Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis

Ehmann, Lisa; Zöller, Michael; Minichmayr, Iris K.; Scharf, Christina; Huisinga, Wilhelm; Zander, Johannes; Kloft, Charlotte

doi:10.1016/j.ijantimicag.2019.06.016

Cited by 56 publications

(85 citation statements)

References 41 publications

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“…3). The majority of the mean PK parameter estimates obtained in our study were in agreement with the ones obtained by other authors and are presented in Table 3 [4, [15][16][17][18][19][20]. The typical clearance values are similar, yet the volume of distribution at steady state (Vss = V 1 + V 2 ) is not consistent between the studies.…”

Section: Discussionsupporting

confidence: 88%

“…Since recommended beta-lactam regimens are often inadequate in septic patients treated with CRRT, the drug concentrations might be too low to ensure adequate bacterial killing, resulting in increased morbidity and mortality, as well as the emergence of antibiotic resistance. Despite numerous studies on meropenem pharmacokinetics in the critically ill patients published to date, there is no consensus on dosing of this widely used antimicrobial in different ICU scenarios [4,[15][16][17][18][19][20]. In this observational single-center cohort study, performed at a tertiary mixed ICU, we aimed to characterize the sources of PK variability of meropenem in a diverse population of critically ill patients receiving CRRT and to perform dosing simulations to assess their probability of target attainment (PTA), in order to provide empirical dosing recommendations.…”

Section: Discussionmentioning

confidence: 99%

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Population pharmacokinetics of standard-dose meropenem in critically ill patients on continuous renal replacement therapy: a prospective observational trial

et al. 2020

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Background The primary objective of this study was to develop a population pharmacokinetic model of meropenem, based on the population of critically ill adult patients undergoing CRRT. The secondary one was to examine the relationship between patient characteristics (covariates) and individual PK parameters. Finally, we aimed to perform Monte Carlo simulations to assess the probability of target attainment (PTA) of %T > MIC considering the uncertainty of PK parameters. Materials and methods The study population included 19 adult critically ill patients on CRRT, receiving 1 g of meropenem in 1-h infusions every 8 h. Blood samples were collected prior to (time zero) and 15, 30, 45, 60, 75, 90, 120, 180, 240 and 480 min after the start of meropenem administration. Population nonlinear mixed-effects modeling was conducted using NONMEM software, Fortran, and Wings for NONMEM. Results A two-compartment model was used to describe the available data. Typical values of the central and peripheral volume of distribution, and the CRRT and inter-compartmental clearance for a theoretical patient with 24.6 g/l albumin concertation were V 1 = 27.9 l, V 2 = 33.7 l, Cl CRRT = 15.1 l/h, and Q = 21.1 l/h. A significant covariate relationship between V 1 and albumin concentration was observed in the data that was described by a power relationship with − 2.87 exponent. Subsequently performed Monte Carlo simulations of the model allowed us to assess the impact of albumin concentration on PTA. The 40%T > 2 mg/l target was reached in more than 90% of subjects after 1-h infusion of 1000 mg q8h and steady-state conditions. The more stringent 100%T > 2 mg/l target requires higher doses and/or longer infusion durations that depend on the albumin concentration. Conclusions The population PK model was successfully developed to describe the time course of meropenem concentrations. The hypoalbuminemia was found to be associated with higher PTA in the CRRT patients after multiple short-term infusions.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of standard-dose meropenem in critically ill patients on continuous renal replacement therapy: a prospective observational trial

et al. 2020

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“…Therefore, the meropenem elimination in our cohort most likely relied solely on the renal replacement therapy in both groups. All other parameter values were comparable to those previously reported for critically ill patients [36]. A multitude of clinical studies of meropenem PK in healthy volunteers and critically ill patients, based on extensive sampling data, described meropenem concentration-time profiles as bi-exponential owing to the vast distribution in blood and into various tissues [38][39][40].…”

Section: Discussionsupporting

confidence: 85%

“…In our study cohort with critically ill patients, no difference in clearance could be shown either, confirming the previous results. Notably, in our patient population, the clearance of approximately 5 L/h was lower than 8.3 to 9.3 L/h as previously reported [35,36], but comparable to a clearance of 4.8 L/h as shown for anuric patients receiving renal replacement therapy [37]. Therefore, the meropenem elimination in our cohort most likely relied solely on the renal replacement therapy in both groups.…”

Section: Discussionsupporting

confidence: 73%

“…A total of 19 critically ill patients were included in this study with eight patients suffering from ACLF and renal failure and 11 patients only from renal failure. ACLF patients had a mean MELD score of 34 (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37), a CLIF-SOFA of 15 (14-15) and a CLIF-lactate score of 59 (57-64). An overview of the patients' characteristics is given in Table 1.…”

Section: Resultsmentioning

confidence: 99%

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Acute-on-chronic liver failure alters meropenem pharmacokinetics in critically ill patients with continuous hemodialysis: an observational study

Grensemann

Busse

König

et al. 2020

Ann. Intensive Care

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Background: Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Adequate dosing of antimicrobial therapy is of central importance to improve outcome. Liver failure may alter antibiotic drug concentrations via changes of drug distribution and elimination. We studied the pharmacokinetics of meropenem in critically ill patients with ACLF during continuous veno-venous hemodialysis (CVVHD) and compared it to critically ill patients without concomitant liver failure (NLF). Methods: In this prospective cohort study, patients received meropenem 1 g tid short-term infusion (SI). Meropenem serum samples were analyzed by high-performance liquid chromatography. A population pharmacokinetic analysis was performed followed by Monte Carlo simulations of (A) meropenem 1 g tid SI, (B) 2 g loading plus 1 g prolonged infusion tid (C) 2 g tid SI, and (D) 2 g loading and continuous infusion of 3 g/day on days 1 and 7. Probability of target attainment (PTA) was assessed for 4× the epidemiological cutoff values for Enterobacterales (4 × 0.25 mg/L) and Pseudomonas spp. (4 × 2 mg/L). Results: Nineteen patients were included in this study. Of these, 8 patients suffered from ACLF. A two-compartment model with linear clearance from the central compartment described meropenem pharmacokinetics. The peripheral volume of distribution (V 2) was significantly higher in ACLF compared to NLF (38.6L versus 19.7L, p = .05). PTA for Enterobacterales was achieved in 100% for all dosing regimens. PTA for Pseudomonas spp.

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Antibiotics, Antivirals, and Antifungals in Critical Care

Shamshirsaz,

Vaught

2024

Critical Care Obstetrics

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Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis

Cited by 56 publications

References 41 publications

Population pharmacokinetics of standard-dose meropenem in critically ill patients on continuous renal replacement therapy: a prospective observational trial

Population pharmacokinetics of standard-dose meropenem in critically ill patients on continuous renal replacement therapy: a prospective observational trial

Acute-on-chronic liver failure alters meropenem pharmacokinetics in critically ill patients with continuous hemodialysis: an observational study

Antibiotics, Antivirals, and Antifungals in Critical Care

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