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Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

ABSTRACT: Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MIC_meropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ?10^7.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with augmented renal clearance (ARC), normal, or impaired renal function (creatinine clearances of 285, 120, or ?10 ml/min, respectively) were generated for three meropenem regimens (2, 1, and 0.5 g administered as 8-hourly 30-min infusions), plus 1 g given 12 hourly with impaired renal function. The time course of total and less-susceptible populations and MICs were determined. Mechanism-based modeling (MBM) was performed using S-ADAPT. All dosing regimens across all renal functions produced similar initial bacterial killing (??2.5 log₁₀). For all regimens subjected to ARC, regrowth occurred after 7 h. For normal and impaired renal function, bacterial killing continued until 23 to 47 h; regrowth then occurred with 0.5- and 1-g regimens with normal renal function (fT_>5×MIC = 56 and 69%, fC_min/MIC < 2); the emergence of less-susceptible populations (?32-fold increases in MIC) accompanied all regrowth. Bacterial counts remained suppressed across 10 days with normal (2-g 8-hourly regimen) and impaired (all regimens) renal function (fT_>5×MIC ? 82%, fC_min/MIC ? 2). The MBM successfully described bacterial killing and regrowth for all renal functions and regimens simultaneously. Optimized dosing regimens, including extended infusions and/or combinations, supported by MBM and Monte Carlo simulations, should be evaluated in the context of ARC to maximize bacterial killing and suppress resistance emergence.

SUBMITTER: Bergen PJ

PROVIDER: S-EPMC5404522 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

Bergen Phillip J PJ Bulitta Jürgen B JB Kirkpatrick Carl M J CMJ Rogers Kate E KE McGregor Megan J MJ Wallis Steven C SC Paterson David L DL Nation Roger L RL Lipman Jeffrey J Roberts Jason A JA Landersdorfer Cornelia B CB

Antimicrobial agents and chemotherapy 20170424 5

Critically ill patients frequently have substantially altered pharmacokinetics compared to non-critically ill patients. We investigated the impact of pharmacokinetic alterations on bacterial killing and resistance for commonly used meropenem dosing regimens. A Pseudomonas aeruginosa isolate (MICmeropenem 0.25 mg/liter) was studied in the hollow-fiber infection model (inoculum ∼107.5 CFU/ml; 10 days). Pharmacokinetic profiles representing critically ill patients with ...[more]

PMID: 28264846

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Project description:PurposeCritically ill patients with preserved or increased renal function have been shown to be at risk of underexposure to meropenem. Although many meropenem population pharmacokinetic (PK) models have been published, there is no large prospective population PK study with rich sampling focusing on patients most at risk of suboptimal pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Therefore, the aim of the present study was to evaluate PK/PD target attainment and to perform a thorough covariate screening using population PK modelling of meropenem in septic patients with preserved or increased renal function.Patients and methodsA single-centre prospective observational PK study was performed in the intensive care unit (ICU) of the University Hospitals Leuven. Patients with severe sepsis or septic shock and treated with meropenem in the ICU were screened for inclusion. Patients were excluded if they received renal replacement therapy or had an estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology collaboration equation <70 mL/min/1.73m2 on the day of PK sampling. Successful PK/PD target attainment was defined as an unbound meropenem trough concentration above 2 mg/L or 8 mg/L. Population PK modelling was performed with NONMEM7.4.ResultsIn total, 58 patients were included, contributing 345 plasma samples over 70 dosing intervals. The 2 mg/L and 8 mg/L targets were successfully attained in 46% and 11% of all dosing intervals, respectively. A two-compartment population PK model with linear elimination and interindividual variability on clearance best described meropenem PK. The estimated creatinine clearance according to the Cockcroft-Gault equation was the only covariate retained during population PK analysis.ConclusionThis study provided detailed insight into meropenem PK in critically ill patients with preserved or increased renal function. We observed poor PK/PD target attainment, for which renal function was the only significant covariate.Trial registrationThis study is registered at ClinicalTrials.gov (NCT03560557).

Project description:BackgroundMeropenem dosing for septic critically patients is difficult due to pathophysiological changes associated with sepsis as well as supportive symptomatic therapies. A prospective single-center study assessed whether fluid retention alters meropenem pharmacokinetics and the achievement of the pharmacokinetic/pharmacodynamic (PK/PD) targets for efficacy.MethodsTwenty-five septic ICU patients (19 m, 6f) aged 32-86 years with the mean APACHE II score of 20.2 (range 11-33), suffering mainly from perioperative intra-abdominal or respiratory infections and septic shock (n = 18), were investigated over three days after the start of extended 3-h i.v. infusions of meropenem q8h. Urinary creatinine clearance (CLcr) and cumulative fluid balance (CFB) were measured daily. Plasma meropenem was measured, and Bayesian estimates of PK parameters were calculated.ResultsEleven patients (9 with peritonitis) were classified as fluid overload (FO) based on a positive day 1 CFB of more than 10% body weight. Compared to NoFO patients (n = 14, 11 with pneumonia), the FO patients had a lower meropenem clearance (CLme 8.5 ± 3.2 vs 11.5 ± 3.5 L/h), higher volume of distribution (V1 14.9 ± 3.5 vs 13.5 ± 4.1 L) and longer half-life (t1/2 1.4 ± 0.63 vs 0.92 ± 0.54 h) (p < 0.05). Over three days, the CFB of the FO patients decreased (11.7 ± 3.3 vs 6.7 ± 4.3 L, p < 0.05) and the PK parameters reached the values comparable with NoFO patients (CLme 12.4 ± 3.8 vs 11.5 ± 2.0 L/h, V1 13.7 ± 2.0 vs 14.0 ± 5.1 L, t1/2 0.81 ± 0.23 vs 0.87 ± 0.40 h). The CLcr and Cockroft-Gault CLcr were stable in time and comparable. The correlation with CLme was weak to moderate (CLcr, day 3 CGCLcr) or absent (day 1 and 2 CGCLcr). Dosing with 2 g meropenem q8h ensured adequate concentrations to treat infections with sensitive pathogens (MIC 2 mg/L). The proportion of pre-dose concentrations exceeding the MIC 8 mg/L and the fraction time with a target-exceeding concentration were higher in the FO group (day 1-3 f Cmin > MIC: 67 vs 27%, p < 0.001; day 1%f T > MIC: 79 ± 17 vs 58 ± 17, p < 0.05).ConclusionsThese findings emphasize the importance of TDM and a cautious approach to augmented maintenance dosing of meropenem to patients with FO infected with less susceptible pathogens, if guided by population covariate relationships between CLme and creatinine clearance.

Project description:BackgroundThe primary objective of this study was to develop a population pharmacokinetic model of meropenem, based on the population of critically ill adult patients undergoing CRRT. The secondary one was to examine the relationship between patient characteristics (covariates) and individual PK parameters. Finally, we aimed to perform Monte Carlo simulations to assess the probability of target attainment (PTA) of %T?>?MIC considering the uncertainty of PK parameters.Materials and methodsThe study population included 19 adult critically ill patients on CRRT, receiving 1 g of meropenem in 1-h infusions every 8 h. Blood samples were collected prior to (time zero) and 15, 30, 45, 60, 75, 90, 120, 180, 240 and 480 min after the start of meropenem administration. Population nonlinear mixed-effects modeling was conducted using NONMEM software, Fortran, and Wings for NONMEM.ResultsA two-compartment model was used to describe the available data. Typical values of the central and peripheral volume of distribution, and the CRRT and inter-compartmental clearance for a theoretical patient with 24.6 g/l albumin concertation were V1?=?27.9 l, V2?=?33.7 l, ClCRRT?=?15.1 l/h, and Q?=?21.1 l/h. A significant covariate relationship between V1 and albumin concentration was observed in the data that was described by a power relationship with - 2.87 exponent. Subsequently performed Monte Carlo simulations of the model allowed us to assess the impact of albumin concentration on PTA. The 40%T?>?2 mg/l target was reached in more than 90% of subjects after 1-h infusion of 1000 mg q8h and steady-state conditions. The more stringent 100%T?>?2 mg/l target requires higher doses and/or longer infusion durations that depend on the albumin concentration.ConclusionsThe population PK model was successfully developed to describe the time course of meropenem concentrations. The hypoalbuminemia was found to be associated with higher PTA in the CRRT patients after multiple short-term infusions.

Dataset Information

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

Publications

Substantial Impact of Altered Pharmacokinetics in Critically Ill Patients on the Antibacterial Effects of Meropenem Evaluated via the Dynamic Hollow-Fiber Infection Model.

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