Reappraisal of the Optimal Dose of Meropenem in Critically Ill Infants and Children: a Developmental Pharmacokinetic-Pharmacodynamic Analysis

ABSTRACT Data of developmental pharmacokinetics (PK) of meropenem in critically ill infants and children with severe infections are limited. We assessed the population PK and defined the appropriate regimen to optimize treatment in this population based on developmental PK-pharmacodynamic (PD) analysis. Blood samples were collected from pediatric intensive care unit patients with severe infection treated with standard dosage regimens for meropenem. Population PK data were analyzed using NONMEM software. Fifty-seven patients (mean age, 2.96 years [range, 0.101 to 14.4]; mean body weight, 15.8 kg [range, 5.0 to 65.0]) were included. A total of 135 meropenem concentrations were obtainable for population PK modeling. The median number of samples per patients was 2 (range, 1 to 4). A two-compartment model with first-order elimination was optimal for PK modeling. Weight and creatinine clearance (estimated by the Schwartz formula) were significantly correlated with the PK parameters of meropenem. The probabilities of target attainment for pathogens with low MICs of 1 and 2 μg/ml were 87.5% and 68.6% following administration of 40 mg/kg/dose (every 8 h [q8h]) as a 4-h infusion and 98.0% and 73.3% with high MICs of 4 and 8 μg/ml following administration of 110 mg/kg/day as a continuous infusion in critically ill infants and children under 70% fT>MIC (the free time during which the plasma concentration of meropenem exceeds the MIC), respectively. The standard dosage regimens for meropenem did not meet an appropriate PD target, and an optimal dosing regimen was established in critically ill infants and children. (This study has been registered at ClinicalTrials.gov under identifier NCT03643497.)

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Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation

Frontiers in Pharmacology ◽

10.3389/fphar.2021.768912 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jae Ha Lee ◽

Dong-Hwan Lee ◽

Jin Soo Kim ◽

Won-Beom Jung ◽

Woon Heo ◽

...

Keyword(s):

Monte Carlo Simulation ◽

Monte Carlo ◽

Extracorporeal Membrane Oxygenation ◽

Creatinine Clearance ◽

Critically Ill ◽

Compartment Model ◽

Standard Regimen ◽

Dosage Regimens ◽

Two Compartment Model ◽

Population Pk

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens.Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC.Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC.Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

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Population Pharmacokinetics and Probability of Target Attainment of Different Dosing Regimens of Ceftazidime in Critically Ill Patients with a Proven or Suspected Pseudomonas aeruginosa Infection

Antibiotics ◽

10.3390/antibiotics10060612 ◽

2021 ◽

Vol 10 (6) ◽

pp. 612

Author(s):

Annabel Werumeus Buning ◽

Caspar J. Hodiamont ◽

Natalia M. Lechner ◽

Margriet Schokkin ◽

Paul W. G. Elbers ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Critically Ill ◽

Critically Ill Patients ◽

Hematologic Malignancy ◽

Compartment Model ◽

Target Attainment ◽

Worst Case ◽

Optimal Dosing ◽

Population Pk ◽

Pseudomonas Aeruginosa Infection

Altered pharmacokinetics (PK) of hydrophilic antibiotics in critically ill patients is common, with possible consequences for efficacy and resistance. We aimed to describe ceftazidime population PK in critically ill patients with a proven or suspected Pseudomonas aeruginosa infection and to establish optimal dosing. Blood samples were collected for ceftazidime concentration measurement. A population PK model was constructed, and probability of target attainment (PTA) was assessed for targets 100% T > MIC and 100% T > 4 × MIC in the first 24 h. Ninety-six patients yielded 368 ceftazidime concentrations. In a one-compartment model, variability in ceftazidime clearance (CL) showed association with CVVH. For patients not receiving CVVH, variability in ceftazidime CL was 103.4% and showed positive associations with creatinine clearance and with the comorbidities hematologic malignancy, trauma or head injury, explaining 65.2% of variability. For patients treated for at least 24 h and assuming a worst-case MIC of 8 mg/L, PTA was 77% for 100% T > MIC and 14% for 100% T > 4 × MIC. Patients receiving loading doses before continuous infusion demonstrated higher PTA than patients who did not (100% T > MIC: 95% (n = 65) vs. 13% (n = 15); p < 0.001 and 100% T > 4 × MIC: 20% vs. 0%; p = 0.058). The considerable IIV in ceftazidime PK in ICU patients could largely be explained by renal function, CVVH use and several comorbidities. Critically ill patients are at risk for underexposure to ceftazidime when empirically aiming for the breakpoint MIC for P. aeruginosa. A loading dose is recommended.

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Optimized meropenem dosage regimens using a pharmacokinetic/pharmacodynamic population approach in patients undergoing continuous venovenous haemodiafiltration with high-adsorbent membrane

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz299 ◽

2019 ◽

Vol 74 (10) ◽

pp. 2979-2983 ◽

Cited By ~ 1

Author(s):

A Padullés Zamora ◽

R Juvany Roig ◽

E Leiva Badosa ◽

J Sabater Riera ◽

X L Pérez Fernández ◽

...

Keyword(s):

Critically Ill ◽

Concomitant Administration ◽

Compartment Model ◽

Central Compartment ◽

Relative Standard Error ◽

Open Label ◽

Dosage Regimens ◽

Optimal Dosing ◽

Continuous Renal Replacement Therapies ◽

Relative Standard

Abstract Background The pharmacokinetics (PK) of antibiotics change during sepsis and continuous renal replacement therapies in critically ill patients. Limited evidence exists on the use of the oXiris® high-adsorbent membrane. Objectives To develop a PK/pharmacodynamic (PD) model for meropenem in critically ill sepsis patients undergoing continuous venovenous haemodiafiltration (CVVHDF) with the oXiris® membrane, and to design an optimal dosing regimen assessed according to the PTA. Methods A prospective, open-label, observational PK trial was performed (EUDRACT 2011-005902-30). We conducted PK studies (plasma and ultrafiltrate) for at least 24 h after concomitant administration of CVVHDF and meropenem 1 g q8h. We constructed a PK model using the non-linear mixed-effects approach (NONMEM 7.3). We evaluated the suitability of different dosage regimens using Monte Carlo simulations and calculated the PTA as the percentage of subjects achieving a given percentage of time above the MIC (fT>MIC). Results The PK of meropenem was best captured by a two-open-compartment model with zero-order input kinetics and first-order elimination. Extracorporeal CL was 7.78 L/h [relative standard error (RSE) 16.45 L/h] and central compartment V (Vc) was 24.9 L (RSE 13.73 L). Simulations showed that, for susceptible Pseudomonas aeruginosa isolates (EUCAST MIC ≤2 mg/L) and attainment of 100%fT>MIC, 500 mg q8h given as extended (EI) or continuous infusion (CI) would be sufficient. For a target of 100%fT>4×MIC, CI of 3000 mg q24h or 2000 mg q8h administered as EI or CI would be required. Conclusions We have constructed a PK model of meropenem in sepsis patients undergoing CVVHDF using the oXiris® membrane. This tool will support physicians when calculating the optimal initial dose.

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Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00531-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4577-4584 ◽

Cited By ~ 16

Author(s):

Abdulaziz S. Alobaid ◽

Steven C. Wallis ◽

Paul Jarrett ◽

Therese Starr ◽

Janine Stuart ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Central Compartment ◽

Lower Probability ◽

Peripheral Compartment ◽

Morbidly Obese ◽

Parameter Estimates ◽

Population Pk ◽

Intercompartmental Clearance

ABSTRACTSevere pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial plasma samples were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m2, respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h; volume of distribution in the central compartment (V1), 11.7 ± 5.8 liters; intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h−1; and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h−1. Higher creatinine clearance (CLCR) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increasedV1, dose adjustment based on CLCRappears to be more important than patient BMI.

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1109. Pharmacokinetics and Exposure of Cefepime in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation (ECMO)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1303 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S646-S646

Author(s):

Abigail K Kois ◽

Jason A Gluck ◽

David P Nicolau ◽

Joseph L Kuti

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Research Study ◽

Scientific Research ◽

Compartment Model ◽

Study Investigator ◽

Population Pk ◽

Infusion Regimen ◽

Susceptibility Breakpoint ◽

Research Grant

Abstract Background ECMO is a life-saving tool utilized in critically ill patients that require respiratory and/or cardiac support. ECMO may also affect the pharmacokinetics (PK) of certain medications, including some antibiotics. Cefepime is a widely used antibiotic in this population due to its broad spectrum activity but limited data are available to guide dosing in patients requiring ECMO. Methods This was a prospective, single-center study of 6 critically ill adult patients requiring ECMO and receiving cefepime 2g q8h as a 3h infusion. After obtaining informed consent, 4-6 blood samples within the dosing interval were collected to determine cefepime concentrations. Population PK was conducted in Pmetrics using R. Final MAP Bayesian parameter estimates were used to simulate free time above MIC (%ƒT >MIC) for various cefepime dosing regimens. The target pharmacodynamic exposure was 70% fT >MIC. Results Patients were between 31-62 years old; 4/6 (66.7%) were on veno-venous (VV) ECMO and 2 veno-arterial (VA) ECMO. Two patients required continuous venovenous hemodiafiltration (CVVHDF) while the other 4 had a CrCL between 92-199 ml/min. A two compartment model fitted the data better than a one compartment model. Median (range) final population PK parameters were: clearance (CL), 9.8 L/h (7.6-33.1); volume of central compartment (VC ), 6.9 L (4.7-49.8); and intercompartment transfer constants (k12), 2.04 h-1 (1.48-2.29); and k21, 1.49 h-1 (0.75-1.71). The 2g q8h (3h infusion) regimen resulted in target exposure in all patients up to an MIC of 8 mg/L (the susceptibility breakpoint for Pseudomonas), with 5/6 patients achieving this at 16 mg/L. A standard 2g q12h (0.5h infusion) regimen would have resulted in 5/6 patients achieving 70% ƒT >MIC at 8 mg/L and 1/6 at 16 mg/L. Conclusion These are the first data describing cefepime PK and exposure attainment in critically ill patients receiving ECMO. Cefepime 2g q8h (3h infusion) achieved target pharmacodynamic exposure up to the susceptibility breakpoint of 8 mg/L in all 6 patients, including 2 with concomitant CVVHDF. Additional studies are warranted to define cefepime PK in patients on ECMO across a robust range of CrCL to guide dosing. Disclosures David P. Nicolau, PharmD, Abbvie, Cepheid, Merck, Paratek, Pfizer, Wockhardt, Shionogi, Tetraphase (Other Financial or Material Support, I have been a consultant, speakers bureau member, or have received research funding from the above listed companies.) Joseph L. Kuti, PharmD, Allergan (Speaker’s Bureau)BioMérieux (Consultant, Research Grant or Support, Speaker’s Bureau)Contrafect (Scientific Research Study Investigator)GSK (Consultant)Merck (Research Grant or Support)Paratek (Speaker’s Bureau)Roche Diagnostics (Research Grant or Support)Shionogi (Research Grant or Support)Summit (Scientific Research Study Investigator)

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Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa187 ◽

2020 ◽

Vol 75 (9) ◽

pp. 2641-2649

Author(s):

Nynke G L Jager ◽

Reinier M van Hest ◽

Jiao Xie ◽

Gloria Wong ◽

Marta Ulldemolins ◽

...

Keyword(s):

Protein Binding ◽

Critically Ill ◽

Critically Ill Patients ◽

Binding Capacity ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Population Pk ◽

Non Linear ◽

Dosing Regimens

Abstract Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

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Clinical features and outcomes of COVID-19 in older adults: a systematic review and meta-analysis

BMC Geriatrics ◽

10.1186/s12877-021-02261-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Sunny Singhal ◽

Pramod Kumar ◽

Sumitabh Singh ◽

Srishti Saha ◽

Aparajit Ballav Dey

Keyword(s):

Systematic Review ◽

Older Adults ◽

Critically Ill ◽

Clinical Features ◽

Older Patients ◽

Clinical Characteristics ◽

Meta Analysis ◽

Severe Infection ◽

Factors Affecting ◽

Pooled Prevalence

Abstract Background Few studies have focused on exploring the clinical characteristics and outcomes of COVID-19 in older patients. We conducted this systematic review and meta-analysis to have a better understanding of the clinical characteristics of older COVID-19 patients. Methods A systematic search of PubMed and Scopus was performed from December 2019 to May 3rd, 2020. Observational studies including older adults (age ≥ 60 years) with COVID-19 infection and reporting clinical characteristics or outcome were included. Primary outcome was assessing weighted pooled prevalence (WPP) of severity and outcomes. Secondary outcomes were clinical features including comorbidities and need of respiratory support. Result Forty-six studies with 13,624 older patients were included. Severe infection was seen in 51% (95% CI– 36-65%, I2–95%) patients while 22% (95% CI– 16-28%, I2–88%) were critically ill. Overall, 11% (95% CI– 5-21%, I2–98%) patients died. The common comorbidities were hypertension (48, 95% CI– 36-60% I2–92%), diabetes mellitus (22, 95% CI– 13-32%, I2–86%) and cardiovascular disease (19, 95% CI – 11-28%, I2–85%). Common symptoms were fever (83, 95% CI– 66-97%, I2–91%), cough (60, 95% CI– 50-70%, I2–71%) and dyspnoea (42, 95% CI– 19-67%, I2–94%). Overall, 84% (95% CI– 60-100%, I2–81%) required oxygen support and 21% (95% CI– 0-49%, I2–91%) required mechanical ventilation. Majority of studies had medium to high risk of bias and overall quality of evidence was low for all outcomes. Conclusion Approximately half of older patients with COVID-19 have severe infection, one in five are critically ill and one in ten die. More high-quality evidence is needed to study outcomes in this vulnerable patient population and factors affecting these outcomes.

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Novel Population Pharmacokinetic Model for Linezolid in Critically Ill Patients and Evaluation of the Adequacy of the Current Dosing Recommendation

Pharmaceutics ◽

10.3390/pharmaceutics12010054 ◽

2020 ◽

Vol 12 (1) ◽

pp. 54 ◽

Cited By ~ 2

Author(s):

Amaia Soraluce ◽

Helena Barrasa ◽

Eduardo Asín-Prieto ◽

Jose Ángel Sánchez-Izquierdo ◽

Javier Maynar ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Standard Dose ◽

Compartment Model ◽

Antimicrobial Treatment ◽

Population Pharmacokinetic ◽

Renal Replacement Therapies ◽

Continuous Renal Replacement Therapies

Antimicrobial treatment in critically ill patients remains challenging. The aim of this study was to develop a population pharmacokinetic model for linezolid in critically ill patients and to evaluate the adequacy of current dosing recommendation (600 mg/12 h). Forty inpatients were included, 23 of whom were subjected to continuous renal replacement therapies (CRRT). Blood and effluent samples were drawn after linezolid administration at defined time points, and linezolid levels were measured. A population pharmacokinetic model was developed, using NONMEM 7.3. The percentage of patients that achieved the pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated (AUC24/MIC > 80 and 100% T>MIC). A two-compartment model best described the pharmacokinetics of linezolid. Elimination was conditioned by the creatinine clearance and by the extra-corporeal clearance if the patient was subjected to CRRT. For most patients, the standard dose of linezolid did not cover infections caused by pathogens with MIC ≥ 2 mg/L. Continuous infusion may be an alternative, especially when renal function is preserved.

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PRONE POSITIONING CAN BE SAFELY PERFORMED IN CRITICALLY ILL INFANTS AND CHILDREN

Pediatric Critical Care Medicine ◽

10.1097/00130478-200609000-00036 ◽

2006 ◽

Vol 7 (5) ◽

pp. 502

Author(s):

Lori D. Fineman ◽

Michelle LaBrecque ◽

Mei-Chiung Shih ◽

Martha A.Q. Curley

Keyword(s):

Critically Ill ◽

Infants And Children ◽

Prone Positioning

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Pharmacokinetics of Amphotericin B Colloidal Dispersion in Critically Ill Patients with Cholestatic Liver Disease

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00690-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5414-5418 ◽

Cited By ~ 5

Author(s):

Stefan Weiler ◽

Elisabeth Überlacher ◽

Julia Schöfmann ◽

Eva Stienecke ◽

Stefan Dunzendorfer ◽

...

Keyword(s):

Steady State ◽

Liver Disease ◽

Amphotericin B ◽

Critically Ill ◽

Critically Ill Patients ◽

Normal Liver ◽

Colloidal Dispersion ◽

Cholestatic Liver Disease ◽

Normal Liver Function ◽

Standard Dosage

ABSTRACTThe pharmacokinetics of lipid-bound and liberated amphotericin B (AMB) was assessed in 11 critically ill patients with cholestatic liver disease (CSLD) and in 9 subjects with normal liver function treated with AMB colloidal dispersion (ABCD). Exposure to lipid-bound AMB was higher in patients with CSLD. Levels of liberated AMB were elevated by CSLD only after the first dose, whereas its pharmacokinetics was unaffected at steady state. The standard dosage of ABCD is probably adequate for patients with CSLD.

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