Efficacy, Safety, and Cost-effectiveness Analysis of Antiviral Agents for Cytomegalovirus Prophylaxis in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with higher non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). But the preferred drug for preventing cytomegalovirus infection is still controversial. We evaluate the efficacy, safety, and cost-effectiveness of antiviral agents based on the most recent studies. METHODS: A pairwise and network meta-analysis was conducted to obtain direct and indirect evidence of antivirals. The cost of allo-HSCT recipients in a teaching hospital was collected, and a cost-effectiveness analysis using a decision tree combined with Markov model was completed from the perspective of allo-HSCT recipients over a lifetime horizon. RESULTS: A total of 19 RCTs involving 3565 patients (8 antivirals) were included. In the network meta-analysis, relative to placebo, letermovir, valacyclovir, and ganciclovir significantly reduced CMV infection incidence; ganciclovir significantly reduced CMV disease incidence; ganciclovir significantly increased the incidence of serious adverse event; none of antivirals significantly reduced all-cause mortality. Based on meta-analysis and Chinese medical data, the incremental cost-effectiveness ratios (ICER) per quality-adjusted life year (QALY) saved for maribavir, acyclovir, valacyclovir, ganciclovir, and letermovir relative to placebo corresponded to US$216 635.70, US$11 590.20, US$11 816.40, US$13 049.90, and US$12 189.40, respectively. One-way sensitivity analysis showed the most influential parameter was discount rate. The probabilistic sensitivity analysis indicated a 53.0% probability of letermovir producing an ICER below the willingness-to-pay threshold of US$38 824.23/QALY. The scenario analysis demonstrated prophylaxis with letermovir is considered cost-effective in the United States. CONCLUSIONS: Currently, letermovir is an effective and well-tolerated treatment for preventing CMV infection, and it might be a cost-effective choice in allo-HSCT recipients in China.

A novel strategy for therapeutic drug monitoring: application of biosensors to quantify antimicrobials in biological matrices.

Over the past few years, therapeutic drug monitoring (TDM) has gained practical significance in antimicrobial precision therapy. Yet two categories of mainstream TDM techniques (chromatographic analysis and immunoassays) that are widely adopted nowadays retain certain inherent limitations. The use of biosensors, an innovative strategy for rapid evaluation of antimicrobial concentrations in biological samples, enables the implementation of point-of-care testing (POCT) and continuous monitoring, which may circumvent the constraints of conventional TDM and provide strong technological support for individualized antimicrobial treatment. This comprehensive review summarizes the investigations that have harnessed biosensors to detect antimicrobial drugs in biological matrices, provides insights into the performance and characteristics of each sensing form, and explores the feasibility of translating them into clinical practice. Furthermore, the future trends and obstacles to achieving POCT and continuous monitoring are discussed. More efforts are necessary to address the four key 'appropriateness' challenges to deploy biosensors in clinical practice, paving the way for personalized antimicrobial stewardship.

Metabolic characteristics of voriconazole - Induced liver injury in rats.

Voriconazole (VOR) - induced liver injury is a common adverse reaction, and can lead to serious clinical outcomes. It is of great significance to describe the metabolic characteristics of VOR - induced liver injury and to elucidate the potential mechanisms. This study investigated the changes of plasma metabolic profiles in a rat model of VOR - induced liver injury by non - targeted metabolomics. Correlation analysis was performed between differentially expressed metabolites and plasma liver function indexes. The metabolites with strong correlation were determined for their predictive performance for liver injury using receiver operating characteristic (ROC) curve analysis. Potential biomarkers were then screened combined with liver pathological scores. Finally, the expression level of genes that involved in lipid metabolism were determined in rat liver to verify the mechanism of VOR - induced liver injury we proposed. VOR - induced liver injury in rats was characterized by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, the lipid droplets accumulation in liver, as well as inflammation and fibrosis. Significant changes of plasma metabolites were observed, with a decrease in lipid metabolites accounting for over 50% of all changed metabolites, and alterations of cholesterol and bile acids metabolites. The decrease of 3 phosphatidylcholine (PC) in plasma could indicate the occurrence of VOR - induced liver injury. Decreased fatty acids (FA) oxidation and bile acid excretion might be the potential mechanisms of VOR - induced liver injury. This study provided new insights into the molecular characterization of VOR - induced liver injury.

A Nomogram for Predicting Survival in Advanced Non-Small-Cell Lung Carcinoma Patients: A Population-Based Study.

Non-small-cell lung cancer (NSCLC) remains the most common malignant cancer. We identified 43140 advanced NSCLC patients from the SEER database to develop and validate a new prognostic model. The prognostic performance was evaluated by P value, concordance index, net reclassification index, integrated discrimination improvement, and decision curve analysis. The following variables were contained in the final prognostic model: age, sex, race, TNM stage, and grade and treatment options. Compared to the AJCC staging system, this prognostic model is conducive to the implementation of individualized clinical treatment schemes and can be an important part of the precise medical care of NSCLC tumors.

Central Nervous System Toxicity of Voriconazole: Risk Factors and Threshold - A Retrospective Cohort Study.

Purpose: Voriconazole (VRC) is an antifungal agent which is used for treatment and prophylaxis of invasive fungal infections. The common clinical adverse reactions mainly include central nervous system (CNS) toxicity and abnormal liver function. These adverse reactions limit the clinical use of voriconazole to a certain extent. Therefore, the aim of this study was to analyze the risk factors of voriconazole neurotoxic side effects and to determine the plasma trough concentration (C min) threshold of voriconazole-induced CNS toxicity, so as to improve the safety of voriconazole treatment. Patients and Methods: This study retrospectively collected the clinical data of 165 patients who received voriconazole and underwent therapeutic drug monitoring (TDM). CNS toxicity was defined using the National Cancer Institute (NCI) criteria, logistic regression was used to analyze the risk factors of CNS toxicity, classification and Regression tree (CART) model was used to determine the C min threshold for CNS toxicity. Results: Voriconazole-related CNS toxicity occurred during treatment in 34 of 165 patients (20.6%) and the median time from administration to onset of CNS toxicity was 6 days (range, 2-19 days). The overall incidence of CNS toxicity was 20.6% (34/165), including visual disturbances in 4.8% (8/165) and nervous system disorders in 15.8% (26/165). C min significantly affects the occurrence of CNS toxicity and the threshold of C min for voriconazole CNS toxicity was determined to be 4.85 mg/L, when C min >4.85 mg/L and ≤4.85 mg/L, the incidence of CNS was 32.9% and 11.6%, respectively. Conclusion: Voriconazole trough concentration of C min is an independent risk factor for CNS toxicity, and the threshold of C min for CNS toxicity is 4.85mg/L. TDM should be routinely performed in patients with clinical use of voriconazole to reduce the occurrence of CNS toxicity of voriconazole.

Evaluation of the current guidelines for antibacterial therapy strategies in patients with cirrhosis or liver failure.

BACKGROUND: Bacterial infections are common complications in patients with cirrhosis or liver failure and are correlated with high mortality. Clinical practice guideline (CPG) is a reference used to help clinicians make decisions. This systematic appraisal aimed to evaluate the methodological quality and summarize the recommendations of reported CPGs in these patients. METHODS: We systematically searched CPGs published from 2008 to 2019. The methodological quality of the included CPGs was assessed using the AGREE II instrument. We extracted and compared recommendations for prophylactic and empirical treatment strategies. RESULTS: Fourteen CPGs with a median overall score of 56.3% were included. The highest domain score was Clarity of Presentation (domain 4, 85.4%), and the lowest was for Stakeholder Involvement (domain 2, 31.3%). Three CPGs had an overall score above 80%, and 6 CPGs had a score above 90% in domain 4. Prophylaxis should be strictly limited to patients with varicose bleeding, low ascites protein levels and a history of spontaneous bacterial peritonitis. Fluoroquinolones (norfloxacin and ciprofloxacin), third-generation cephalosporins (G3) (ceftriaxone and cefotaxime) and trimethoprim-sulfamethoxazole (SXT) are recommended for preventing infections in patients with cirrhosis or liver failure. G3, ß-lactam/ß-lactamase inhibitor combinations (BLBLIs) and carbapenems are recommended as the first choice in empirical treatment according to local epidemiology of bacterial resistance. CONCLUSIONS: The methodological quality of CPGs focused on patients with cirrhosis or liver failure evaluated by the AGREE II instrument is generally poor. Three CPGs that were considered applicable without modification and 6 CPGs that scored above 90% in domain 4 should also be paid more attention to by healthcare practitioners. Regarding recommendations, norfloxacin, ciprofloxacin, ceftriaxone, cefotaxime, and SXT are recommended for prophylactic treatment appropriately. G3, BLBLIs, and carbapenems are recommended for use in empirical treatment strategies.

Construction of a Nomogram for Predicting Survival in Elderly Patients With Lung Adenocarcinoma: A Retrospective Cohort Study.

Elderly patients with non-small-cell lung cancer (NSCLC) exhibit worse reactions to anticancer treatments. Adenocarcinoma (AC) is the predominant histologic subtype of NSCLC, is diverse and heterogeneous, and shows different outcomes and responses to treatment. The aim of this study was to establish a nomogram that includes the important prognostic factors based on the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. We collected 53,694 patients of older than 60 who have been diagnosed with lung AC from the SEER database. Univariate and multivariate Cox regression analyses were used to screen the independent prognostic factors, which were used to construct a nomogram for predicting survival rates in elderly AC patients. The nomogram was evaluated using the concordance index (C-index), calibration curves, net reclassification index (NRI), integrated discrimination improvement (IDI), and decision-curve analysis (DCA). Elderly AC patients were randomly divided into a training cohort and validation cohort. The nomogram model included the following 11 prognostic factors: age, sex, race, marital status, tumor site, histologic grade, American Joint Committee for Cancer (AJCC) stage, surgery status, radiotherapy status, chemotherapy status, and insurance type. The C-indexes of the training and validation cohorts for cancer-specific survival (CSS) (0.832 and 0.832, respectively) based on the nomogram model were higher than those of the AJCC model (0.777 and 0.774, respectively). The CSS discrimination performance as indicated by the AUC was better in the nomogram model than the AJCC model at 1, 3, and 5 years in both the training cohort (0.888 vs. 0.833, 0.887 vs. 0.837, and 0.876 vs. 0.830, respectively) and the validation cohort (0.890 vs. 0.832, 0.883 vs. 0.834, and 0.880 vs. 0.831, respectively). The predicted CSS probabilities showed optimal agreement with the actual observations in nomogram calibration plots. The NRI, IDI, and DCA for the 1-, 3-, and 5-year follow-up examinations verified the clinical usability and practical decision-making effects of the new model. We have developed a reliable nomogram for determining the prognosis of elderly AC patients, which demonstrated excellent discrimination and clinical usability and more accurate prognosis predictions. The nomogram may improve clinical decision-making and prognosis predictions for elderly AC patients.

Determining the optimal PD-1/PD-L1 inhibitors for the first-line treatment of non-small-cell lung cancer with high-level PD-L1 expression in China.

BACKGROUND AND OBJECTIVE: The programmed death 1 and ligand (PD-1/PD-L1) inhibitors have significantly altered therapeutic perspectives on non-small-cell lung cancer (NSCLC). However, their efficacy and safety are unknown since direct clinical trials have not yet been performed on them. It is also necessary to determine the economics of PD-1/PD-L1 inhibitors due to their high cost. The aim was to evaluate the efficacy, safety, and cost-effectiveness of PD-1/PD-L1 inhibitor monotherapy for advanced NSCLC patients in China with high PD-L1 expression as first-line treatment. METHODS: From the PubMed, Cochrane, and Web of Science databases, we retrieved survival, progression, and safety data on PD-1/PD-L1 inhibitor monotherapy for advanced NSCLC patients. A network meta-analysis (NMA) was performed to consider PD-1/PD-L1 inhibitors in efficacy and safety. A Markov model with a full-lifetime horizon was adopted. Clinical and utility data were collected through the trial. The cost per quality-adjusted life year (QALY) was as incremental cost-effectiveness ratio (ICER). Sensitivity analyses were performed. RESULTS: This study included five phase III clinical trials using four drugs: nivolumab, pembrolizumab, atezolizumab, and durvalumab. The NMA demonstrated that the four drugs had similar efficacy and safety, while pembrolizumab and atezolizumab were better for than for nivolumab (hazard ratio (HR) = 0.66, 95% confidence intervals (CIs): 0.46-0.95 and HR = 0.59, 95%CI: 0.37-0.94) in progression-free survival (PFS), and the risk of a severe adverse event was higher for atezolizumab than for nivolumab and pembrolizumab. Compared with nivolumab, durvalumab, pembrolizumab, and atezolizumab had QALY of 0.19, 0.38, and 0.53, respectively, which induced ICERs of $ 197,028.8/QALY, $ 111,859.0/QALY, and $ 76,182.3/QALY, respectively. CONCLUSION: The efficacy and safety are similar among types of PD-1/PD-L1-inhibitor monotherapy. The cost-effectiveness of nivolumab appears optimal, but the other PD-1/PD-L1 inhibitors are not as cost-effective for the first-line treatment of advanced NSCLC in China.

Pharmacokinetic/Pharmacodynamic Adequacy of Novel ß-Lactam/ß-Lactamase Inhibitors against Gram-Negative Bacterial in Critically Ill Patients.

The optimal regimens of novel ß-lactam/ß-lactamase inhibitors (BLBLIs), ceftazidime/avibactam, ceftolozane/tazobactam, and meropenem/vaborbactam, are not well defined in critically ill patients. This study was conducted to identify optimal regimens of BLBLIs in these patients. A Monte Carlo simulation was performed using the published data to calculate the joint probability of target attainment (PTA) and the cumulative fraction of response (CFR). For the target of ß-lactam of 100% time with free drug concentration remains above minimal inhibitory concentrations, the PTAs of BLBLIs standard regimens were <90% at a clinical breakpoint for Enterobacteriaceae and Pseudomonas aeruginosa. For ceftazidime/avibactam, 2000 mg/500 mg/8 h by 4 h infusion achieved >90% CFR for Escherichia coli; even for 4000 mg/1000 mg/6 h by continuous infusion, CFR for Klebsiella pneumoniae was <90%; the CFRs of 3500 mg/875 mg/6 h by 4 h infusion and 4000 mg/1000 mg/8 h by continuous infusion were appropriate for Pseudomonas aeruginosa. For ceftolozane/tazobactam, the CFR of standard regimen was >90% for Escherichia coli, however, 2000 mg/1000 mg/6 h by continuous infusion achieved <90% CFRs for Klebsiella pneumoniae and Pseudomonas aeruginosa. For meropenem/vaborbactam, standard regimen achieved optimal attainments for Escherichia coli and Klebsiella pneumoniae; 2000 mg/2000 mg/6 h by 5 h infusion, 2500 mg /2500 mg/6 h by 4 h infusion, 3000 mg/3000 mg/6 h by 3 h infusion and 4000 mg/4000 mg/8 h by 5 h infusion achieved >90% CFRs for Pseudomonas aeruginosa. The CFRs of three BLBLIs were similar for Escherichia coli, but meropenem/vaborbactam were superior for Klebsiella pneumoniae and Pseudomonas aeruginosa.

Choosing Optimal Antibiotics for the Treatment of Patients Infected With Enterobacteriaceae: A Network Meta-analysis and Cost-Effectiveness Analysis.

Overuse of carbapenems has led to the increasing carbapenem-resistant Enterobacteriaceae. It is still unknown whether other antibiotics [especially novel ß-lactam/ß-lactamase inhibitor combinations (BL/BLIs)] are better than carbapenems in the treatment of Enterobacteriaceae. A systematic literature search was performed to identify randomized controlled trials (RCTs) assessing the efficacy and safety of any antibiotics on Enterobacteriaceae infections. We carried out a traditional paired meta-analysis to compare ceftazidime/avibactam to comparators. Network meta-analysis (NMA) was conducted to integrate direct and indirect evidence of all interventions. Moreover, cost-effectiveness analysis using a combined decision analytical Markov model was completed for the treatment of patients with complex urinary tract infection (cUTI). A total of 25 relevant RCTs were identified, comprising 15 different interventions. Ceftazidime/avibactam exhibited comparable efficacy and safety with comparators (carbapenems) in the paired meta-analysis. In the NMA, the surface under the cumulative ranking curve probabilities showed that in terms of efficacy, the interventions with the highest-ranking were meropenem/vaborbactam, meropenem, imipenem/cilastatin, ceftriaxone, ceftazidime/avibactam, and ceftolozane/tazobactam [but no significant difference between any two antibiotics (p > 0.05)]. Regarding safety, ceftazidime/avibactam had a higher incidence of adverse events than that of piperacillin/tazobactam (relative risk = 0.74, 95% confidence interval = 0.59-0.94). Based on drug and hospitalization costs in China, the incremental cost-effectiveness ratio per quality-adjusted life-year gained in the patients with cUTI for meropenem, ceftazidime/avibactam, and ceftolozane/tazobactam compared to imipenem/cilastatin were US$579, US$24569, and US$29040, respectively. The role of these BL/BLIs to serve as alternatives to carbapenems requires large-scale and high-quality studies to validate.

Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance.

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

Clinical Efficacy and Cost-Effectiveness of ß-Lactam/ß-Lactamase Inhibitor Combinations and Carbapenems in Liver Cirrhosis Patients with Gram-Negative Bacteria Bloodstream Infection.

BACKGROUND: Gram-negative bacteria bloodstream infection (GNB-BSI) results in considerable mortality and hospitality costs in cirrhotic patients. ß-lactam/ß-lactamase inhibitor combinations (BLBLIs) and carbapenems (CARs) are widely recommended for treating GNB-BSI in cirrhotic patients, while the efficacy and cost-effectiveness of two strategies have never been evaluated. Therefore, we conducted a retrospective cohort study to evaluate the efficacy and the cost-effectiveness of BLBLIs and CARs. PATIENTS AND METHODS: Cirrhotic patients with GNB-BSI treated by BLBLIs or CARs were included. A propensity score-matching analysis was performed to compare the efficacy between BLBLIs and CARs. A decision tree was used to estimate the clinical outcomes and direct costs of treating BSI using two strategies from the patients' perspective. RESULTS: No statistically significant difference was found between the BLBLIs (n = 41) group and the CARs (n = 43) group regarding the time to defervescence (2.4 ± 0.2 vs 2.5 ± 0.3, P = 0.94). Thirty-seven patients from each group were matched in propensity-score-matched cohort, and there was no significant difference between two groups in terms of the time to defervescence (2.4 ± 0.3 vs 2.4 ± 0.3, P = 0.75) and success rate (86.5% vs 78.4%; OR = 0.57; P = 0.36). Based on the drug and hospital costs in China, cefoperazone/sulbactam was cost-effective in the present analysis under the willingness-to-pay threshold (¥64,644). CONCLUSION: The efficacy of BLBLIs is similar to CARs. Cefoperazone/sulbactam could be a cost-effective therapy in cirrhotic patients with GNB-BSI. Carbapenems-sparing regimens should be encouraged in regions with a low prevalence of MDR bacteria.