Optimisation of imipenem regimens in patients with impaired renal function by pharmacokinetic-pharmacodynamic target attainment analysis of plasma and urinary concentration data

Objectives: To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens. Methods: A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration ( fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs ≤ 16 μg/mL was compared between proposed and standard regimens. Results: At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in ≥95% PTA versus ≥76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (≥98%) versus standard regimens (≥93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (≥93%) was comparable with those of standard regimens (≥91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens. Conclusion: Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs ≤ 16 μg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing.

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Relationships of Urinary Beta2- microglobulin in Neonates with Impaired Renal Function in Different Stages of Hypoxic Ischaemic Encephalopathy

Bangladesh Journal of Child Health ◽

10.3329/bjch.v37i1.15348 ◽

2013 ◽

Vol 37 (1) ◽

pp. 22-26

Author(s):

M Banerjee ◽

SK Majumdar ◽

Md Shahidullah

Keyword(s):

Renal Function ◽

Serum Creatinine ◽

Impaired Renal Function ◽

Large Scale ◽

Perinatal Asphyxia ◽

Conclusive Evidence ◽

Stage Iii ◽

Clinical Staging ◽

Urinary Concentration ◽

Case Group

Hypoxic Ischaemic Encephalopathy (HIE) is a sequelae of neonates suffering from severe perinatal asphyxia. It may also cause impaired renal function due to acute tubular necrosis followed by elevation of urinary concentration of certain low molecular weight proteins like ?2- microglobulin. This study was designed to evaluate the urinary ?2- microglobulin level in neonates with HIE patients those who have impaired renal function. This prospective case control study was carried out in the Neonatal unit of the department of Pediatrics and in the Labor ward of the department of Obstetrics and Gynecology Bangabandhu Sheik Mujib Medical University, Dhaka during the period of 1st July 2005 to 30th June 2006. This study was designed to estimate urinary ?2- micro globulin level in the asphyxiated newborn as well normal newborns to see any significant changes and to find out its relation with over all outcomes of newborns with perinatal asphyxia. In this study, 42 term newborn babies before 24 hours of age, those who failed to take spontaneous breathing within 5 minutes of the complete delivery were taken as cases and 40 healthy term newborns were taken as control. Asphyxiated newborns were divided into three groups depending on the sarnat and sarnat clinical staging of HIE. Mean±SD value of urinary ?-2- micro globulin in case group 4.1 ± 2.79 mg/l and in the control was 1.35 ± 1.08 mg/l. It shows significant (p<0.01) rise of urinary ?-2 micro globulin levels in case group. The degree of rise of urinary ?-2- micro globulin was related with the severity of HIE but blood urea and serum creatinine levels were not increased significantly in stage I and stage II except in stage III HIE patients. It was concluded from this study that raised urinary â2- microglobulin level may be related with HIE patients irrespective of clinical staging but serum creatinine and blood urea were found to be elevated only in stage III HIE patients. But to draw a conclusive evidence regarding relationship of urinary ?2 microglobulin with advance stages of HIE in neonates with impaired renal function require further large scale study. DOI: http://dx.doi.org/10.3329/bjch.v37i1.15348 BANGLADESH J CHILD HEALTH 2013; VOL 37 (1) : 22-26

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Population pharmacokinetic–pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function: Dosing considerations for Acinetobacter baumannii infections

Journal of Infection and Chemotherapy ◽

10.1016/j.jiac.2014.12.005 ◽

2015 ◽

Vol 21 (4) ◽

pp. 284-289 ◽

Cited By ~ 7

Author(s):

Yuta Yokoyama ◽

Kazuaki Matsumoto ◽

Kazuro Ikawa ◽

Erika Watanabe ◽

Norifumi Morikawa ◽

...

Keyword(s):

Renal Function ◽

Acinetobacter Baumannii ◽

Impaired Renal Function ◽

Population Pharmacokinetic ◽

Target Attainment

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1302. Cefiderocol Population Pharmacokinetics and Probability of Target Attainment in Plasma and Epithelial Lining Fluid in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1485 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S665-S665

Author(s):

Takayuki Katsube ◽

Nao Kawaguchi ◽

Roger Echols ◽

Toshihiro Wajima ◽

David P Nicolau

Keyword(s):

Renal Function ◽

Urinary Tract ◽

Healthy Subjects ◽

Epithelial Lining ◽

Infection Site ◽

Target Attainment ◽

Research Support ◽

Concentration Data ◽

Epithelial Lining Fluid ◽

Gram Negative

Abstract Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with activity against a broad range of Gram-negative bacteria. The aim of this study was to perform population pharmacokinetic (PopPK) analysis and evaluate probability of target attainment (PTA) in plasma and epithelial lining fluid (ELF) based on a modeling and simulation approach. Methods PopPK analysis in plasma was conducted using 3427 concentration data from 425 patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), complicated urinary tract infection (cUTI), or acute uncomplicated pyelonephritis in 3 Phase 2 or 3 studies (NCT03032380, NCT02714595, and NCT02321800), and 91 subjects without any infection in Phase 1 studies. In addition, intrapulmonary modeling was conducted using ELF concentration data from 7 pneumonia patients (NCT03862040) and 20 healthy subjects. Monte-Carlo simulations were performed by generating 1000 virtual patients for each infection site (pneumonia, BSI/sepsis, or cUTI) to predict PTA for 75% of time for which free drug concentration in plasma or ELF (only pneumonia patients) exceeds the minimum inhibitory concentration (MIC; 0.25–16 µg/mL) over dosing interval following CFDC 2 g q8h infused over 3 hours with dose adjustment based on renal function, including augmented renal clearance. Results The developed PopPK model described the plasma and ELF CFDC concentrations. Creatinine clearance, body weight, infection site, and albumin concentration were statistically significant covariates on CFDC PK in plasma. There were no clinically significant differences in CFDC plasma exposure based on infection site or with/without ventilation. The penetration ratio of ELF to free plasma in pneumonia patients (0.340) was 1.3-fold higher than that in healthy subjects (0.263). As shown in the table below, plasma PTA was >90% against MICs ≤4 μg/mL, regardless of infection site and renal function. ELF PTA in pneumonia patients was >90% against MICs ≤2 μg/mL and >85% against MICs ≤4 μg/mL, regardless of renal function. Table. Probability of Target Attainment for 75% fT>MIC or 75% fT>MIC,ELF Conclusion The recommended dosing regimen (2 g, q8h, 3-hr infusion) adjusted by renal function provided adequate exposure to CFDC in patients with infections caused by Gram-negative pathogens, irrespective of infection site and renal function. Disclosures Takayuki Katsube, PhD, Shionogi & Co., Ltd. (Employee) Nao Kawaguchi, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Toshihiro Wajima, PhD, Shionogi & Co., Ltd. (Employee) David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)

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