Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis

Tsai, Danny; Stewart, Penelope; Goud, Rajendra; Gourley, Stephen A.; Hewagama, Saliya; Krishnaswamy, Sushena; Wallis, Steven C.; Lipman, Jeffrey; Roberts, Jason A.

doi:10.1016/j.ijantimicag.2016.08.015

Cited by 30 publications

(15 citation statements)

References 17 publications

(17 reference statements)

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“…The final model accounted for up to 94% of the variability in meropenem concentrations and adequately fitted the drug concentration-time data. Our findings are in line with those observed in other patient populations (16,(20)(21)(22). Population pharmacokinetics of meropenem during CI was previously assessed only once, among postsurgical patients receiving the fixed dose of 3 g/day (22).…”

Section: Discussionsupporting

confidence: 90%

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

Cojutti

Sartor

Righi

et al. 2017

Antimicrob Agents Chemother

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We assessed the population pharmacokinetics of high-dose continuous-infusion (HDCI) meropenem in a cohort of patients with carbapenemase (KPC)-producing (KPC-Kp) infections. Monte Carlo simulations were used to define the permissible HDCI meropenem regimens that could be safely considered for the treatment of KPC-Kp infections due to meropenem-resistant strains. Permissible doses were arbitrarily defined as those associated with a ≤10% to 15% likelihood of meropenem steady-state concentrations () of >100 mg/liter. Probabilities of target attainment (PTA) of four incremental pharmacodynamic determinants for meropenem efficacy (100% T, 100% T, 100% T, and 100% T, where "T" represents the time during which the plasma concentration of this time-dependent antibacterial agent is maintained above the MIC for the pathogen) in relation to different classes of renal function were calculated. The cumulative fractions of response (CFR) for the permissible HDCI meropenem regimens were calculated against the MIC distribution of the KPC-Kp clinical isolates that were collected routinely at our University Hospital between 2013 and 2016 ( = 169). Ninety-seven meropenem were included in the analysis. The final model included creatinine clearance (CrCL) as a covariate and explained 94% of the population variability. Monte Carlo simulations based on licensed dosages of up to 6 g/day predicted an acceptable PTA (>80%) of 100% T against KPC-Kp with a meropenem MIC of ≤32 mg/liter in patients with a CrCL level of <130 ml/min. Dosages of 8 g/day were needed for achieving the same target in patients with CrCL at levels of 130 to 200 ml/min. In dealing with pathogens with a meropenem MIC of 64 mg/liter, HDCI regimens using meropenem at higher than licensed levels should be considered. In these cases, real-time therapeutic drug monitoring could be a useful adjunct for optimized care. The predicted CFR were >75% in all of the classes of renal function.

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Section: Discussionsupporting

confidence: 90%

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

Cojutti

Sartor

Righi

et al. 2017

Antimicrob Agents Chemother

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“…Previous studies have revealed large inter-patient variability in meropenem concentrations after standard dosing in critically ill patients [ 22 – 24 ], which resulted in inadequate meropenem exposure in a relevant fraction of patients [ 23 , 25 ]. However, in most of these studies, only limited numbers of patients and/or rather homogeneous patient sub-groups have been investigated.…”

Section: Introductionmentioning

confidence: 99%

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study

et al. 2017

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BackgroundSevere bacterial infections remain a major challenge in intensive care units because of their high prevalence and mortality. Adequate antibiotic exposure has been associated with clinical success in critically ill patients. The objective of this study was to investigate the target attainment of standard meropenem dosing in a heterogeneous critically ill population, to quantify the impact of the full renal function spectrum on meropenem exposure and target attainment, and ultimately to translate the findings into a tool for practical application.MethodsA prospective observational single-centre study was performed with critically ill patients with severe infections receiving standard dosing of meropenem. Serial blood samples were drawn over 4 study days to determine meropenem serum concentrations. Renal function was assessed by creatinine clearance according to the Cockcroft and Gault equation (CLCRCG). Variability in meropenem serum concentrations was quantified at the middle and end of each monitored dosing interval. The attainment of two pharmacokinetic/pharmacodynamic targets (100%T>MIC, 50%T>4×MIC) was evaluated for minimum inhibitory concentration (MIC) values of 2 mg/L and 8 mg/L and standard meropenem dosing (1000 mg, 30-minute infusion, every 8 h). Furthermore, we assessed the impact of CLCRCG on meropenem concentrations and target attainment and developed a tool for risk assessment of target non-attainment.ResultsLarge inter- and intra-patient variability in meropenem concentrations was observed in the critically ill population (n = 48). Attainment of the target 100%T>MIC was merely 48.4% and 20.6%, given MIC values of 2 mg/L and 8 mg/L, respectively, and similar for the target 50%T>4×MIC. A hyperbolic relationship between CLCRCG (25–255 ml/minute) and meropenem serum concentrations at the end of the dosing interval (C8h) was derived. For infections with pathogens of MIC 2 mg/L, mild renal impairment up to augmented renal function was identified as a risk factor for target non-attainment (for MIC 8 mg/L, additionally, moderate renal impairment).ConclusionsThe investigated standard meropenem dosing regimen appeared to result in insufficient meropenem exposure in a considerable fraction of critically ill patients. An easy- and free-to-use tool (the MeroRisk Calculator) for assessing the risk of target non-attainment for a given renal function and MIC value was developed.Trial registrationClinicaltrials.gov, NCT01793012. Registered on 24 January 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1829-4) contains supplementary material, which is available to authorized users.

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“…The dosing regimen for piperacillin, which was coadministered with tazobactam (Tazopip; Aspen Pharmacare, Sydney, Australia), was at the discretion of the treating intensivist. Inclusion and exclusion criteria, details of sampling, demographic data collected, and sample handling were previously published (8).…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

Tsai

Stewart

Goud

et al. 2016

Antimicrob Agents Chemother

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iThere are no available pharmacokinetic data to guide piperacillin dosing in critically ill Australian Indigenous patients despite numerous reported physiological differences. This study aimed to describe the population pharmacokinetics of piperacillin in critically ill Australian Indigenous patients with severe sepsis. A population pharmacokinetic study of Indigenous patients with severe sepsis was conducted in a remote hospital intensive care unit. Plasma samples were collected over two dosing intervals and assayed by validated chromatography. Population pharmacokinetic modeling was conducted using Pmetrics. Nine patients were recruited, and a two-compartment model adequately described the data. The piperacillin clearance (CL), volume of distribution of the central compartment (V c ), and distribution rate constants from the central to the peripheral compartment and from the peripheral to the central compartment were 5.6 ؎ 3.2 liters/h, 14.5 ؎ 6.6 liters, 1.5 ؎ 0.4 h ؊1 , and 1.8 ؎ 0.9 h ؊1 , respectively, where CL and V c were found to be described by creatinine clearance (CL CR ) and total body weight, respectively. In this patient population, piperacillin demonstrated high interindividual pharmacokinetic variability. CL CR was found to be the most important determinant of piperacillin pharmacokinetics.

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Optimising meropenem dosing in critically ill Australian Indigenous patients with severe sepsis

Cited by 30 publications

References 17 publications

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

Population Pharmacokinetics of High-Dose Continuous-Infusion Meropenem and Considerations for Use in the Treatment of Infections Due to KPC-Producing Klebsiella pneumoniae

Role of renal function in risk assessment of target non-attainment after standard dosing of meropenem in critically ill patients: a prospective observational study

Pharmacokinetics of Piperacillin in Critically Ill Australian Indigenous Patients with Severe Sepsis

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