scholarly journals Evaluating Ciprofloxacin Dosing for Pseudomonas aeruginosa Infection by Using Clinical Outcome-Based Monte Carlo Simulations

2005 ◽  
Vol 49 (10) ◽  
pp. 4009-4014 ◽  
Author(s):  
Sheryl Zelenitsky ◽  
Robert Ariano ◽  
Godfrey Harding ◽  
Alan Forrest
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Monte Carlo ◽  
Clinical Outcome ◽  
Monte Carlo Simulations ◽  
Standard Dose ◽  
High Dose ◽  
Target Attainment ◽  
Real Patient ◽  
Dosing Regimens ◽  
Cure Rates

ABSTRACT Pseudomonas aeruginosa causes serious infections whose outcome is highly dependent on antimicrobial therapy. The goal of this study was to predict the relative efficacies of three ciprofloxacin dosing regimens for P. aeruginosa infection using clinical outcome-based Monte Carlo simulations (MCS) with “real patient” demographics, pharmacokinetics, MICs, and pharmacodynamics (PDs). Each cohort consisted of 1,000 simulated study subjects. Three ciprofloxacin dosing regimens were studied, including (i) the recommended standard dose of 400 mg given intravenously (i.v.) every 12 h (q12h), (ii) the recommended high dose of 400 mg i.v. q8h, and (iii) a novel, PD-targeted regimen to attain a ƒAUC/MIC value of >86. Probability of target attainment (PTA) and probability of cure (POC) were determined for each regimen. POC with the standard dose was at least 0.90 if pathogen MICs were ≤0.25 μg/ml but only 0.59 or 0.27 if MICs were 0.5 or 1 μg/ml, respectively. Predicted cure rates in these MIC categories were significantly higher at 0.72 and 0.40 with the high dose and 0.91 and 0.72 with the PD-targeted regimen(P < 0.0001). Analyses based on the local susceptibility profile produced PTA and POC estimates of 0.44 and 0.74 with the standard ciprofloxacin dose, 0.58 and 0.81 with the high dose, and 0.84 and 0.93 with the PD-targeted regimen, respectively. In conclusion, as demonstrated by clinical outcome-based MCSs, the highest recommended ciprofloxacin dose of 400 mg i.v. q8h should be used in the treatment of P. aeruginosa infection to improve PD target attainment and clinical cure. However, even this appears ineffective if pathogen MICs are 1 μg/ml, warranting the consideration of a lower MIC breakpoint, ≤0.5 μg/ml.

scholarly journals Optimizing gentamicin dosing in different pediatric age groups using population pharmacokinetics and Monte Carlo simulation

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Ragia H. Ghoneim ◽  
Abrar K. Thabit ◽  
Manar O. Lashkar ◽  
Ahmed S. Ali
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Population Pharmacokinetics ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Concentration Data ◽  
Once Daily ◽  
Dosing Regimens ◽  
Gentamicin Concentration

Abstract Introduction The use of once daily dosing of aminoglycosides in pediatrics is increasing but studies on dose optimization targeting the pediatric population are limited. This study aimed to derive a population pharmacokinetic model of gentamicin and apply it to design optimal dosing regimens in pediatrics. Methods Population pharmacokinetics of gentamicin in pediatrics was described from a retrospective chart review of plasma gentamicin concentration data (peak/ trough levels) of pediatric patients (1 month − 12 years), admitted to non-critically ill pediatrics. Monte Carlo simulations were performed on the resulting pharmacokinetic model to assess the probability of achieving a Cmax/MIC target of 10 mg/L over a range of gentamicin MICs of 0.5–2 mg/L and once daily gentamicin dosing regimens. Results: A two-compartment model with additive residual error best described the model with weight incorporated as a significant covariate for both clearance and volume of distribution. Monte Carlo simulations demonstrated a good probability of target attainment even at a MIC of 2 mg/L, where neonates required doses of 6-7 mg/kg/day and older pediatrics required lower daily doses of 4–5 mg/kg/day while maintaining trough gentamicin concentration below the toxicity limit of 1 mg/L. Conclusion: Once daily dosing is a reasonable option in pediatrics that allows target attainment while maintaining trough gentamicin level below the limits of toxicity.

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 2562. Re-Appraisal of Aminoglycoside (AG) Susceptibility Testing Breakpoints Based on the Application of Pharmacokinetics–Pharmacodynamics (PK-PD) and Contemporary Microbiology Surveillance Data

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S71-S71 ◽  
Author(s):  
Sujata M Bhavnani ◽  
Nikolas J Onufrak ◽  
Jeffrey P Hammel ◽  
David R Andes ◽  
John S Bradley ◽  
...  
Keyword(s):  
Susceptibility Testing ◽  
Surveillance Data ◽  
Simulated Patients ◽  
High Dose ◽  
Target Attainment ◽  
In Vitro Susceptibility ◽  
Population Pk ◽  
Dosing Regimens

Abstract Background Resistance to AGs and numerous other classes continues to emerge. To ensure that susceptibility is accurately characterized and that clinicians have reliable data to select effective agents, appropriate in vitro susceptibility testing interpretive criteria (susceptible breakpoints [BKPTs]) are crucial to ensure optimal patient care. Recently, USCAST, the USA voice to EUCAST/EMA, evaluated the BKPTs for the 3 most commonly used AGs, gentamicin, tobramycin, and amikacin [Bhavnani et al., IDWeek 2016; P-1977]. As a result of consultation from interested parties, which included evaluating AG dosing regimens provided in the US-FDA product package inserts and simulated patients with varying creatinine clearance, these BKPTS were reassessed. Methods Data sources considered included longitudinal US reference MIC distributions using in vitro surveillance data collected over 18 years, QC performance (MIC, disk diffusion), population pharmacokinetics (PK), and in vivo PK-PD models. Using population PK models, PK-PD targets for efficacy and Monte Carlo simulation, percent probabilities of PK-PD target attainment by MIC after administration of traditional and extended interval AG dosing regimens were evaluated among simulated patients. Epidemiological cut-off and PK-PD BKPTs were considered when recommending BKPTs for AG–pathogen pairs. Results An example of PK-PD target attainment analysis output is provided in Figure 1 and a subset of recommended AG BKPTs for 3 pathogens is shown in Table 1. Updated USCAST BKPTs, which were based on the application of population PK and PK-PD models, simulation techniques, and contemporary MIC distribution statistics, are generally lower than those of EUCAST/EMA, USA-FDA, and CLSI. Adequate PK-PD target attainment was not achieved for some AG-pathogen pairs, even when high-dose AG dosing regimens and PK-PD targets for stasis were evaluated (e.g., gentamicin vs. P. aeruginosa; amikacin vs. S. aureus). Conclusion These revised AG BKPT recommendations, which will be made freely available to EUCAST, USA-FDA, and CLSI, will be finalized after considering comments from additional interested stakeholders. This process will be followed in an effort to bring harmonization to global BKPTs for AGs. Disclosures All authors: No reported disclosures.

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.

Ion Beam Induced Intermixing of Wsi0.45 on GaAs

1988 ◽  
Vol 128 ◽  
Author(s):  
S. J. Pearton ◽  
K. T. Short ◽  
K. S. Jones ◽  
A. G. Baca ◽  
C. S. Wu
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Ion Beam ◽  
Dose Range ◽  
Device Fabrication ◽  
Electrical Activation ◽  
High Dose ◽  
Dislocation Loops ◽  
Semiconductor Interface ◽  
High Level

ABSTRACTThe systematics of ion beam induced intermixing of WSi0.45 on GaAs have been studied after through-implantation of Si or O in the dose range 1013 − 5 × 1016 cm−2. SIMS profiling shows significant knock-on of Si and W into the GaAs at the high dose range in accordance with Monte Carlo simulations, but there is virtually no electrical activation (≤0.1%) of this Si after normal implant annealing (900°C, 10 sec). This appears to be a result of the high level of disorder near the metal-semiconductor interface, which is not repaired by annealing. This damage consists primarily of dislocation loops extending a few hundred angstroms below the end of range of the implanted ions. Extrapolation of the ion doses used in this work to the usual doses used in GaAs device fabrication would imply that ion-induced intermixing of WSix will not be significant in through-implantation processes.

Genetic Polymorphisms Associated with Clinical Outcome in the Intergroup Trial S9321, Comparing High Dose Therapy with Standard Dose Therapy for Myelomaon, on Behalf of ECOG, SWOG, CALGB, and the Bank on a Cure.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1495-1495
Author(s):  
Rafael Santana-Davila ◽  
John Crowley ◽  
Brian Durie ◽  
Bart Barlogie ◽  
Philip Greipp ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Genetic Polymorphisms ◽  
Median Survival ◽  
Dose Regimen ◽  
Standard Dose ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Intergroup Trial

Abstract Genetic variations in patient populations likely contribute to disease progression and therapeutic outcomes. We have begun a systematic approach to examine the association of genetic variations (ie. functional, single nucleotide polymorhisms, SNPs) involved in myeloma growth promotion, metabolic events, drug responses, and DNA repair on clinical outcome in the intergroup trial S9321. This trial tested a single high dose regimen with autologous stem cell support against a conventional dose regimen, with further randomization of responders to maintenance with interferon or not, in newly diagnosed patients with multiple myeloma. ECOG, CALGB and SWOG enrolled 899 patients with newly diagnosed MM to receive VAD induction x 4 cycles followed by randomization to PBSC-supported high dose therapy (HDT) versus standard dose therapy (SDT) of VBMCP, using CTX 4.5 g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or HDT were randomized to IFN or no maintenance. Specimens were distributed through ECOG for biologic correlative studies, including candidate SNP analysis. SNP assays have been developed using the Sequenom Mass-extend platform for functional SNPs in IL-6, IL-1, IL-RA, IL-10, TNF, Lta, TGFb, MDR1, MPO, CYP3A4, GST (M, P, T), ERCC2 and XRCC1, and are being evaluated on 803 DNA samples prepared from patients enrolled in S9321. Preliminary findings (n=135) demonstrate functional genetic variants of IL-10 (position -1082), IL-1 (position +3953), TGFb (postion -509), and TNFa (position -308) are showing trends associated with differences in progression free survival; and variants in IL-6 (position -174) are associated with response. Median survival of the IL-10 variants was 31 months for A/A low producer alleles versus 19 months for the G/G high producer alleles (p=.5). For TNFa, 2 cases with the high producer A/A alleles died within a year, while the median survival for the lower producer G/G alleles was 2 years (p=.04). For patients with the high producer C/C/ allele of IL-1 (n=67), median survival was 2 years, versus 5 patients with the T/T low producer alleles that had a median survival greater than 5 years (preliminary p=.29). While these preliminary results are now only suggestive of trends in genetic polymorphisms associated with clinical outcome, completion of the full SNP panel on the entire sample base should provide a extensive association study, and analysis of potential differences in therapy arms of the trial. The full panel and association studies will be presented.ααββααα

scholarly journals Population Pharmacokinetics of Conventional and Intermittent Dosing of Liposomal Amphotericin B in Adults: a First Critical Step for Rational Design of Innovative Regimens

2012 ◽  
Vol 56 (10) ◽  
pp. 5303-5308 ◽  
Author(s):  
William W. Hope ◽  
Joanne Goodwin ◽  
Timothy W. Felton ◽  
Michael Ellis ◽  
David A. Stevens
Keyword(s):  
Monte Carlo ◽  
Optimal Design ◽  
Monte Carlo Simulations ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B ◽  
High Dose ◽  
Pharmacokinetic Data ◽  
Informative Sampling ◽  
Sampling Times

ABSTRACTThere is increased interest in intermittent regimen of liposomal amphotericin B, which may facilitate use in ambulatory settings. Little is known, however, about the most appropriate dosage and schedule of administration. Plasma pharmacokinetic data were acquired from 30 patients receiving liposomal amphotericin B for empirical treatment of suspected invasive fungal infection. Two cohorts were studied. The first cohort received 3 mg of liposomal amphotericin B/kg of body weight/day; the second cohort received 10 mg of liposomal amphotericin B/kg at time zero, followed by 5 mg/kg at 48 and 120 h. The levels of liposomal amphotericin B were measured by high-pressure liquid chromatography (HPLC). The pharmacokinetics were estimated by using a population methodology. Monte Carlo simulations were performed. D-optimal design was used to identify maximally informative sampling times for both conventional and intermittent regimens for future studies. A three-compartment pharmacokinetic model best described the data. The pharmacokinetics for both conventional and intermittent dosing were linear. The estimates for the mean (standard deviation) for clearance and the volume of the central compartment were 1.60 (0.85) liter/h and 20.61 (15.27) liters, respectively. Monte Carlo simulations demonstrated considerable variability in drug exposure. Bayesian estimates for clearance and volume increased in a linear manner with weight, but only the former was statistically significant (P= 0.039). D-optimal design provided maximally informative sampling times for future pharmacokinetic studies. The pharmacokinetics of a conventional and an intermittently administered high-dose regimen liposomal amphotericin B are linear. Further pharmacokinetic-pharmacodynamic preclinical and clinical studies are required to identify safe and effective intermittent regimens.

scholarly journals Imipenem dosing recommendations for patients undergoing continuous renal replacement therapy: systematic review and Monte Carlo simulations

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Dhakrit Rungkitwattanakul ◽  
Taniya Charoensareerat ◽  
Pathakorn Kerdnimith ◽  
Nutsinee Kosumwisaisakul ◽  
Piyakamol Teeranaew ◽  
...  
Keyword(s):  
Systematic Review ◽  
Monte Carlo ◽  
Renal Replacement Therapy ◽  
Monte Carlo Simulations ◽  
Continuous Renal Replacement Therapy ◽  
Replacement Therapy ◽  
Optimal Dose ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Dosing Regimens

Abstract Background The appropriate dosing of imipenem for critically ill AKI patients undergoing CRRT remains scarce. Purpose This study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving continuous renal replacement therapy (CRRT) and (2) to define the optimal imipenem dosing regimens in these populations via Monte Carlo simulations. Methods The databases of PubMed, Embase, and ScienceDirect were searched from inception to May 2020. We used the Medical Subject Headings of “Imipenem,” “CRRT,” and “pharmacokinetics” or related terms or synonym to identify the studies for systematic reviews. A one-compartment pharmacokinetic model was conducted to predict imipenem levels for the initial 48 h of therapy. The pharmacodynamic target was 40% of free drug level above 4 times of the MIC (40% fT > 4 MIC). The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. Results Eleven articles were identified and included for our systematic review. The necessary pharmacokinetic parameters such as the volume of distribution and the CRRT clearance were mentioned in 100 and 90.9%, respectively. None of the current studies reported the complete necessary parameters. A regimen of 750 mg q 6 h was the optimal dose for the predilution-CVVH and CVVHD modality with two effluent rates (25 and 35 mL/kg/h) for the pharmacodynamic target of 40% fT > 4MIC. Conclusions None of the current studies showed the complete necessary pharmacokinetic parameters for drug dosing. Pharmacodynamic target significantly contributed to imipenem dosing regimens in these patients. Different effluent rates and types of CRRT had minimal impact on dosing regimens. Clinical validation of the recommendation is necessary.

Pharmacokinetics and Pharmacodynamics of Linezolid in Patients With Sepsis Receiving Continuous Venovenous Hemofiltration and Extended Daily Hemofiltration

2020 ◽  
Vol 221 (Supplement_2) ◽  
pp. S279-S287
Author(s):  
Junbo Zheng ◽  
Zhidan Sun ◽  
Lei Sun ◽  
Xing Zhang ◽  
Guiying Hou ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Inhibitory Concentration ◽  
Compartment Model ◽  
Blood Levels ◽  
Continuous Venovenous Hemofiltration ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Target Attainment ◽  
Blood Samples ◽  
Failure Assessment

Abstract Background This prospective study compared pharmacokinetics (PK) and pharmacodynamics (PD) of linezolid in patients with sepsis receiving continuous venovenous hemofiltration (CVVH) with patients receiving extended daily hemofiltration (EDH). Methods Patients with sepsis treated with linezolid and CVVH or EDH were included. Serial blood samples were collected and linezolid concentrations measured. PKs were analyzed using Pmetrics. Monte Carlo simulations were used to evaluate PD target achievement. Results From 20 patients, 320 blood samples were collected for PK and PD analysis. PK profiles of linezolid were best described by a 2-compartment model. PK parameters were not significantly different between EDH and CVVH groups and were associated with body weight, renal replacement therapy (RRT) duration, and sequential organ failure assessment score. Monte Carlo simulations showed poor fractional target attainment for a minimum inhibitory concentration (MIC) of 2 mg/L with standard 600 mg intravenous administration every 12 hours. Conclusions Patients with sepsis receiving RRT exhibited variability in PK/PD parameters for linezolid. PK parameters were not significantly different between CVVH- and EDH-treated patients. Higher probability of target attainment would be achievable at a MIC of 2 mg/L in EDH patients. Higher linezolid doses should be considered for patients on RRT to achieve adequate blood levels.

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