β-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance

ABSTRACTAugmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of ≥120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due toPseudomonas aeruginosa. There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r= −0.21,P= 0.01), trough concentrations of piperacillin (r= −0.28,P= 0.0071), concentrations at 50% of the dosage interval (r= −0.41,P< 0.0001), and total body clearance of piperacillin (r= 0.39,P= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain β-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

Download Full-text

Select Critically ill Patients at Risk of Augmented Renal Clearance: Experience in a Malaysian Intensive Care Unit

Anaesthesia and Intensive Care ◽

10.1177/0310057x1404200606 ◽

2014 ◽

Vol 42 (6) ◽

pp. 715-722 ◽

Cited By ~ 15

Author(s):

S. Adnan ◽

S. Ratnam ◽

S. Kumar ◽

D. Paterson ◽

J. Lipman ◽

...

Keyword(s):

Intensive Care Unit ◽

At Risk ◽

Intensive Care ◽

Serum Creatinine ◽

Creatinine Clearance ◽

Renal Clearance ◽

Critically Ill ◽

Critically Ill Patients ◽

Augmented Renal Clearance ◽

Drug Concentrations

Augmented renal clearance (ARC) refers to increased solute elimination by the kidneys. ARC has considerable implications for altered drug concentrations. The aims of this study were to describe the prevalence of ARC in a select cohort of patients admitted to a Malaysian intensive care unit (ICU) and to compare measured and calculated creatinine clearances in this group. Patients with an expected ICU stay of >24 hours plus an admission serum creatinine concentration <120 μmol/l, were enrolled from May to July 2013. Twenty-four hour urinary collections and serum creatinine concentrations were used to measure creatinine clearance. A total of 49 patients were included, with a median age of 34 years. Most study participants were male and admitted after trauma. Thirty-nine percent were found to have ARC. These patients were more commonly admitted in emergency ( P=0.03), although no other covariants were identified as predicting ARC, likely due to the inclusion criteria and the study being under-powered. Significant imprecision was demonstrated when comparing calculated Cockcroft-Gault creatinine clearance (Crcl) and measured Crcl. Bias was larger in ARC patients, with Cockcroft-Gault Crcl being significantly lower than measured Crcl ( P <0.01) and demonstrating poor correlation (rs=-0.04). In conclusion, critically ill patients with ‘normal’ serum creatinine concentrations have varied Crcl. Many are at risk of ARC, which may necessitate individualised drug dosing. Furthermore, significant bias and imprecision between calculated and measured Crcl exists, suggesting clinicians should carefully consider which method they employ in assessing renal function.

Download Full-text

Pharmacokinetics of vancomycin in adult cystic fibrosis patients.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.1.186 ◽

1996 ◽

Vol 40 (1) ◽

pp. 186-190 ◽

Cited By ~ 18

Author(s):

R A Pleasants ◽

E L Michalets ◽

D M Williams ◽

W M Samuelson ◽

J R Rehm ◽

...

Keyword(s):

Cystic Fibrosis ◽

Standard Deviation ◽

Creatinine Clearance ◽

Total Body Clearance ◽

Elimination Rate ◽

Clinical Score ◽

Pharmacokinetic Parameters ◽

The Mean ◽

Total Body ◽

Body Clearance

Although the depositions of many antibiotics are altered in cystic fibrosis patients, that of vancomycin has not been studied. To assess vancomycin pharmacokinetics, 10 adult cystic fibrosis patients were given a parenteral dose of vancomycin (15 mg/kg) during the first 72 h of hospitalization for acute bronchopulmonary exacerbation. Blood samples were obtained at 0, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 15, and 24 h. The mean (standard deviation) weight, measured creatinine clearance, and Taussig clinical score were 51 (13) kg, 130 (39) ml/min/1.73 m2, and 64 (13), respectively. Multicompartmental pharmacokinetic parameters were best described by a two-compartment model. The mean (standard deviation) volume of distribution, total body clearance, and terminal elimination rate constant were 0.58 (0.15) liter/kg, 91 (19) ml/min/1.73 m2, and 0.123 (0.05) h-1, respectively. These values were consistent with vancomycin pharmacokinetic parameters obtained in previous studies of healthy adult volunteers. Vancomycin dosages predicted by using a two-compartment Bayesian model were approximately 15 mg/kg every 8 to 12 h. There were poor correlations between clinical score or creatinine clearance and any pharmacokinetic parameter (r values of < 0.32). The coefficient of correlation between urine flow rate and total body clearance was 0.7 (P < 0.05). Adult cystic fibrosis patients exhibit a disposition of vancomycin similar to that exhibited by healthy adults, and thus cystic fibrosis does not alter vancomycin pharmacokinetics.

Download Full-text

Single -Dose Pefloxacin Pharmacokinetics and Metabolism in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD)

Peritoneal Dialysis International ◽

10.1177/089686089101100112 ◽

1991 ◽

Vol 11 (1) ◽

pp. 59-63 ◽

Cited By ~ 4

Author(s):

Paul Nikolaidis ◽

Scott E. Walker ◽

Nicholas Dombros ◽

Achilleas Tourkantonis ◽

Tom W. Paton ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Continuous Ambulatory Peritoneal Dialysis ◽

Half Life ◽

Total Body Clearance ◽

Serum Concentrations ◽

Drug Concentrations ◽

Elimination Half ◽

The Mean ◽

Total Body ◽

Body Clearance

Seven adult patients on continuous ambulatory peritoneal dialysis (CAPD) received one dose of pefloxacin, a novel quinolone antibiotic, orally and intravenously on two separate occasions to characterize the pharmacokinetics and metabolism of the drug. Concentrations of both pefloxacin and its active metabolite N-desmethylpefloxacin (norfloxacin) were measured in serum and dialysate by HPLC. Half-life, total body clearance and peritoneal clearance were determined. The overall elimination half-life was 19.9h. Relative to the IV dose the bioavailability following oral administration of pefloxacin was 76%. The mean serum and dialysate concentrations were similar up to 24 h after the oral or IV dose. After a 6 h dwell time the dialysate concentration of pefloxacin was 2.24 mg/L which is above the MICgo for most bacteria responsible for peritonitis in CAPD patients. The peritoneal clearance of pefloxacin averaged 2.5 mL/min. Serum concentrations of the metabolite norfloxacin were less than 0.5 mg/L during the 24 h study period. We conclude that pefloxacin might be equally effective in the treatment of peritonitis of CAPD after oral or IV administration. Since the peritoneal clearance contributes insignificantly to the elimination of pefloxacin during CAPD, the proposed maintenance regimen of an oral or IV 400 mg dose/day seems to be a reasonable therapy for infections in CAPD patients.

Download Full-text

Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance

Antibiotics ◽

10.3390/antibiotics10101238 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1238

Author(s):

Sixuan Zhao ◽

Na He ◽

Yahui Zhang ◽

Chuhui Wang ◽

Suodi Zhai ◽

...

Keyword(s):

Creatinine Clearance ◽

Renal Clearance ◽

Pharmacokinetic Model ◽

Area Under The Curve ◽

Volume Of Distribution ◽

Chinese Patients ◽

Population Pharmacokinetic ◽

Augmented Renal Clearance ◽

Population Pharmacokinetic Modeling ◽

Target Therapeutic Range

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400–650 mg·h/L, trough concentration: 10–20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.

Download Full-text

Augmented Renal Clearance: What Have We Known and What Will We Do?

Frontiers in Pharmacology ◽

10.3389/fphar.2021.723731 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yifan Luo ◽

Yidan Wang ◽

Yue Ma ◽

Puxiu Wang ◽

Jian Zhong ◽

...

Keyword(s):

Risk Factors ◽

Renal Function ◽

Animal Models ◽

Treatment Failure ◽

Renal Clearance ◽

Clinical Treatment ◽

Research Progress ◽

Therapeutic Drug ◽

Augmented Renal Clearance ◽

Drug Concentrations

Augmented renal clearance (ARC) is a phenomenon of increased renal function in patients with risk factors. Sub-therapeutic drug concentrations and antibacterial exposure in ARC patients are the main reasons for clinical treatment failure. Decades of increased research have focused on these phenomena, but there are still some existing disputes and unresolved issues. This article reviews information on some important aspects of what we have known and provides suggestion on what we will do regarding ARC. In this article, we review the current research progress and its limitations, including clinical identification, special patients, risk factors, metabolism, animal models and clinical treatments, and provide some promising directions for further research in this area.

Download Full-text

Augmented renal clearance: a retrospective, cohort study of urinary creatinine clearance in critically ill patients in the United Kingdom

Journal of International Medical Research ◽

10.1177/03000605211015573 ◽

2021 ◽

Vol 49 (5) ◽

pp. 030006052110155

Author(s):

Brian W Johnston ◽

David Perry ◽

Martyn Habgood ◽

Miland Joshi ◽

Anton Krige

Keyword(s):

Risk Factors ◽

United Kingdom ◽

Creatinine Clearance ◽

Renal Clearance ◽

Repeated Measures ◽

Apache Ii ◽

Apache Ii Score ◽

Augmented Renal Clearance ◽

Urinary Creatinine ◽

The United Kingdom

Objective Augmented renal clearance (ARC) is associated with sub-therapeutic antibiotic, anti-epileptic, and anticoagulant serum concentrations leading to adverse patient outcomes. We aimed to describe the prevalence and associated risk factors for ARC development in a large, single-centre cohort in the United Kingdom. Methods We conducted a retrospective observational study of critically unwell patients admitted to intensive care between 2014 and 2016. Urinary creatinine clearance was used to determine the ARC prevalence during the first 7 days of admission. Repeated measures logistic regression was used to determine risk factors for ARC development. Results The ARC prevalence was 47.0% (95% confidence interval [95%CI]: 44.3%–49.7%). Age, sex, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and sepsis diagnosis were significantly associated with ARC. ARC was more prevalent in younger vs. older (odds ratio [OR] 0.95 [95%CI: 0.94–0.96]), male vs. female (OR 0.32 [95%CI: 0.26–0.40]) patients with lower vs. higher APACHE II scores (OR 0.94 [95%CI: 0.92–0.96]). Conclusions This patient group probably remains unknown to many clinicians because measuring urinary creatinine clearance is not usually indicated in this group. Clinicians should be aware of the ARC risk in this group and consider measurement of urinary creatinine clearance.

Download Full-text

Pharmacokinetics of Intravenous Piperacillin Administration in Patients Undergoing On-Line Hemodiafiltration

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01670-08 ◽

2009 ◽

Vol 53 (8) ◽

pp. 3266-3268 ◽

Cited By ~ 4

Author(s):

Kook-Hwan Oh ◽

Chiweon Kim ◽

Hankyu Lee ◽

Hajeong Lee ◽

Ji Yong Jung ◽

...

Keyword(s):

Standard Deviation ◽

Total Body Clearance ◽

Volume Of Distribution ◽

Pharmacokinetic Parameters ◽

Recovery Method ◽

Elimination Half ◽

On Line ◽

The Mean ◽

Total Body ◽

Body Clearance

ABSTRACT The pharmacokinetic characteristics of piperacillin sodium were studied in five volunteers undergoing on-line hemodiafiltration (HDF). The subjects were given 2 g of piperacillin sodium intravenously over 1 min and placed on on-line HDF for 4 h starting at 60 min after the piperacillin infusion. Noncompartmental models were employed for estimation of the pharmacokinetic parameters, and intradialytic piperacillin clearance was calculated by the recovery method. The mean volume of distribution and the elimination half-life were 0.27 ± 0.13 liter/kg (mean ± standard deviation) and 1.1 ± 0.6 h, respectively. The total body clearance of piperacillin was 0.19 ± 0.08 liter/h/kg. Piperacillin clearance through on-line HDF was 0.11 ± 0.06 liter/h/kg. The mean serum piperacillin concentration was 4.0 ± 1.9 μg/ml at the end of the 4-h on-line HDF session. The concentration of infused piperacillin recovered in the dialysate was 527 ± 236 mg (26.3% ± 11.8%). We suggest the replacement of 500 mg of piperacillin after each on-line HDF session.

Download Full-text