Fu-Der Wang

Background: Infections caused by Klebsiella pneumoniae are common and result in high mortality rates. In vitro studies demonstrated the potency of cefoperazone/sulbactam (CPZ/SUL) against Klebsiella pneumoniae. However, the clinical efficacy of CPZ/SUL for the treatment of K. pneumoniae bacteremia has not been studied. Objectives: This study aimed to associate the clinical outcomes of patients with bacteremia with the minimal inhibitory concentrations (MICs) of CPZ/SUL against the causative K. pneumoniae isolates. Methods: This multicenter, retrospective study was conducted in Taiwan between July 2017 and April 2021. Patients with K. pneumoniae bacteremia treated with CPZ/SUL were enrolled in this study. CPZ/SUL MICs were determined using the agar dilution method. Data on the patients’ clinical outcomes and characteristics were collected and analyzed. Results: In total, 201 patients were enrolled. Among the causative K. pneumoniae isolates, 180 (89.5%) were susceptible to CPZ/SUL. Most patients (n = 156, 77.6%) had favorable outcomes. The 30-day mortality rate was 11.9% (n = 24). Multivariate risk analyses showed that higher APACHE II score (Odds Ratio [OR], 1.14; Confidence Interval [CI], 1.07–1.21; p < 0.001), metastatic tumors (OR, 5.76; CI, 2.31–14.40; p < 0.001), and causative K. pneumoniae CPZ/SUL MICs > 16 µg/ml (OR, 4.30; CI, 1.50–12.27; p = 0.006) were independently associated with unfavorable outcomes. Conclusion: Patients with K. pneumoniae bacteremia treated with CPZ/SUL at a ratio 1:1 had favorable outcomes when the CPZ/SUL MICs were ≤ 16 µg/ml. Patients with higher APACHE II scores and metastatic tumors had unfavorable outcomes.

Background. The Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins. Method. We conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 μg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 μg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 μg of UB-612 (n = 3,875, 18–85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose. Results. No vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs. Conclusion. UB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines. Trial Registration. ClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742. Funding. UBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

Reassessing the continuing need for and choice of antibiotics by using an antibiotic “time out’’ program may reduce unnecessary treatment. This study aimed to explore the effect of an antibiotic stewardship program (ASP) on the antibiotics consumption, incidence of resistant bacterial infections and overall hospital mortality in a tertiary medical center during the study period 2012–2014. An ASP composed of multidisciplinary strategies including pre-prescription approval and post-approval feedback and audit, and a major “time out’’ intervention (shorten the default antibiotic prescription duration) usage was introduced in year 2013. Consumption of antibiotics was quantified by calculating defined daily doses (DDDs). Interrupted time series (ITS) analysis was used to explore the changes of antibiotics consumption before and after intervention, accounting for temporal trends that may be unrelated to intervention. Our results showed that following the intervention, DDDs showed a decreased trend in overall (in particular the major consumed penicillins and cephalosporins), in both intensive care unit (ICU) and non-ICU, and in non-restrictive versus restrictive antibiotics. Importantly, ITS analysis showed a significantly slope change since intervention (slope change p value 0.007), whereas the incidence of carbapenem-resistant and vancomycin-resistant pathogens did not change significantly. Moreover, annual overall mortality rates were 3.0%, 3.1% and 3.1% from 2012 to 2014, respectively. This study indicates that implementing a multi-disciplinary strategy to shorten the default duration of antibiotic prescription can be an effective manner to reduce antibiotic consumption while not compromising resistant infection incidence or mortality rates.

(1) Background: The presentation of chronic pulmonary aspergillosis (CPA) ranges from single granuloma to fibrosis in the affected lung. CPA can be divided into five categories according to European Respirology Society (ERS) guidance but is usually assessed by clinical physicians. Computer-based quantitative lung parenchyma analysis in CPA and its correlation with clinical manifestations, systemic inflammation, and angiogenesis have never been investigated. (2) Method: Forty-nine patients with CPA and 36 controls were prospectively enrolled. Pulmonary function tests (forced vital capacity (FVC), forced expiratory volume in one second (FEV₁), and FEV₁/FCV) and biomarkers in the peripheral blood (the chemokines interleukin (IL)-1B, IL-6, IL-10, IL-8, CRP, ESR, MMP1, MMP7, MMP8, TNF-α, calprotectin, SDF-1α, and VEGFA) were measured before antifungal treatment. The disease severity was categorized into mild, moderate, and severe based on chest computed tomography (CT) images. The oxygen demand and overall mortality until the end of the study were recorded. Quantitative parenchyma analysis was performed using the free software 3Dslicer. (3) Results: The results of quantitative parenchyma analysis concorded with the visual severity from the chest CT, oxygen demand, FVC, and FEV₁ in the study subjects. The decrease in kurtosis and skewness of the lung density histograms on CT, increase in high attenuation area (HAA), and reduced lung volume were significantly correlated with increases in the PMN %, CRP, IL-1B, SDF-1α, MMP1, and Calprotectin in peripheral blood in the multivariable regression analysis. TNF-α and IL-1B at study entry and the CPA severity from either a visual method or computer-based evaluation were predictors of long-term mortality. (4) Conclusion: The computer-based parenchyma analysis in CPA agreed with the categorization on a visual basis and was associated with the clinical outcomes, chemokines, and systemic proinflammation profiles.

Several studies have demonstrated that malnutrition is a negative prognostic factor for clinical outcomes. However, there is limited evidence for the effect of malnutrition on clinical outcomes in patients with candidemia. We investigated the relationship between malnutrition and all-cause 28-day mortality among patients with non-albicans candidemia. Between July 2011 and June 2014, all adult patients with non-albicans candidemia, including C. tropicalis, C. glabrata, C. parapsilosis and so on, were enrolled. The Malnutrition Universal Screening Tool (MUST) scores were used to determine the patients’ nutritional status before the onset of candidemia. A total of 378 patients were enrolled; 43.4% developed septic shock and 57.1% had a high risk of malnutrition (MUST ≥ 2). The all-cause 28-day mortality rate was 40.7%. The Cox proportional hazards model revealed that C. tropicalis (HR, 2.01; 95% CI, 1.24–3.26; p = 0.005), Charlson comorbidity index (HR, 1.10; 95% CI, 1.03–1.18; p = 0.007), Foley catheter use (HR, 1.68; 95% CI, 1.21–1.35; p = 0.002), concomitant bacterial infections (HR, 1.55; 95% CI, 1.11–2.17; p = 0.010), low platelet count (HR, 3.81; 95% CI, 2.45–5.91; p < 0.001), not receiving antifungals initially (HR, 4.73; 95% CI, 3.07–7.29; p < 0.001), and MUST ≥ 2 (HR, 1.54; 95% CI, 1.09–2.17; p = 0.014) were independently associated with all-cause 28-day mortality. A simple screening tool for nutritional assessment should be used for patients with non-albicans candidemia to detect early clinical deterioration, and a tailored nutritional care plan should be established for malnourished individuals, to improve their clinical outcomes.

Background: Colistin is widely used in the treatment of nosocomial infections caused by carbapenem-resistant gram-negative bacilli (CR-GNB). Colistin-induced nephrotoxicity is one of the major adverse reactions during colistin treatment. Comparisons of colistin-induced nephrotoxicity between different formulations of colistin are rarely reported. Methods: In this retrospective cohort study, we enrolled intensive care unit–admitted patients if they had culture isolates of CR-GNB and underwent intravenous treatment with colistin. The occurrence of acute kidney injury (AKI) during intravenous treatment with colistin was recorded. The occurrence of colistin-induced nephrotoxicity was compared between two formulations of colistin, Locolin®, and Colimycin®. Treatment outcomes associated with the occurrence of colistin-induced nephrotoxicity were also investigated. Results: Among 195 patients, 95 who were treated with Locolin® and 100 who were treated with Colimycin® were included for analysis. Patients treated with Locolin® had a higher rate of occurrence of stage 2 (46.3% vs. 32%, p = 0.040) and stage 3 (29.5% vs. 13%, p = 0.005) AKI than did those treated with Colimycin®. In multivariate analysis, the presence of septic shock (adjusted odds ratio [aOR] 2.17, 95% confidence interval [CI] 1.10–4.26) and inappropriate colistin dosage (aOR 2.52, 95% CI 1.00–6.33) were clinical factors associated with colistin-induced nephrotoxicity. Treatment with Colimycin® was an independent factor associated with a lower risk of colistin-induced nephrotoxicity (aOR 0.37, 95% CI 0.18–0.77). The mortality rate was comparable between patients with and without colistin-induced nephrotoxicity. Conclusions: The risk of colistin-induced nephrotoxicity significantly varied in different formulations of colistin in critically ill patients. Colistin-induced nephrotoxicity was not associated with increased mortality rate.

Background: Chronic infections played a detrimental role on health outcomes in the aged population, and had complex associations with lymphocyte subsets distribution. Our study aimed to explore the predictive roles of chronic infections, lymphopenia, and lymphocyte subsets on unexpected admission and mortality in the institutionalized oldest-old during 3 year follow-up period.Results: There were 163 participants enrolled prospectively with median age of 87.3 years (IQR: 83.1–90.2), male of 88.3%, and being followed for 156.4 weeks (IQR: 136.9–156.4 weeks). The unexpected admission and mortality rates were 55.2 and 24.5% respectively. The Cox proportional hazards models demonstrated the 3rd quartile of cytomegalovirus IgG (OR: 3.26, 95% CI: 1.55–6.84), lymphopenia (OR: 2.85, 95% CI: 1.2–6.74), and 1st quartile of CD19⁺B cell count (OR: 2.84, 95% CI: 1.29–6.25) predicted elevated risks of unexpected admission after adjusting for potential confounders; while the 3rd quartile of CD3⁺T cell indicated a reduced risk of mortality (OR: 0.19, 95% CI: 0.05–0.71). Negative association between CMV IgG and CD19⁺B cell count suggested that CMV infection might lead to B cell depletion via decreasing memory B cells repertoire.Conclusions: CMV infection, lymphopenia, and CD19⁺B cell depletion might predict greater risk of unexpected admission, while more CD3⁺T cell would suggest a reduced risk of mortality among the oldest-old population. A non-linear or U-shaped relationship was supposed between health outcomes and CMV infection, CD3⁺T cell, or CD19⁺B cell counts. Further prospective studies with more participants included would be needed to elucidate above findings.

BackgroundColistin is widely used for the treatment of nosocomial infections caused by carbapenem-resistant gram-negative bacilli (CR-GNB). Colistin-induced nephrotoxicity is one of the major adverse reactions during colistin treatment. Comparisons of colistin-induced nephrotoxicity between different formulations of colistin are rarely reported. MethodsWe conducted a retrospective cohort study that enrolled ICU-admitted patients with cultured isolates of CR-GNB and treatment with intravenous colistin. Occurrences of acute kidney injury (AKI) during treatment with intravenous colistin were recorded. Colistin-induced nephrotoxicity between two formulations of colistin, Locolin® and Colimycin®, were compared. The treatment outcomes associated with the occurrence of colistin-induced nephrotoxicity were also investigated.ResultsA total of 195 patients, 95 treated with Locolin® and 100 treated with Colimycin®, were included for analysis. Patients treated with Locolin® had a higher rate of occurrence of stage 2 (46.3% vs. 32%, p=0.040) and stage 3 (29.5% vs. 13%, p=0.005) AKI than did those treated with Colimycin®. In multivariate analysis, the presence of septic shock (adjusted odds ratio (aOR) 2.07, 95% confidence interval (CI) 1.05–4.06), and inappropriate colistin dosage (aOR 2.49, 95% CI 1.01–60.16) were clinical factors associated with colistin-induced nephrotoxicity. Treatment with Colimycin® was an independent factor associated with a lower risk of colistin-induced nephrotoxicity (aOR 0.36, 95% CI 0.17-0.74). Other clinical factors associated with colistin-induced nephrotoxicity included the presence of septic shock (aOR 2.17, 95% CI 1.10-4.26) and inappropriate colistin dosage (aOR 2.52, 95% CI 1.00-6.33). A comparable mortality rate was noted between patients with and without colistin-induced nephrotoxicity. ConclusionsThe risk of colistin-induced nephrotoxicity significantly varied in different formulations of colistin in critically ill patients. Colistin-induced nephrotoxicity was not associated with increased mortality.