Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

Ulldemolins, Marta; Soy, Dolors; Llauradó-Serra, Mireia; Vaquer, Sergi; Castro, Pedro; Rodríguez, Alejandro; Pontes, Caridad; Calvo, Gonzalo; Torres, Antoni; Martín‐Loeches, Ignacio

doi:10.1128/aac.00712-15

Cited by 69 publications

(72 citation statements)

References 46 publications

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“…A bolus dose preceding the EI would increase the Cmax as well as the Cp in the first hour. However, several other studies have shown that an EI without a preceding bolus is equally effective in conditions such as ventilator-associated pneumonia, febrile neutropenia with bacteraemia, hematopoietic stem cell transplantation, suspected Gram-negative infections and critically ill patients with septic shock requiring continuous renal replacement therapy [10,13,[24][25][26][27][28][29]. In most of these studies, Cp remained greater than MIC for a greater fraction of time with the EI of meropenem without a prior bolus, compared to a 1-h infusion administration of meropenem.…”

Section: Table 4 Simulation Results On the First And Third Days Showimentioning

confidence: 99%

“…It is pertinent to mention here that rather than using a population pharmacokinetics (popPK) analysis, we resorted to compartment modeling for the estimation of Vd and Cl for each patient from which PK profiles were simulated for various dosing scenarios. Several authors in the past have used the popPK approach to analyze such data [24,29]. While popPK is very informative to identify the sources and correlates of variability, the relatively small sample size would have affected the model estimates.…”

Section: Table 4 Simulation Results On the First And Third Days Showimentioning

confidence: 99%

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Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria

Kothekar

Divatia

Myatra

et al. 2020

Ann. Intensive Care

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Background: Optimal anti-bacterial activity of meropenem requires maintenance of its plasma concentration (Cp) above the minimum inhibitory concentration (MIC) of the pathogen for at least 40% of the dosing interval (fT > MIC > 40). We aimed to determine whether a 3-h extended infusion (EI) of meropenem achieves fT > MIC > 40 on the first and third days of therapy in patients with severe sepsis or septic shock. We also simulated the performance of the EI with respect to other pharmacokinetic (PK) targets such as fT > 4 × MIC > 40, fT > MIC = 100, and fT > 4 × MIC = 100.Methods: Arterial blood samples of 25 adults with severe sepsis or septic shock receiving meropenem 1000 mg as a 3-h EI eight hourly (Q8H) were obtained at various intervals during and after the first and seventh doses. Plasma meropenem concentrations were determined using a reverse-phase high-performance liquid chromatography assay, followed by modeling and simulation of PK data. European Committee on Antimicrobial Susceptibility Testing (EUCAST) definitions of MIC breakpoints for sensitive and resistant Gram-negative bacteria were used. Results:A 3-h EI of meropenem 1000 mg Q8H achieved fT > 2 µg/mL > 40 on the first and third days, providing activity against sensitive strains of Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii. However, it failed to achieve fT > 4 µg/mL > 40 to provide activity against strains susceptible to increased exposure in 33.3 and 39.1% patients on the first and the third days, respectively. Modeling and simulation showed that a bolus dose of 500 mg followed by 3-h EI of meropenem 1500 mg Q8H will achieve this target. A bolus of 500 mg followed by an infusion of 2000 mg would be required to achieve fT > 8 µg > 40. Targets of fT > 4 µg/mL = 100 and fT > 8 µg/mL = 100 may be achievable in two-thirds of patients by increasing the frequency of dosing to six hourly (Q6H). Conclusions:In patients with severe sepsis or septic shock, EI of 1000 mg of meropenem over 3 h administered Q8H is inadequate to provide activity (fT > 4 µg/mL > 40) against strains susceptible to increased exposure, which requires © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article' s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article' a bolus of 500 mg followed by EI of 1500 mg Q8H. While fT > 8 µg/mL > 40 require escalation of EI dose, fT > 4 µg/ mL = 100 and fT > 8 µg/mL = 100 require escalation of both EI dose and frequency.

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Section: Table 4 Simulation Results On the First And Third Days Showimentioning

confidence: 99%

Section: Table 4 Simulation Results On the First And Third Days Showimentioning

confidence: 99%

Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria

Kothekar

Divatia

Myatra

et al. 2020

Ann. Intensive Care

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“…A flowchart of study selection for each drug is provided in Figure . A total of 2082 articles were identified and screened, with 130 studies included in the final analysis . Some studies provided PK parameters for two drugs (e.g.…”

Section: Resultsmentioning

confidence: 99%

Scaling beta‐lactam antimicrobial pharmacokinetics from early life to old age

Lonsdale

Baker

Kipper

et al. 2018

Brit J Clinical Pharma

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“…The effect of the residual renal function of the patient on meropenem dosing requirements was investigated by Ulldemolins et al; the authors found that the volume of residual diuresis was important with urine outputs greater than 500 mL/day, requiring an additional dose per 24-h period or administration by an extended infusion [11].…”

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confidence: 99%

“…Each of these reports, like most RRT pharmacokinetic studies, observed high pharmacokinetic variability highlighting that comparison of mean parameter values or concentrations can be misleading. Therefore, understanding the distribution of these values is important to understand the range of dosing possibilities for any drug-RRT combination.The effect of the residual renal function of the patient on meropenem dosing requirements was investigated by Ulldemolins et al; the authors found that the volume of residual diuresis was important with urine outputs greater than 500 mL/day, requiring an additional dose per 24-h period or administration by an extended infusion [11].Further exploration of the role of changing the method of infusion of beta-lactams was separately performed by Shotwell et al [12] and Jamal et al [13,14]. Shotwell and colleagues analysed piperacillin concentrations in 68 CRRT patients.…”

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confidence: 99%

What’s new in pharmacokinetics of antimicrobials in AKI and RRT?

2017

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Acute kidney injury (AKI) remains a very common occurrence in critically ill patients and is associated with decreased survival in severe sepsis [1]. Effective treatment for these patients is mostly through treatment of the underlying pathology as well as supportive care with renal replacement therapy (RRT). Optimised pharmacotherapy is of heightened importance to ensure maximal outcomes for critically ill patients with AKI receiving RRT, although the pharmacokinetics of many drugs can change dramatically in these patients, making effective dosing a challenge.The purpose of this paper is to describe the new developments in antibiotic dosing and pharmacokinetics in critically ill patients with AKI and receiving RRT.The overwhelming body of recent literature aims to understand how to better dose these compounds in critically ill patients receiving different forms of RRT, with far more data being generated for continuous than for intermittent RRT. Little data is available in AKI without RRT. Very few data on other classes of drugs are available which is largely due to the fact that many have negligible RRT clearance because of high protein binding, hepatic clearance or large volumes of distribution (e.g. most anticonvulsants), have dosing that is titrated to effect (e.g. analgesics and sedatives) or have readily available therapeutic drug monitoring (TDM).Recent pharmacokinetic studies of antibiotics have moved away from a drug-based dosing approach, where each drug has a given dose regardless of type of RRT, to a strategy where the specific drug dose accounts for the modality of RRT (e.g. intermittent, prolonged or continuous convective and/or diffusive RRT) and the associated settings (e.g. blood or ultrafiltration flow rate, filter material and surface area).Most of the studies continue to evaluate only pharmacokinetic endpoints and include small cohorts which limits the generalizability of findings. On the other hand, some comparative studies have been useful to better elucidate the effect of different approaches to RRT, including different modalities (i.e. intermittent and prolonged intermittent RRT and CRRT). It is hoped that the forthcoming SaMpling Antibiotics in Renal Replacement Therapy (SMARRT) study (ACTRN12613000241730), endorsed by the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG), will address many of these issues. Further to this, use of ex vivo models of RRT are providing suitable doses for drugs to be subsequently tested in clinical pharmacokinetic studies [2]. Such models are very useful as the interaction between changing RRT modalities and settings on drug clearance, as well as potentially significant drug adsorption to the RRT membrane, can be more accurately calculated without the complicating effects of biology.Important knowledge has been generated recently that has aimed to quantify the effect of the dose and type of RRT used. Using a meta-review methodology of published studies, Jamal et al. highlighted the importance of CRRT dose where they found th...

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Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

Cited by 69 publications

References 46 publications

Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria

Clinical pharmacokinetics of 3-h extended infusion of meropenem in adult patients with severe sepsis and septic shock: implications for empirical therapy against Gram-negative bacteria

Scaling beta‐lactam antimicrobial pharmacokinetics from early life to old age

What’s new in pharmacokinetics of antimicrobials in AKI and RRT?

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