Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal Dysfunction

ABSTRACT Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed, and data were analyzed with Pmetrics with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance (CLCR) and body weight described between-patient variability in clearance and central volume of distribution (V), respectively. Mean ± standard deviation (SD) parameter estimates for unbound ceftolozane and tazobactam, respectively, were CL of 7.2 ± 3.2 and 25.4 ± 9.4 liters/h, V of 20.4 ± 3.7 and 32.4 ± 10 liters, rate constant for distribution of unbound ceftolozane or tazobactam from central to peripheral compartment (Kcp) of 0.46 ± 0.74 and 2.96 ± 8.6 h−1, and rate constant for distribution of unbound ceftolozane or tazobactam from peripheral to central compartment (Kpc) of 0.39 ± 0.37 and 26.5 ± 8.4 h−1. With dosing at 1.5 g and 3.0 g every 8 h (q8h), the fractional target attainment (FTA) against Pseudomonas aeruginosa was ≥85% for directed therapy (MIC ≤ 4 mg/liter). However, for empirical coverage (MIC up to 64 mg/liter), the FTA was 84% with the 1.5-g q8h regimen when creatinine clearance is 180 ml/min/1.73 m2, whereas the 3.0-g q8h regimen consistently achieved an FTA of ≥85%. For a target of 40% of time the free drug concentration is above the MIC (40% fT>MIC), 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen is present, in which case 1.5-g dosing could be used. If a higher target of 100% fT>MIC is required, a 1.5-g loading dose plus a 4.5-g continuous infusion may be adequate.

Download Full-text

Population Pharmacokinetics of Tigecycline in Critically Ill Patients with Severe Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00345-17 ◽

2017 ◽

Vol 61 (8) ◽

Cited By ~ 14

Author(s):

Jiao Xie ◽

Jason A. Roberts ◽

Abdulaziz S. Alobaid ◽

Claire Roger ◽

Yan Wang ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Critically Ill ◽

Rate Constant ◽

Critically Ill Patients ◽

Bacterial Infections ◽

Time Course ◽

Central Compartment ◽

Peripheral Compartment ◽

Parameter Estimates ◽

Content Type

ABSTRACT We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC0–24/MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intra-abdominal infections, ≥4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m2, respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means ± standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 ± 1.11 liters/h; volume in the central compartment, 72.50 ± 21.18 liters; rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 ± 0.16 h−1; and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 ± 0.30 h−1. A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus for an AUC0–24/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI.

Download Full-text

Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01321-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6471-6476 ◽

Cited By ~ 40

Author(s):

Suzanne L. Parker ◽

Frantzeska Frantzeskaki ◽

Steven C. Wallis ◽

Chryssa Diakaki ◽

Helen Giamarellou ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Patients ◽

Pharmacokinetic Analysis ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Blood Samples ◽

The Mean ◽

Dosing Intervals

ABSTRACTThis study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CLCR) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (Vc) described the data adequately. Calculated CLCRwas supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h,Vcof 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

Download Full-text

Population Pharmacokinetics of Colistin Methanesulfonate and Formed Colistin in Critically Ill Patients from a Multicenter Study Provide Dosing Suggestions for Various Categories of Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01733-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3284-3294 ◽

Cited By ~ 466

Author(s):

S. M. Garonzik ◽

J. Li ◽

V. Thamlikitkul ◽

D. L. Paterson ◽

S. Shoham ◽

...

Keyword(s):

Renal Replacement Therapy ◽

Creatinine Clearance ◽

Replacement Therapy ◽

Critically Ill ◽

Critically Ill Patients ◽

Multidrug Resistant ◽

Parameter Estimates ◽

Highly Active ◽

Dosing Regimens ◽

Colistin Methanesulfonate

ABSTRACTWith increasing clinical emergence of multidrug-resistant Gram-negative pathogens and the paucity of new agents to combat these infections, colistin (administered as its inactive prodrug colistin methanesulfonate [CMS]) has reemerged as a treatment option, especially for critically ill patients. There has been a dearth of pharmacokinetic (PK) data available to guide dosing in critically ill patients, including those on renal replacement therapy. In an ongoing study to develop a population PK model for CMS and colistin, 105 patients have been studied to date; these included 12 patients on hemodialysis and 4 on continuous renal replacement therapy. For patients not on renal replacement, there was a wide variance in creatinine clearance, ranging from 3 to 169 ml/min/1.73 m2. Each patient was treated with a physician-selected CMS dosage regimen, and 8 blood samples for PK analysis were collected across a dosage interval on day 3 or 4 of therapy. A linear PK model with two compartments for CMS and one compartment for formed colistin best described the data. Covariates included creatinine clearance on the total clearance of CMS and colistin, as well as body weight on the central volume of CMS. Model-fitted parameter estimates were used to derive suggested loading and maintenance dosing regimens for various categories of patients, including those on hemodialysis and continuous renal replacement. Based on our current understanding of colistin PK and pharmacodynamic relationships, colistin may best be used as part of a highly active combination, especially for patients with moderate to good renal function and/or for organisms with MICs of ≥1.0 mg/liter.

Download Full-text

Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00242-18 ◽

2018 ◽

Vol 62 (6) ◽

pp. e00242-18 ◽

Cited By ~ 6

Author(s):

Fekade B. Sime ◽

Janine Stuart ◽

Jenie Butler ◽

Therese Starr ◽

Steven C. Wallis ◽

...

Keyword(s):

Single Dose ◽

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Central Venous Access ◽

Plasma Concentrations ◽

Parameter Estimates ◽

Pharmacokinetic Data ◽

Albumin Concentration ◽

Data Set

ABSTRACT To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period (Cmax), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC0–∞), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution (V), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC0–∞ was 39% of the values reported for heathy volunteers. The AUC0–∞ was only 52% of the steady-state AUC0–24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in this cohort of critically ill patients compared to those in healthy volunteers and hematology patients.

Download Full-text

Population Pharmacokinetics of Piperacillin in Nonobese, Obese, and Morbidly Obese Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01276-16 ◽

2017 ◽

Vol 61 (3) ◽

Cited By ~ 21

Author(s):

Abdulaziz S. Alobaid ◽

Steven C. Wallis ◽

Paul Jarrett ◽

Therese Starr ◽

Janine Stuart ◽

...

Keyword(s):

Critical Illness ◽

Population Pharmacokinetics ◽

Critically Ill ◽

Critically Ill Patients ◽

Central Compartment ◽

Pharmacokinetic Analysis ◽

Peripheral Compartment ◽

Morbidly Obese ◽

Obese Patients ◽

Intercompartmental Clearance

ABSTRACT The treatment of infections in critically ill obese and morbidly obese patients is challenging because of the combined physiological changes that result from obesity and critical illness. The aim of this study was to describe the population pharmacokinetics of piperacillin in a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients who received piperacillin-tazobactam were classified according to their body mass index (BMI) as nonobese, obese, and morbidly obese. Plasma samples were collected, and piperacillin concentrations were determined by a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were performed using Pmetrics software. Thirty-seven critically ill patients (including 12 obese patients and 12 morbidly obese patients) were enrolled. The patients' mean ± standard deviation age, weight, and BMI were 50 ± 15 years, 104 ± 35 kg, and 38.0 ± 15.0 kg/m2, respectively. The concentration-time data were best described by a two-compartment linear model. The mean ± SD parameter estimates for the final covariate model were a clearance of 14.0 ± 7.1 liters/h, a volume of distribution of the central compartment of 49.0 ± 19.0 liters, an intercompartmental clearance from the central compartment to the peripheral compartment of 0.9 ± 0.6 liters · h−1, and an intercompartmental clearance from the peripheral compartment to the central compartment of 2.3 ± 2.8 liters · h−1. A higher measured creatinine clearance and shorter-duration infusions were associated with a lower likelihood of achieving therapeutic piperacillin exposures in patients in all BMI categories. Piperacillin pharmacokinetics are altered in the presence of obesity and critical illness. As with nonobese patients, prolonged infusions increase the likelihood of achieving therapeutic concentrations.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03508-14 ◽

2014 ◽

Vol 58 (12) ◽

pp. 7324-7330 ◽

Cited By ~ 50

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.

Download Full-text

1087. Imipenem-Cilastatin-Relebactam (I/R) Pharmacokinetics (PK) in Critically Ill Patients with Augmented Renal Clearance (ARC)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1281 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S635-S635

Author(s):

Andrew J Fratoni ◽

John W Mah ◽

David P Nicolau ◽

Joseph L Kuti

Keyword(s):

Protein Binding ◽

Critically Ill ◽

Critically Ill Patients ◽

Research Study ◽

Plasma Concentrations ◽

Scientific Research ◽

Central Compartment ◽

Peripheral Compartment ◽

Study Investigator ◽

Research Grant

Abstract Background Imipenem (IMI) and relebactam (REL) are predominantly excreted via glomerular filtration. ARC is a common syndrome in critically ill patients with sepsis, whereby increased renal blood flow may result in enhanced solute clearance; therefore, sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the PK of I/R in critically-ill patients with confirmed ARC. Methods Infected patients in the intensive care unit with ARC (CrCl ≥130 mL/min) received a single dose of I/R 1.25g as a 30min infusion. Blood samples were collected over 6 hours (hr) for IMI and REL concentration determination by a validated LC/MS/MS assay. Protein binding was assessed at 0.5hr by ultrafiltration (UF). An 8hr urine creatinine (UCr) collection was performed to confirm ARC. IMI and REL plasma concentrations were fitted to compartmental models in WinNonlin. Simulated concentration vs time profiles were used to assess attainment of pharmacodynamic (PD) targets for IMI (30%fT >MIC) and REL (fAUC:MIC 18) at the susceptibility breakpoint of 2 mg/L. Results Five patients (60% female) completed the study. Mean (SD) age, weight, and APACHE II were 43 (14) years, 90 (15) kg, and 16 (6), respectively. All patients had confirmed ARC with CrCl of 160.6 ± 47.0 mL/min (range: 135-244mL/min) based on UCr. Both IMI and REL concentrations fitted a 2-compartment better than 1-compartment model. IMI PK was: clearance, 17.9 ± 8.7 L/hr; volume of central compartment, 15.6 ± 11.2 L; volume of peripheral compartment, 10.6 ± 5.4 L; and intercompartmental clearance, 16.6 ± 14.5 L/hr. REL PK parameters were 11.9 ± 7.5 L/hr, 17.0 ± 11.3 L, 13.5 ± 9.9 L, and 13.4 ± 11.1 L/hr, respectively. Half-life was 1.5 ± 0.5 for IMI and 2.8 ± 2.2 hr for REL. Protein binding for IMI ranged from 0-10%, while REL was 0-14%. IMI fT >MIC ranged from 40-90%, and REL fAUC:MIC ranged from 22.6-59.0. Conclusion These are the first data to describe IMI and REL PK in critically-ill infected patients with ARC. Despite plasma clearance values greater than those reported in healthy volunteers and patients in clinical trials, I/R 1.25g as a 30 minute infusion provided optimal exposure in all patients for isolates with MICs ≤2 mg/L. 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)

Download Full-text

Effects of uric acid, creatinine clearance, and infusion duration on the population pharmacokinetics of meropenem in critically ill patients

10.21203/rs.3.rs-471732/v2 ◽

2021 ◽

Author(s):

Yi Chang Zhao ◽

Yang Zou ◽

Yi Wen Xiao ◽

Feng Wang ◽

Bi Kui Zhang ◽

...

Keyword(s):

Uric Acid ◽

Creatinine Clearance ◽

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Peripheral Compartment ◽

Infusion Time ◽

Injection Duration ◽

Severe Infections

Abstract Background: Meropenem is a carbapenem antibiotic that has demonstrated excellent in vitro activity against gram-negative clinical isolates and is commonly used in critically ill patients. This study aimed to find the pharmacokinetic/ pharmacodynamic of meropenem in critically ill patients and whether prolonged injection duration is really beneficial to meropenem therapy. Method: We included 209 samples in 64 patients in this prospective study. PPK analysis and Monte Carlo dosing simulations were developed using Phoenix.Results: A two-compartment model described the data adequately. Clearance (CL), volume (V), clearance of peripheral compartment (CL2), volume of peripheral compartment (V2) were 6.15 L/h, 2.83 L/h, 17.40L, and 17.48L, respectively. Creatinine clearance and uric acid were significant covariates. Patients with creatinine clearance of 60 ml/min or less and uric acid greater than 400 μmol/l could achieve the target > 90% under the minimum inhibitory concentration (MIC) of 8 mg/L, even with the administration dose of 500 mg/8 h with a 2-h infusion. Prolonging the infusion time significantly improved the therapeutic effect when MIC＜4. However, for the pharmacodynamic (PD) effects of 100% fT > MIC and 100% fT > 4MIC, no significant statistical difference was observed in critically ill patients.Conclusions: Critically ill patients with lower creatinine clearance and higher uric acid levels were likely to need a lower dosage of meropenem. Prolonged infusion time were not always beneficial for those who need a higher therapeutic target (100% fT > MIC,100% fT > 4 MIC) or with MIC 4mg/L. Increasing dose or alternative therapeutic strategies may be required for critically ill patients with drug-resistant or severe infections. The study is of great significance to guide the rational use of meropenem in critically ill patients.Trial registration: The trial was registered in the China Clinical Trial (ChiCTR1900020672). Registered on 12 January 2019.

Download Full-text

Does prolonged infusion time really improve the efficacy of meropenem therapy? A prospective study in critically ill patients

10.21203/rs.3.rs-471732/v3 ◽

2021 ◽

Author(s):

Yi Chang Zhao ◽

Yang Zou ◽

Yi Wen Xiao ◽

Feng Wang ◽

Bi Kui Zhang ◽

...

Keyword(s):

Uric Acid ◽

Prospective Study ◽

Creatinine Clearance ◽

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Peripheral Compartment ◽

Infusion Time ◽

Prolonged Infusion

Download Full-text

Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function

Pharmaceutics ◽

10.3390/pharmaceutics13101690 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1690

Author(s):

Idoia Bilbao-Meseguer ◽

Helena Barrasa ◽

Eduardo Asín-Prieto ◽

Ana Alarcia-Lacalle ◽

Alicia Rodríguez-Gascón ◽

...

Keyword(s):

Renal Function ◽

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Compartment Model ◽

Volume Of Distribution ◽

Parameter Estimates ◽

Population Modelling ◽

Two Compartment Model ◽

Relative Standard

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

Download Full-text