PHARMACOKINETICS OF VANCOMYCIN IN CRITICALLY ILL PATIENTS IN THAILAND

Objective: The pharmacokinetics and pharmacodynamics of drugs in critically ill patients are difficult to predict due to complex pathophysiological changes. Vancomycin is an antibiotic commonly used to treat serious gram positive bacterial infections in critically ill patients and the treatment goal is to rapidly achieve and maintain therapeutic concentrations. We assessed the pharmacokinetics of vancomycin in critically ill patients to help guide dosing.Methods: A total of 138 patients with 299 vancomycin serum concentrations were included in this analysis. Vancomycin serum concentrations were measured using a fluorescence polarization immunoassay. Population pharmacokinetic parameters were estimated using nonlinear mixed effects regression. Age, creatinine clearance (CrCL) and body weight were tested as potential covariates in the pharmacokinetic model.Results: Vancomycin concentration-time profiles were best described by a two-compartment pharmacokinetic model with an additive error model for between subject variability. Creatinine clearance significantly influenced vancomycin clearance (CL). Mean population pharmacokinetic parameters (% between subject variability) were: CL 3.39 l/h (13%), central compartment volume of distribution (V1) 24.92 l (26%); and peripheral compartment volume of distribution (V2) 24.6 (37%).Conclusion: Higher clearance and a smaller volume of distribution of vancomycin was observed in critically-ill patients compared to those reported in non-critically ill patients with a similar distribution of renal function and body weight. Close monitoring of vancomycin serum concentrations is warranted in critically ill patients with dose interval adjustments based on the patient's creatinine clearance.Â

ผลของโปรแกรมควบคุมการใช้ยาปฏิชีวนะในผู้ป่วยหนักศัลยกรรมโรงพยาบาลมหาราชนครเชียงใหม่ Effects of Antibiotic Restriction Program in Critical Care Surgery Patients at Maharaj Nakorn Chiang Mai Hospital

Objective: To evaluate the outcome of the antibiotic restriction programwith regard to the resistance patterns of nosocomial infection betweenbefore and after program implementation. Secondary objective was tocompare mortality, antibiotic consumption and expenditure between the twoperiods. Method: In this retrospective cohort research, we recruitedpatients in critical care surgical ward at Maharaj Nakorn Chiang MaiHospital between year 2008 (before) and year 2009 – 2011 (after).Results: The findings showed an increase in the percentage of organisms’resistant to the restricted antibiotics after program implementation for bothA. baumannii and P. aeruginosa. Only the percentages of A. baumanniiresistant to meropenem and cefoperazone-sulbactam (P = 0.042 and0.018, respectively) and the percentage of P. aeruginosa resistant toimipenem (P = 0.011) before and after the program implementation werestatistically significant. However, P. aeruginosa resistant to cefoperazonesulbactamwas decreased (P = 0.375). Mortality rate did not changesignificantly after the program. There were declines of gross antibioticutilization (measured by defined daily dose, DDD/1000 patient-days) andexpenditure of all restricted antibiotics after the program (13.3% and 25.9%,respectively). Conclusion: The antibiotic restriction program by aninfectious disease specialist did not decrease the percentage of organismsresistant to the restricted antibiotics but succeed in the reduction inantibiotics utilization and expenditure, with no difference in mortality.Keywords: antibiotic restriction program, antibiotic resistance, antibioticconsumption, antibiotic expenditur

Quantitative Prediction of CYP3A4‐ and CYP3A5‐Mediated Drug Interactions

We verified a physiologically‐based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5‐mediated drug‐drug interactions (DDIs). A midazolam (MDZ)–ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics‐informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (FG) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7–3.4 and 3.9–4.7‐fold in intravenous administration and 11.4–13.4 and 17.0–19.7‐fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A‐mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers

Quantitative prediction of midazolam-ketoconazole drug -drug interaction

Ketoconazole (KTZ) is commonly used by pharmaceutical companies to characterize the worst-case drug interaction for CYP3A substrates under development. Doses of 200 mg and 400 mg of KTZ have been used in human drug interaction studies with midazolam (MDZ). However, large variations in the magnitude of interaction are observed. No single study has compared the inhibitory effect of 200 mg vs. 400 mg of KTZ. Thus, it is unclear whether the worst-case drug interaction study requires 400 mg of KTZ or if a 200 mg dose would suffice. CYP3A5 genotype may in part explain individual variability in metabolism and drug-drug interactions exhibited by CYP3A substrates due to its polymorphic and racially diverse expression. Twenty-four healthy volunteers completed this three-phase, randomized, crossover study. Intravenous (IV) and oral (PO) MDZ were administered on consecutive days alone (control) or on day 6 (IV) and 7 (PO) of KTZ 200 mg or 400 mg daily. Serum samples were assayed for MDZ and KTZ by HPLC-MS. CYP3A5 genotype was determined using allele specific real-time PCR (CYP3A5*3 and *6) and allelic discrimination real-time PCR (CYP3A5*7). The extent of CYP3A inhibition by KTZ was dose dependent with a significantly greater effect following 400 mg KTZ compared to 200 mg KTZ. The baseline systemic and oral clearance values were significantly greater in the group with at least one copy of CYP3A5 functional allele as compared to the group with no functional allele. There was no difference in the extent of interaction after 200 mg or 400 mg KTZ daily between the groups with no and at least one CYP3A5 functional allele. However, the ratios between control and treatment phases of the 1\u27OH MDZ area under the concentration vs. time curve (AUC) over MDZ AUC among expression groups was significantly different after 200 mg but not after 400 mg KTZ. A model defining KTZ and MDZ pharmacokinetics and employing a stochastic approach for a quantitative drug interaction prediction was developed. The interaction model predicted the extent of interaction reported in published articles. Further research is needed to define the interaction and the variance models

Factors associated with mortality in immunocompetent patients with hospital-acquired pneumonia

Aim: The aim of the study is to determine the factors associated with 28-day mortality in immunocompetent patients with hospital-acquired pneumonia (HAP). Methods: This was a 42-month retrospective cohort study in Chiang Kham Hospital. Patients with HAP diagnosed between January 2013 and June 2016 who did not have an immunocompromised status were recruited into the study. Statistical Analysis Used: Univariable and multivariable binary logistic regression analyses were performed to determine the factors associated with mortality in patients with HAP. Results: A total of 181 HAP patients. The most causative pathogens were nonfermenting Gram-negative bacilli. Fifty-two (28.7%) patients had died within 28 days after HAP diagnosis. Multivariable analysis demonstrated that mechanical ventilation (MV) dependency (adjusted odds ratio [OR] = 3.58, 95% confidence interval [CI] 1.53–8.37, P = 0.003), antibiotic duration (adjusted OR = 0.79, 95% CI 0.70–0.88, P < 0.001), acute kidney injury (adjusted OR = 5.93, 95% CI 1.29–27.22, P = 0.022), and hematologic diseases (adjusted OR = 11.45, 95% CI 1.61–81.50, P = 0.015) were the significant factors associated with 28-day mortality. Conclusions: The factors associated with mortality were MV dependency, HAP duration of treatment, acute kidney injury, and hematologic disease. Early recognition of these factors in immunocompetent patients with HAP and treatment with intensive care may improve the outcome

Influence of Hemodialysis on Gentamicin Pharmacokinetics, Removal During Hemodialysis, and Recommended Dosing

Background and Objectives: Aminoglycoside antibiotics are commonly used in chronic kidney disease stage 5 patients. The purpose of this study was to characterize gentamicin pharmacokinetics, dialytic clearance, and removal by hemodialysis and to develop appropriate dosing strategies

Physiologically Based Pharmacokinetic Model of Mechanism-Based Inhibition of CYP3A by Clarithromycin

The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3Aas in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e.g., midazolam, failed to account for nonlinear metabolism of clarithromycin. A semiphysiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and non-CYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. KI and kinact values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 μM for Ki and 0.4 and 4 h−1 for kinact in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6-fold change in intravenous midazolam area under the plasma concentration-time curve (AUC) after 500 mg of clarithromycin orally twice daily was consistent with clinical observations. Although the mean predicted 5.3-fold change in the AUC of oral midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in KI, kinact, and CYP3A half-life than hepatic CYP3A. This semiphysiologically based pharmacokinetic model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Furthermore, this model framework can be applied to other mechanism-based inhibitors