PD-1-Expressing SARS-CoV-2-Specific CD8+ T Cells Are Not Exhausted, but Functional in Patients with COVID-19.

Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1- cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.

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.

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.

Evolution of neutralizing antibodies through vaccination and breakthrough infections in the era of COVID-19 endemicity.

Despite a high vaccination rate, the COVID-19 pandemic continues with immune-evading Omicron variants. The success of additional antigenic stimulation through breakthrough infection (BI) and updated vaccination in overcoming antigenic imprinting needs to be determined. Participants in a long-term follow-up cohort of healthcare worker (HCW) vaccinee were categorized according to their infection/vaccination status. Anti-SARS-CoV-2 spike/nucleocapsid protein antibodies were measured, and plaque reduction neutralization tests (PRNTs) against wild-type (WT), BA.5, BN.1, and XBB.1.5 were conducted. The neutralization activity of intravenous immunoglobulin (IVIG) products was evaluated to assess the immune status of the general population. Ninety-five HCWs were evaluated and categorized into seven groups. The WT PRNT ND50 value was highest regardless of infection/vaccination status, and groups with recent antigenic stimulation showed high PRNT titers overall. Groups with double Omicron stimulation, either by BI plus BA.4/5 bivalent vaccination or repeated BI, exhibited significantly higher BA.5 and BN.1 PRNT to WT PRNT ratios than those with single Omicron stimulation. Overall group immunity was estimated to be boosted in January 2023, reflecting the effect of the BA.4/5 bivalent booster and additional BIs, but slightly declined in June 2023. A substantial increase in the antibody concentrations of IVIG products was noticed in 2022, and recently produced IVIG products exhibited a substantial level of cross-reactive neutralizing activity against emerging variants. Neutralizing activity against emerging variants could be enhanced by repeated antigenic stimulation via BI and/or updated vaccination. Overall group immunity was elevated accordingly, and IVIG products showed substantial activity against circulating strains.

Clinical utility of quantitative immunoassays and surrogate virus neutralization tests for predicting neutralizing activity against the SARS-CoV-2 Omicron BA.1 and BA.5 variants.

Developing new antibody assays for emerging SARS-CoV-2 variants is challenging. SARS-CoV-2 surrogate virus neutralization tests (sVNT) targeting Omicron BA.1 and BA.5 have been devised, but their performance needs to be validated in comparison with quantitative immunoassays. First, using 1749 PRNT-positive sera, we noticed that log-transformed optical density (OD) ratio of wild-type (WT) sVNT exhibited better titer-correlation with plaque reduction neutralization test (PRNT) than % inhibition value. Second, we tried 798 dilutional titration tests with 103 sera, but nonlinear correlation between OD ratio and antibody concentration limited titration of sVNT. Third, the titer-correlations of two sVNT kits for BA.1 and two quantitative immunoassays for WT were evaluated with BA.1 and BA.5 PRNT. All tested kits exhibited a linear correlation with PRNT titers, but the sVNT kits exhibited high false-negative rates (cPass-BA.1 kit, 45.4% for BA.1 and 44.2% for BA.5; STANDARD F-BA.1 kit, 1.9% for BA.1 and 2.2% for BA.5), while quantitative immunoassays showed 100% sensitivity. Linear mixed-effects model suggested superior titer-correlation with PRNT for quantitative immunoassays compared to sVNT kits. Taken together, the use of quantitative immunoassays for WT, rather than rapid development of new kits, would be practical for predicting neutralizing activities against emerging new variants.

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.

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.

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.

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.

Clinical Characteristics and Risk Factors for Mortality in Critical COVID-19 Patients Aged 50 Years or Younger During Omicron Wave in Korea: Comparison With Patients Older Than 50 Years of Age.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has caused the death of thousands of patients worldwide. Although age is known to be a risk factor for morbidity and mortality in COVID-19 patients, critical illness or death is occurring even in the younger age group as the epidemic spreads. In early 2022, omicron became the dominant variant of the COVID-19 virus in South Korea, and the epidemic proceeded on a large scale. Accordingly, this study aimed to determine whether young adults (aged ≤ 50 years) with critical COVID-19 infection during the omicron period had different characteristics from older patients and to determine the risk factors for mortality in this specific age group. METHODS: We evaluated 213 critical adult patients (high flow nasal cannula or higher respiratory support) hospitalized for polymerase chain reaction-confirmed COVID-19 in nine hospitals in South Korea between February 1, 2022 and April 30, 2022. Demographic characteristics, including body mass index (BMI) and vaccination status; underlying diseases; clinical features and laboratory findings; clinical course; treatment received; and outcomes were collected from electronic medical records (EMRs) and analyzed according to age and mortality. RESULTS: Overall, 71 critically ill patients aged ≤ 50 years were enrolled, and 142 critically ill patients aged over 50 years were selected through 1:2 matching based on the date of diagnosis. The most frequent underlying diseases among those aged ≤ 50 years were diabetes and hypertension, and all 14 patients who died had either a BMI ≥ 25 kg/m² or an underlying disease. The total case fatality rate among severe patients (S-CFR) was 31.0%, and the S-CFR differed according to age and was higher than that during the delta period. The S-CFR was 19.7% for those aged ≤ 50 years, 36.6% for those aged > 50 years, and 38.1% for those aged ≥ 65 years. In multivariate analysis, age (odds ratio [OR], 1.084; 95% confidence interval [CI], 1.043-1.127), initial low-density lipoprotein > 600 IU/L (OR, 4.782; 95% CI, 1.584-14.434), initial C-reactive protein > 8 mg/dL (OR, 2.940; 95% CI, 1.042-8.293), highest aspartate aminotransferase > 200 IU/L (OR, 12.931; 95% CI, 1.691-98.908), and mechanical ventilation implementation (OR, 3.671; 95% CI, 1.294-10.420) were significant independent predictors of mortality in critical COVID-19 patients during the omicron wave. A similar pattern was shown when analyzing the data by age group, but most had no statistical significance owing to the small number of deaths in the young critical group. Although the vaccination completion rate of all the patients (31.0%) was higher than that in the delta wave period (13.6%), it was still lower than that of the general population. Further, only 15 (21.1%) critically ill patients aged ≤ 50 years were fully vaccinated. Overall, the severity of hospitalized critical patients was significantly higher than that in the delta period, indicating that it was difficult to find common risk factors in the two periods only with a simple comparison. CONCLUSION: Overall, the S-CFR of critically ill COVID-19 patients in the omicron period was higher than that in the delta period, especially in those aged ≤ 50 years. All of the patients who died had an underlying disease or obesity. In the same population, the vaccination rate was very low compared to that in the delta wave, indicating that non-vaccination significantly affected the progression to critical illness. Notably, there was a lack of prescription for Paxlovid for these patients although they satisfied the prescription criteria. Early diagnosis and active initial treatment was necessary, along with the proven methods of vaccination and personal hygiene. Further studies are needed to determine how each variant affects critically ill patients.

Bile duct anastomosis does not promote bacterial contamination of autologous blood salvaged during living donor liver transplantation.

Bile duct surgeries are conventionally considered to promote bacterial contamination of the surgical field. However, liver transplantation recipients' bile produced by the newly implanted liver graft from healthy living donors may be sterile. We tested bacterial contamination of autologous blood salvaged before and after bile duct anastomosis (BDA) during living donor liver transplantation (LDLT). In 29 patients undergoing LDLT, bacterial culture was performed for four blood samples and one bile sample: two from autologous blood salvaged before BDA (one was nonleukoreduced and another was leukoreduced), two from autologous blood salvaged after BDA (one was nonleukoreduced and another was leukoreduced), and one from bile produced in the newly implanted liver graft. The primary outcome was bacterial contamination. The risk of bacterial contamination was not significantly different between nonleukoreduced autologous blood salvaged before BDA and nonleukoreduced autologous blood salvaged after BDA (44.8% and 31.0%; odds ratio 0.33, 95% confidence interval 0.03-1.86; p = 0.228). No bacteria were found after leukoreduction in all 58 autologous blood samples. All bile samples were negative for bacteria. None of the 29 patients, including 13 patients who received salvaged autologous blood positive for bacteria, developed postoperative bacteremia. We found that bile from the newly implanted liver graft is sterile in LDLT and BDA does not increase the risk of bacterial contamination of salvaged blood, supporting the use of blood salvage during LDLT even after BDA. Leukoreduction converted all autologous blood samples positive for bacteria to negative. The clinical benefit of leukoreduction for salvaged autologous blood on post-LDLT bacteremia needs further research.

Pharmacokinetic/pharmacodynamic parameters of vancomycin for predicting clinical outcome of enterococcal bacteremia.

PURPOSE: To find pharmacokinetic/pharmacodynamic parameters of vancomycin associated with the optimal outcome of severe infection due to Enterococcus species. METHODS: We retrospectively reviewed enterococcal bacteremia cases treated with vancomycin from January 2015 to December 2020. The primary outcome was 30-day mortality. We calculated cutoff values of the ratio of vancomycin area under the concentration-time curve over 24 h to the minimum inhibitory concentration (AUC24/MIC) and trough concentration (Ctrough) during the initial 72 h of treatment. The optimal cutoff value was determined using the Youden index. Binary variables created based on these cutoffs were further assessed using multivariable analysis. RESULTS: A total of 65 patients were included. The majority (87.7%) had solid or hematologic malignancies. Thirty-day mortality and nephrotoxicity occurred in nine (13.4%) and 14 (21.5%) patients, respectively. Both vancomycin AUC24/MIC and Ctrough showed fair performance in predicting 30-day mortality (AUC of receiver-operator curve for AUC24/MIC, 0.712; 95% confidence interval [CI] 0.539-0.886; AUC for Ctrough, 0.760; 95% CI 0.627-0.892; pairwise AUC comparison: p = 0.570). Ctrough ≥ 13.94 µg/mL, but not AUC24/MIC ≥ 504, had a significant association with 30-day mortality after adjusting for confounders (odds ratio, 8.40; 95% CI 1.60-86.62; p = 0.010). CONCLUSION: Mean Ctrough ≥ 13.94 µg/mL during the initial 72 h was associated with higher 30-day mortality in enterococcal bacteremia. Further studies are warranted to elucidate optimal pharmacokinetic targets for enterococcal bacteremia.

Risk Factors for Coronavirus Disease 2019 (COVID-19)-Associated Pulmonary Aspergillosis in Critically Ill Patients: A Nationwide, Multicenter, Retrospective Cohort Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is often accompanied by secondary infections, such as invasive aspergillosis. In this study, risk factors for developing COVID-19-associated pulmonary aspergillosis (CAPA) and their clinical outcomes were evaluated. METHODS: This multicenter retrospective cohort study included critically ill COVID-19 patients from July 2020 through March 2021. Critically ill patients were defined as patients requiring high-flow respiratory support or mechanical ventilation. CAPA was defined based on the 2020 European Confederation of Medical Mycology and the International Society for Human and Animal Mycology consensus criteria. Factors associated with CAPA were analyzed, and their clinical outcomes were adjusted by a propensity score-matched model. RESULTS: Among 187 eligible patients, 17 (9.1%) developed CAPA, which is equal to 33.10 per 10,000 patient-days. Sixteen patients received voriconazole-based antifungal treatment. In addition, 82.4% and 53.5% of patients with CAPA and without CAPA, respectively, received early high-dose corticosteroids (P = 0.022). In multivariable analysis, initial 10-day cumulative steroid dose > 60 mg of dexamethasone or dexamethasone equivalent dose) (adjusted odds ratio [OR], 3.77; 95% confidence interval [CI], 1.03-13.79) and chronic pulmonary disease (adjusted OR, 4.20; 95% CI, 1.26-14.02) were independently associated with CAPA. Tendencies of higher 90-day overall mortality (54.3% vs. 35.2%, P = 0.346) and lower respiratory support-free rate were observed in patients with CAPA (76.3% vs. 54.9%, P = 0.089). CONCLUSION: Our study showed that the dose of corticosteroid use might be a risk factor for CAPA development and the possibility of CAPA contributing to adverse outcomes in critically ill COVID-19 patients.

Poor outcomes of early recurrent post-transplant bloodstream infection in living-donor liver transplant recipients.

Bloodstream infection (BSI) is a common complication after living-donor liver transplantation (LDLT). Some patients develop recurrent BSIs. We evaluated the impacts of early recurrent BSIs (ER-BSIs) on outcomes in LDLT recipients. LDLT cases between 2008 and 2016 were included. Early BSI (E-BSI) was defined as a BSI event that occurred within 2 months after LDLT. ER-BSIs were defined as new-onset BSIs within 2 months due to another pathogen at a ≥ 48-h interval or a relapse of BSIs by the same pathogen at a ≥ 1-week interval, with negative cultures in between. The primary objective was evaluating the all-cause mortality of each group of LDLT recipients (90 days and 1 year). The secondary objectives were analyzing associated factors of each all-cause mortality and risk factors for early single BSI and ER-BSI. Among 727 LDLT recipients, 108 patients experienced 149 events of E-BSI with 170 isolated pathogens. Twenty-eight patients (25.9%, 28/108) experienced ER-BSI. The 1-year survival rates of patients without BSI, with early single BSI event, and with ER-BSIs were 92.4%, 81.3%, and 28.6%, respectively. ER-BSI was the most significant risk factor for 1-year mortality (adjusted HR = 5.31; 95% CI = 2.27-12.40). Intra-abdominal and/or biliary complications and early allograft dysfunction were risk factors for both early single BSI and ER-BSI. Interestingly, longer cold ischemic time and recipient operative time were associated with ER-BSI. LDLT recipients with ER-BSI showed very low survival rates accompanied by intra-abdominal complications. Clinicians should prevent BSI recurrence by being aware of intra-abdominal complications.

Impact of antiviral treatment on long-term prognosis in non-immunocompromised patients with CMV reactivation.

BACKGROUND: Reactivation of human cytomegalovirus (CMV) occurs in non-immunocompromised patients with or without specific organ involvement, but it is still unknown whether it has a clinical implication on long-term prognosis or not. METHODS: A retrospective cohort study evaluating non-immunocompromised adult patients with CMV reactivation was conducted during the period between January 2010 and February 2018. Patients were divided into ganciclovir-treated and non-treated groups. Patients who died within 30 days from CMV reactivation were excluded as they died from complex causes of conditions. Survivors were followed for 30-months to evaluate long-term prognosis. RESULTS: A total of 136 patients with CMV reactivation was included, consisting of 66 ganciclovir-treated (48.5%) and 70 non-treated (51.5%) patients. Overall, patients were old-aged (median 70 years old) and most were treated with pneumonia of any cause (91.2%). More patients in ganciclovir-treated group were treated at intensive care unit (43.9% vs 24.3%, respectively) and had higher viral load over 5000 copies/ml (48.5% vs 22.9%) than non-treated group (all P < 0.05). Primary and secondary endpoints including 30-months survival (28.0 vs 38.9%, respectively) and 12-months survival (40.3% vs 49.2%) were not statistically different between the ganciclovir-treated and non-treated groups. In the multivariate analyses, ganciclovir treatment was not associated with 30-months survival (HR 1.307, 95% CI 0.759-2.251) and 12-months survival (HR 1.533, 95% CI 0.895-2.624). CONCLUSION: In a retrospective cohort study evaluating non-immunocompromised patients with CMV reactivation, ganciclovir treatment was not associated with long-term prognosis. Antiviral treatment in this condition would not be necessary unless organ involvement is suspected.

Impact of Difficult-to-Treat Resistance in Gram-negative Bacteremia on Mortality: Retrospective Analysis of Nationwide Surveillance Data.

BACKGROUND: Clinically relevant categorization of antimicrobial resistance is critical to mitigating the threat it poses. Difficult-to-treat resistance (DTR) is a recently proposed category defined as nonsusceptibility to all first-line antibiotic agents. METHODS: A retrospective study was conducted with nonduplicate cases of gram-negative bloodstream infection (GNBSI) caused by 4 major taxa (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter species) identified from a nationwide surveillance database. DTR was defined as nonsusceptibility to all the ß-lactams and fluoroquinolones tested. Patient characteristics and mortality were compared between DTR GNBSI and GNBSI caused by carbapenem-resistant but not DTR and extended-spectrum cephalosporin-resistant but not DTR isolates using Centers for Disease Control and Prevention definitions. Adjusted odds ratios (aORs) for 30-day in-hospital mortality were examined for DTR in overall and in propensity score-matched cohorts. RESULTS: A total of 1167 episodes of monomicrobial GNBSI were identified, and 147 (12.6%) of the isolates were DTR. The majority of DTR isolates were Acinetobacter species (79.6%) and P. aeruginosa (17.7%). DTR infections were associated with previous antibiotic use, healthcare contact, ventilator use, and lower respiratory tract infection. Crude mortality for GNBSI caused by DTR was 50.3%. A multivariable model showed that only DTR, but not other categories, was significantly associated with mortality (adjusted odds ratio [aOR], 3.58 [95% confidence interval {CI}, 1.27-10.19]). DTR was also a significant predictor for mortality in the analysis of propensity score-matched cohorts (aOR, 3.48 [95% CI, 1.82-6.79]). CONCLUSIONS: In patients with GNBSI, DTR was associated with higher mortality than those in other resistance categories. Our findings suggest that DTR could be useful for surveillance and prognostication.

Clinical factors influencing the performance of bacterial multiplex polymerase chain reaction in patients with community-onset pneumonia.

The etiologic diagnostic yield of community-onset pneumonia (COP) using conventional methods is low. Bacterial multiplex polymerase chain reaction (mPCR) has been shown to be more sensitive than conventional methods. This study assessed the clinical factors influencing bacterial mPCR results in patients with COP. Patients with COP admitted to a tertiary care hospital between November 2015 and April 2016 were retrospectively assessed. Conventional methods included culture-based methods and serology for Mycoplasma pneumoniae. Bacterial mPCR that could identify Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, and Legionella pneumophilia was performed. Bacterial mPCR was performed in a total of 342 patients with COP in the study. Bacterial mPCR alone provided etiology in 99 patients. The total etiologic diagnosis rates improved from 22.2 to 51.1% when bacterial mPCR was added to conventional methods. Additional diagnostic benefits of bacterial mPCR were more prominent in the prior antibiotic non-exposure group (77.8% vs 63.5%, P = 0.015) and in the low-risk group with low CURB 65 score (62.6% vs 44.9%, P = 0.005). Patients who required ICU care, those with healthcare-associated pneumonia (HCAP), and patients with any underlying diseases were not associated with the additional pathogen detection rates using bacterial mPCR. By supplementing conventional diagnostic methods with bacterial mPCR-based methods, the overall pathogen detection rates improved in patients with COP. Moreover, the additional diagnostic usefulness of bacterial mPCR was significantly higher in patients without prior antibiotic exposure and in the mild-to-moderate-risk group with lower CURB 65 score.

Pathogenic significance of hemorrhagic pneumonia in hematologic malignancy patients with Stenotrophomonas maltophilia bacteremia: clinical and microbiological analysis.

Hemorrhagic pneumonia (HP) is known as the clinical manifestation of Stenotrophomonas maltophilia infection, while catheter-related blood stream infection (CRBSI) is the common clinical presentation of S. maltophilia bacteremia (SMB). The purpose of this study is to evaluate the risk factors for mortality in hematologic malignancy patients with SMB and to analyze clinical and microbiological characteristics of HP associated with SMB and CRBSI. SMB cases of patients with a hematologic malignancy were collected from 2006 through 2016. The overall 30-day mortality rate and mortality risk factors were assessed. The expression of major virulence-associated genes from S. maltophilia isolates, which included genes encoding type-1 fimbriae (smf-1), proteases (StmPr1 and StmPr2), and esterase (Smlt3773), from the blood of patients with HP and CRBSI was investigated. The phenotypic and genotypic traits were also compared. A total of 118 cases of SMB were included. The overall 30-day mortality rate was 61.0%. A multivariable analysis showed that HP was the most important risk factor for mortality (adjusted OR = 106.41; 95% CI = 5.18-2184.55). Although no statistical significance was observed in microbiological analysis, isolates from HP have a trend toward a higher protease activity (93.8% vs. 73.3%, P = 0.172). Clinical analysis showed that thrombocytopenia (P = 0.037) and prolonged neutropenia (P = 0.043) were significant factors associated with HP. Our data, which includes hematologic malignancy patients with SMB, suggest that HP is the significant risk factor for mortality and that the unique characteristics of patients and microbes contribute to the pathogenesis.

Changing epidemiology of non-albicans candidemia in Korea.

An epidemiologic surveillance of non-albicans candidemia for a 6-year period was conducted in Korea. Compared to the published epidemiologic data for the previous 6 years, an increase of C. glabrata (from 21.3% to 28.5%) and a decrease of C. parapsilosis (from 36.5% to 24.7%) were noticed. During the study period, C. tropicalis (36.4%) was most frequently isolated non-albicans Candida, followed by C. glabrata (28.5%), C. parapsilosis (24.7%), and C. krusei (2.6%). Replacement of primary amphotericin B treatment with echinocandins (P < 0.001) eliminated amphotericin B resistance (from 7.8% in 2011 to 0% in 2014).

Evaluation of a Carbapenem-Saving Strategy Using Empirical Combination Regimen of Piperacillin-Tazobactam and Amikacin in Hemato-Oncology Patients.

We implemented a carbapenem-saving strategy in hemato-oncology patients from 2013, using an empirical combination of piperacillin-tazobactam and amikacin for high-risk hemato-oncology patients with febrile neutropenia, who remain hemodynamically unstable > 72 hours despite initial cefepime treatment. All-cause mortality was not different between the two periods (6.54 and 6.57 deaths per 1,000 person-day, P = 0.926). Group 2 carbapenem use significantly decreased after strategy implementation (78.43 vs. 67.43 monthly days of therapy, P = 0.018), while carbapenem-resistant gram-negative bacilli did not show meaningful changes during the study period. Our carbapenem-saving strategy could effectively suppress carbapenem use without an increase of overall mortality.