scholarly journals Optimal empiric treatment for KPC-2-producing Klebsiella pneumoniae infections in critically ill patients with normal or decreased renal function using Monte Carlo simulation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guoan Wang ◽  
Wei Yu ◽  
Yushan Cui ◽  
Qingyi Shi ◽  
Chen Huang ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Renal Function ◽  
Klebsiella Pneumoniae ◽  
Critically Ill ◽  
Normal Renal Function ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Daily Dose

Abstract Background Limited clinical studies describe the pharmacodynamics of fosfomycin (FOS), tigecycline (TGC) and colistin methanesulfonate (CMS) in combination against KPC-producing Klebsiella pneumoniae (KPC-Kp). Population pharmacokinetic models were used in our study. Monte Carlo simulation was conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) of each agent alone and in combination against KPC-Kp in patients with normal or decreased renal function. Results The simulated regimen of FOS 6 g q8h reached ≥90% PTA against a MIC of 64 mg/L in patients with normal renal function. For patients with renal impairment, FOS 4 g q8h could provide sufficient antimicrobial coverage against a MIC of 128 mg/L. And increasing the daily dose could result to the cut-off value to 256 mg/L in decreased renal function. For TGC, conventional dosing regimens failed to reach 90% PTA against a MIC of 2 mg/L. Higher loading and daily doses (TGC 200/400 mg loading doses followed by 100 mg q12h/200 mg q24h) were needed. For CMS, none achieved 90% PTA against a MIC of 2 mg/L in normal renal function. Against KPC-Kp, the regimens of 200/400 mg loading dose followed by 100 q12h /200 mg q24h achieved > 80% CFRs regardless of renal function, followed by CMS 9 million IU loading dose followed by 4.5/3 million IU q12h in combination with FOS 8 g q8h (CFR 75–91%). Conclusions The use of a loading dose and high daily dose of TGC and CMS in combination with FOS can provide sufficient antimicrobial coverage against critically ill patients infected with KPC-Kp.

scholarly journals Multicenter Population Pharmacokinetic Study of Colistimethate Sodium and Colistin Dosed as in Normal Renal Function in Patients on Continuous Renal Replacement Therapy

2018 ◽  
Vol 63 (2) ◽  
pp. e01957-18 ◽  
Author(s):  
Anne B. Leuppi-Taegtmeyer ◽  
Laurent Decosterd ◽  
Michael Osthoff ◽  
Nicolas J. Mueller ◽  
Thierry Buclin ◽  
...  
Keyword(s):  
Renal Function ◽  
Body Weight ◽  
Renal Replacement Therapy ◽  
Continuous Renal Replacement Therapy ◽  
Normal Renal Function ◽  
Maintenance Dose ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Optimal Dosing ◽  
Colistimethate Sodium

ABSTRACT Intravenous colistimethate sodium (CMS) is used to treat infections with multiresistant Gram-negative bacteria. Optimal dosing in patients undergoing continuous renal replacement therapy (CRRT) is unclear. In a prospective study, we determined CMS and colistin pharmacokinetics in 10 critically ill patients requiring CRRT (8 underwent continuous venovenous hemodialysis [CVVHD]; median blood flow, 100 ml/min). Intensive sampling was performed on treatment days 1, 3, and 5 after an intravenous CMS loading dose of 9 million international units (MU) (6 MU if body weight was <60 kg) with a consecutive 3-MU (respectively, 2 MU) maintenance dose at 8 h. CMS and colistin concentrations were determined by liquid chromatography with mass spectroscopy. A model-based population pharmacokinetic analysis incorporating CRRT settings was applied to the observations. Sequential model building indicated a monocompartmental distribution for both CMS and colistin, with interindividual variability in both volume and clearance. Hematocrit was shown to affect the efficacy of drug transfer across the filter. CRRT clearance accounted for, on average, 41% of total CMS and 28% of total colistin clearance, confirming enhanced elimination of colistin compared to normal renal function. Target colistin steady-state trough concentrations of at least 2.5 mg/liter were achieved in all patients receiving 3 MU at 8 h. In conclusion, a loading dose of 9 MU followed after 8 h by a maintenance dose of 3 MU every 8 h independent of body weight is expected to achieve therapeutic colistin concentrations in patients undergoing CVVHD using low blood flows. Colistin therapeutic drug monitoring might help to further ensure optimal dosing in individual patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02081560.)

scholarly journals Population Pharmacokinetics of Piperacillin following Continuous Infusion in Critically Ill Patients and Impact of Renal Function on Target Attainment

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Vibeke Klastrup ◽  
Anders Thorsted ◽  
Merete Storgaard ◽  
Steffen Christensen ◽  
Lena E. Friberg ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Content Type ◽  
Daily Dose ◽  
Linear Elimination ◽  
Severe Infections

ABSTRACT Pharmacokinetic changes are often seen in patients with severe infections. Administration by continuous infusion has been suggested to optimize antibiotic exposure and pharmacokinetic/pharmacodynamic (PK/PD) target attainment for β-lactams. In an observational study, unbound piperacillin concentrations (n = 196) were assessed in 78 critically ill patients following continuous infusion of piperacillin-tazobactam (ratio 8:1). The initial dose of 8, 12, or 16 g (piperacillin component) was determined by individual creatinine clearance (CRCL). Piperacillin concentrations were compared to the EUCAST clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter), and the following PK/PD targets were evaluated: 100% free time (fT) > 1× MIC and 100% fT > 4× MIC. A population pharmacokinetic model was developed using NONMEM 7.4.3 consisting of a one-compartment disposition model with linear elimination separated into nonrenal and renal (linearly increasing with patient CRCL) clearances. Target attainment was predicted and visualized for all individuals based on the utilized CRCL dosing algorithm. The target of 100% fT > 1× MIC was achieved for all patients based on the administered dose, but few patients achieved the target of 100% fT > 4× MIC. Probability of target attainment for a simulated cohort of patients showed that increasing the daily dose by 4-g increments (piperacillin component) did not result in substantially improved target attainment for the 100% fT > 4× MIC target. To conclude, in patients with high CRCL combined with high-MIC bacterial infections, even a continuous infusion (CI) regimen with a daily dose of 24 g may be insufficient to achieve therapeutic concentrations.

scholarly journals Population Pharmacokinetic Study of the Suitability of Standard Dosing Regimens of Amikacin in Critically Ill Patients with Open-Abdomen and Negative-Pressure Wound Therapy

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Cédric Carrié ◽  
Faustine Delzor ◽  
Stéphanie Roure ◽  
Vincent Dubuisson ◽  
Laurent Petit ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Body Weight ◽  
Monte Carlo Simulations ◽  
Critically Ill ◽  
Negative Pressure ◽  
Critically Ill Patients ◽  
Open Abdomen ◽  
Population Pharmacokinetic ◽  
Pressure Therapy ◽  
Dosing Regimens

ABSTRACT The aim was to assess the appropriateness of recommended regimens for empirical MIC coverage in critically ill patients with open-abdomen and negative-pressure therapy (OA/NPT). Over a 5-year period, every critically ill patient who received amikacin and who underwent therapeutic drug monitoring (TDM) while being treated by OA/NPT was retrospectively included. A population pharmacokinetic (PK) modeling was performed considering the effect of 10 covariates (age, sex, total body weight [TBW], adapted body weight [ABW], body surface area [BSA], modified sepsis-related organ failure assessment [SOFA] score, vasopressor use, creatinine clearance [CLCR], fluid balance, and amount of fluids collected by the NPT over the sampling day) in patients who underwent continuous renal replacement therapy (CRRT) or did not receive CRRT. Monte Carlo simulations were employed to determine the fractional target attainment (FTA) for the PK/pharmacodynamic [PD] targets (maximum concentration of drug [Cmax]/MIC ratio of ≥8 and a ratio of the area under the concentration-time curve from 0 to 24 h [AUC0–24]/MIC of ≥75). Seventy critically ill patients treated by OA/NPT (contributing 179 concentration values) were included. Amikacin PK concentrations were best described by a two-compartment model with linear elimination and proportional residual error, with CLCR and ABW as significant covariates for volume of distribution (V) and CLCR for CL. The reported V) in non-CRRT and CRRT patients was 35.8 and 40.2 liters, respectively. In Monte Carlo simulations, ABW-adjusted doses between 25 and 35 mg/kg were needed to reach an FTA of >85% for various renal functions. Despite an increased V and a wide interindividual variability, desirable PK/PD targets may be achieved using an ABW-based loading dose of 25 to 30 mg/kg. When less susceptible pathogens are targeted, higher dosing regimens are probably needed in patients with augmented renal clearance (ARC). Further studies are needed to assess the effect of OA/NPT on the PK parameters of antimicrobial agents.

scholarly journals New Colistin Population Pharmacokinetic Data in Critically Ill Patients Suggesting an Alternative Loading Dose Rationale

2014 ◽  
Vol 58 (12) ◽  
pp. 7324-7330 ◽  
Author(s):  
N. Grégoire ◽  
O. Mimoz ◽  
B. Mégarbane ◽  
E. Comets ◽  
D. Chatelier ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Multidrug Resistant ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Loading Dose ◽  
Liquid Chromatography Tandem Mass

ABSTRACTColistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventy-three critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (Cmax) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t1/2) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate.

scholarly journals Bioactivity of enoxaparin in critically ill patients with normal renal function

2012 ◽  
Vol 74 (5) ◽  
pp. 806-814 ◽  
Author(s):  
Ghazaleh Gouya ◽  
Stefan Palkovits ◽  
Stylianos Kapiotis ◽  
Christian Madl ◽  
Gottfried Locker ◽  
...  
Keyword(s):  
Renal Function ◽  
Critically Ill ◽  
Normal Renal Function ◽  
Critically Ill Patients

scholarly journals Area under the Curve-Based Dosing of Vancomycin in Critically Ill Patients Using 6-Hour Urine Creatinine Clearance Measurement

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Bita Shahrami ◽  
Farhad Najmeddin ◽  
Saeideh Ghaffari ◽  
Atabak Najafi ◽  
Mohammad Reza Rouini ◽  
...  
Keyword(s):  
Renal Function ◽  
Creatinine Clearance ◽  
Critically Ill ◽  
Normal Renal Function ◽  
Critically Ill Patients ◽  
Area Under The Curve ◽  
Total Daily Dose ◽  
Pharmacokinetic Parameters ◽  
Concentration Data ◽  
Urine Creatinine

Background. The area under the curve- (AUC-) guided vancomycin dosing is the best strategy for individualized therapy in critical illnesses. Since AUC can be calculated directly using drug clearance (CLvan), any parameter estimating CLvan will be able to achieve the goal of 24-hour AUC (AUC24 h). The present study was aimed to determine CLvan based on 6-hour urine creatinine clearance measurement in critically ill patients with normal renal function. Method. 23 adult critically ill patients with an estimated glomerular filtration rate (eGFR) ≥60 mL/min who received vancomycin infusion were enrolled in this pilot study. Vancomycin pharmacokinetic parameters were determined for each patient using serum concentration data and a one-compartment model provided by MONOLIX software using stochastic approximation expectation-maximization (SAEM) algorithm. Correlation of CLvan with the measured creatinine clearance in 6-hour urine collection (CL6 h) and estimated creatinine clearance by the Cockcroft–Gault formula (CLCG) was investigated. Results. Data analysis revealed that CL6 h had a stronger correlation with CLvan rather than CLCG (r = 0.823 vs. 0.594; p < 0.001 vs. 0.003). The relationship between CLvan and CL6 h was utilized to develop the following equation for estimating CLvan: CLvan (mL/min) = ─137.4 + CL6 h (mL/min) + 2.5 IBW (kg) (R2 = 0.826, p < 0.001 ). Regarding the described model, the following equation can be used to calculate the empirical dose of vancomycin for achieving the therapeutic goals in critically ill patients without renal impairment: total daily dose of vancomycin (mg) = (─137.4CL6-h (mL/min) + 2.5 IBW (kg)) × 0.06 AUC24 h (mg.hr/L). Conclusion. For AUC estimation, CLvan can be obtained by collecting urine in a 6-hour period with good approximation in critically ill patients with normal renal function.

scholarly journals Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

2016 ◽  
Vol 60 (11) ◽  
pp. 6550-6557 ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Maintenance Dose ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Intercompartmental Clearance

ABSTRACTOur objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n= 6) and morbidly obese (n= 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

scholarly journals Pharmacokinetic Assessment of Vancomycin Loading Dose in Critically Ill Patients

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Osvaldo Álvarez ◽  
Jose Cristian Plaza-Plaza ◽  
Manuel Ramirez ◽  
Alexis Peralta ◽  
Cristián A. Amador ◽  
...  
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Serum Levels ◽  
The Body ◽  
Critically Ill Patient ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Trough Serum ◽  
Number Of Patients

ABSTRACT The vancomycin loading dose (LD) of 25 to 30 mg/kg is a frequently practiced strategy to achieve effective concentrations from the first-treatment dose. However, considering only the body weight for dosing might be inadequate in critically ill patients due to pharmacokinetics changes. We sought to assess achieving optimal trough serum levels of vancomycin and AUC0–24/MIC in the first 24 h of treatment by using an LD based on population pharmacokinetic parameters of critically ill patients. We performed a concurrent cohort study over 22 months of patients with severe sepsis who received intravenous vancomycin. The patients were treated with three different strategies to initiate vancomycin: without an LD (group A), with an LD of 25 to 30 mg/kg (group B), and with an LD based on population pharmacokinetic parameters of the critically ill patient (group C). An optimal trough serum concentration was achieved in 5, 9, and 83% of patients in groups A, B, and C, respectively. The number of patients that reached optimal AUC0–24 was 2 of 18 (11%), 5 of 11 (46%), and 11 of 12 (92%) in groups A, B, and C, respectively. The statistical analysis for both parameters revealed significant differences in group C with respect to other groups. The administration of the LD calculated from population pharmacokinetic parameters from the beginning of therapy is a more efficient strategy to obtain adequate trough serum concentrations and AUC0–24/MIC in critical patients.

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