Population pharmacokinetics of meropenem in burn patients

Doh, Kyoung Chan; Woo, Heungjeong; Hur, Jun; Yim, Haejun; Kim, Jimyon; Chae, Hiun-Suk; Han, Seunghoon; Yim, Dong‐Seok

doi:10.1093/jac/dkq317

Cited by 50 publications

(51 citation statements)

References 18 publications

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“…Our population mean volume of distribution at steady state (27.6 liters) scaled by FFM fell well within the range of estimates from other studies that typically reported 23 to 34 liters in nonobese patients (24)(25)(26)(27)(28). This suggested that scaling the volume of distribution by FFM was reasonable.…”

Section: Discussionsupporting

confidence: 84%

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

Wittau

Scheele

Kurlbaum

et al. 2015

Antimicrob Agents Chemother

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c Meropenem 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/m 2 ). 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. W hile antimicrobial resistance is one of the greatest threats to human health, the number of new antibiotics against multidrug-resistant bacteria declined drastically over the last 3 decades (1-3). Meropenem continues to serve as an important component of our antibiotic armamentarium and covers a large range of clinically relevant pathogens for antibiotic therapy, including those causing intra-abdominal infections or infections of the subcutaneous tissue. Meropenem is a potent, broad-spectrum ␤-lactam antibiotic that yields relatively rapid bacterial killing and is among the first antibiotic options for treatment of severe infections; it covers most of the pathogens relevant for intra-abdominal infections (4). Meropenem is a hydrophilic molecule, and it is unknown whether meropenem penetrates well into the subcutaneous tissue and peritoneal fluid of obese patients.Obese patients are at a high risk of postoperative and hospitalrelated infections (5), and optimal management of these infections is crucial to improve the outcome of obese patients with severe infections. The selection of the antibiotic and dose are critical to manage those infections (5, 6). Recommended daily doses are based on pharmacokinetic/pharmacodynamic (PK/PD) studies usually conducted in nonobese healthy volunteers (5). However, PK variables may differ in obese and nonobese patients, potentially resulting in inadequate antibiotic plasma and tissue concentrations. Thus, PK studies in obese, noninfected individuals are essential to avoid the risk of over-or underdosing.Only a few studies have assessed the PK of meropenem in obese patients (4-8), and some of these studies found considerably different clearances and volumes of distribution in obese and nonobese patients. These studies did not perform population pharmacokinetic modeling and did not assess the peritoneal fluid and subcutaneous tissue penetration of meropenem in obese patients.As meropenem is a hydrophilic molecule, it is important to determine whether its PK is...

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Section: Discussionsupporting

confidence: 84%

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

Wittau

Scheele

Kurlbaum

et al. 2015

Antimicrob Agents Chemother

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“…Other studies used a two-compartment model to characterize the total concentration of meropenem in plasma (55)(56)(57)(58). These models were shown to underpredict free meropenem concentrations in critically ill patients, and a onecompartment model had the least bias in predicting free meropenem concentration (21).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae

Albiero

Mazucheli

et al. 2016

Antimicrob Agents Chemother

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“…In the ideal situation and when the decision to adjust (or not) for all models is in agreement with the conclusion made based on the observed concentration, for the given ith opportunity, the colors moving across the mosaic plot horizontally will be the same as the color in the observed column. An example of this type of agreement is represented by the 70th dose adjustment decision coded black to increase the daily dose administered, which was based on the ob- (8) would have led to similar dose adjustment changes of 62% (P ϭ 0.51), 62% (P Ͻ 0.05), 60% (P ϭ 0.69), and 59% (P Ͻ 0.05) of the time as determined by observed concentrations, respectively. The other three methods agreed with the decisions based on the observed concentrations Ͻ55% (P Ͻ 0.05 for all three) of the time.…”

Section: Patient Characteristics and Dosing Datamentioning

confidence: 99%

“…Population pharmacokinetic models that quantify the effect of demographic, pathophysiological, and other drug-related factors on drug disposition should be considered valuable in the critical care setting for accurately predicting individualized and optimized antibiotic doses for patients who exhibit profoundly altered and rapidly changing pharmacokinetics. The models can be applied to predict appropriate empirical doses or be used to guide dose adaptation as part of a therapeutic drug monitoring (TDM) intervention.Several pharmacokinetic models have been developed for meropenem from different subpopulations of patients (7)(8)(9)(10)(11)(12)(13)(14). In order to establish a TDM program for meropenem to optimize meropenem dosing, the question arises as to which pharmacokinetic model best predicts the meropenem concentrations in a heterogeneous cohort of critically ill patients.…”

mentioning

confidence: 99%

“…Several pharmacokinetic models have been developed for meropenem from different subpopulations of patients (7)(8)(9)(10)(11)(12)(13)(14). In order to establish a TDM program for meropenem to optimize meropenem dosing, the question arises as to which pharmacokinetic model best predicts the meropenem concentrations in a heterogeneous cohort of critically ill patients.…”

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confidence: 99%

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Comparison of the Accuracy and Precision of Pharmacokinetic Equations To Predict Free Meropenem Concentrations in Critically Ill Patients

Wong

Farkas

Sussman

et al. 2015

Antimicrob Agents Chemother

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h Population pharmacokinetic analyses can be applied to predict optimized dosages for individual patients. The aim of this study was to compare the prediction performance of the published population pharmacokinetic models for meropenem in critically ill patients. We coded the published population pharmacokinetic models with covariate relationships into dosing software to predict unbound meropenem concentrations measured in a separate cohort of critically ill patients. The agreements between the observed and predicted concentrations were evaluated with Bland-Altman plots. The absolute and relative bias and precision of the models were determined. The clinical implications of the results were evaluated according to whether dose adjustments were required from the predictions to achieve a meropenem concentration of >2 mg/liter throughout the dosing interval. A total of 157 free meropenem concentrations from 56 patients were analyzed. Eight published population pharmacokinetic models were compared. The models showed an absolute bias in predicting the unbound meropenem concentrations from a mean percent difference (95% confidence interval [CI]) of ؊108.5% (؊119.9% to ؊97.3%) to 19.9% (7.3% to 32.7%), while absolute precision ranged from ؊249.1% (؊263.4% to ؊234.8%) to 31.9% (17.6% to 46.2%) and ؊178.9% (؊196.9% to ؊160.9%) to 175.0% (157.0% to 193.0%). A dose change was required in 44% to 64% of the concentration results. Seven of the eight equations evaluated underpredicted free meropenem concentrations. In conclusion, the overall accuracy of these models supports their inclusion in dosing software and application for individualizing meropenem doses in critically ill patients to increase the likelihood of achievement of optimal antibiotic exposures. Meropenem, a carbapenem antibiotic with broad-spectrum activities against both Gram-positive and Gram-negative bacteria, is commonly used in critically ill patients with life-threatening infections. Vital to the success of this treatment is early and appropriate antibiotic therapy. Selecting the correct dose is as important, but this process is highly challenging in critically ill patients because of the variable and difficult-to-predict pharmacokinetics in these patients (1, 2). Dose optimization of meropenem should be considered imperative because suboptimal antibiotic exposures might jeopardize the clinical outcomes and potentially increase the emergence of antibiotic resistance (3).Meropenem is a time-dependent antibiotic: its clinical and microbiological efficacy is related to the percentage of the dosing interval in which the free drug concentration remains above the MIC of the pathogenic organism (fT ϾMIC ) (4, 5). The in vitro bactericidal activity of carbapenems is optimal at an fT ϾMIC of Ն40%; however, a target fT ϾMIC of 100% has been suggested in critically ill patients (6). Population pharmacokinetic models that quantify the effect of demographic, pathophysiological, and other drug-related factors on drug disposition should be considered valuable in the crit...

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Population pharmacokinetics of meropenem in burn patients

Cited by 50 publications

References 18 publications

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

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

Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae

Comparison of the Accuracy and Precision of Pharmacokinetic Equations To Predict Free Meropenem Concentrations in Critically Ill Patients

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