Darren Tishler

Pharmacokinetics of Intravenous Linezolid in Moderately to Morbidly Obese Adults

ABSTRACT The pharmacokinetics of linezolid was assessed in 20 adult volunteers with body mass indices (BMI) of 30 to 54.9 kg/m2 receiving 5 intravenous doses of 600 mg every 12 h. Pharmacokinetic analyses were conducted using compartmental and noncompartmental methods. The mean (±standard deviation) age, height, and weight were 42.2 ± 12.2 years, 64.8 ± 3.5 in, and 109.5 ± 18.2 kg (range, 78.2 to 143.1 kg), respectively. Linezolid pharmacokinetics in this population were best described by a 2-compartment model with nonlinear clearance (original value, 7.6 ± 1.9 liters/h), which could be inhibited to 85.5% ± 12.2% of its original value depending on the concentration in an empirical inhibition compartment, the volume of the central compartment (24.4 ± 9.6 liters), and the intercompartment transfer constants (K12 and K21) of 8.04 ± 6.22 and 7.99 ± 5.46 h−1, respectively. The areas under the curve for the 12-h dosing interval (AUCτ) were similar between moderately obese and morbidly obese groups: 130.3 ± 60.1 versus 109.2 ± 25.5 μg · h/ml (P = 0.32), and there was no significant relationship between the AUC or clearance and any body size descriptors. A significant positive relationship was observed for the total volume of distribution with total body weight (r2 = 0.524), adjusted body weight (r2 = 0.587), lean body weight (r2 = 0.495), and ideal body weight (r2 = 0.398), but not with BMI (r2 = 0.171). Linezolid exposure in these obese participants was similar overall to that of nonobese patients, implying that dosage adjustments based on BMI alone are not required, and standard doses for patients with body weights up to approximately 150 kg should provide AUCτ values similar to those seen in nonobese participants.

Ethnic variation in weight loss, but not co-morbidity remission, after laparoscopic gastric banding and Roux-en-Y gastric bypass

BACKGROUND Demographic factors such as ethnicity may affect bariatric surgery outcomes. We examined weight loss and co-morbidities outcomes in African American, Caucasian, and Hispanic patients who underwent laparoscopic gastric banding (LAGB) and Roux-en-Y gastric bypass (RYGB). The primary aim was to investigate demographic differences in weight loss and co-morbidities outcomes. METHODS We retrospectively examined weight change and co-morbidities outcomes in our prospective database. A total of 1,903 patients underwent LAGB or RYGB between January 1, 2005 and March 31, 2012. Of those, 1828 completed their 1-year follow-up visit (9-15 mo) and had complete data. We excluded patients who were missing ethnicity information, resulting in a final cohort of 1,684 patients. Multivariate analyses and χ2 tests were used to examine demographic variables in body mass index (BMI) change, percent excess weight loss (%EWL), and remission of co-morbidities. We also examined weight loss outcomes at 2- and 3-year follow-up. RESULTS Overall, those who underwent RYGB had a lower BMI and greater %EWL at 1, 2, and 3 years compared to those who had undergone LAGB. Overall, African American patients had a higher postoperative BMI than either Caucasian or Hispanic patients. African American patients also showed less %EWL than Caucasian and Hispanic patients. When we examined within surgery type, ethnic differences between African American and Caucasian patients were present across all 3 years in RYGB, but there were no ethnic differences by year 3 in LAGB. Additionally, African American and Hispanic patients no longer differed by year 3 in RYGB and by year 2 in LAGB. There were no significant ethnic differences in remission of diabetes, hyperlipidemia, hypertension, and sleep apnea at 1 year. CONCLUSION Our study found significant ethnic differences in the postoperative BMI and %EWL, which were more pronounced in patients undergoing RYGB than LAGB at the 3-year time point. These weight loss differences did not translate to a lower rate of co-morbidities remission.

Gastric bypass surgery as treatment of recalcitrant gastroparesis

BACKGROUND Few treatments for idiopathic and diabetic gastroparesis exist beyond symptom management, and no study has described gastric surgery for gastroparesis in obese and morbidly obese patients. The objective of this study was to describe treatment of recalcitrant gastroparesis in obese adults with Roux-en-Y gastric bypass (RYGB) surgery. METHODS A retrospective review was conducted of adult patients who underwent laparoscopic RYGB. Clinical data pre- and postsurgery and at a follow-up of up to 2 years were reviewed. Total symptom scores for gastroparetic symptom severity and frequency were compared presurgery and at follow-up using paired t tests. RESULTS Seven obese and morbidly obese patients (body mass index [BMI] = 39.5, range = 33-54; 6 women) with idiopathic or diabetic gastroparesis reported marked symptom improvement, and total symptom scores significantly decreased after RYGB. All 4 patients who were taking prokinetics preoperatively no longer required their medication after surgery. Three patients required prolonged treatment with antinausea medications in the postoperative period. Mean BMI change was 9.1 units and mean percent excess weight lost was 71.6 lbs. No perioperative complications were experienced. Two required readmissions due to various concerns (dysphagia, nausea, anastomotic ulcer). CONCLUSIONS In our cohort, no patients required the use of prokinetics after surgery and everyone experienced significant improvement in symptoms. Importantly, we found that RYGB is a safe surgical treatment for gastroparesis in obese patients. Our results indicate that gastroparesis, primarily believed to result in being underweight, can present in morbid obesity and can be markedly improved with RYGB.

Comparative physiogenomic analyses of weight loss in response to 2 modes of bariatric surgery: demonstration with candidate neuropsychiatric and cardiometabolic genes.

BACKGROUND Surgical weight loss response is variable, with suboptimal outcomes in some patients. We hypothesized that genetic biomarkers may be related to weight change. METHODS We tested 330 single nucleotide polymorphisms (SNPs) in genes relevant to metabolic regulation in 161 patients whose decrease in body mass index (BMI), 1 year after laparoscopic adjustable gastric banding (LAGB) or Roux-en-Y gastric bypass (RYGB), was small (lowest quartile response) or large (highest quartile response). LAGB patients whose BMI decreased≤4.7 or≥10.2 units comprised groups I (n = 43) and II (n = 40), respectively. RYGB patients whose BMI decreased≤13.6 or≥19.8 units comprised groups III (n = 39) and IV (n = 39), respectively. Within each surgery, SNPs with large differences in reference allele frequency (z score>2, corresponding to values displaced 2 standard deviations [SD] from the mean for all SNPs) in low versus high quartiles, were identified. We compared reference allele frequencies, within surgical procedure, using the χ(2) test (using Bonferroni correction for multiple testing). RESULTS The mean percent excess weight losses (±SD) corresponding to groups I, II, III, and IV were: 16 (±12), 64 (±30), 55 (±16), and 75 (±17), respectively. SNPs with z score>2 were identified in genes involved in LAGB response, lipid metabolic regulation (APOE, rs439401; APOC4, rs2288911), neural processes (DRD3, rs167771; HTR3 B, rs3758987), and xeno- or endobiotic metabolism (CYP3 A4, rs12333983); and for RYGB response, in lipid transport (SCARB1, rs10846744), folate metabolism (MTHFR, rs2066470), regulation of glycolysis in immune cells (HIF1 A, rs1951795), vitamin K cycling (VKORC1, rs2359612), and xeno- or endobiotic metabolism (CYP3 A4, rs2242480). For LAGB response, APOE SNP frequencies were significantly different. CONCLUSIONS With further validation, information derived from patient DNA may be useful to predict surgical weight loss outcomes and guide selection of surgical approach.

Effects of statin therapy on weight loss and diabetes in bariatric patients

BACKGROUND Bariatric surgeries are considered effective treatments for weight loss and improved diabetes control. Statins increase diabetes onset in prospective clinical trials and many bariatric patients with metabolic disease are concurrently on statins. OBJECTIVES We retrospectively examined the relationship of statin therapy to weight loss, diabetes mellitus onset and remission, and metabolic outcomes after bariatric surgery. SETTING Hospital. METHODS A total of 1575 patients (1231 women) underwent laparoscopic adjustable gastric banding (n = 1035), Roux-en-Y gastric bypass (n = 468), or sleeve gastrectomy (n = 72) and were categorized as to statin use (n = 671 statin users) and diabetes status (n = 557 patients with diabetes) preoperatively and at one year follow-up. RESULTS New onset cases of diabetes did not differ between patients on and not on preoperative statins (3 versus 4 new diabetes cases, respectively), but diabetes resolved after surgery in 159 (23.7%) patients on preoperative statins and in only 124 (13.7%) patients not on preoperative statins (χ2 = 26.1; P<.01). Patients ceasing statin therapy experienced more diabetes remission (n = 85 or 35.7%) than patients consistently using statin therapy at both time points (n = 57 or 17.0%; χ2 = 27.3; P< .01). CONCLUSION In contrast to expectations, our results suggest that diabetes resolves with bariatric surgery more often in patients maintained on statin therapy than in those never on statin therapy whereas cessation of statin therapy is associated with the greatest reductions in diabetes prevalence. These results indicate an impact of statin use on metabolic outcomes following bariatric surgery; a randomized control trial is needed to examine carefully this relationship.

Comment on: Predicting potentially preventable hospital readmissions following bariatric surgery

Readmission following Bariatric Surgery. PLoS ONE 2012;7:e32506. [25] Goldfield NI, McCullough EC, Hughes JS, et al. Identifying Potentially Preventable Readmissions. Health Care Financing Review 2008;30:75–91. [26] 3 MTM Health Information Systems. Potentially Preventable Readmissions Classification System: Methodology Overview. Document number GRP-139 05/08. May 2008. [27] Saunders J, Ballantyne GH, Belsley B, et al. One year readmission rates at a high volume bariatric surgery center: Laparoscopic adjustable gastric banding, laparoscopic gastric bypass and vertical banded gastroplasty Roux-en-Y gastric bypass. Obesity Surgery 2008;18: 1233–40. [28] Elixhauser A, Syeiner C, Harris D. Co-morbidity measures for use with Administrative Data. Med Care 1998;36:8–27. [29] Hutter MM, Schirmer BD, Jones DB, et al. First Report from the American College of Surgeons Bariatric Surgery Center Network: Laparoscopic Sleeve Gastrectomy has Morbidity and Effectiveness Positioned Between the Band and the Bypass. Ann Surg 2011;254: 410–22.