scholarly journals Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Mathias Wittau ◽  
Stephan Paschke ◽  
Max Kurlbaum ◽  
Jan Scheele ◽  
Neang S. Ly ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Peritoneal Fluid ◽  
Subcutaneous Tissue ◽  
Plasma Concentrations ◽  
Fat Free Mass ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Obese Patients ◽  
Target Attainment ◽  
Tissue Penetration

ABSTRACT Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m2) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.)

scholarly journals Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery

2015 ◽  
Vol 59 (10) ◽  
pp. 6241-6247 ◽  
Author(s):  
Mathias Wittau ◽  
Jan Scheele ◽  
Max Kurlbaum ◽  
Claas Brockschmidt ◽  
Anna M. Wolf ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Peritoneal Fluid ◽  
Subcutaneous Tissue ◽  
Area Under The Curve ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Target Attainment ◽  
Fourth Dose

ABSTRACTMeropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m2). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.)

Plasma and tissue pharmacokinetics of fosfomycin in morbidly obese and non-obese surgical patients: a controlled clinical trial

2019 ◽  
Vol 74 (8) ◽  
pp. 2335-2340 ◽  
Author(s):  
Christoph Dorn ◽  
David Petroff ◽  
Nancy Neumann ◽  
Alexander Kratzer ◽  
Nahed El-Najjar ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Peak Plasma ◽  
Subcutaneous Tissue ◽  
Plasma Concentrations ◽  
Surgical Patients ◽  
Pharmacokinetic Analysis ◽  
Controlled Clinical Trial ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Tissue Pharmacokinetics

Abstract Objectives To assess the pharmacokinetics and tissue penetration of fosfomycin in obese and non-obese surgical patients. Methods Fifteen obese patients undergoing bariatric surgery and 15 non-obese patients undergoing major intra-abdominal surgery received an intravenous single short infusion of 8 g of fosfomycin. Fosfomycin concentrations were determined by LC-MS/MS in plasma and microdialysate from subcutaneous tissue up to 8 h after dosing. The pharmacokinetic analysis was performed in plasma and interstitial fluid (ISF) by non-compartmental methods. Results Thirteen obese patients (BMI 38–50 kg/m2) and 14 non-obese patients (BMI 0–29 kg/m2) were evaluable. The pharmacokinetics of fosfomycin in obese versus non-obese patients were characterized by lower peak plasma concentrations (468 ± 139 versus 594 ± 149 mg/L, P = 0.040) and higher V (24.4 ± 6.4 versus 19.0 ± 3.1 L, P = 0.010). The differences in AUC∞ were not significant (1275 ± 477 versus 1515 ± 352 mg·h/L, P = 0.16). The peak concentrations in subcutaneous tissue were reached rapidly and declined in parallel with the plasma concentrations. The drug exposure in tissue was nearly halved in obese compared with non-obese patients (AUC∞ 1052 ± 394 versus 1929 ± 725 mg·h/L, P = 0.0010). The tissue/plasma ratio (AUCISF/AUCplasma) was 0.86 ± 0.32 versus 1.27 ± 0.34 (P = 0.0047). Conclusions Whereas the pharmacokinetics of fosfomycin in plasma of surgical patients were only marginally different between obese and non-obese patients, the drug exposure in subcutaneous tissue was significantly lower in the obese patients.

scholarly journals LINEA ALBA COLLAGEN ASSESSMENT IN MORBIDLY OBESE PATIENTS

2016 ◽  
Vol 29 (suppl 1) ◽  
pp. 8-11
Author(s):  
João Vicente Machado GROSSI ◽  
Felipe Fernandes NICOLA ◽  
Ivan Alberto ZEPEDA ◽  
Martina BECKER ◽  
Eduardo Neubarth TRINDADE ◽  
...  
Keyword(s):  
Subcutaneous Tissue ◽  
Healing Process ◽  
Age Groups ◽  
Immunohistochemical Analysis ◽  
Control Group ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Age Group ◽  
Tissue Thickness ◽  
Linea Alba

ABSTRACT Background: The evaluation of collagen in the abdominal wall has been increasingly studied because of the relevance on collagen in the healing process after laparotomy. Aim: To evaluate the amount of collagen in the linea alba of patients undergoing laparotomic bariatric surgery and comparing with non-obese cadavers. Methods: Were evaluated 88 samples of aponeurosis from abdominal linea alba of 44 obese patients (obesity group) and 44 non-obese cadavers (control group). The samples were collected in 2013 and 2104, and were sorted according to age (18-30, 31-45 and 46-60), gender, BMI, waist and cervical circumference, and subcutaneous tissue thickness. Material for biopsy was collected from the supraumbilical region of the linea alba for immunohistochemical analysis differentiating collagen type 1 and type 3 and the 1/3 ratio. Image-Pro Plus pixel counting software was used to measure the amount of collagen. Results: The obesity group evidenced mean age 44.11±9.90 years; 18-30 age group had three (6.8%) obese individuals; 31-45 had 22 (50%) and 46-60 had 19 (43.1%). Females were present in 81.8% (n=36); BMI (kg/m²) was 48.81±6.5; waist circumference (cm) was 136.761±13.55; subcutaneous tissue thickness (cm) 4.873±0.916. Considering age groups, gender and BMI, there were statistical differences in all tests when compared with the cadavers. Conclusion: The amount of collagen in the linea alba above the umbilical region in the morbidly obese patients was smaller than in the non-obese cadavers in the same age group.

scholarly journals Osteopontin Expression in Human and Murine Obesity: Extensive Local Up-Regulation in Adipose Tissue but Minimal Systemic Alterations

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1350-1357 ◽  
Author(s):  
Florian W. Kiefer ◽  
Maximilian Zeyda ◽  
Jelena Todoric ◽  
Joakim Huber ◽  
René Geyeregger ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Plasma Concentrations ◽  
Morbidly Obese ◽  
Low Grade ◽  
Obese Patients ◽  
Multifunctional Protein ◽  
Inflammatory Processes ◽  
Low Grade Inflammation

Obesity is associated with a chronic low-grade inflammation characterized by macrophage infiltration of adipose tissue (AT) that may underlie the development of insulin resistance and type 2 diabetes. Osteopontin (OPN) is a multifunctional protein involved in various inflammatory processes, cell migration, and tissue remodeling. Because these processes occur in the AT of obese patients, we studied in detail the regulation of OPN expression in human and murine obesity. The study included 20 morbidly obese patients and 20 age- and sex-matched control subjects, as well as two models (diet-induced and genetic) of murine obesity. In high-fat diet-induced and genetically obese mice, OPN expression was drastically up-regulated in AT (40 and 80-fold, respectively) but remained largely unaltered in liver (&lt;2-fold). Moreover, OPN plasma concentrations remained unchanged in both murine models of obesity, suggesting a particular local but not systemic importance for OPN. OPN expression was strongly elevated also in the AT of obese patients compared with lean subjects in both omental and sc AT. In addition, we detected three OPN isoforms to be expressed in human AT and, strikingly, an obesity induced alteration of the OPN isoform expression pattern. Analysis of AT cellular fractions revealed that OPN is exceptionally highly expressed in AT macrophages in humans and mice. Moreover, OPN expression in AT macrophages was strongly up-regulated by obesity. In conclusion, our data point toward a specific local role of OPN in obese AT. Therefore, OPN could be a critical regulator in obesity induced AT inflammation and insulin resistance.

scholarly journals Branched-Chain Amino Acid Oxidation Is Elevated in Adults with Morbid Obesity and Decreases Significantly after Sleeve Gastrectomy

2020 ◽  
Vol 150 (12) ◽  
pp. 3180-3189
Author(s):  
Hong Chang Tan ◽  
Jean W Hsu ◽  
Jean-Paul Kovalik ◽  
Alvin Eng ◽  
Weng Hoong Chan ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Sleeve Gastrectomy ◽  
Plasma Concentrations ◽  
Fat Free Mass ◽  
Acid Oxidation ◽  
Morbidly Obese ◽  
Healthy Weight ◽  
Leucine Oxidation ◽  
Branched Chain Amino Acid ◽  
Branched Chain

ABSTRACT Background Plasma concentrations of branched-chain amino acids (BCAAs) are elevated in obese individuals with insulin resistance (IR) and decrease after bariatric surgery. However, the metabolic mechanisms are unclear. Objectives Our objectives are to compare leucine kinetics between morbidly obese and healthy-weight individuals cross-sectionally, and to prospectively evaluate changes in the morbidly obese after sleeve gastrectomy. We hypothesized that leucine oxidation is slower in obese individuals and increases after surgery. Methods Ten morbidly obese [BMI (in kg/m2) ≥32.5, age 21–50 y] and 10 healthy-weight participants (BMI &lt;25), matched for age (median ∼30 y) but not gender, were infused with [U-13C6] leucine and [2H5] glycerol to quantify leucine and glycerol kinetics. Morbidly obese participants were studied again 6 mo postsurgery. Primary outcomes were kinetic parameters related to BCAA metabolism. Data were analyzed by nonparametric methods and presented as median (IQR). Results Participants with obesity had IR with an HOMA-IR (4.89; 4.36–8.76) greater than that of healthy-weight participants (1.32; 0.99–1.49; P &lt; 0.001) and had significantly faster leucine flux [218; 196–259 compared with 145; 138–149 μmol · kg fat-free mass (FFM)−1 · h−1], oxidation (24.0; 17.9–29.8 compared with 16.1; 14.3–18.5 μmol · kg FFM−1 · h−1), and nonoxidative disposal (204; 190–247 compared with 138; 129–140 μmol · kg FFM−1 · h−1) (P &lt; 0.017 for all). After surgery, the morbidly obese had a marked improvement in IR (3.54; 3.06–6.08; P = 0.008) and significant reductions in BCAA concentrations (113; 95–157 μmol/L) and leucine oxidation (9.37; 6.85–15.2 μmol · kg FFM−1 · h−1) (P = 0.017 for both). Further, leucine flux in this group correlated significantly with IR (r = 0.78, P &lt; 0.001). Conclusions BCAA oxidation is not impaired but elevated in individuals with morbid obesity. Plasma BCAA concentrations are lowered after surgery owing to slower breakdown of body proteins as insulin's ability to suppress proteolysis is restored. These findings suggest that IR is the underlying cause and not the consequence of elevated BCAAs in obesity.

scholarly journals Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

2017 ◽  
Vol 61 (3) ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Critical Illness ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Peripheral Compartment ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Intercompartmental Clearance

ABSTRACT The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h−1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h−1. A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.

scholarly journals Assessment of the Body Composition and the Loss of Fat-Free Mass through Bioelectric Impedance Analysis in Patients Who Underwent Open Gastric Bypass

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Wilson Rodrigues de Freitas Junior ◽  
Elias Jirjoss Ilias ◽  
Paulo Kassab ◽  
Roberto Cordts ◽  
Paulo Gustavo Porto ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Gastric Bypass ◽  
Impedance Analysis ◽  
Fat Free Mass ◽  
Morbidly Obese ◽  
Obese Patients ◽  
Bioelectric Impedance Analysis ◽  
Open Gastric Bypass ◽  
Bioelectric Impedance ◽  
The World

Background. Bariatric surgery is considered an effective option for the management of morbid obesity. The incidence of obesity has been gradually increasing all over the world reaching epidemic proportions in some regions of the world. Obesity can cause a reduction of up to 22% in the life expectancy of morbidly obese patients.Objective. The objective of this paper is to assess the weight loss associated with the first 6 months after bariatric surgery using bioelectric impedance analysis (BIA) for the evaluation of fat mass and fat-free mass.Method. A total of 36 morbidly obese patients were subjected to open gastric bypass surgery. The patients weight was monitored before and after the procedure using the bioelectric impedance analysis.Results. Bariatric surgery resulted in an average percentage of weight loss of 28.6% (40 kg) as determined 6 months after the procedure was performed. Analysis of the different components of body weight indicated an undesirable loss of fat-free mass along with the reduction of total body weight.Conclusion. Open gastric bypass induced a significant loss of total weight and loss of fat-free mass in patients six months after the surgery. The use of bioelectric impedance analysis resulted in an appropriate estimation of the total weight components in individuals subjected to bariatric surgery allowing a more real analysis of the variation of weight after the surgery.

The effect of isoniazid intake on ethionamide pharmacokinetics and target attainment in multidrug-resistant tuberculosis patients.

2021 ◽  
Author(s):  
Maxwell T. Chirehwa ◽  
Richard Court ◽  
Mariana de Kock ◽  
Lubbe Wiesner ◽  
Nihal de Vries ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Fat Free Mass ◽  
Hepatic Extraction ◽  
Target Attainment ◽  
Post Dose ◽  
Tuberculosis Patients ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Disposition Model

Ethionamide is recommended as part of regimens to treat multidrug-resistant and rifampicin-resistant tuberculosis. The study was conducted to (i) describe the distribution of ethionamide minimum inhibitory concentrations (MICs), (ii) describe the pharmacokinetics of ethionamide, and (iii) determine the probability of attaining target AUC 0-24 /MIC values associated with suppression of resistant subpopulation and microbial kill. Participants received 15–20 mg/kg of ethionamide daily (in 500 or 750 mg doses), as part of a multidrug regimen. Pretreatment MICs of ethionamide for M. tuberculosis sputum isolates were determined using Sensititre MYCOTB MIC plates. Plasma concentrations of ethionamide (measured pre-dose and at 2, 4, 6, 8 and 10 hours post-dose) were available for 84 patients. A one-compartment disposition model including a liver compartment capturing hepatic extraction, best described ethionamide pharmacokinetics. Clearance and volume were allometrically scaled using fat-free mass. Isoniazid co-administration reduced ethionamide clearance by 31% resulting in a 44% increase in AUC 0-24 . The median (range) MIC (n=111) was 2.5 mg/L (<0.3 to >40 mg/L). Simulations showed increased daily doses of ethionamide (1 250 mg, 1 500 mg, and 1 750 mg for patients weighing ≤45 kg, 46-70 kg, and >70 kg, respectively) resulted in the probability of attaining a f AUC 0-24 /MIC ratio ≥ 42 in more than 90% of patients, only at the lowest MIC of 0.3 mg/L. The WHO recommended doses of ethionamide do not achieve target concentrations even for the lowest MIC measured in the cohort.

scholarly journals Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

2016 ◽  
Vol 60 (11) ◽  
pp. 6550-6557 ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Maintenance Dose ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Intercompartmental Clearance

ABSTRACTOur objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n= 6) and morbidly obese (n= 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

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