scholarly journals Population Pharmacokinetics of Tigecycline in Critically Ill Patients with Severe Infections

2017 ◽  
Vol 61 (8) ◽  
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.

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

2019 ◽  
Vol 63 (10) ◽  
Author(s):  
Fekade B. Sime ◽  
Melissa Lassig-Smith ◽  
Therese Starr ◽  
Janine Stuart ◽  
Saurabh Pandey ◽  
...  
Keyword(s):  
Creatinine Clearance ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Rate Constant ◽  
Critically Ill Patients ◽  
Plasma Concentrations ◽  
Peripheral Compartment ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Dosing Regimens

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.

scholarly journals Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Anne-Grete Märtson ◽  
Kim C. M. van der Elst ◽  
Anette Veringa ◽  
Jan G. Zijlstra ◽  
Albertus Beishuizen ◽  
...  
Keyword(s):  
Critically Ill ◽  
Rate Constant ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Content Type ◽  
The Mean

ABSTRACT The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h−1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h−1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h−1. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

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

2017 ◽  
Vol 61 (3) ◽  
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.

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

2016 ◽  
Vol 60 (8) ◽  
pp. 4577-4584 ◽  
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.

scholarly journals Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

2015 ◽  
Vol 59 (10) ◽  
pp. 6471-6476 ◽  
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.

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

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)

scholarly journals Population Pharmacokinetics of Meropenem and Vaborbactam Based on Data from Non-Infected Subjects and Infected Patients

2021 ◽  
Author(s):  
M. Trang ◽  
D.C. Griffith ◽  
S.M. Bhavnani ◽  
J.S. Loutit ◽  
M.N. Dudley ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Time Course ◽  
Phase 1 ◽  
Type Equation ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Phase 3 ◽  
Two Phase ◽  
Tract Infections

Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the USA and Europe to treat patients with complicated urinary tract infections and in Europe, other serious bacterial infections, including hospital- acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time-course of meropenem and vaborbactam using pooled data from two Phase 1 and two Phase 3 studies. Multi-compartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment (Vc) increased with increasing body surface area, and CL, Vc, and volume of the peripheral compartment were systematically different in Phase 1 non-infected subjects relative to Phase 3 infected patients, respectively. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.

scholarly journals A Population Pharmacokinetics and Pharmacodynamic Approach To Optimize Tazobactam Activity in Critically Ill Patients

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Shamir N. Kalaria ◽  
Mathangi Gopalakrishnan ◽  
Emily L. Heil
Keyword(s):  
Critically Ill ◽  
Critically Ill Patients ◽  
Bacterial Infections ◽  
Compartment Model ◽  
Time Profile ◽  
Gram Negative ◽  
Content Type ◽  
Dosing Regimens ◽  
Concentration Threshold

ABSTRACT The percentage of the time that the free drug concentration remains above a concentration threshold (%fT > concentration threshold) has frequently been identified to be the optimal pharmacokinetic (PK)-pharmacodynamic (PD) target of interest for tazobactam using in vitro infection models. Similar in vitro models suggested that an 85% fT > concentration threshold of 2 μg/ml for tazobactam is required to demonstrate a 2-log10-unit decrease in the number of CFU per milliliter from that at the baseline at 24 h for high-level β-lactamase-producing Escherichia coli strains. The objective of this study was to characterize the tazobactam concentrations in a cohort of critically ill patients with Gram-negative bacterial infections, determine if traditional dosing regimens achieve a prespecified PK/PD target of an 80% fT > concentration threshold of 2 μg/ml, and propose alternative dosing regimens. Hospitalized critically ill adult patients receiving piperacillin-tazobactam (TZP) for a culture-positive Gram-negative bacterial infection were eligible to consent for study inclusion. Two blood samples were drawn, one during the midpoint of the dosing interval and one at the time of the trough concentration once the patient achieved PK steady state. A population PK model was developed using Phoenix NLME (v8.1) software to characterize the observed concentration-time profile of tazobactam, explore potential covariates to explain the variability in the clearance and volume parameters, and to simulate potential dosing regimens that would achieve the PK/PD target. The PK of tazobactam were adequately described by a one-compartment model with first-order elimination in 18 patients who provided consent. The final model incorporated creatinine clearance as a covariate on clearance. Simulations demonstrated target attainments of less than 50% for tazobactam using traditional dosing regimens (4/0.5 g over 30 min every 6 h). Target attainments of greater than 75% were achieved when using extended infusion times of 4 to 6 h or when administering TZP as a continuous infusion (16/2 g over 24 h). Traditional tazobactam dosing regimens fail to achieve conservative PK/PD targets in critically ill patients. Increases in the tazobactam dose or prolongation of the infusion rate may be warranted to achieve activity against β-lactamase-producing Gram-negative bacteria.

Sign in / Sign up

Export Citation Format

Share Document