Estimation of linezolid exposure in patients with hepatic impairment using machine learning based on a population pharmacokinetic model.

PURPOSE: To investigate the pharmacokinetic changes of linezolid in patients with hepatic impairment and to explore a method to predict linezolid exposure. METHODS: Patients with hepatic impairment who received linezolid were recruited. A population pharmacokinetic model (PPK) was then built using NONMEM software. And based on the final model, virtual patients with rich concentration values was constructed through Monte Carlo simulations (MCS), which were used to build machine learning (ML) models to predict linezolid exposure levels. Finally, we investigated the risk factors for thrombocytopenia in patients included. RESULTS: A PPK model with population typical values of 3.83 L/h and 34.1 L for clearance and volume of distribution was established, and the severe hepatic impairment was identified as a significant covariate of clearance. Then, we built a series of ML models to predict the area under 0 -24 h concentration-time curve (AUC0-24) of linezolid based on virtual patients from MCS. The results showed that the Xgboost models showed the best predictive performance and were superior to the methods for estimating linezolid AUC0-24 based on though concentration or daily dose. Finally, we found that baseline platelet count, linezolid AUC0-24, and combination with fluoroquinolones were independent risk factors for thrombocytopenia, and based on this, we proposed a method for calculating the toxicity threshold of linezolid. CONCLUSION: In this study, we successfully constructed a PPK model for patients with hepatic impairment and used ML algorithm to estimate linezolid AUC0-24 based on limited data. Finally, we provided a method to determine the toxicity threshold of linezolid.

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.

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.

A standard dose of linezolid puts patients with hepatic impairment at risk of overexposure.

PURPOSE: The purpose of this retrospective observational study conducted in patients with hepatic impairment was to assess the variability of linezolid trough concentrations, to determine the risk factors for linezolid overexposure, and to investigate the effect of linezolid overexposure on linezolid-induced thrombocytopenia. METHODS: All enrolled patients received a standard dose (600 mg every 12 h) of linezolid and underwent therapeutic drug monitoring. The Child-Pugh-Turcotte score was used to divide patients into three groups: mild, moderate, and severe hepatic impairment. The risk factors for linezolid overexposure (Cmin > 8 mg/L) and linezolid-induced thrombocytopenia were examined using logistic regression. And the Kaplan-Meier curve was used to describe the association between linezolid overexposure and linezolid-induced thrombocytopenia. RESULTS: Seventy-seven patients were included, 37 (48.1%) of whom experienced linezolid overexposure. Patients with severe hepatic impairment had a substantially higher median Cmin of linezolid than those with mild (20.7 mg/L vs 5.51 mg/L, P < 0.001) or moderate (20.7 mg/L vs 6.70 mg/L, P = 0.001) hepatic impairment. Severe hepatic impairment was significantly associated with linezolid overexposure (OR 7.037, 95%CI 1.426-34.727, P = 0.017). After linezolid treatment, linezolid-induced thrombocytopenia occurred in 32 (41.6%) patients, and Cmin > 8 mg/L was a significant predictor of linezolid-induced thrombocytopenia (OR 3.024, 95%CI 1.083-8.541, P = 0.035). CONCLUSION: Patients with hepatic impairment who received standard doses of linezolid are at greater risk of linezolid overexposure, which may lead to a higher incidence of linezolid-induced thrombocytopenia.

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.

Plasma trough concentration distribution and safety of high-dose teicoplanin for patients with augmented renal clearance.

WHAT IS KNOWN AND OBJECTIVE: There are few reports on the distribution of the plasma trough concentration (Cmin ) of teicoplanin in patients with augmented renal clearance (ARC) and on the safety of a high-dose regimen (HD; 800 mg loading dose for q12h three times followed by an 800 mg qd maintenance dose). The objective of this study was to determine the Cmin values of teicoplanin in ARC patients using HD teicoplanin to provide a reference for individualized medication. METHODS: Data on patients treated with teicoplanin from January 2019 to January 2021 were collected retrospectively and divided into ARC (creatinine clearance rate [CCr] >130 ml/min, n = 22) and non-ARC (60 ml/min ≤ CCr ≤130 ml/min, n = 24) groups. The Cmin values in the two patient groups were analysed during the HD and the low-dose regimen (LD; all other regimens) on the third day of medication and during the dose maintenance period. Liver and kidney function indexes were also analysed before and after medication. RESULTS AND DISCUSSIONS: On the third day of the HD, Cmin did not differ significantly between the ARC and non-ARC groups (17.3 ± 9.2 mg/L [mean ± SD] vs. 15.5 ± 7.9 mg/L, p = 0.663), while Cmin in the ARC group was significantly lower for the LD (6.8 ± 3.9 mg/L, p = 0.039). During the dose maintenance period, Cmin in the ARC group when receiving the HD (18.3 ± 5.1 mg/L) was significantly lower than that in the non-ARC group (25.5 ± 11.9 mg/L, p = 0.016) and significantly higher than that for the LD (12.2 ± 6.3 mg/L, p = 0.022). Nephrotoxicity and hepatotoxicity incidence rates did not differ significantly between these groups. WHAT IS NEW AND CONCLUSION: These results suggest that it is necessary to apply a loading dose of 800 mg (but not higher) q12h three times for patients with ARC, with 800 mg needed as a maintenance dose during severe infection, and 600 mg or 400 mg for mild infection.

Determination of tigecycline in human lung epithelial cells and polymorphonuclear neutrophils by liquid chromatography/tandem mass spectrometry and its application in a cellular pharmacokinetics study.

RATIONALE: In order to characterize the intracellular pharmacokinetic properties of tigecycline, we developed and fully validated a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for quantification of tigecycline in human lung epithelial (BEAS-2B) cells and polymorphonuclear neutrophils (PMNs). METHODS: Tetracycline was used as an internal standard and chromatographic separation was achieved on a C18 Hypersil Gold aQ column using two mobile phases, a solution of water (containing 0.1% formic acid) and acetonitrile. The flow rate was 0.4 mL/min for 5.0 min. Tigecycline drug uptake was evaluated by incubating the BEAS-2B cells and the PMNs for up to 3 h at tigecycline concentrations of 1 mg/L. RESULTS: The assay was linear over the tested concentration range of 0.01-2 mg/L for tigecycline in BEAS-2B cells and PMNs (r2 >0.99). The inter- and inter-day precisions (RSD, %) were <10.02% and the accuracies (%) were within the range of 85-115%. The uptake study showed that after incubation with tigecycline (1 mg/L) for 3 h at 37°C, the intracellular peak concentration of BEAS-2B cells was 14.44 ± 7.12 mg/L at 1 h, and 41.43 ± 25.66 mg/L in PMNs at 20 min. The mean intracellular concentrations fluctuated in the range of 0.8-14.44 mg/L in BEAS-2B cells and 10.14-41.43 mg/L in PMNs for 1 mg/L tigecycline exposure. CONCLUSIONS: Validated LC/MS/MS is a simple, rapid, and sensitive method for determining the intracellular concentration of tigecycline, and tigecycline has good penetrations both in human BEAS-2B cells and PMNs. The method can be efficiently used for future studies of the intracellular pharmacokinetics of tigecycline.

Evidence-based Guideline for Therapeutic Drug Monitoring of Vancomycin: 2020 Update by the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society.

BACKGROUND: Clinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015. METHODS: Our updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System. RESULTS: We partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions. CONCLUSIONS: We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.

A prognostic model for elderly patients with squamous non-small cell lung cancer: a population-based study.

BACKGROUND: Squamous cell carcinoma (SCC) is a main pathological type of non-small cell lung cancer. It is common among elderly patients with poor prognosis. We aimed to establish an accurate nomogram to predict survival for elderly patients (≥ 60 years old) with SCC based on the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: The gerontal patients diagnosed with SCC from 2010 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. The independent prognostic factors were identified using multivariate Cox proportional hazards regression analysis, which were utilized to conduct a nomogram for predicting survival. The novel nomogram was evaluated by Concordance index (C-index), calibration curves, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). RESULTS: 32,474 elderly SCC patients were included in the analysis, who were randomly assigned to training cohort (n = 22,732) and validation cohort (n = 9742). The following factors were contained in the final prognostic model: age, sex, race, marital status, tumor site, AJCC stage, surgery, radiation and chemotherapy. Compared to AJCC stage, the novel nomogram exhibited better performance: C-index (training group: 0.789 vs. 0.730, validation group: 0.791 vs. 0.733), the areas under the receiver operating characteristic curve of the training set (1-year AUC: 0.846 vs. 0.791, 3-year AUC: 0.860 vs. 0.801, 5-year AUC: 0.859 vs. 0.794) and the validation set (1-year AUC: 0.846 vs. 0.793, 3-year AUC: 0.863 vs. 0.806, 5-year AUC: 0.866 vs. 0.801), and the 1-, 3- and 5-year calibration plots. Additionally, the NRI and IDI and 1-, 3- and 5-year DCA curves all confirmed that the nomogram was a great prognosis tool. CONCLUSIONS: We constructed a novel nomogram that could be practical and helpful for precise evaluation of elderly SCC patient prognosis, thus helping clinicians in determining the appropriate therapy strategies for individual SCC patients.

Safety and Efficacy of Tigecycline in Intensive Care Unit Patients Based on Therapeutic Drug Monitoring.

OBJECTIVE: Tigecycline exerts significant beneficial effects against drug-resistant bacterial infections. The largely empirical medications used in clinical practice are often associated with wide individual differences in efficacy and safety. We investigated the associations between the pharmacokinetics of tigecycline and its efficacy and safety in intensive care unit (ICU) patients, with the aim of facilitating clinical applications of tigecycline. METHODS: ICU patients who were prescribed tigecycline in a hospital setting were prospectively included. Factors related to the clinical efficacy and safety of tigecycline were assessed by univariate and multivariate analyses. RESULTS: This study included 45 patients, from whom a total of 63 blood samples were collected to determine steady-state trough plasma concentrations (Cmin) of tigecycline. The Cmin of tigecycline was 417.1 ± 263.8 ng/mL (mean ± SD). The multivariate analysis showed that the APACHE II scores [odds ratio (OR) = 0.874, 95% confidence interval (CI) = 0.733-0.901, P = 0.048] were significantly correlated with the efficacy of tigecycline, whereas there was no correlation between Cmin of tigecycline and efficacy. In safety, the risk factors significantly associated with hepatotoxicity were sex (OR = 0.562, 95% CI = 0.191-0.774, P = 0.023), APACHE II score (OR = 1.061, 95% CI = 1.039-1.392, P = 0.045), and Cmin (OR = 1.210, 95% CI = 1.014-1.336, P = 0.008). The optimal cut-off for hepatotoxicity in ICU patients treated with tigecycline was 474.8 ng/mL. CONCLUSIONS: There was considerable variability in the Cmin of tigecycline among the ICU patients in this study and it is at risk of high exposure in women. Cmin can be a useful predictor of hepatotoxicity with a cut-off of 474.8 ng/mL.

Therapeutic Drug Monitoring Coupled With Bayesian Forecasting Could Prevent Vancomycin-Associated Nephrotoxicity in Renal Insufficiency Patients: A Prospective Study and Pharmacoeconomic Analysis.

BACKGROUND: Vancomycin is a critical antibiotic used in important infections, and therapeutic drug monitoring (TDM) is recommended. Bayesian forecasting is demonstrated to provide an approach that can improve trough concentration monitoring for dose adjustment. The objective of this study was to determine whether TDM coupled with a Bayesian approach could increase trough concentration target attainment and prevent vancomycin-associated nephrotoxicity in patients with renal insufficiency. METHODS: A prospective study was performed using propensity score matching to provide covariate balance in renal insufficiency patients with gram-positive bacterial infections treated with vancomycin. Patients were divided into non-TDM (84 cases) and TDM (84 cases) groups, and their clinical outcomes were compared. The primary endpoints were probability of trough concentration target attainment and incidence of vancomycin-associated nephrotoxicity. A decision-tree model was developed to assess the cost effectiveness of TDM to prevent vancomycin-associated nephrotoxicity. RESULTS: Of the 168 eligible patients, 69 from each group (non-TDM and TDM) were matched based on propensity scores. In the matched cohort, trough concentration target attainment was higher with TDM (P = 0.003). Furthermore, reaching toxic trough concentrations was avoided (P = 0.027) in the TDM group. Multivariate logistic regression analysis confirmed that TDM practice independently reduced the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients (P = 0.021). According to this reduced nephrotoxicity, the incremental cost-effectiveness ratios of ¥22,638 per nephrotoxic episode prevented was found for vancomycin TDM. CONCLUSIONS: TDM coupled with Bayesian forecasting led to an increase in trough concentration target attainment and a decrease in the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients. In this high-risk population, TDM was demonstrated to be a cost-effective procedure.

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.

Factors influencing caspofungin plasma concentrations in kidney transplant patients with high incidence of invasive fungal infections.

WHAT IS KNOWN AND OBJECTIVE: Caspofungin is commonly used in kidney transplant patients for prophylaxis or treatment of invasive fungal infections (IFIs) caused by Candida spp. and Aspergillus spp. Factors such as concomitant medications, co-morbidity and rejection often cause caspofungin pharmacokinetic parameters alterations in kidney transplant patients. Here, we aimed to investigate factors influencing caspofungin plasma concentrations and evaluate its prophylaxis and treatment efficiency for IFIs in kidney transplant patients. METHODS: The prophylaxis and treatment efficiency of caspofungin for IFIs were assessed in 164 kidney transplant patients in the study. Six hundred and fifty-two caspofungin trough concentrations (Cmin ) from the 164 patients were monitored by the liquid chromatography-tandem mass spectrometry method. Basic demographic variables, baseline disease, surgery, rejection, indwelling catheter, coinfection, concomitant medication and other caspofungin-related factors were collected. Univariate and multivariate analyses were used to assess factors influencing caspofungin plasma concentrations. RESULTS AND DISCUSSION: The success rates were 94.96% (132/139) for caspofungin prevention and 80% (20/25) for caspofungin for IFIs. Caspofungin Cmin in the kidney recipients varied largely compared with healthy volunteers (0.10-12.25 mg/L vs. 1.12-1.78 mg/L). Caspofungin Cmin significantly increased in patients with continuous renal replacement therapy before transplantation (P = .001), concomitant medication of cyclosporine A (CsA, P = .009), ALB concentration of > 30 g/L (P = .019). WHAT IS NEW AND CONCLUSION: This is an uncontrolled observational study of caspofungin as prophylaxis or treatment for IFIs in kidney transplant patients. Caspofungin could be an effective and well-tolerated option for antifungal prophylaxis and treatment in kidney transplant patients, and a number of factors could influence caspofungin Cmin in these patients.

Treatment efficacy of tigecycline in comparison to cefoperazone/ sulbactam alone or in combination therapy for carbapenenm-resistant Acinetobacter baumannii infections.

Tigecycline (TGC) and cefoperazone/sulbactam (CPS) both have been shown good in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAB) isolates. We aim to compare the efficacy of TGC versus CPS for CRAB infections. We conducted a retrospective cohort study of patients with CRAB at a single center in China from 2013 to 2015. Outcomes comprised in-hospital mortality, clinical and microbiological response. The method of inverse probability of treatment weighting and multivariable logistic regression analysis incorporated with propensity score were employed to estimate the effect of treatment groups. There were 130 subjects included in our study. The patients in TGC, CPS and TGC plus CPS combination group were 42, 66, and 22, respectively. After adjustment, in-hospital mortality was lower in CPS group than TGC group (weighted OR 0.173; 95% CI 0.06-0.497; P=0.001) but without differences in clinical success and microbiological eradication (P>0.05). TGC monotherapy had a similar outcome with TGC plus CPS combination group. This is the first study comparing the efficacy of tigecycline and cefoperazone/sulbactam for CRAB infections. Cefoperazone/sulbactam appears to be more efficacious than tigecycline during treatment.

Correction to: Procalcitonin-guided antibiotic therapy in critically ill adults: a meta-analysis.

After publication of the original article [1], the authors have reported that the software developers had used a new amended version of the software called "v0.9.5.10" instead of "v0.9.5.5", which is referred to in the original article.

Paediatric acute kidney injury induced by vancomycin monotherapy versus combined vancomycin and meropenem.

WHAT IS KNOWN AND OBJECTIVE: Increasing reports of the combined use of vancomycin (VAN) and piperacillin/tazobactam leading to higher nephrotoxicity have led to carbapenems being recommended as an alternative option to combine with VAN when nephrotoxicity is a major concern. However, whether carbapenems also increase the nephrotoxicity of VAN is unclear. This study aimed to determine whether meropenem is a suitable drug to combine with VAN based on whether meropenem enhances the nephrotoxicity of VAN. METHODS: This retrospective cohort study enrolled hospitalized children ranging in age from 1 month to 18 years at two tertiary hospitals from 1 February 2017 to 1 February 2018. Patients treated with either VAN or combined VAN and meropenem (VM) for more than 48 hours were eligible for inclusion. Those with underlying kidney diseases or abnormal age-adjusted baseline serum creatinine (SCr) at admission were excluded. Propensity score matching (PSM) was applied to the patients to balance factors associated with acute kidney injury (AKI). In addition, VAN trough concentrations were also compared. AKI was defined as an increase in SCr by ≥50% from baseline or by ≥0.3 mg/dL sustained over at least two consecutive measurements ranging from the time of initiation until 72 hours after the completion of VAN therapy. RESULTS AND DISCUSSION: The eligibility criteria were met by 183 of 243 identified patients: 101 patients received VAN alone and 82 received VM. PSM resulted in 154 hospitalized children being included (77 patients in each group). The incidence of AKI was 10.7% (8/77) in both of the compared groups, while the VAN trough concentration was significantly higher in the VM group (9.0 mg/L) than in the VAN group (6.6 mg/L, P = 0.007) after controlling for confounders. WHAT IS NEW AND CONCLUSION: Despite the elevated VAN trough concentration, meropenem did not increase the nephrotoxicity of VAN and might therefore be an acceptable antibiotic to combine with VAN when necessary.

A strategy for designing voriconazole dosage regimens to prevent invasive pulmonary aspergillosis based on a cellular pharmacokinetics/pharmacodynamics model.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in immunosuppressed patients. Voriconazole is commonly used to prevent and treat IPA in the clinic, but the optimal prophylactic antifungal regimen is unknown. The objective of this study was to clarify the mechanism underlying how voriconazole prevents IPA based on a target cellular pharmacokinetics/pharmacodynamics model, with the aim of identifying a way to design an optimal prophylactic antifungal regimen. METHODS: A nystatin assay was used to establish a target-cells model for A. fumigatus infection. An inhibitory effect sigmoid Emax model was developed to explore the cellular PK/PD breakpoint, and Monte Carlo simulation was used to design the prophylactic antifungal regimen. RESULTS: The intracellular activity of voriconazole in the target cells varied with its concentration, with the minimum inhibitory concentration (MIC) being an important determinant. For A. fumigatus strains AF293 and AF26, voriconazole decreased the intracellular inoculum by 0.79 and 0.84 lg cfu, respectively. The inhibitory effect sigmoid Emax model showed that 84.01% of the intracellular inoculum was suppressed by voriconazole within 24 h, and that a PK/PD value of 35.53 for the extracellular voriconazole concentration divided by MIC was associated with a 50% suppression of intracellular A. fumigatus. The Monte Carlo simulation results showed that the oral administration of at least 200 mg of voriconazole twice daily was yielded estimated the cumulative fraction of response value of 91.48%. Concentration of voriconazole in the pulmonary epithelial lining fluid and the plasma of > 17.77 and > 1.55 mg/L, respectively, would ensure the PK/PD > 35.53 for voriconazole against most isolates of A. fumigatus and may will be benefit to prevent IPA in clinical applications. CONCLUSIONS: This study used a target cellular pharmacokinetics/pharmacodynamics model to reveal a potential mechanism underlying how voriconazole prevents IPA and has provided a method for designing voriconazole prophylactic antifungal regimen in immunosuppressed patients.

Poor prognosis of nucleophosmin overexpression in solid tumors: a meta-analysis.

BACKGROUND: Nucleophosmin is a non-ribosomal nucleolar phosphoprotein that is found primarily in the nucleolus region of cell nucleus, plays multiple important roles in tumor processes. Accumulated previous studies have reported a potential value of NPM acted as a biomarker for prognosis in various solid tumors, but the results were more inconsistency. We performed this meta-analysis to precisely evaluate the prognostic significance of NPM in solid tumors. METHODS: Clinical data were collected from a comprehensive literature search in PubMed, Web of Science, Embase, and China National Knowledge Infrastructure databases (up to October, 2017). A total of 11 studied with 997 patients were used to assess the association of NPM expression and patients' overall survival (OS). The hazard ratio (HR) or odds ratio (OR) with its 95% confidence intervals (CI) were calculated to estimate the effect. RESULTS: The pooled results indicated that higher expression of NPM was observably correlated with poor OS in solid tumor (HR = 1.85, 95% CI: 1.44-2.38, P < 0.001). Furthermore, high expression of NPM was associated with some phenotypes of tumor aggressiveness, such as tumor stage (4 studies, III/IV vs. I/II, OR = 5.21, 95% CI: 2.72-9.56, P < 0.001), differentiation grade (poor vs. well/moderate, OR = 1.82, 95% CI: 1.01-3.27, P = 0.046). CONCLUSION: This meta-analysis indicated that NPM may act as a valuable prognosis biomarker and a potential therapeutic target in human solid tumors.

Trends in and correlations between antibiotic consumption and resistance of Staphylococcus aureus at a tertiary hospital in China before and after introduction of an antimicrobial stewardship programme.

The overuse of antibiotics and the rapid emergence of antibiotic resistance prompted the launch of an antimicrobial stewardship programme in 2011. This study aimed to investigate the trends and correlations between antibiotic consumption and resistance of Staphylococcus aureus in a tertiary hospital of northwest China from 2010 to 2016. Trends were analysed by linear regression, and correlations were assessed by an autoregressive integrated moving average model. The total consumption of antibiotics halved during the 7-year study period, while the rates of resistance of S. aureus decreased significantly or remained stable; methicillin-resistant S. aureus (MRSA) declined markedly, from 73.3% at the beginning of the study to 41.4% by the end. This latter decrease was significantly correlated with the consumption of several classes of antibiotics. In conclusion, reduction in antibiotic use impacted significantly on resistance rates and contributed to a decline in MRSA prevalence.

Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis.

BACKGROUND: Posaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs). METHODS: Bibliographic databases were searched (from inception to September 2017) to select studies including the clinical outcomes below and above concentration cut-off value of 0.5 mg/L and 0.7 mg/L. The reliability of the results were evaluated with trial sequential analysis (TSA). RESULTS: Twenty-eight studies with 1930 patients included were analyzed. The results of our pooled analysis demonstrated that patients with posaconazole plasma concentrations over 0.5 mg/L were twice more likely to achieve successful responses compared with those with lower concentrations (odds ratio, OR = 1.98, 95% confidence interval, CI 1.09-3.58, P = 0.02) while the threshold, 0.7 mg/L showed no significant difference (OR = 1.84, 95% CI 0.94-3.63, P = 0.08). The TSA results showed that there was sufficient information to support these findings. CONCLUSIONS: An optimal posaconazole concentration target of 0.5 mg/L is suggested to ensure the clinical prophylactic efficacy and may help reduce the dosage and dose-dependent toxicity comparing with the target of 0.7 mg/L.