Phylogenetic Analysis Based on Whole Genome Sequences, Antibiotic Resistance, and Virulence of Salmonella enterica Clinical Isolates from South Korea.

Salmonella is a major cause of foodborne disease and frequently causes human salmonellosis in South Korea. In this study, we investigated the genome diversity, antimicrobial resistance, and virulence of clinical isolates of Salmonella enterica from South Korea. We collected 42 S. enterica subsp. enterica isolates from two hospitals in South Korea. Whole genome sequences were determined. Serovars and sequence types (STs) based on multilocus sequence typing (MLST) were identified from whole genome sequences. Phylogenetic trees based on whole genome sequences and a minimum spanning tree based on MLST were constructed. Human serum resistance assays and gentamicin protection assays were performed to assess in vitro virulence. Nineteen serovars were identified among 42 clinical isolates, including nine Salmonella Typhi isolates. There were inconsistencies between serogroups and phylogenetic clusters in the phylogenetic tree and minimum spanning tree, but high clonality of S. Typhi was observed. Salmonella Typhi isolates were divided into two clusters, corresponding to ST1 and ST2. Isolates of serovars Typhimurium and I4,[5],12:i:- clustered into a group, and a hybrid isolate between the two serovars was identified. Four ciprofloxacin-resistant isolates were identified among nine S. Typhi isolates, and all isolates of S. Enteritidis and S. Panama were resistant to colistin. The gentamicin protection assay revealed that serogroup D1 was significantly less virulent than the other serogroups. Our study suggests high diversity of S. enterica clinical isolates from South Korea and non-monophyly of serogroups. In addition, subgroups of S. Typhi isolates and a hybrid isolate between serovars Typhimurium and I4,[5],12:i:- were identified.

Diagnostic performance of the (1-3)-ß-d-glucan assay in patients with different risks for invasive fungal diseases.

We evaluated the diagnostic performance of the ß-d-glucan (BDG) test (Beijing Gold Mountain River Tech) in diagnosing invasive fungal disease (IFD) and its variations among patients with different risks. Patients ≥18 years old who underwent a serum BDG test (positive cutoff value >80 pg/ml) from April 2017 through May 2018 were collected consecutively. Patients were classified into three groups: group 1, patients with host factors as defined by the prior 2008 European Organization for Research and Treatment (EORTC) criteria; group 2, those with extended host factors in 2020 EORTC criteria; and group 3, those without any risk factor mentioned in the criteria. IFD was defined by 2020 EORTC criteria, but BDG was not considered. Diagnostic performance of the serum BDG test was measured by the area under the curve (AUC) of the receiver-operating characteristic curve. Among 469 patients, 15.4% (72/469) were diagnosed with IFD (48/191 [25.1%], 14/144 [9.7%], and 10/134 [7.5%] in groups 1, 2, and 3, respectively). The BDG assay showed fair performance (AUC 0.748 [95% CI: 0.688-0.810]). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 77.8%, 60.7%, 26.4%, and 93.8%, respectively. PPV was higher in group 1, and NPV was higher in group 3. Additionally, diagnostic odds ratios were 6.73, 2.88, and 5.92 in groups 1, 2, and 3. Immunosuppressant use, non-IFD/Candida colonization, and central venous catheter were associated with false positivity. Clinicians should cautiously interpret the BDG assay, considering the various diagnostic performances depending on the different levels of risk.

We evaluated the diagnostic performance of the serum ß-d-glucan test in patients with varying risks for invasive fungal diseases. The test showed acceptable performance, but its predictive values differed among risk groups, highlighting the need for tailored interpretation.

Antimicrobial activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales: a cross-combination and dose-escalation titration study with relebactam and vaborbactam.

With the introduction of ceftazidime-avibactam worldwide, the antimicrobial activity of new ß-lactam/ß-lactamase inhibitors (BL/BLIs) needs to be investigated. From January 2020 to June 2023, Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales were collected. With a broth microdilution test of new BL/BLIs, cross-activity test with nine combinations of BLs and new BLIs and dose-escalation titration test for non-susceptible isolates were conducted to investigate inhibitory activities of new BLIs. A total of 188 isolates was collected and most isolates (186/188, 98.9%) carried the KPC-2 gene exclusively, while two isolates (1.1%) co-harbored NDM-1. Among the 186 KPC-2-producing isolates, 184 (98.9%) were susceptible to ceftazidime-avibactam, 173 (93.0%) to imipenem-relebactam, and 184 (98.9%) to meropenem-vaborbactam. All isolates non-susceptible to imipenem-relebactam or meropenem-vaborbactam became susceptible when avibactam replaced relebactam or vaborbactam, with 7 of 11 (63.6%) imipenem-relebactam non-susceptible isolates and both (100.0%) of the meropenem-vaborbactam non-susceptible isolates. When the minimum inhibitory concentrations (MICs) of BLs were compared using log2 scales, combinations with avibactam showed statistically significant efficacy in lowering MICs compared to relebactam and vaborbactam (all P < 0.05). In the dose-escalation test of new BLIs, increasing dose of all new BLIs corresponded to increased susceptibility to BLs. Ceftazidime-avibactam exhibited excellent susceptibility against KPC-2-producing Enterobacterales unless co-harboring metallo-ß-lactamase. The cross-combination test against non-susceptible isolates suggests that the inhibitory activity of avibactam was superior to those of relebactam or vaborbactam. Increasing the dose of new BLIs produced increased susceptibility to BLs, suggesting that high-concentration regimen need to be developed. IMPORTANCE: This study investigated 188 Klebsiella pneumoniae carbapenemase (KPC)-2-producing Enterobacterales collected from January 2020 to June 2023 in a tertiary care hospital of Korea. Most isolates were susceptible to ceftazidime-avibactam (98.9%) and meropenem-vaborbactam (98.9%), while susceptibility to imipenem-relebactam was lower (93.0%). The cross-combination test using nine combinations of the individual ß-lactams (BLs) and new ß-lactamase inhibitors (BLIs) showed that the inhibitory activity of avibactam was significantly superior to relebactam or vaborbactam when the Log2 MIC of BLs were compared for each combination with BLIs (all P < 0.05). The dose-escalation test of new BLIs demonstrated that increasing doses of new BLIs corresponded to increased susceptibility to BLs. Taken together, this study illustrates the excellent activity of ceftazidime-avibactam against KPC-2-producing Enterobacterales and suggests further investigation into high-concentration regimens for potentially non-susceptible clinical isolates.

Dual-Mode Graphene Field-Effect Transistor Biosensor with Isothermal Nucleic Acid Amplification.

Despite a substantial increase in testing facilities during the pandemic, access remains a major obstacle, particularly in low-resource and remote areas. This constraint emphasizes the need for high-throughput potential point-of-care diagnostic tools in environments with limited resources. Loop-mediated isothermal amplification (LAMP) is a promising technique, but improvements in sensitivity are needed for accurate detection, especially in scenarios where the virus is present in low quantities. To achieve this objective, we present a highly sensitive detection approach of a dual-mode graphene-based field-effect transistor (G-FET) biosensor with LAMP. The G-FET biosensor, which has a transparent graphene microelectrode array on a glass substrate, detects LAMP products in less than 30 min using both observable color changes and Dirac point voltage measurements, even in samples with low viral concentrations. This dual-mode G-FET biosensor emerges as a potential alternative to conventional RT-PCR for severe acute respiratory syndrome-associated coronavirus (SARS-CoV)-2 detection or point-of-care testing, particularly in resource-constrained scenarios such as developing countries. Moreover, its capacity for colorimetric detection with the naked eye enhances its applicability in diverse settings.

Extensively drug-resistant Enterobacter ludwigii co-harbouring MCR-9 and a multicopy of blaIMP-1 in South Korea.

In this study, we describe an Enterobacter ludwigii clinical isolate that is resistant to both carbapenems and colistin in South Korea. Antimicrobial susceptibility testing revealed that E. ludwigii CRE2104-31 was non-susceptible to all tested antibiotics except fosfomycin. Whole genome sequencing identified a 323-kbp IncHI2 plasmid, pCRE2104-31a, that was co-harbouring mobile colistin resistance (mcr)-9.1 and blaIMP-1. In comparison with other full plasmids, pCRE2104-31a exhibited the closest similarity to a plasmid from the Klebsiella pneumoniae strain CNR48 from France, with 19.9% query coverage and 99% identity. Notably, we observed five tandem repeats of blaIMP-1 and aac(6')-Il genes, accompanied by multiple attCs within a class I integron on the Tn402-like transposon. The unit of blaIMP-1-attC-aac(6')-Il-attC might have accumulated due to multiple convergent events. In addition to mcr-9.1 and blaIMP-1, various other antibiotic resistance-associated genes were identified in the plasmid, as follows: blaTEM-1B, aph(3')-I, aph(3')-Ia, aac(6')-Il, aac(6')-IIc, aac(6')-IIa, aph(6)-Id, aph(3'')-Ib, aadA2b, aac(6')-Ib3, sul, dfrA19, qnrB2, aac(6')-Ib-cr, ere(A), and qacE. A conjugation assay showed that the mcr-9.1/blaIMP-1-co-bearing plasmid was self-transmissible to E. coli J53. However, colistin and carbapenem resistance could not be transferred to E. coli due to high incompatibility. The convergence of mcr and carbapenemase genes is thought to be host-dependent among Enterobacteriaceae. The emergence of extensively drug-resistant E. ludwigii co-harbouring MCR-9.1 and a multicopy of blaIMP-1 would pose a significant threat within the compatible Enterobacteriaceae.

Effect of a Latent Tuberculosis Infection Programme for Healthcare Workers in a Country with an Intermediate Tuberculosis Burden.

BACKGROUND: Management of latent tuberculosis infection (LTBI) among healthcare workers (HCWs) is crucial for the prevention of nosocomial tuberculosis (TB) transmission. We aimed to determine the effect of an LTBI programme for HCWs in a tertiary care hospital in a country with an intermediate TB burden. METHODS: In 2013, baseline LTBI screening was implemented for newly hired doctors and nurses, along with annual screening of HCWs in high-risk departments. HCWs with LTBI were also provided with treatment. Since 2017, all HCWs without an LTBI test result have been tested for LTBI. We assessed the annual incidence of active TB among HCWs between 2013 and 2020. Additionally, we evaluated the incidence of active TB among HCWs employed at the hospital in 2020, with a specific focus on those who had undergone LTBI tests between 2013 and 2018, considering their LTBI test results and treatment status. MEASUREMENT AND MAIN RESULTS: The incidence of active TB among HCWs significantly decreased between 2013 and 2020. The average risk reduction for pulmonary TB was 10.2% per year (95% CI, 1.0-19.0; p = 0.034). Among HCWs employed at the hospital in 2020, 4,354 individuals underwent LTBI tests between 2013 and 2018. Out of them, 927 (21.3%) tested positive. Nine (1.5%) out of 588 without LTBI treatment developed active TB. Among the 1,285 HCWs who underwent follow-up testing, 62 (4.8%) converted, and one (4.3%) out of the 23 without treatment developed active TB. None of those who received treatment were diagnosed with active TB. CONCLUSION: The LTBI programme significantly reduced the incidence of active TB in HCWs. LTBI screening and treatment should be implemented, particularly in countries with a high or intermediate TB burden.

Risk factors and clinical outcomes of cytomegalovirus diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation.

PURPOSE: This study aims to evaluate the risk factors and prognosis for CMV diseases in hematologic malignancy patients without hematopoietic stem-cell transplantation (HSCT). METHODS: We performed a case-control study (1:2) between 2012 and 2022. Adults with pathologic-confirmed CMV diseases (n=60) among hematologic malignancy patients were matched and compared to whom without CMV disease. RESULTS: Lymphoma was the most common underlying malignancy, and gastrointestinal tract involvement was the most common CMV disease. In the case group, high-dose steroid administration and transfusion within one month before diagnosis were higher (p<0.001). Steroid administration (aOR=5.78; 95% confidence interval: 1.25-26.68, p=0.024), red blood cell transfusion within one month (aOR=14.63; 2.75-77.76, p=0.002), low BMI (aOR=13.46, 2.07-87.45, p=0.006), and hypoalbuminemia (aOR=26.48, 5.93-118.17, p<0.001) were independent risk factors associated with CMV disease. The 30-day mortality was higher in the case group and CMV disease was significantly associated with all-cause mortality (aOR=14.41, 3.23-64.31, p<0.001). CONCLUSION: In hematologic malignancy patients without HSCT, risk factors for CMV organ disease included high-dose steroid administration and RBC transfusion within one month, low BMI, and hypoalbuminemia. Overall mortality was significantly higher with CMV disease, and CMV disease occurrence was a significant risk factor for mortality.

False-positive Aspergillus galactomannan immunoassay in the glucose component of total parenteral nutrition products.

IMPORTANCE: This manuscript describes an occurrence of false-positive GM tests in patients receiving TPN products from a manufacturer who had recently changed the supplier of the glucose component. We describe the clinical presentation of nine false-positive cases and the results of serologic and microbiological investigations of the TPN products suspected of contamination with GM. Attempts to detect GM in parenteral nutrition products were made since the detection of GM in sodium gluconate-containing solutions in 2007, but none of them identified the source of elevated GM indexes in TPN products. However, the present study demonstrated that the glucose component of the TPN products contained a high level of GM antigen, which caused false-positive GM assay results. The source of GM was glucoamylase, which was derived from A. niger in the manufacturing process. Physicians and clinical microbiology laboratories should be aware of this issue to improve interpretation and patient care.

Clinical Utility of Sero-Immunological Responses Against SARS-CoV-2 Nucleocapsid Protein During Subsequent Prevalence of Wild-Type, Delta Variant, and Omicron Variant.

As nucleocapsid protein of severe acute respiratory syndrome coronavirus 2 is immunogenic but not targeted in vaccines, it could be useful in distinguishing natural infection from vaccination. We aimed to investigate the clinical utility of sero-immunological responses against the nucleocapsid protein. Nucleocapsid antibody immunoassay study with 302 coronavirus disease 2019 (COVID-19) patients showed lower titers in immunocompromised patients (P < 0.001), higher titers in higher severity (P = 0.031), and different seroconversion rates and titers according to variants of concern. Longitudinal evaluation of nucleocapsid antibodies using 513 samples from 291 COVID-19 patients revealed that it could persist up to 556 days from symptom onset. Interferon gamma release assay against the nucleocapsid protein showed poor response, precluding the deduction of a cut-off for the nucleocapsid protein. In conclusion, nucleocapsid antibody provides instructive clues about the immunogenicity of nucleocapsid proteins by different seroconversion rates and titers according to the severity of infection, host immune status, and different variants of concern.

Genetic alterations in methicillin-susceptible Staphylococcus aureus associated with high vancomycin minimum inhibitory concentration.

BACKGROUND: There are many reports on gene mutations observed in methicillin-resistant Staphylococcus aureus (MRSA) showing reduced susceptibility to vancomycin. However, there are limited studies on the genetic alterations that contribute to high vancomycin minimum inhibitory concentrations (MICs) in methicillin-susceptible S. aureus (MSSA). This study aimed to compare MSSA strains with high vancomycin MICs with those with low MICs, and to identify specific genetic alterations associated with increased vancomycin MICs. METHODS: In total, 124 MSSA strains were analysed, with 62 having vancomycin MICs of 1-2 mg/L (MS-HV) and the remaining 62 having MICs <1 mg/L (MS-LV) as control. Polymerase chain reaction amplification and sequencing were conducted to identify point mutations and amino acid changes in the vraSR, graRS and walRK operons and rpoB gene. The number of single nucleotide polymorphisms (SNPs) and specific mutations in the indicated gene were compared between the two groups. RESULTS: The MS-HV strains had a significantly higher median number of SNPs in studied genes than the MS-LV strains (5 vs 3; P < 0.0001), with higher frequency of SNPs in the graR and walK genes. The MS-HV strains also displayed a significantly higher prevalence of specific mutations in the graR gene (V135I, I136V and V136I) compared with the MS-LV strains. The odds of having a high vancomycin MIC was 5.54 times higher in strains with a mutation in the graR gene, and 5.32 times higher in strains with a mutation in the walK gene, compared with those without these mutations. CONCLUSIONS: Mutations in the graR and walK genes may contribute to reduced vancomycin susceptibility in MSSA. This study gives key insights into the mechanisms underlying this phenomenon.

Loss of Neutralizing Activity of Tixagevimab/Cilgavimab (Evusheld™) Against Omicron BN.1, a Dominant Circulating Strain Following BA.5 During the Seventh Domestic Outbreak in Korea in Early 2023.

Tixagevimab/cilgavimab is a monoclonal antibody used to prevent coronavirus disease 2019 among immunocompromised hosts and maintained neutralizing activity against early omicron variants. Omicron BN.1 became a dominant circulating strain in Korea early 2023, but its susceptibility to tixagevimab/cilgavimab is unclear. We conducted plaque reduction neutralization test (PRNT) against BN.1 in a prospective cohort (14 patients and 30 specimens). BN.1 PRNT was conducted for one- and three-months after tixagevimab/cilgavimab administration and the average PRNT ND50 of each point was lower than the positive cut-off value of 20 (12.9 ± 4.5 and 13.2 ± 4.2, respectively, P = 0.825). In the paired analyses, tixagevimab/cilgavimab-administered sera could not actively neutralize BN.1 (PRNT ND50 11.5 ± 2.9, P = 0.001), compared with the reserved activity against BA.5 (ND50 310.5 ± 180.4). Unlike virus-like particle assay, tixagevimab/cilgavimab was not active against BN.1 in neutralizing assay, and would not be effective in the present predominance of BA.2.75 sublineages.

Trend of immunity against measles and varicella zoster virus in healthcare workers in Korea.

OBJECTIVE: To examine the seroprevalence of measles and varicella zoster virus (VZV) among healthcare workers (HCW) and evaluate the concordance between self-reported history of previous disease or vaccination and seropositivity. DESIGN: A seroprevalence study and survey. SETTING: A university-affiliated tertiary care hospital. PARTICIPANTS: All HCWs working in high-risk services in 2017 underwent serologic tests and survey; all new HCWs employed in the subsequent years, serologic tests only. METHODS: A serologic study was conducted using chemiluminescence immunoassay (2017) or enzyme immunoassays (2018 and later). HCWs who underwent serological testing in 2017 completed a self-administered questionnaire on their history of infection and vaccination. RESULTS: A total of 10,278 and 9607 HCWs underwent serologic tests for measles and VZV IgG, respectively, from 2017 to 2022. The overall seropositivity rates for measles and VZV were 78.1 % and 92.8 %, respectively. Measles seropositivity declined gradually from >90 % in the HCWs born in the 1960s to <80 % in those born in the 1990s. There was a significant difference in measles seropositivity between the birth cohorts (BCs) 1967-1984 and 1985-1999 (P < 0.001; odds ratio, 1.16; 95 % confidence interval, 1.14-1.18). The seropositivity for VZV was stable, at >90 % in all BCs. The self-reported vaccination history was not independently associated with seropositivity, and the negative predictive value of the survey was very low (9.6 % and 13.1 %, respectively). CONCLUSIONS: Measles seropositivity showed a substantial decline among HCWs born in 1985 or later, while varicella seropositivity remained high. The self-reported vaccination history was not sufficiently reliable for screening HCWs.

Impact of vancomycin resistance in Enterococcus faecium bloodstream infection on mortality: A retrospective analysis of nationwide surveillance data.

OBJECTIVES: It is unclear whether the poor outcome of patients with severe vancomycin-resistant enterococci (VRE) infection is attributable to vancomycin resistance or to Enterococcus faecium (Efm), which predominates among VRE. METHODS: Retrospective study of a prospectively identified cohort from nationwide surveillance. A cohort of consecutive, nonduplicate episodes of monomicrobial bloodstream infections (BSIs) caused by Efm in 2016 was selected. The primary outcome was all-cause, 30-day, in-hospital mortality. Inverse probability weighting was applied using the propensity score for vancomycin-resistant Efm (VREfm) BSI. RESULTS: A total of 241 Efm BSI episodes were included, of which 59 (24.5%) were VREfm. Patients with VREfm BSI were younger but had similar comorbidities to those with vancomycin-sensitive Efm (VSEfm) BSI. Multivariable logistic regression revealed that younger age, previous piperacillin-tazobactam use, and steroid use were significant risk factors for VREfm BSI, but 30-day in-hospital mortality did not differ significantly between groups (35.6% and 23.6% for VREfm and VSEfm, respectively; odds ratio, 1.79; 95% confidence interval, 0.95-3.37; P = 0.101). However, Cox regression with inverse probability weighting revealed that vancomycin resistance was independently associated with an increased risk of mortality (adjusted hazard ratio, 2.18; 95% confidence interval, 1.03-4.62; P = 0.041). CONCLUSION: In patients with Efm BSI, vancomycin resistance was independently associated with mortality.

Comparing the Synergistic and Antagonistic Interactions of Ciprofloxacin and Levofloxacin Combined with Rifampin against Drug-Resistant Staphylococcus aureus: A Time-Kill Assay.

BACKGROUND: Treatment of device-related infections by drug-resistant Staphylococcus aureus can be challenging, and combination therapy has been proposed as a potential solution. We compared the effectiveness of levofloxacin-rifampin and ciprofloxacin-rifampin combinations in killing methicillin-resistant S. aureus (MRSA) using a time-kill assay. METHODS: We randomly selected 15 vancomycin-susceptible S. aureus (VSSA) strains, 3 vancomycin-intermediate S. aureus (VISA) strains, and 12 heterogeneous VISA (hVISA) strains from the Asian Bacterial Bank. Time-kill experiments were performed in duplicate for each isolate. Viable bacterial counts were determined at 0 h, 4 h, 8 h, and 24 h for the ciprofloxacin- and levofloxacin-rifampin combinations at 1× MIC and 0.5× MIC. We compared synergistic and antagonistic interactions between the two combinations. RESULTS: The viable bacterial count significantly decreased after 24 h of exposure to ciprofloxacin-rifampin and levofloxacin-rifampin combinations, with synergy observed more frequently in isolates exposed to ciprofloxacin-rifampin (43.3%) than levofloxacin-rifampin (20.0%) (p = 0.0082). The synergistic interactions of both combinations were more frequently observed in resistant strains with high MICs of ciprofloxacin (≥16 mg/L) and levofloxacin (≥8 mg/L). Levofloxacin tended to exhibit more frequent antagonistic interactions with rifampin than ciprofloxacin, although there was no statistical difference in antagonism between the two combinations. CONCLUSIONS: Our study demonstrated that ciprofloxacin exhibits superior synergistic activity against MRSA strains, including VISA/hVISA, when combined with rifampin compared with levofloxacin. High MICs of fluoroquinolones were found to predict synergism. Our results suggest that ciprofloxacin may be a more effective choice than levofloxacin for combination therapy with rifampin in the treatment of MRSA infections.

Triple immune modulator therapy for aberrant hyperinflammatory responses in severe COVID-19.

A dysregulated hyperinflammatory response is a key pathogenesis of severe COVID-19, but optimal immune modulator treatment has not been established. To evaluate the clinical effectiveness of double (glucocorticoids and tocilizumab) and triple (plus baricitinib) immune modulator therapy for severe COVID-19, a retrospective cohort study was conducted. For the immunologic investigation, a single-cell RNA sequencing analysis was performed in serially collected PBMCs and neutrophil specimens. Triple immune modulator therapy was a significant factor in a multivariable analysis for 30-day recovery. In the scRNA-seq analysis, type I and II IFN response-related pathways were suppressed by GC, and the IL-6-associated signature was additionally downregulated by TOC. Adding BAR to GC and TOC distinctly downregulated the ISGF3 cluster. Adding BAR also regulated the pathologically activated monocyte and neutrophil subpopulation induced by aberrant IFN signals. Triple immune modulator therapy in severe COVID-19 improved 30-day recovery through additional regulation of the aberrant hyperinflammatory immune response.

Breakthrough invasive fungal infection in patients with myeloid malignancy receiving posaconazole tablet prophylaxis: Clinical features, risk factors, and posaconazole profiles.

Posaconazole (PSC) delayed-release tablet prophylaxis is the standard of care for preventing invasive fungal infection (IFI) in patients with acute myeloid leukemia undergoing myelosuppressive chemotherapy. The clinical features, risk factors, and PSC profiles of breakthrough IFI (bIFI) in patients receiving PSC tablet prophylaxis were investigated. A single-center retrospective cohort study was conducted, including adult patients with myeloid malignancy who received prophylactic PSC tablets while undergoing chemotherapy from June 2016 to June 2021. Logistic regression analysis was used to identify risk factors for bIFI. A receiver operating characteristic curve was used to predict the relationship between PSC trough level at steady state and bIFI. A total of 434 patients with myeloid malignancy who received PSC tablets were screened. A total of 10 patients with bIFI were compared with 208 non-IFI patients. There were four proven and six probable IFI cases, nine due to Aspergillus, and one due to Fusarium species. The bIFI patients had higher in-hospital mortality (30.0%) than the non-IFI patients (1.9%; P < 0.001). History of allogeneic hematopoietic stem cell transplantation (odds ratio [OR] 6.27; 95% confidence interval [CI] 1.63-24.09), prolonged neutropenia ≥28 days (OR 4.33; 95% CI 1.20-15.70), and low plasma PSC concentration <0.7 µg/ml (OR 16.33; 95% CI 4.15-64.26) were risk factors for bIFI. The optimal cutoff value of plasma PSC concentration predicting bIFI was 0.765 µg/ml (sensitivity, 60.0%; specificity, 91.3%; area under the curve, 0.746). bIFI was not uncommon in patients with myeloid malignancy receiving PSC tablet prophylaxis and associated with poor outcomes. Therapeutic drug monitoring may still be necessary, even in patients receiving PSC tablets.

Invasive fungal infections increase mortality in acute myeloid leukemia patients. This study investigated breakthrough invasive fungal infection cases in patients receiving posaconazole tablet prophylaxis. Our results will contribute to improving the outcome of patients with myeloid malignancy.

Neutralizing activity against Omicron BA.5 after tixagevimab/cilgavimab administration comparable to those after Omicron BA.1/BA.2 breakthrough infections.

Introduction: The effect of tixagevimab/cilgavimab (Evusheld™; AstraZeneca, UK) should be evaluated in the context of concurrent outbreak situations. Methods: For serologic investigation of tixagevimab/cilgavimab during the BA.5 outbreak period, sera of immunocompromised (IC) hosts sampled before and one month after tixagevimab/cilgavimab administration and those of healthcare workers (HCWs) sampled one month after a 3rd shot of COVID-19 vaccines, five months after BA.1/BA.2 breakthrough infection (BI), and one month after BA.5 BI were investigated. Semi-quantitative anti-spike protein antibody (Sab) test and plaque reduction neutralizing test (PRNT) against BA.5 were performed. Results: A total of 19 IC hosts (five received tixagevimab/cilgavimab 300 mg and 14 received 600 mg) and 41 HCWs (21 experienced BA.1/BA.2 BI and 20 experienced BA.5 BI) were evaluated. Baseline characteristics did not differ significantly between IC hosts and HCWs except for age and hypertension. Sab significantly increased after tixagevimab/cilgavimab administration (median 130.2 BAU/mL before tixagevimab/cilgavimab, 5,665.8 BAU/mL after 300 mg, and 10,217 BAU/mL after 600 mg; both P < 0.001). Sab of one month after the 3rd shot (12,144.2 BAU/mL) or five months after BA.1/BA.2 BI (10,455.8 BAU/mL) were comparable with that of tixagevimab/cilgavimab 600 mg, while Sab of one month after BA.5 BI were significantly higher (22,216.0 BAU/mL; P < 0.001). BA.5 PRNT ND50 significantly increased after tixagevimab/cilgavimab administration (median ND50 29.6 before tixagevimab/cilgavimab, 170.8 after 300 mg, and 298.5 after 600 mg; both P < 0.001). The ND50 after tixagevimab/cilgavimab 600 mg was comparable to those of five months after BA.1 BI (ND50 200.9) while ND50 of one month after the 3rd shot was significantly lower (ND50 107.6; P = 0.019). The ND50 of one month after BA.5 BI (ND50 1,272.5) was highest among tested groups, but statistical difference was not noticed with tixagevimab/cilgavimab 600 mg. Conclusion: Tixagevimab/cilgavimab provided a comparable neutralizing activity against the BA.5 with a healthy adult population who were vaccinated with a 3rd shot and experienced BA.1/BA.2 BI.

Clinical effectiveness of zoster vaccine live in kidney transplant recipients immunized prior to transplantation: a retrospective single-centre cohort study.

OBJECTIVES: Kidney transplant (KT) recipients have an increased risk of herpes zoster (HZ) and its complications. Although recombinant zoster vaccine is favoured over zoster vaccine live (ZVL), ZVL is also recommended to prevent HZ for KT candidates. We aimed to evaluate the clinical effectiveness of ZVL in KT recipients immunized before transplantation. METHODS: Adult patients who received kidney transplantation from January 2014 to December 2018 were enrolled. Patients were observed until HZ occurrence, death, loss of allograft, loss to follow-up, or 5 years after transplantation. The inverse probability of the treatment-weighted Cox proportional hazard model was used to compare the incidence of HZ after transplantation between vaccinated and unvaccinated patients. RESULTS: A total of 84 vaccinated and 340 unvaccinated patients were included. The median age was higher in the vaccinated group (57 vs. 54 years, p 0.003). Grafts from deceased donors were more frequently transplanted in the unvaccinated group (16.7% vs. 51.8%, p < 0.001). Five-year cumulative HZ incidence was 11.9%, which translated to 26.27 (95% CI, 19.33-34.95) per 1000 person-years. The incidence in the vaccinated and unvaccinated groups was 3.9% and 13.7%, respectively. After adjustment, vaccination showed significant protective effectiveness against HZ (adjusted hazard ratio, 0.18, 95% CI, 0.05-0.60). In addition, all four cases of disseminated zoster occurred in the unvaccinated group. DISCUSSION: Our study, the first on the clinical effectiveness of zoster vaccines for KT recipients, suggests that ZVL before transplantation effectively prevents HZ.

Augmented humoral and cellular immunity against severe acute respiratory syndrome coronavirus 2 after breakthrough infection in kidney transplant recipients who received 3 doses of coronavirus disease 2019 vaccine.

Diminished immune response to coronavirus disease 2019 (COVID-19) vaccines and breakthrough infection (BI) is a major concern for solid organ transplant recipients. Humoral and cellular immune responses of kidney transplant (KT) recipients after a third COVID-19 vaccination were investigated compared to matched health care workers. Anti-severe acute respiratory syndrome coronavirus 2 spike protein antibody and severe acute respiratory syndrome coronavirus 2 specific interferon-gamma releasing assay (IGRA) were assessed. A total of 38 KT recipients, including 20 BI and 18 noninfection, were evaluated. In the KT BI group, antibody titers were significantly increased (median 5 to 724, binding antibody units/mL (P = 0.002) after the third vaccination, but IGRA responses were negligible. After BI, antibody titers increased (median 11 355 binding antibody unit/mL; P < 0.001) and there was a significant increase of IGRA responses to spike proteins (Spike1-Nil, median 0.05 to 0.41 IU/mL; P = 0.009). Antibody titers and IGRA responses were significantly higher in the BI than in the noninfection group after 6 months. Immune responses were stronger in the health care worker than in the KT cohort, but the gap became narrower after BI. In conclusion, KT recipients who experienced BI after 3 COVID-19 vaccinations acquired augmented humoral and cellular immune responses.