Population pharmacokinetics of daptomycin in critically ill patients receiving extracorporeal membrane oxygenation.

BACKGROUND: Daptomycin is widely used in critically ill patients for Gram-positive bacterial infections. Extracorporeal membrane oxygenation (ECMO) is increasingly used in this population and can potentially alter the pharmacokinetic (PK) behaviour of antibiotics. However, the effect of ECMO has not been evaluated in daptomycin. Our study aims to explore the effect of ECMO on daptomycin in critically ill patients through population pharmacokinetic (PopPK) analysis and to determine optimal dosage regimens based on both efficacy and safety considerations. METHODS: A prospective, open-label PK study was carried out in critically ill patients with or without ECMO. The total concentration of daptomycin was determined by UPLC-MS/MS. NONMEM was used for PopPK analysis and Monte Carlo simulations. RESULTS: Two hundred and ninety-three plasma samples were collected from 36 critically ill patients, 24 of whom received ECMO support. A two-compartment model with first-order elimination can best describe the PK of daptomycin. Creatinine clearance (CLCR) significantly affects the clearance of daptomycin while ECMO has no significant effect on the PK parameters. Monte Carlo simulations showed that, when the MICs for bacteria are  ≥1 mg/L, the currently recommended dosage regimen is insufficient for critically ill patients with CLCR > 30 mL/min. Our simulations suggest 10 mg/kg for patients with CLCR between 30 and 90 mL/min, and 12 mg/kg for patients with CLCR higher than 90 mL/min. CONCLUSIONS: This is the first PopPK model of daptomycin in ECMO patients. Optimal dosage regimens considering efficacy, safety, and pathogens were provided for critical patients based on pharmacokinetic-pharmacodynamic analysis.

Up-regulation of paired-related homeobox 2 promotes cardiac fibrosis in mice following myocardial infarction by targeting of Wnt5a.

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired-related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha-smooth muscle actin (α-SMA). Both Prrx2 and Wnt5a gene expressions were up-regulated in mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus-mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia-induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF-ß increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF-ß on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to up-regulate Wnt5a gene expression. In conclusions, targeting Prrx2-Wnt5a signalling should be considered to improve cardiac remodelling in patients with ischaemic heart diseases.

Statins improve cardiac endothelial function to prevent heart failure with preserved ejection fraction through upregulating circRNA-RBCK1.

Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.

The Differences in the Epidemiology and Predictors of Death between Candidemia Acquired in Intensive Care Units and Other Hospital Settings.

OBJECTIVE: The burden of candidemia is shifting from intensive care units (ICU) to non-ICU settings. This study aimed to define the differences in epidemiology and predictors of death between ICU-acquired candidemia (ICUAC) and non-ICUAC. METHODS: We conducted a retrospective study of 80 patients with ICUAC and 147 patients with non-IUCAC at five hospitals. RESULTS: The distribution of Candida species and resistance to antifungal agents did not differ between the ICUAC and non-ICUAC groups. ICUAC patients received more echinocandins and less triazoles, as well as more adequate antifungal therapy than non-ICUAC patients (all p<0.05). ICUAC patients had a significantly higher average acute physiology and chronic health evaluation (APACHE) II score (21.0±7.9 vs. 17.8±8.6; p<0.01), Sequential Organ Failure Assessment score (9.2±5.5 vs. 7.4±3.9; p<0.05) and day-90 mortality rate (52.5% vs. 36.7%; p<0.05) when compared to non-ICUAC patients. Using a multivariate logistic analysis, adequate antifungal therapy was found to be the only protective factor for death in both groups. Respiratory failure supported with invasive mechanical ventilation, renal failure supported with replacement therapy and an APACHE II score ≥20 were independent predictors of death in ICUAC patients, while age ≥60 years, concurrent bacteremia and APACHE II score ≥20 were independent predictors of death in non-ICUAC patients. CONCLUSION: The Candida species and antifungal resistance profiles in patients with ICUAC were similar to non-ICUAC patients, but led to worse outcomes. The protective and risk factors for death may therefore be relevant for the clinical management of patients with candidemia in ICU and non-ICU settings.

Antibiotics exposure, risk factors, and outcomes with Candida albicans and non-Candida albicans candidemia. Results from a multi-center study.

OBJECTIVE: To define the differences in antibiotics exposure, risk factors, and outcome in hospitalized patients with Candida albicans (C. albicans) and non-C. albicans candidemia. METHODS: This is a multi-center retrospective study of 132 patients with candidemia from 5 tertiary-care educational hospitals in Shandong, China conducted between January 2009 and June 2010. Fifty-six of 132 (42.4%) patients had candidemia due to C. albicans and 76/132 (57.6%) had non-C. albanians candidemia. RESULTS: Patients with non-C. albicans candidemia received anti-anaerobic agents more often (23.7% versus 8.9%; p=0.027) and beta-lactam/beta-lactamase inhibitors less often (34.2% versus 51.8%; p=0.043) than those with C. albicans candidemia. Independent risk factors of non-C. albicans candidemia were prior anti-anaerobic and antifungal therapies and central venous catheter placement. Overall, 30-day mortality was higher for patients with C. albicans than non-C. albicans candidemia (50% versus 31.6%; p=0.032). Multivariate logistic regression analysis revealed that C. albicans candidemia, advanced age, and concomitant bacteremia were associated with death due to candidemia. CONCLUSION: Patients who received anti-anaerobic or antifungal agents were likely to develop non-C. albicans candidemia. Candida albicans infection was associated with poorer prognosis. An awareness of these factors is needed to guide therapy and decrease the high mortality of candidemia.