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Vancomycin Pharmacokinetics in Obese Patients with Sepsis or Septic Shock.


  • 影响因子:3.15
  • DOI:10.1002/phar.2367
  • 作者列表:"Masich AM","Kalaria SN","Gonzales JP","Heil EL","Tata AL","Claeys KC","Patel D","Gopalakrishnan M
  • 发表时间:2020-01-19

STUDY OBJECTIVES:Obese patients with sepsis or septic shock may have altered vancomycin pharmacokinetics compared with the general population, which may result in improper dosing or inadequate drug concentrations. The objective of this study was to characterize vancomycin pharmacokinetics in obese patients with sepsis or septic shock, and to develop a novel pharmacokinetic dosing model based on pharmacokinetic-pharmacodynamic target requirements. DESIGN:Prospective, observational pharmacokinetic study. SETTING:Large quaternary academic medical center. PATIENTS:Sixteen obese (body mass index ≥30 kg/m2 ) adults with sepsis and either a gram-positive bacteremia or requiring vasopressor support (septic shock), who were receiving vancomycin between November 2016 and June 2018, were included. Patients were excluded if they were receiving renal replacement therapy or extracorporeal membrane oxygenation, treatment for central nervous system infections, pregnant or receiving vancomycin for surgical prophylaxis. INTERVENTION:Four blood samples per patient were collected following a single dose of vancomycin; one peak serum vancomycin level (within 1-2 hours of infusion completion), two random levels during the dosing interval, and one trough level (within 30-60 minutes of the next dose) were measured. MEASUREMENTS AND MAIN RESULTS:A population pharmacokinetic model was developed to describe vancomycin concentrations over time. Simulations to determine optimal dosing were performed using the pharmacokinetic model with different ranges of creatinine clearance (CrCl) and different vancomycin daily doses. Median age of the patients was 62 years; median body mass index was 36.1 kg/m2 , Acute Physiology and Chronic Health Evaluation (APACHE) II score was 26, and Sequential Organ Failure Assessment (SOFA) score was 11. Eleven patients (69%) had an acute kidney injury. Median initial vancomycin dose was 15 mg/kg; median vancomycin trough concentration was 17 mg/L. A one-compartment model best characterized the pharmacokinetics of vancomycin in obese patients with sepsis or septic shock. Volume of distribution was slightly increased in this population (0.8 L/kg) compared with the general population (0.7 L/kg). Only CrCl effect on drug clearance was found to be significant (decrease in the objective function value by 16.4 points), confirming that it is a strong predictor of vancomycin clearance. CONCLUSION:To our knowledge, this study provides the first population-based pharmacokinetic model in obese patients with sepsis or septic shock. The nomograms generated from this pharmacokinetic model provides a simplified approach to vancomycin dosing in this patient population.


研究目的: 与一般人群相比,肥胖的脓毒症或脓毒休克患者可能改变了万古霉素的药代动力学,这可能导致药物剂量不当或药物浓度不足。本研究的目的是表征脓毒症或脓毒休克肥胖患者万古霉素的药代动力学特征,并根据药代动力学-药效学目标要求开发一种新的药代动力学给药模型。 设计: 前瞻性、观察性药代动力学研究。 单位: 大型第四纪学术医学中心。 患者: 16 例肥胖 (体重指数 ≥ 30千克 kg/m2) 成人脓毒症和革兰氏阳性菌血症或需要血管加压药支持 (脓毒休克), 包括 2016年11月至 2018年6月期间接受万古霉素治疗的患者。如果患者接受肾脏替代治疗或体外膜肺氧合,治疗中枢神经系统感染,怀孕或接受万古霉素手术预防,则排除患者。 干预: 单剂量万古霉素后,每例患者收集四份血样; 一个峰值血清万古霉素水平 (输注完成 1-2 小时内),给药间隔期间两个随机水平, 并测量一个谷值 (在下一个剂量的 30-60 分钟内)。 测量和主要结果: 开发了一个群体药代动力学模型来描述万古霉素随时间的浓度。使用具有不同肌酐清除率 (CrCl) 范围和不同万古霉素日剂量的药代动力学模型进行模拟以确定最佳给药。患者的中位年龄为 62 岁; 中位体重指数为 36.1千克 kg/m2,急性生理与慢性健康评估 (APACHE) ⅱ 评分为 26 分,序贯器官衰竭评估 (SOFA) 分数为 11。11 例 (69%) 患者有急性肾损伤。万古霉素初始剂量中位数为 15 mg/kg; 万古霉素谷浓度中位数为 17 mg/L。一室模型最好地表征了万古霉素在肥胖脓毒症或脓毒休克患者中的药代动力学。与普通人群 (0.8 L/kg) 相比,该人群的分布量略有增加 (0.7 L/kg)。仅发现 CrCl 对药物清除率的影响显著 (目标函数值降低 16.4 分),证实其是万古霉素清除率的强预测因子。 结论: 据我们所知,本研究提供了第一个基于人群的脓毒症或脓毒休克肥胖患者的药代动力学模型。从该药代动力学模型生成的列线图提供了在该患者人群中万古霉素给药的简化方法。



作者列表:["Stephen Morehen","Benoit Smeuninx","Molly Perkins","Paul Morgan","Leigh Breen"]

METHODS:Maintaining adequate daily protein intake is important to maintain muscle mass throughout the lifespan. In this regard, the overnight period has been identified as a window of opportunity to increase protein intake in the elderly. However, it is unknown whether pre-sleep protein intake affects next-morning appetite and, consequently, protein intake. Therefore, the purpose of the current study was to investigate the effects of a pre-sleep protein drink on next-morning appetite, energy intake and metabolism. Twelve older individuals (eight males, four females; age: 71.3 ± 4.2 years) took part in a single-blind randomised cross-over study. After a standardised dinner, participants consumed either a 40-g protein drink, isocaloric maltodextrin drink, or placebo water control before bedtime. Next-morning appetite, energy intake, resting metabolic rate (RMR), respiratory exchange rate (RER), and plasma acylated ghrelin, leptin, glucose, and insulin concentrations were assessed. No between-group differences were observed for appetite and energy intake at breakfast. Furthermore, RMR, RER, and assessed blood markers were not significantly different between any of the treatment groups. Pre-sleep protein intake does not affect next-morning appetite and energy intake and is therefore a viable strategy to increase daily protein intake in an older population.

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作者列表:["Tzi-Peng Yang","Hsiao-Mei Chen","Chao-Chin Hu","Li-Yuan Chen","Fen-Fen Shih","Disline Manli Tantoh","Kuan-Jung Lee","Yi-Chia Liaw","Rong-Tzong Tsai","Yung-Po Liaw"]

METHODS:Leptin (LEP) regulates glucose metabolism and energy storage in the body. Osteoarthritis (OA) is associated with the upregulation of serum LEP. LEP promoter methylation is associated with obesity. So far, few studies have explored the association of BMI and OA with LEP methylation. We assessed the interaction between body mass index (BMI) and OA on LEP promoter methylation. Data of 1114 participants comprising 583 men and 558 women, aged 30−70 years were retrieved from the Taiwan Biobank Database (2008−2015). Osteoarthritis was self-reported and cases were those who reported having ever been clinically diagnosed with osteoarthritis. BMI was categorized into underweight, normal weight, overweight, and obesity. The mean LEP promoter methylation level in individuals with osteoarthritis was 0.5509 ± 0.00437 and 0.5375 ± 0.00101 in those without osteoarthritis. The interaction between osteoarthritis and BMI on LEP promoter methylation was significant (p-value = 0.0180). With normal BMI as the reference, the mean LEP promoter methylation level was significantly higher in obese osteoarthritic individuals (β = 0.03696, p-value = 0.0187). However, there was no significant association between BMI and LEP promoter methylation in individuals without osteoarthritis, regardless of BMI. In conclusion, only obesity was significantly associated with LEP promoter methylation (higher levels) specifically in osteoarthritic patients.

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作者列表:["Wulan, Siti N.","Schrauwen-Hinderling, Vera B.","Westerterp, Klaas R.","Plasqui, Guy"]

METHODS:Background For the same BMI, South Asians have a higher body fat percentage, a higher liver fat content and a more adverse metabolic profile than whites. South Asians may have a lower fat oxidation than whites, which could result in an unfavorable metabolic profile when exposed to increased high-fat foods consumption and decreased physical activity as in current modern lifestyle. Objective To determine substrate partitioning, liver fat accumulation and metabolic profile in South Asian and white men in response to overfeeding with high-fat diet under sedentary conditions in a respiration chamber. Design Ten South Asian men (BMI, 18–29 kg/m^2) and 10 white men (BMI, 22–33 kg/m^2), matched for body fat percentage, aged 20–40 year were included. A weight maintenance diet (30% fat, 55% carbohydrate, and 15% protein) was given for 3 days. Thereafter, a baseline measurement of liver fat content (1H-MRS) and blood parameters was performed. Subsequently, subjects were overfed (150% energy requirement) with a high-fat diet (60% fat, 25% carbohydrate, and 15% protein) over 3 consecutive days while staying in a respiration chamber mimicking a sedentary lifestyle. Energy expenditure and substrate use were measured for 3 × 24-h. Liver fat and blood parameters were measured again after the subjects left the chamber. Results The 24-h fat oxidation as a percentage of total energy expenditure did not differ between ethnicities ( P  = 0.30). Overfeeding increased liver fat content ( P  = 0.02), but the increase did not differ between ethnicities ( P  = 0.64). In South Asians, overfeeding tended to increase LDL-cholesterol ( P  = 0.08), tended to decrease glucose clearance ( P  = 0.06) and tended to elevate insulin response ( P  = 0.07) slightly more than whites. Conclusions Despite a similar substrate partitioning and similar accretion of liver fat, overfeeding with high-fat under sedentary conditions tended to have more adverse effects on the lipid profile and insulin sensitivity in South Asians.

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