent for transcription-reverse transcription concerted reaction (TRC) to detect SARS-CoV-2 N2 gene, used with the automated rapid isothermal nucleic acid amplification test (NAAT) analyzer TRCReady®-80. Sensitivity and specificity of TRCReady® SARS-CoV-2 i was assessed by comparison with the results of real-time reverse transcription-polymerase chain reaction (RT-PCR) using nasopharyngeal swab samples. From November 2020 to March 2021, a total of 441 nasopharyngeal swabs were obtained and analyzed both with TRCReady® SARS-CoV-2 i and RT-PCR. Sensitivity and specificity of TRCReady® SARS-CoV-2 i were 94.6% (53/56) and 99.2% (382/385), respectively. Reaction time to positivity of TRCReady® SARS-CoV-2 i ranged from 1.166 to 9.805 (median: 2.887) min, and minimum detection sensitivity of TRCReady® SARS-CoV-2 i was 9 copies per test, with reaction time as 5.014 min. Detection of SARS-CoV-2 gene from nasopharyngeal swab sample using TRCReady® SARS-CoV-2 i shows comparative diagnostic test accuracy with RT-PCR, and can be used as a useful test to diagnose SARS-CoV-2 infection.

Modified Drug-Susceptibility Testing and Screening Culture Agar for Colistin-Susceptible Enterobacteriaceae Isolates Harboring a Mobilized Colistin Resistance Gene mcr-9.

Three isolates of the Enterobacter cloacae complex harboring mcr-9, a member of the colistin resistance mcr gene family encoded on plasmids, were susceptible to colistin, with MICs of 0.125 to 0.5 µg/mL in standard broth microdilution (BMD) tests using cation-adjusted Mueller-Hinton broth (CA-MHB) in accordance with European Committee on Antimicrobial Susceptibility Testing guidelines. In contrast, their MICs for colistin were significantly higher (4 to 128 µg/mL) when BMD tests were performed using brain-heart infusion (BHI) medium, Luria-Bertani (LB) broth, tryptic soy broth (TSB), or CA-MHB supplemented with casein, tryptonen or peptone. Colistin significantly induced mcr-9 expression in a dose-dependent manner when these mcr-9-positive isolates were cultured in BHI or CA-MHB supplemented with peptone/casein. Pretreatment of mcr-9-positive isolates and Escherichia coli DH5α harboring mcr-9 with colistin significantly increased their survival rates against LL-37, a human antimicrobial peptide. Electrospray ionization time-of-flight mass spectrometry analysis showed that a lipid A moiety of lipopolysaccharide was partially modified by phosphoethanolamine in E. coli DH5α harboring mcr-9 when treated with colistin. Of 93 clinical isolates of Enterobacteriaceae, only the mcr-9-positive isolates showed MICs to colistin that were at least 32 times higher in BHI than in CA-MHB. These mcr-9-positive isolates grew on a modified BHI agar, MCR9-JU, containing 3 µg/mL colistin. These results suggest that the BMD method using BHI is useful when performed together with the BMD method using CA-MHB to detect mcr-9-positive isolates and that MCR9-JU agar is useful in screening for Enterobacteriaceae isolates harboring mcr-9 and other colistin-resistant isolates.

Investigation for the efficacy of COVID-19 vaccine in Japanese CKD patients treated with hemodialysis.

Background: Dialysis patients are predisposed to severe disease and have a high mortality rate in coronavirus disease 2019 (COVID-19) due to their comorbidities and immunocompromised conditions. Therefore, dialysis patients should be prioritized for vaccination. This study aimed to examine how long the effects of the vaccine are maintained and what factors affect antibody titers. Methods: Hemodialysis patients (HD group) and age- and sex-matched non-dialysis individuals (Control group), receiving two doses of BNT162b2 vaccine, were recruited through the Japanese Society for Dialysis Therapy (JSDT) Web site in July 2021. Anti-SARS-CoV-2 immunoglobulin (IgG) (SARS-CoV-2 IgG titers) was measured before vaccination, 3 weeks after the first vaccination, 2 weeks after the second vaccination, and 3 months after the second vaccination, and was compared between Control group and HD group. Factors affecting SARS-CoV-2 IgG titers were also examined using multivariable regression analysis and stepwise regression analysis (least AIC). In addition, we compared adverse reactions in Control and HD groups and examined the relationship between adverse reactions and SARS-CoV-2 IgG titers. Results: Our study enrolled 123 participants in the Control group (62.6% men, median age 67.0 years) and 206 patients in the HD group (64.1% men, median age 66.4 years). HD group had significantly lower SARS-CoV-2 IgG titers at 3 weeks after the first vaccination (p < 0.0001), 2 weeks after second vaccination (p = 0.0002), and 3 months after the second vaccination (p = 0.045) than Control group. However, the reduction rate of SARS-CoV-2 IgG titers between 2 weeks and 3 months after the second vaccination was significantly smaller in HD group than in Control (p = 0.048). Stepwise regression analysis revealed that dialysis time was identified as the significant independent factors for SARS-CoV-2 IgG titers at 2 weeks after the second vaccination in HD group (p = 0.002) and longer dialysis time resulted in higher maximum antibody titers. The incidences of fever and nausea after the second vaccination were significantly higher in the HD group (p = 0.039 and p = 0.020). Antibody titers in those with fever were significantly higher than those without fever in both groups (HD: p = 0.0383, Control: p = 0.0096). Conclusion: HD patients had significantly lower antibody titers than age- and sex-matched non-dialysis individuals over 3 months after vaccination. Dialysis time was identified as a factor affecting SARS-CoV-2 IgG titers in HD group, with longer dialysis time resulting in higher maximum SARS-CoV-2 IgG titers.