Completion and Adverse Drug Events of Latent Tuberculosis Infection Treatment in Patients Receiving Dialysis: Predictors and Impacts of Different Regimens in a Prospective Cohort Study.

Although patients with end-stage renal disease receiving maintenance hemodialysis are at high risk for tuberculosis, the optimal treatment regimen for latent tuberculosis infection (LTBI) in this group has scarcely been studied for predictors of completion rate and adverse drug events (ADE). We prospectively enrolled dialysis patients for LTBI intervention from three medical centers in Taiwan. LTBI treatments were 3 months of weekly rifapentine plus isoniazid (3HP) and 9 months of daily isoniazid (9H). Completion rate, ADE, and reasons for treatment termination were recorded. Factors associated with treatment termination and ADE were analyzed using multivariate logistic regression. In all, 91 treatment courses (41 9H and 50 3HP) were surveyed. The completion rates were 61% for 9H and 82% for 3HP (P = 0.046). Use of 9H and development of ADE with a grade of ≥2 (≥grade 2 ADE) were associated with treatment termination. Hypersensitivity occurred in 29.2% of subjects in the 3HP group and 10.8% in the 9H group (P = 0.035) and independently correlated with 3HP regimen, diabetes mellitus (DM), and peritoneal dialysis (PD). Similarly, the independent predictors of ≥grade 2 ADE were use of 3HP regimen, presence of DM, and use of PD, whereas ≥grade 3 ADE were associated with eosinophil counts of >700/mm3 after 2 weeks of LTBI treatment even after adjustment for age and gender. In conclusion, for patients on dialysis, 3HP showed a higher rate of completion but also a higher rate of ≥grade 2 ADE than 9H. In addition, DM and PD were risk factors for ≥grade 2 ADE. Eosinophilia after 2-week treatment might be an alert for severe ADE.

Tp0136 targets fibronectin (RGD)/Integrin ß1 interactions promoting human microvascular endothelial cell migration.

Lesion healing without treatment is a unique clinical characteristic of the early stages of syphilis infection. Angiogenesis, which involves endothelial cell migration, is an important process in wound healing. Tp0136, an outer membrane protein of T. pallidum, has the ability to bind host fibronectin-producing cells, which plays a crucial role in the pathogenesis of syphilis. In this research, we purposed to analyze the role of Tp0136 in the migration of human microvascular endothelial (HMEC-1) cells and to explore the related mechanism. First, Tp0136 significantly promoted HMEC-1 cell migration. Furthermore, the levels of C-C motif ligand 2 (CCL2) mRNA and protein expression rose with the concentration and time increasing of Tp0136. The migration of HMEC-1 cells was significantly suppressed by an anti-CCL2 antibody and a CCR2 (the CCL2 receptor) inhibitor. Further study revealed that, in cells pretreated with anti-fibronectin antibody, anti-integrin ß1 antibody or RGD (Arg-Gly-Asp), the expression levels of CCL2 induced by Tp0136 were notably decreased. Additionally, after pretreatment with an anti-fibronectin antibody, an anti-integrin ß1 antibody or RGD, the migration of HMEC-1 cells treated with Tp0136 was obviously suppressed. These results show that Tp0136 promots the migration of HMEC-1 cells by inducing CCL2 expression via the interaction of the fibronectin RGD domain with integrin ß1 and the CCL2/CCR2 signaling pathway, and these interactions may contribute to the mechanisms that increase the capacity for self-healing syphilis infection.

Impact of high plasma concentrations of linezolid in Taiwanese adult patients- therapeutic drug monitoring in improving adverse drug reactions.

BACKGROUND: Previous studies have shown that the development of thrombocytopenia was associated with the elevated plasma concentration of linezolid, but little is known about the relationship between other uncommon adverse drug reactions (ADRs) and plasma concentration. The appropriate dosing adjustment has remained controversial. This prospective observational study was conducted to investigate the association between the plasma concentration of linezolid, ADRs, and clinical outcomes. METHODS: Adult patients on linezolid treatment undergoing at least one therapeutic drug monitoring (TDM) were enrolled. The association between linezolid concentrations and ADRs was examined by multivariate Cox regression model. Predictors of linezolid concentrations was determined by linear regression model. The cut-off point of linezolid concentration and the effect of dosing adjustments based on TDM was also explored. RESULTS: Of 50 patients enrolled in the study, plasma concentrations were 1.5-3 times higher than what was described in the prescribing information. The median minimum concentration (Cmin) was significantly higher in patients with thrombocytopenia compared to patients without thrombocytopenia (13.0 vs. 7.2 µg/mL, P = 0.0273), and a higher median maximum concentration was also observed in patients with lactic acidosis (33.0 vs. 27.5 µg/mL, P = 0.0420). The Cmin was elevated in patients with advanced age and severely impaired renal function. Dosing adjustment tailored by early TDM with the upper limit of Cmin 9 µg/mL may improve platelet counts. CONCLUSION: Elevated linezolid concentrations were associated with thrombocytopenia and lactic acidosis. TDM-guided dosing adjustment could be considered as a pragmatic way to mitigate thrombocytopenia.

Prediction factors of weight control intention in Chinese young adults.

BACKGROUND: Weight control is a widespread phenomenon among young adults, especially in women. AIM: This study aimed to determine the prediction factors of weight control intention in a young Chinese sample. METHODS: A cross-sectional study was conducted with 963 (276 male and 687 female; mean age 21.8 ± 4.4 years) adult students from a university in Taiwan. The data were collected from October 2016 to January 2017. Body mass index (BMI), the Chinese version of the Weight Self-Stigma Questionnaire, the Body Areas Satisfaction Scale and the Media Influence Questionnaire were used as data collection instruments. RESULTS: The participants with weight control intention had higher BMI, weight self-stigma and media influence scores and lower body satisfaction scores than those without the intention. Female sex, BMI, weight self-stigma, body satisfaction and media influence were significant predictors of weight control intention for all participants. CONCLUSION: Before conducting weight loss programmes, the perception of weight self-stigma and the influence of social media on body image should be confirmed, particularly in women with intention to lose weight.

Latent Tuberculosis Infection Increases in Kidney Transplantation Recipients Compared With Transplantation Candidates: A Neglected Perspective in Tuberculosis Control.

BACKGROUND: The prevalence and incidence of latent tuberculosis infection (LTBI) in patients with kidney transplantation remain unclear. METHODS: In this prospective study, we enrolled kidney transplantation candidates (KTCs) and recipients (KTRs) from 2014 to 2018. We defined LTBI as a positive result of QuantiFERON-TB Gold In-tube (QFT). We analyzed the predictors for LTBI acquisition and followed up on QFT assay test for 2 years among those initially without LTBI. RESULTS: Of 425 patients enrolled, 305 (71.8%) patients belonged to the KTC group and 120 (28.2%) to the KTR group. The initial QFT showed positive results in 32 (10.5%) and 24 (20.0%) patients in the KTC and KTR groups, respectively (P = .009). The QFT response value in patients with LTBI was higher in the KTR group than in the KTC group (1.85 vs 1.06 IU/mL, P = .046). Multivariate logistic regression showed that old age, absence of bacillus Calmette-Guérin (BCG) scar, presence of donor-specific antibody, and KTR group were independent factors for positive LTBI. For participants with initial negative QFT, positive QFT conversion within a 2-year follow-up was higher after kidney transplantation (20%) than in KTCs (5.5%) (P = .034). CONCLUSIONS: This study is the first cohort to follow up LTBI status in patients with kidney transplantation and shows its higher prevalence and incidence in KTRs. It indicates that surveillance of LTBI after renal transplantation is important. In addition to status of kidney transplantation, old age, no BCG vaccination, and positive donor-specific antibody are also positive predictors for LTBI.

Metabolomics analysis of plasma reveals voriconazole-induced hepatotoxicity is associated with oxidative stress.

Voriconazole is one of the most frequently used antifungal drugs for the initial treatment of invasive aspergillosis, but liver-related adverse events occur frequently and usually lead to drug discontinuation. Moreover, the mechanism of voriconazole-induced hepatotoxicity remains unsettled. A holistic understanding of its mechanism is critical to prevent liver-related adverse events. Metabolomics has been demonstrated to be a helpful strategy for investigating drug-induced toxicity. This study aimed to utilize human plasma samples to investigate the mechanism of voriconazole-induced hepatotoxicity through a metabolomics approach. Patients that were administered voriconazole were classified into a voriconazole-induced hepatotoxicity group and control group (n = 65, 18% hepatotoxicity). Plasma samples were analyzed by targeted metabolomics using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry. The obtained peak areas for each metabolite were utilized for correlation analysis, fold change evaluation, and univariate statistical tests to identify metabolites associated with voriconazole-induced hepatotoxicity. This study showed a significantly lower glutamine-to-glutamate ratio (p = .04) and a higher ß-N-acetylglucosamine (p = .003) in the voriconazole-induced hepatotoxicity group, implying the presence of oxidative stress. Other significant metabolites also indicated several adaptive responses to oxidative stress in patients with voriconazole-induced toxicity, including cell repair, energy production, and alteration to bile acid hemostasis. Furthermore, a metabolite panel consisting of α-ketoglutarate, glycocholate, and ß-N-acetylglucosamine demonstrated better performance for detecting voriconazole-induced hepatotoxicity than conventional liver function tests. These metabolomics findings reveal that voriconazole-induced hepatotoxicity is associated with oxidative stress.

Therapeutic drug monitoring of the teicoplanin trough level after the loading doses in patients receiving venoarterial extracorporeal membrane oxygenation.

BACKGROUND: The optimal loading dose of teicoplanin in patients receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) has never been determined by therapeutic drug monitoring. This study investigated the appropriateness of proposed loading dose regimens of teicoplanin when administered to patients receiving VA-ECMO by using a previously proposed loading dosage and measuring the teicoplanin trough concentration (Ctrough). METHODS: Patients who initiated teicoplanin therapy while receiving VA-ECMO were enrolled. Every included patient received four loading doses of teicoplanin at a dose of 12 mg/kg. The first three doses were administered 12 h apart, and the fourth dose was administered 24 h after the third dose. Blood samples were collected before administering the maintenance dose (i.e., the fifth dose), and the teicoplanin Ctrough was measured. Serum teicoplanin levels were determined using an Agilent 1290 ultra-high performance liquid chromatography system. RESULTS: The teicoplanin Ctrough was successfully tested in 11 patients. Their median age was 68.2 years, and 81.8% of them were men. The median of each loading dose was 11.6 (range, 10.7-12.8) mg/kg. The median teicoplanin Ctrough was 22.01 (range, 14.85-44.84) mg/L. All patients had a Ctrough of more than 10 mg/L, whereas 90.9% (10/11) of the patients achieved a Ctrough of more than 15 mg/L. CONCLUSION: The loading dosage consisting of four doses of teicoplanin administered within the first 72 h at a dose of 12 mg/kg/dose could achieve an adequate therapeutic Ctrough of teicoplanin in patients receiving VA-ECMO.

Metabolomics Investigation of Voriconazole-Induced Hepatotoxicity in Mice.

Voriconazole (VCZ) is a widely used triazole drug for the treatment of serious incidence of invasive fungal infections (IFIs), and its most commonly reported clinical side effect is hepatotoxicity. The mechanism of VCZ-induced hepatotoxicity is unclear, and no specific marker can be used for prediction and diagnosis. This study aims to apply the targeted metabolomics approach to identify specific VCZ-induced metabolites related to hepatotoxicity via liquid chromatography-triple quadrupole mass spectrometry (LC-QqQ-MS) in a C57BL/6 mouse model. Mice treated with three repeated doses of 40 mg/kg VCZ by tail vein injection to induce hepatotoxicity (VCZ-induced hepatotoxicity group, n = 8) were compared with mice without treatment (control group, n = 10). Both liver tissue and plasma were collected and analyzed to propose underlying mechanisms associated with VCZ-induced hepatotoxicity. The results indicated that the metabolites associated with oxidative stress were altered, and alterations in the metabolites involved in glutathione biosynthesis were noticed. The ratio of glutamine to glutamate showed a significant reduction in the VCZ-induced hepatotoxicity group compared to the control group, suggesting that glutamine might be transformed into glutamate for glutathione biosynthesis. Accordingly, we proposed that VCZ-induced hepatotoxicity is associated with oxidative stress to cause cell dysfunction, leading to alterations in energy metabolism, the urea cycle, and nucleoside metabolism. To the best of our knowledge, this is the first study to apply metabolomics for investigating the mechanism of VCZ-induced hepatotoxicity.

Thymoquinone inhibits metastasis of renal cell carcinoma cell 786-O-SI3 associating with downregulation of MMP-2 and u-PA and suppression of PI3K/Src signaling.

Phytochemicals represent an important source of novel anticancer and chemotherapeutic agents. Thymoquinone (TQ) is the major bioactive phytochemical derived from the seeds of Nigella sativa and has shown potent anticancer activities. In this study, we aimed to investigate the anticancer activity of Thymoquinone on the human renal carcinoma cell 786-O-SI3 and the underlying mechanism. By using cell proliferation assay, wound healing, and invasion assay, we found that Thymoquinone did not affect the viability of 786-O-SI3 and human kidney-2, but clearly inhibited the migration and invasion of 786-O-SI3. Further zymography and immunoblotting analysis showed that Thymoquinone downregulated the activity and expression of matrix metalloproteinase (MMP)-2 and urokinase-type plasminogen activator (u-PA) and attenuated the adhesion of 786-O-SI3 to type I and type IV collagen. Kinase cascade assay indicated that Thymoquinone inhibited the phosphorylation of phosphatidylinositol 3-kinase, Akt, Src, and Paxillin. In addition, Thymoquinone also decreased the level of fibronectin, N-cadherin, and Rho A. In parallel, Thymoquinone dose-dependently suppressed the transforming growth factor (TGF)-ß-promoted u-PA activity and expression, as well as the cell motility and invasion of 786-O-SI3. Furthermore, tumor xenograft model revealed that Thymoquinone in vivo inhibited the 786-O-SI3 metastasizing to the lung. Collectively, these findings indicate that Thymoquinone inhibits the metastatic ability of 786-O-SI3, suggesting that Thymoquinone might be beneficial to promote the chemotherapy for renal cell carcinoma.

Survival in Patients with Candida glabrata Bloodstream Infection Is Associated with Fluconazole Dose.

Robust pharmacodynamic indices that align fluconazole dose or exposure with outcomes in invasive candidiasis due to Candida glabrata remain elusive. The purpose of this retrospective multicenter study was to evaluate a cohort of 127 patients with C. glabrata fungemia treated with fluconazole, using adjusted analyses to identify risk factors for 28-day death. No significant correlations were found between fluconazole area under the curve (AUC), AUC/MIC ratio, or MIC and survival. In multivariate logistic regression analyses, however, higher average fluconazole dose (odds ratio [OR], 1.006 [95% confidence interval [CI], 1.001 to 1.010]; P = 0.008), average fluconazole dose of ≥400 mg (OR, 3.965 [95% CI, 1.509 to 10.418]; P = 0.005), and higher fluconazole dose on day 1 of therapy (OR, 1.007 [95% CI, 1.002 to 1.011]; P = 0.002) were found to be independent predictors of 28-day survival. Additionally, the presence of a central venous catheter at the time of infection was found to be a significant risk factor for death. In conclusion, we found fluconazole dose to be an independent predictor of 28-day survival for patients with C. glabrata fungemia, with doses of ≥400 mg/day being associated with 28-day survival rates approaching 90%. These data indicate the use and efficacy of fluconazole in the treatment of this serious infection. Aggressive dosing appears to be necessary when fluconazole is used for the treatment of C. glabrata fungemia, irrespective of MIC.

Early linezolid-associated lactic acidosis in a patient with Child's class C liver cirrhosis and end stage renal disease.

Linezolid, an oxazolidinone antibiotic, does not required dose adjustment in patients with Child's class A and B liver cirrhosis. The dose adjustment data for Child's class C liver cirrhosis is inadequate. We reported a case of Child's class C liver cirrhosis, in which lactic acidosis, an adverse effect related to prolonged use, occurred only after two weeks of linezolid treatment. A 63-year old male had underlying diseases, such as end-stage renal disease (ESRD) and Child's class C liver cirrhosis, and was admitted for hepatic encephalopathy management and liver transplantation evaluation. Spontaneous bacterial peritonitis and septic shock occurred during admission. Because ascites culture revealed vancomycin-resistant Enterococci (VRE), daptomycin was initially prescribed. Subsequently, VRE bacteremia occurred, and infective endocarditis was confirmed. Following treatment failure with daptomycin use, intravenous linezolid (600 mg q12h) was added for synergic effect. VRE bacteremia quickly resolved following linezolid treatment, and vasopressor use was reduced. Despite stable hemodynamics, lactic acidosis still persisted, and linezolid therapeutic drug monitoring was ordered. High linezolid trough concentration (49 mg/L) was found by therapeutic drug monitoring, and linezolid-associated lactic acidosis was highly suspected. Therefore, linezolid treatment was stopped and patient's lactic acid level returned to normal after one week. VRE bacteremia recurred after discontinuation of linezolid; therefore, linezolid was re-prescribed at the lower dose (600 mg). Linezolid trough concentration was within the therapeutic range this time (6.1 mg/L), and lactic acidosis did not occur when linezolid dose was reduced. Therefore, empirically decreased dose and therapeutic drug monitoring should be considered in patients with Child's class C liver cirrhosis and ESRD.

Estimation and Correction of the Blood Volume Variations of Dried Blood Spots Using a Postcolumn Infused-Internal Standard Strategy with LC-Electrospray Ionization-MS.

Dried blood spots (DBSs) have had a long history in disease screening in newborns but have gained attention in recent years in the medical care of adults because of the growing importance of personalized medicine. DBSs have several advantages, such as easy transportation, cost-effectiveness, and minimally invasive biological sampling. There are two strategies to process DBS samples. One method takes a fixed diameter of subsample, and another requires the extraction of the whole spot. The whole-spot extraction method is less affected by hematocrit-caused errors, but it requires calibration of the blood volume. We propose a novel strategy using a postcolumn infused-internal standard (PCI-IS) method with liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) for estimating and correcting blood volume variations on the DBS cards. By using PCI-IS to measure the extent of ion suppression in the first ion suppression zone in the chromatogram, the blood volume on the DBS cards can be calculated and further calibrated. We used reference blood samples with different volumes (5 to 25 µL) to construct a calibration curve between the blood volume and the extent of ion suppression. The calibration curve was used to estimate the blood volume on the DBS cards collected from 6 volunteers, with 5 designated volumes from each volunteer. The estimation accuracy of the PCI-IS method was between 74.5% and 120.3%. The validated PCI-IS method was used to estimate and calibrate blood volume variation and also to quantify the voriconazole concentration for 26 patients undergoing voriconazole therapy. A high correlation was found for the quantification results between the DBS samples and the conventionally used plasma samples (r = 0.97). The PCI-IS method was demonstrated to be a simple and accurate method for estimating and calibrating the blood volume variation on DBS cards, which greatly facilitates using the DBS method for therapeutic drug monitoring (TDM) for improving the efficacy and safety of drug therapy.

A Larger Dose of Vancomycin Is Required in Adult Neurosurgical Intensive Care Unit Patients Due to Augmented Clearance.

BACKGROUND: The objective of this study was to explore the pharmacokinetics of vancomycin and determine an appropriate dosage regimen for vancomycin in adult neurosurgical intensive care unit (ICU) patients. METHODS: First, a 20-month therapeutic drug monitoring database at a medical center was used to retrospectively analyze the pharmacokinetic parameters of vancomycin in adult neurosurgical patients. Significant covariates were selected through Pearson or Spearman correlation tests and multiple linear regressions. Pharmacokinetic models were built using significant covariates to predict vancomycin clearance. Second, a 12-month prospective cohort of neurosurgical ICU patients was recruited to validate the models. Urine and cerebrospinal fluid samples were collected, and vancomycin concentrations were determined using a high-performance liquid chromatography assay. The relation between the model-predicted and observed pharmacokinetic parameters was assessed by Pearson correlation. RESULTS: In the retrospective cohort, 98 sets of peak/trough serum concentrations obtained from 73 patients were analyzed. These patients had a mean age of 54 ± 16 years, an estimated creatinine clearance (eClCr) of 83 ± 29 mL/min, a total vancomycin clearance (ClVan) of 101 ± 41 mL/min, and a volume of distribution (Vd) of 0.93 ± 0.27 L/kg. In a subgroup analysis, the ClVan of ICU patients was higher than the ClVan of non-ICU patients (1.57 ± 0.34-fold versus 1.16 ± 0.32-fold of eClCr, P < 0.05). Fifteen patients enrolled in the prospective cohort had an average age of 67 ± 12 years, an eClCr of 108 ± 44 mL/min, a ClVan of 112 ± 29 mL/min, and a Vd of 1.03 ± 0.55 L/kg. CONCLUSIONS: Adult neurosurgical ICU patients have a significantly elevated ClVan. In this study, 2 dosing equations were derived to achieve optimal serum vancomycin concentrations for this special population.

Thermal Blanket to Improve Thermoregulation in Preterm Infants: A Randomized Controlled Trial.

OBJECTIVE: To determine the effectiveness of temperature-controlled thermal blanket as additional thermoprotection. DESIGN: Randomized controlled prospective study. SETTING: Single-center tertiary neonatal unit. PATIENTS: Inborn very low-birth-weight (< 1,500 g) infants. INTERVENTIONS: Infants were prospectively assigned to thermal blanket group or control at 1:1 ratio. Additional to radiant warmers, a prewarmed blanket of Blanketrol II (Cincinnati Sub-Zero Products, Cincinnati, OH) was applied as mattress for thermal blanket group. The outcomes included temperature and blood pressure changes. We defined hypothermia as temperature less than 36°C and hypotension as mean arterial pressure less than index infant's gestational age in weeks. MEASUREMENTS AND MAIN RESULT: Total 80 very low-birth-weight infants were allocated, and there was no between-group demographic dissimilarity. At 30th minute, fewer infants in thermal blanket group were hypothermic (43% vs 68%; p = 0.025). These infants had significantly lower prevalence of hypotension, which associated with less dopamine use in the first 6 hours of life (25% vs 50%; p = 0.016). There was no hyperthermia more than 37.5°C episode. CONCLUSIONS: By using thermal blanket to provide additional thermal protection for very low-birth-weight infants, the degree of hypothermia was improved, which related to fewer hypotensive cases and less dopamine usage.

Sheltering effect and indirect pathogenesis of carbapenem-resistant Acinetobacter baumannii in polymicrobial infection.

The role of carbapenem-resistant Acinetobacter baumannii (CRAb) in polymicrobial infection remains elusive. Having observed the ability of CRAb to shelter other susceptible bacteria from carbapenem killing, we sought to determine the factors contributing to this sheltering effect by transforming different recombinant plasmids into recipient A. baumannii cells. The sheltering effects of CRAb were reproduced in recipient A. baumannii cells that highly expressed carbapenem-hydrolyzing class D ß-lactamases (CHDLs) through their associated strong promoter. With the use of Western blot analysis and a bioassay, the highly expressed CHDLs were found to be extracellularly released and led to hydrolysis of carbapenem. The level of extracellular CHDLs increased after challenge with a higher concentration of CHDL substrates, such as carbapenem and ticarcillin. This increased CHDL may, in part, be attributed to cell lysis, as indicated by the presence of extracellular gyrase. In the planktonic condition, the sheltering effect for the cocultured susceptible bacteria might represent an indirect and passive effect of the CRAb self-defense mechanism, because coculture with the susceptible pathogen did not augment the amount of the extracellular CHDLs. Polymicrobial infection caused by CRAb and a susceptible counterpart exerted higher pathogenicity than monomicrobial infection caused by either pathogen alone in mice receiving carbapenem therapy. This study demonstrated that CHDL-producing CRAb appears to provide a sheltering effect for carbapenem-susceptible pathogens via the extracellular release of CHDLs and, by this mechanism, can enhance the pathogenesis of polymicrobial infection in the presence of carbapenem therapy.

Enhancing the identification of voriconazole-associated hepatotoxicity by targeted metabolomics.

Voriconazole-associated hepatotoxicity is a common condition that generally manifests as elevated liver enzymes and can lead to drug discontinuation. Careful monitoring of voriconazole-associated hepatotoxicity is needed but there are no specific plasma biomarkers for this condition. Metabolomics has emerged as a promising technique for investigating biomarkers associated with drug-induced toxicity. The aim of this study was to use targeted metabolomics to evaluate seven endogenous metabolites as potential biomarkers of voriconazole-associated hepatotoxicity. Patients undergoing therapeutic drug monitoring of voriconazole were classified into a hepatotoxicity group (18 patients) or a control group (153 patients). Plasma samples were analysed using ultra-high-performance liquid chromatography coupled to mass spectrometry. Metabolite concentrations in the two groups were compared. Areas under the receiver operating characteristic (AUROC) curves generated from logistic regressions were used to correlate the concentrations of these seven metabolites with voriconazole trough concentrations and conventional liver biochemistry tests. Glycocholate and α-ketoglutarate levels were significantly higher in the hepatotoxicity group compared with the control group (false discovery rate-corrected P < 0.001 and P = 0.024, respectively). The metabolites glycocholate (AUROC = 0.795) and α-ketoglutarate (AUROC = 0.696) outperformed voriconazole trough concentrations (AUROC = 0.555) and approached the performance of alkaline phosphatase (AUROC = 0.876) and total bilirubin (AUROC = 0.815). A panel of glycocholate combined with voriconazole trough concentrations (AUROC = 0.827) substantially improved the performance of voriconazole trough concentrations alone in predicting hepatotoxicity. In conclusion, the panel integrating glycocholate with voriconazole trough concentrations has great potential for identifying voriconazole-associated hepatotoxicity.

Recurrence of Diabetic Foot Complications: A Domino Effect Leading to Lethal Consequences-Insights From a National Longitudinal Study.

Background: Foot complications are common in people with diabetes mellitus (DM), leading to increased health care utilization, heightened mortality risk, and notable recurrence rates even after treatment. This retrospective cohort study aimed to investigate the impact of repeated occurrence of DM-related foot complications on the risk of all-cause mortality and to identify the potential risk factors associated with repeated events. Methods: People with DM admitted with foot complications (ulcer, skin and soft tissue infection, or osteomyelitis) from 2012 to 2014 were identified from Taiwan's National Health Insurance Research Database, with a 3-year follow-up for repeated events. We categorized the study subjects based on their cumulative number of hospital admissions with foot complications. Logistic regression was conducted to explore the potential risk factors associated with repeated diabetic foot events. Kaplan-Meier curves and Cox proportional hazard models were used to examine the associations between repeated diabetic foot events and all-cause mortality. Results: In this study, 28 754 eligible individuals were enrolled and classified into 3 groups: no repeated diabetic foot events (76.1%), 1 repeated event (16.0%), and 2 or more repeated events (7.9%). Logistic regression revealed that advanced age, male sex, congestive heart failure, dyslipidemia, hypertension, nephropathy, retinopathy, neuropathy, peripheral vascular disease, diabetes-related preventable hospitalizations, and outpatient visits due to diabetic foot were significantly associated with repeated events of diabetic foot complications. Compared with those with no repeated events, the adjusted hazard ratios for all-cause mortality were 1.26 (95% CI, 1.19-1.34) for 1 repeated event and 1.36 (95% CI, 1.26-1.47) for 2 or more repeated events. Conclusions: The significant association between repeated diabetic foot and elevated mortality risk highlights the critical necessity for proactive and targeted patient care within clinical practice. More research to delve into the predictive factors related to the repeated occurrence of diabetic foot is needed to provide additional insights for prevention strategies.

Early Therapeutic Drug Monitoring Optimizes Teicoplanin Use in Febrile Neutropenic Patients with Hematological Malignancies.

INTRODUCTION: A target trough concentration (Cmin) of teicoplanin ≥ 15-20 mg/L between the fourth and sixth day has been suggested for severe infections or management of febrile neutropenia (FN). Owing to no reports discussing the impact of early target attainment on treatment outcomes, this study aimed to evaluate the dose-Cmin relationship and clinical outcome and estimate the optimal early target Cmin for FN in patients with hematological malignancies. METHODS: This single-center, prospective study enrolled patients with hematological malignancies who were treated with teicoplanin either as an empirical antibiotic for FN or as targeted treatment for Gram-positive bacteria. Blood samples were collected on day three (48 h) post-loading doses, day 5 (96 h), and day 8 (when applicable) and determined by ultrahigh-pressure liquid chromatography-triple quadruple mass spectrometry. A total of 117 samples from 47 patients with FN (27 men, 20 women) were consecutively analyzed. A two-tailed α value of 0.05 was considered statistically significant. RESULTS: The mean Cmin values at 48 h, 96 h, and on day 8 were 23.4, 21.4, and 27.8 mg/L, respectively. The patients achieving Cmin ≥ 20 mg/L at 48 h had a higher likelihood of treatment success. The areas under the receiver operating characteristic curves were 0.71 for clinical efficacy and the cutoff value of Cmin at 48 h was 18.85 mg/L (95% confidence interval 0.55-0.87; P = 0.018). CONCLUSIONS: The Cmin of teicoplanin after completion of loading doses could predict the treatment response, with a target concentration ≥ 18.85 mg/L.

Ten-year epidemiology and risk factors of cytomegalovirus infection in hematopoietic stem cell transplantation patients in Taiwan.

BACKGROUND: Cytomegalovirus (CMV) can cause infection and critical diseases in hematopoietic stem cell transplantation (HSCT) recipients. This study aimed to explore the cumulative incidence and risk factors for CMV infection and disease among HSCT recipients in Taiwan. METHODS: This retrospective cohort study using the Taiwan Blood and Marrow Transplantation Registry (TBMTR) included HSCT recipients between 2009 and 2018 in Taiwan. The primary outcome was cumulative incidence of CMV infection or disease at day 100 after HSCT. Secondary outcomes included day 180 cumulative incidence of CMV infection or disease, infection sites, risk factors for CMV infection or disease, survival analysis, and overall survival after CMV infection and disease. RESULTS: There were 4394 HSCT recipients included in the study (2044 auto-HSCT and 2350 allo-HSCT). The cumulative incidence of CMV infection and disease was significantly higher in allo-HSCT than in auto-HSCT patients at day 100 (53.7% vs. 6.0%, P < 0.0001 and 6.1% vs. 0.9%, P < 0.0001). Use of ATG (HR 1.819, p < 0.0001), recipient CMV serostatus positive (HR 2.631, p < 0.0001) and acute GVHD grades ≥ II (HR 1.563, p < 0.0001) were risk factors for CMV infection, while matched donor (HR 0.856, p = 0.0180) and myeloablative conditioning (MAC) (HR 0.674, p < 0.0001) were protective factors. CONCLUSION: The study revealed a significant disparity in terms of the incidence, risk factors, and clinical outcomes of CMV infection and disease between auto and allo-HSCT patients. These findings underscore the importance of considering these factors in the management of HSCT recipients to improve outcomes related to CMV infections.

Fluconazole versus an echinocandin for Candida glabrata fungaemia: a retrospective cohort study.

OBJECTIVES: We studied whether fluconazole or echinocandin treatment of Candida glabrata fungaemia results in superior outcomes. METHODS: A multicentre, retrospective study was performed with 224 adult patients who received ≥ 5 days of therapy with either fluconazole or an echinocandin as their first antifungal treatment after collection of a blood culture that grew C. glabrata. The primary outcome was day 14 complete response. RESULTS: Patients in the echinocandin group were generally more ill, both at baseline and at the time of the index culture. Day 14 complete response was obtained in 58/127 (46%) and 50/97 (52%) of the fluconazole and echinocandin patients, respectively (P=0.383). Logistic regression found intensive care unit admission to be associated with failure [OR 0.456 (0.217-0.957), P=0.038] and echinocandin therapy to be associated with day 14 complete response [OR 2.305 (1.124-4.727), P=0.023]. Twenty-eight day survival was similar between the fluconazole and echinocandin groups and logistic regression did not reveal antifungal therapy choice to be independently predictive of mortality. For patients treated with fluconazole, a dose:MIC ratio >12.5 (when compared with a ratio ≤ 12.5) was associated with a significantly higher day 14 complete response [4/20 (20%) ≤ 12.5 versus 50/102 (49%) >12.5, P=0.025]. CONCLUSIONS: Severity of illness and choice of antifungal predict response in patients with C. glabrata fungaemia. Antifungal choice, however, does not influence mortality. In addition, new CLSI C. glabrata fluconazole susceptibility breakpoints are predictive of response when fluconazole is dosed appropriately.