Monte Carlo Simulation Methodologies for β‐Lactam/β‐Lactamase Inhibitor Combinations: Effect on Probability of Target Attainment Assessments

2019 ◽  
Vol 60 (2) ◽  
pp. 172-180
Author(s):  
James M. Kidd ◽  
Gary E. Stein ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Target Attainment ◽  
Lactamase Inhibitor

scholarly journals 1507. Pharmacodynamic Target Attainment of Daptomycin Against Staphylococcus aureus for Treatment of Pediatric Osteomyelitis

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S548-S549
Author(s):  
Grant Stimes ◽  
Jennifer E Girotto ◽  
Joshua D Courter
Keyword(s):  
Staphylococcus Aureus ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Pediatric Patients ◽  
Age Groups ◽  
Pharmacokinetic Studies ◽  
Pharmacokinetic Models ◽  
Limited Data ◽  
Target Attainment ◽  
Starting Point

Abstract Background Daptomycin (DAP) is lipopeptide that frequently is used to treat infections caused by Staphylococcus aureus in adult patients. There are limited data using daptomycin in pediatric patients for the treatment of osteomyelitis caused by S. aureus. This study’s objective is to describe pharmacodynamic (PD) target attainment of daptomycin in pediatric patients with osteomyelitis. Methods Medline was queried to obtain PD targets, pediatric pharmacokinetic models, and bone penetration information to build a model for DAP. A 10,000 subject Monte Carlo simulation was performed to estimate steady-state concentrations in the bone. Simulations modeled 30-minute infusions with using 12 mg/kg/dose IV q24h for patients less than 7 years and 10 mg/kg/dose IV q24h for patients 7 years and older. Goal PD targets were: AUC24: MIC of 666 μg hours/mL for log1 killing and AUC24: MIC of 1,061 for log2 killing. The CLSI breakpoint of 1 mg/L was used as a starting point and MIC’s were analyzed below that level. Results PD target attainment in percentages is listed for DAP below in Tables 1 and 2 and are separated by age groups of patients. Conclusion The studied DAP doses did not reach any PD target attainment at the CLSI breakpoint of 1 mg/L. Based on these data, DAP should not be empirically used to treat SA osteomyelitis unless the exact MIC is known. Furthermore, modern pediatric pharmacokinetic studies of DAP for pediatric osteomyelitis are warranted. Disclosures All authors: No reported disclosures.

Simplifying Piperacillin/Tazobactam Dosing: Pharmacodynamics of Utilizing Only 4.5 or 3.375 g Doses for Patients With Normal and Impaired Renal Function

2016 ◽  
Vol 30 (6) ◽  
pp. 593-599 ◽  
Author(s):  
Abrar K. Thabit ◽  
Mordechai Grupper ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Renal Function ◽  
Impaired Renal Function ◽  
Inhibitory Concentration ◽  
Prolonged Infusion ◽  
Target Attainment ◽  
Dosing Regimens ◽  
Function Range ◽  
Prescribing Information

Objectives: To evaluate the pharmacodynamic exposure of piperacillin/tazobactam across the renal function range using 4.5 or 3.375 g dosing regimens. Methods: A 5000-patient Monte Carlo simulation was conducted to determine the probability of achieving 50% free time above the minimum inhibitory concentration ( fT > MIC) for piperacillin. Proposed regimens, using solely 4.5 or 3.375 g strengths, were compared with regimens listed in piperacillin/tazobactam prescribing information over creatinine clearance (CrCl) ranges of 120 mL/min to hemodialysis. The probability of target attainment (PTA) at MICs ≤ 16 μg/mL was compared between proposed and standard regimens. Results: At CrCl 41 to 120 mL/min, prolonged infusions of 4.5 g (3 hours) and 3.375 g (4 hours) every 6 hours resulted in ≥95% PTA versus ≥76% for standard regimens (0.5 hour). At CrCl 20 to 40 mL/min, 4.5 and 3.375 g every 8 hours as prolonged infusions achieved slightly higher PTA (≥98%) versus standard regimens (≥93%). Similarly, PTA achieved with prolonged infusions of 4.5 and 3.375 g every 12 hours (≥93%) was comparable with those of standard regimens (≥91%) at CrCl 1 to 19 mL/min. In hemodialysis, 100% PTA was achieved with prolonged infusion regimens. Conclusion: Piperacillin/tazobactam regimens designed around the 4.5 or 3.375 g dose and prolonged infusions provided similar or better PTA at MICs ≤ 16 μg/mL compared with standard regimens. These observations may support the stocking and use of a single piperacillin/tazobactam strength to simplify dosing.

scholarly journals Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

2004 ◽  
Vol 48 (12) ◽  
pp. 4718-4724 ◽  
Author(s):  
Thomas P. Lodise ◽  
Ben Lomaestro ◽  
Keith A. Rodvold ◽  
Larry H. Danziger ◽  
George L. Drusano
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Linear Model ◽  
Pharmacokinetic Model ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Raw Data ◽  
Dosing Interval ◽  
Pharmacodynamic Profile

ABSTRACT The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 μg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r 2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.

scholarly journals Population Modeling and Monte Carlo Simulation Study of the Pharmacokinetics and Antituberculosis Pharmacodynamics of Rifampin in Lungs

2009 ◽  
Vol 53 (7) ◽  
pp. 2974-2981 ◽  
Author(s):  
Sylvain Goutelle ◽  
Laurent Bourguignon ◽  
Pascal H. Maire ◽  
Michael Van Guilder ◽  
John E. Conte ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Bactericidal Effect ◽  
Population Pharmacokinetic ◽  
Good Precision ◽  
Target Attainment ◽  
Time Curve ◽  
Monte Carlo Simulation Study ◽  
Population Pharmacokinetic Modeling ◽  
Target Values

ABSTRACT Little information exists on the pulmonary pharmacology of antituberculosis drugs. We used population pharmacokinetic modeling and Monte Carlo simulation to describe and explore the pulmonary pharmacokinetics and pharmacodynamics of rifampin (RIF; rifampicin). A population pharmacokinetic model that adequately described the plasma, epithelial lining fluid (ELF), and alveolar cell (AC) concentrations of RIF in a population of 34 human volunteers was made by use of the nonparametric adaptive grid (NPAG) algorithm. The estimated concentrations correlated well with the measured concentrations, and there was little bias and good precision. The results obtained with the NPAG algorithm were then imported into Matlab software to perform a 10,000-subject Monte Carlo simulation. The ability of RIF to suppress the development of drug resistance and to induce a sufficient bactericidal effect against Mycobacterium tuberculosis was evaluated by calculating the proportion of subjects achieving specific target values for the maximum concentration of drug (C max)/MIC ratio and the area under the concentration-time curve from time zero to 24 h (AUC0-24)/MIC ratio, respectively. At the lowest MIC (0.01 mg/liter), after the administration of one 600-mg oral dose, the rates of target attainment for C max/MIC (≥175) were 95% in ACs, 48.8% in plasma, and 35.9% in ELF. Under the same conditions, the target attainment results for the killing effect were 100% in plasma (AUC0-24/MIC ≥ 271) but only 54.5% in ELF (AUC0-24/MIC ≥ 665). The use of a 1,200-mg RIF dose was associated with better results for target attainment. The overall results suggest that the pulmonary concentrations obtained with the standard RIF dose are too low in most subjects. This work supports the need to evaluate higher doses of RIF for the treatment of patients with tuberculosis.

scholarly journals Pharmacodynamic Profiling of Antimicrobials against Gram-negative Respiratory Isolates from Canadian Hospitals

2011 ◽  
Vol 22 (4) ◽  
pp. 132-136 ◽  
Author(s):  
Rebecca A. Keel ◽  
George G. Zhanel ◽  
Sheryl Zelenitsky ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
Pseudomonas Aeruginosa ◽  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Enterobacter Cloacae ◽  
The Other ◽  
Prolonged Infusion ◽  
Target Attainment ◽  
Dosing Regimens ◽  
Dose Dependent

The objective of this study was to assess the profile of a variety of dosing regimens for common intravenous antibiotics against contemporaryEnterobacter cloacae,Escherichia coli,Klebsiella pneumoniaeandPseudomonas aeruginosaisolates collected in Canada during 2009, using pharmacodynamic modelling techniques. Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. These results support that the currently recommended antimicrobial dosing regimens generally attain acceptable exposures to achieve the requisite pharmacodynamic targets against the Enterobacteriaceae species; however, they fall short of obtaining optimal bactericidal exposures againstP aeruginosa.BACKGROUND: With diminishing antimicrobial potency, the choice of effective empirical therapy has become more challenging. Thus, the pharmacodynamic evaluation of potential therapies is essential to identify optimal agents, doses and administration strategies.METHODS: Monte Carlo simulation was conducted for standard and/or prolonged infusion regimens of cefepime, ceftazidime, ceftriaxone, ciprofloxacin, doripenem, ertapenem, meropenem and piperacillin/tazobactam. Minimum inhibitory concentrations were obtained forEscherichia coli(n=64 respiratory isolates),Enterobacter cloacae(n=53),Klebsiella pneumoniae(n=75) andPseudomonas aeruginosa(n=273) throughout Canada. The cumulative fraction of response (CFR) was calculated using bactericidal targets for each regimen against each species. A CFR ≥90% was defined as optimal.RESULTS: All cefepime, doripenem, ertapenem and meropenem regimens achieved optimal exposures against Enterobacteriaceae, whereas target attainment was organism and dose dependent for the other agents. Prolonged infusion doripenem and meropenem 1 g and 2 g every 8 h, along with standard infusion doripenem and meropenem 2 g every 8 h, were the only regimens to attain optimal exposures againstP aeruginosa. Ciprofloxacin had the lowest CFR againstP aeruginosa,followed by cefepime. Among theP aeruginosaisolates collected in the intensive care unit (ICU) compared with the wards, differences of 0.5% to 10% were noted in favour of non-ICU isolates for all agents; however, marked differences (10% to 15%) in CFR were observed for ciprofloxacin in favour of ICU isolates.CONCLUSION: Standard dosing of cefepime, doripenem, ertapenem and meropenem has a high likelihood of obtaining optimal pharmacodynamic indexes against these Enterobacteriaceae. ForP aeruginosa, aggressive treatment with high-dose and/or prolonged infusion regimens are likely required to address the elevated resistance rates of respiratory isolates from Canada.

scholarly journals Simplified Aztreonam Dosing in Patients with End-Stage Renal Disease: Results of a Monte Carlo Simulation

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Alan E. Gross ◽  
Hongmei Xu ◽  
Diansong Zhou ◽  
Nidal Al-Huniti
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Renal Disease ◽  
Creatinine Clearance ◽  
End Stage Renal Disease ◽  
Target Attainment ◽  
Once Daily ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACT The manufacturer-recommended aztreonam dosing for patients with creatinine clearance values of <10 ml/min/1.73 m2 is complex. It is not known whether simpler posthemodialysis dosing administered once daily or thrice weekly can reliably achieve pharmacodynamic goals. We found that 1 or 2 g administered once daily after hemodialysis had >90% probability of target attainment up to MICs of 4 or 8 mg/liter, respectively. Thrice-weekly dosing should generally be avoided, except in nonsevere infections with MICs of ≤0.5 mg/liter.

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