The impact of the fluconazole trailing effect on the persistence of Candida albicans bloodstream infection when treated with fluconazole.

OBJECTIVES: The trailing effect of Candida species is a phenomenon characterized by reduced but persistent growth at antifungal concentrations above the MIC. We assessed the impact of trailing growth on the persistence of Candida albicans candidemia in patients receiving fluconazole (FLC) therapy. METHODS: We retrospectively investigated candidemia isolates at three hospitals in southern Taiwan between 2013 and 2020. Patients treated with FLC for FLC-susceptible C. albicans candidemia were enrolled. The degree of trailing was determined as the average growth above the MIC divided by the measured growth at the lowest drug concentration using the EUCAST method and classified into four categories: residual (0.1-5%), slight (6-10%), moderate (11-15%), and heavy trailers (>15%). RESULTS: Among isolates from 190 patients, the proportions of heavy trailers at 24 hours, 48 hours, and 72 hours were 63.7% (121/190), 63.2% (120/190), and 74.7% (142/190), respectively. Persistent candidemia was observed in 17 (8.9 %) patients. The proportion of persistent C. albicans candidemia in heavy trailing isolates at 48 hours was higher than in isolates without heavy trailing (13.3% [16/120] vs. 1.4% [1/70], p = 0.007). A multivariate analysis showed that immunosuppression (OR = 7.92; 95% CI: 2.38-26.39, p = 0.001), hospitalization days after the index date of C. albicans identification (OR = 1.03; 95% CI: 1.01-1.05, p = 0.011), and heavy trailing isolates at 48 hours (OR = 10.04; 95% CI: 1.27-79.88, p = 0.029) were independent factors for persistent candidemia. DISCUSSION: The current study revealed that heavy trailing in C. albicans isolates is associated with persistent candidemia in patients receiving FLC treatment.

Application of machine learning for mortality prediction in patients with candidemia: Feasibility verification and comparison with clinical severity scores.

BACKGROUND: Clinical severity scores, such as acute physiology, age, chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), Pitt Bacteremia Score (PBS), and European Confederation of Medical Mycology Quality (EQUAL) score, may not reliably predict candidemia prognosis owing to their prespecified scorings that can limit their adaptability and applicability. OBJECTIVES: Unlike those fixed and prespecified scorings, we aim to develop and validate a machine learning (ML) approach that is able to learn predictive models adaptively from available patient data to increase adaptability and applicability. METHODS: Different ML algorithms follow different design philosophies and consequently, they carry different learning biases. We have designed an ensemble meta-learner based on stacked generalisation to integrate multiple learners as a team to work at its best in a synergy to improve predictive performances. RESULTS: In the multicenter retrospective study, we analysed 512 patients with candidemia from January 2014 to July 2019 and compared a stacked generalisation model (SGM) with APACHE II, SOFA, PBS and EQUAL score to predict the 14-day mortality. The cross-validation results showed that the SGM significantly outperformed APACHE II, SOFA, PBS, and EQUAL score across several metrics, including F1-score (0.68, p < .005), Matthews correlation coefficient (0.54, p < .05 vs. SOFA, p < .005 vs. the others) and the area under the curve (AUC; 0.87, p < .005). In addition, in an independent external test, the model effectively predicted patients' mortality in the external validation cohort, with an AUC of 0.77. CONCLUSIONS: ML models show potential for improving mortality prediction amongst patients with candidemia compared to clinical severity scores.

Vitamin D and Diabetic Kidney Disease.

Vitamin D is a hormone involved in many physiological processes. Its active form, 1,25(OH)2D3, modulates serum calcium-phosphate homeostasis and skeletal homeostasis. A growing body of evidence has demonstrated the renoprotective effects of vitamin D. Vitamin D modulates endothelial function, is associated with podocyte preservation, regulates the renin-angiotensin-aldosterone system, and has anti-inflammatory effects. Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease worldwide. There are numerous studies supporting vitamin D as a renoprotector, potentially delaying the onset of DKD. This review summarizes the findings of current research on vitamin D and its role in DKD.

Correlation of Vitek 2 and Agar dilution for levofloxacin susceptibility testing and clinical outcomes of Enterobacterales bacteremia with 2019 CLSI breakpoints.

In 2019, the CLSI lowered the susceptible levofloxacin breakpoints for Enterobacterales from a MIC of ≤2 µg/mL to ≤0.5 µg/mL. The study evaluated the correlation between the susceptibility profiles obtained by the Vitek 2 and agar dilution (AD) methods in levofloxacin MIC ≤2 µg/mL isolates and its clinical impacts. Two hundred fifty-three Enterobacterales isolates and 222 patients treated with levofloxacin for Enterobacterales bacteremia were enrolled for analysis. There was 86.2% categorical agreement, 5 very major errors, and 30 minor errors based on the 2019 CLSI breakpoints. Higher levofloxacin MICs (1 or 2 µg/mL) determined using Vitek 2 or AD predicted early clinical failure (P < 0.001 for Vitek 2 and P = 0.001 for AD). In conclusion, Vitek 2 performance for levofloxacin susceptibility testing of Enterobacterales declined according to the 2019 CLSI criteria compared with the pre-2019 criteria. Although discrepant results were obtained, the MICs measured by Vitek 2 could still predict treatment outcomes.

Clinical effectiveness of beta-lactams versus fluoroquinolones as empirical therapy in patients with diabetes mellitus hospitalized for urinary tract infections: A retrospective cohort study.

BACKGROUND: Diabetic patients are at risk of severe urinary tract infections (UTIs). Due to the emerging resistance rates to fluoroquinolones and ß-lactams, we aimed to evaluate the effectiveness of ß-lactams versus fluoroquinolones as empirical therapy for diabetic patients hospitalized for UTIs. METHODS: A retrospective cohort study was conducted in a medical center in Taiwan between 2016 and 2018. Patients with type 2 diabetes, aged ≥20 and hospitalized for UTIs were enrolled. Patients with UTI diagnosis within one year before the admission, co-infections at the admission, or ≥2 pathogens in the urine cultures were excluded. The primary outcome was empiric treatment failure. RESULTS: 298 patients were followed for at least 30 days after the admission. Escherichia coli (61.07%) was the most common pathogen. The resistance rates of the pathogens to levofloxacin were 28.52% and 34.22% according to the historical Clinical and Laboratory Standards Institute (CLSI) breakpoints and the updated 2019 CLSI breakpoints, respectively. The resistance rates of ceftazidime and cefepime were 21.81% and 11.41%, respectively. Empirical ß-lactams were associated with less treatment failure compared to fluoroquinolones (adjusted OR = 0.32, 95% CI = 0.17-0.60). Beta-lactams were associated with less treatment failure than fluoroquinolones when appropriatness was determined by the pre-2019 CLSI breakpoints but not the 2019 CLSI breakpoints. CONCLUSIONS: In diabetic patients hospitalized for UTIs, ß-lactams were associated with less empiric treatment failure compared to fluoroquinolones when the resistance rate to fluoroquinolone is higher than ß-lactams. The updated 2019 CLSI breakpoint for fluoroquinolone was better than pre-2019 CLSI breakpoints to correlate with treatment outcomes for hospitalized UTIs in diabetic patients.

Investigating the effectiveness of adjuvant therapy for patients with hormone receptor-positive ductal carcinoma in situ.

BACKGROUND: This study compared the recurrence risk of single versus dual adjuvant radiotherapy (RT) and hormonal therapy (HT) following breast-conserving surgery (BCS) in patients with hormone receptor-positive ductal carcinoma in situ (DCIS). METHODS: This retrospective cohort study used the Taiwan Cancer Registry database linking to the Taiwan National Health Insurance data from 2011 to 2016. We compared the recurrence risk between BCS-based regimens in Cox regressions and presented as adjusted hazard ratio (HR) and 95% confidence interval (95%CI). RESULTS: The 1,836 study cohort with a low-to-intermediate risk of recurrence was grouped into BCS alone (6.1%), BCS+RT (6.2%), BCS+HT (23.4%) and BCS+HT+RT (64.3%) according to the initial treatments. During the follow-up (median: 3.3 years), the highest 5-year recurrence-free survival rate was in BCS+RT (94.1%) group and followed by BCS+HT+RT (92.8%), BCS+HT (87.4%) and BCS alone (84.9%). Of the single adjuvant therapies, RT was more effective than HT. Both BCS+HT (HR: 1.52, 95%CI: 0.99-2.35) and BCS+RT (HR: 1.10, 95%CI: 0.50-2.41) did not significantly increase recurrence risk comparing against the BCS+HT+RT group. CONCLUSION: Single adjuvant demonstrated a similar subsequent recurrence risk with dual adjuvant. This study supports the proposition to de-escalate adjuvant treatments in patients with low-to-intermediate risk of DCIS recurrence.

Central Venous Catheter Penetrating the Spinal Canal via the Spinal Foramen: A Case Report and Literature Review.

The insertion of a neck central venous catheter (CVC) is a common procedure in medical practice; however, malposition and complications frequently occur. A 66-year-old woman had CVC inserted through the right internal jugular vein. CVC malposition was observed on chest radiography and computed tomography. The catheter was accidentally inserted via the vertebral vein and had entered the C6-C7 intervertebral foramen, penetrating the spinal canal with the tip at the T2 epidural space. We present this rare CVC complication to demonstrate the possibility of incorrect insertion of the catheter and penetration of the spinal canal, possibly causing neuronal damage.

Clinical Impact of the Revised 2019 CLSI Levofloxacin Breakpoints in Patients with Enterobacterales Bacteremia.

The Clinical and Laboratory Standards Institute (CLSI) revised the fluoroquinolone MIC breakpoints for Enterobacterales in 2019, based on pharmacokinetic/pharmacodynamic analyses. However, clinical evidence supporting these breakpoint revisions is limited. A retrospective study was conducted at 3 hospitals in Taiwan between January 2017 and March 2019. Patients treated with levofloxacin for bacteremia caused by members of the Enterobacterales with high MICs (1 or 2 µg/ml; levofloxacin susceptible by pre-2019 CLSI breakpoints) were compared with those with low-MIC bacteremia (≤0.5 µg/ml; levofloxacin susceptible by 2019 CLSI breakpoints) to assess therapeutic effectiveness by multivariable logistic regression. The primary outcome was 30-day mortality, and the secondary outcome was the emergence of levofloxacin-resistant isolates within 90 days after levofloxacin initiation. A total of 308 patients were eligible for the study. Kaplan-Meier analysis showed that patients infected with high-MIC isolates (n = 63) had a significantly lower survival rate than those infected with low-MIC isolates (n = 245) (P = 0.001). Multivariable logistic regression revealed that high levofloxacin MIC was a predictor of 30-day mortality (odds ratio [OR], 6.05; 95% confidence interval [CI], 1.51 to 24.18; P = 0.011). We consistently found similar results in a propensity score-matched cohort (OR, 5.38; 95% CI, 1.06 to 27.39; P = 0.043). The emergence of levofloxacin-resistant isolates was more common in the high-MIC group than the low-MIC group (25.0% versus 7.5%; P = 0.065). An estimated area under the concentration-time curve/MIC ratio of ≥87 was significantly associated with better survival (P = 0.002). In conclusion, patients infected with isolates with levofloxacin MICs within the pre-2019 CLSI susceptible range of 1 or 2 µg/ml exhibited higher mortality than those infected with isolates with MICs of ≤0.5 µg/ml.

Usefulness of EQUAL Candida Score for predicting outcomes in patients with candidaemia: a retrospective cohort study.

BACKGROUND: The European Confederation of Medical Mycology (ECMM) Quality of Clinical Candidaemia Management (EQUAL) score is a tool designed by the ECMM to measure guideline adherence. The current study investigated the association between EQUAL scores and clinical outcomes. METHODS: This retrospective study was conducted in three hospitals in Taiwan. Patients with candidaemia between January 2014 and July 2018 were enrolled. Guideline adherence was evaluated using EQUAL score indicators. Clinical outcomes and predictors of 30-day mortality were investigated. RESULTS: A total of 384 patients were enrolled. The overall mean EQUAL score was 8.91 ± 3.42 (9.42 ± 3.60 in survivors vs. 8.10 ± 2.94 in non-survivors, p < 0.001). Higher scores were positively correlated with survival (p < 0.001). Scores of 16-22 indicated the highest survival rates (p for trend <0.001). The Kaplan-Meier plot revealed that patients with EQUAL scores ≥10 exhibited significantly higher survival rates (p < 0.001) than those with scores <10. Multivariable analysis revealed that EQUAL scores ≥10 (odds ratio (OR) 0.37, 95% confidence interval (CI) 0.19-0.74), advanced age (OR 1.02, 95% CI 1.00-1.04), septic shock (OR 4.42, 95% CI 2.09-9.36), high sequential organ failure assessment scores (OR 4.28, 95% CI 2.15-8.52), intravascular catheter-related source (OR 0.42, 95% CI 0.19-0.94) and central venous catheter retention (OR 5.41, 95% CI 2.06-14.24) were independent predictors of 30-day mortality. DISCUSSION: Greater guideline adherence with a higher EQUAL score was significantly associated with survival. An EQUAL score cutoff point <10 predicted 30-day mortality.

Upregulation of FcγRIIB by resveratrol via NF-κB activation reduces B-cell numbers and ameliorates lupus.

Resveratrol, an anti-inflammatory agent, can inhibit pro-inflammatory mediators by activating Sirt1, which is a class III histone deacetylase. However, whether resveratrol can regulate inhibitory or anti-inflammatory molecules has been less studied. FcγRIIB, a receptor for IgG, is an essential inhibitory receptor of B cells for blocking B-cell receptor-mediated activation and for directly inducing apoptosis of B cells. Because mice deficient in either Sirt1 or FcγRIIB develop lupus-like diseases, we investigated whether resveratrol can alleviate lupus through FcγRIIB. We found that resveratrol enhanced the expression of FcγRIIB in B cells, resulting in a marked depletion of plasma cells in the spleen and notably in the bone marrow, thereby decreasing serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB by resveratrol involved an increase of Sirt1 protein and deacetylation of p65 NF-κB (K310). Moreover, increased binding of phosphor-p65 NF-κB (S536) but decreased association of acetylated p65 NF-κB (K310) and phosphor-p65 NF-κB (S468) to the -480 promoter region of Fcgr2b gene was responsible for the resveratrol-mediated enhancement of FcγRIIB gene transcription. Consequently, B cells, especially plasma cells, were considerably reduced in MRL/lpr mice, leading to improvement of nephritis and prolonged survival. Taken together, we provide evidence that pharmacological upregulation of FcγRIIB expression in B cells via resveratrol can selectively reduce B cells, decrease serum autoantibodies and ameliorate lupus nephritis. Our findings lead us to propose FcγRIIB as a new target for therapeutic exploitation, particularly for lupus patients whose FcγRIIB expression levels in B cells are downregulated.