Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients

Fish, Douglas N.; Teitelbaum, Isaac; Abraham, Edward

doi:10.1128/aac.49.6.2421-2428.2005

Cited by 67 publications

(55 citation statements)

References 43 publications

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“…The impacts of two CRRT procedures, CVVH and CVVHDF, on the disposition of doripenem and doripenem-M-1 were also rigorously assessed. The mean Sc and Sa for doripenem were comparable with those from previous reports of imipenem and meropenem, in which the same hemofilter was used (10,13,21). The CL CRRT of doripenem accounted for 25 to 32% of the observed CL, and the mean values ranged from 82 to 92% of simultaneous CL urea values, clearly indicating that either mode of CRRT has a marked effect on the disposition of doripenem, which needs to be accounted for with an increase in the daily doripenem dosage.…”

Section: Discussionsupporting

confidence: 75%

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Influence of Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodiafiltration on the Disposition of Doripenem

Cirillo

Vaccaro

Balis

et al. 2011

Antimicrob Agents Chemother

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‫؍‬ 5). Healthy volunteers were also assessed (n ‫؍‬ 12). Concentrations of doripenem and the primary metabolite doripenem-M-1 were measured in plasma and ultrafiltrate or ultrafiltrate/dialysate by a validated liquid chromatography-tandem mass spectrometry method. In dialysisdependent subjects, levels of systemic exposure to doripenem and doripenem-M-1 were approximately 3-and 5-fold greater, respectively, than those in healthy subjects: for doripenem, 98 g ⅐ h/ml for CVVH and 77 g ⅐ h/ml for CVVHDF versus 32 g ⅐ h/ml for healthy subjects, and for doripenem-M-1, 24 g ⅐ h/ml for CVVH and 22 g ⅐ h/ml for CVVHDF versus 4.7 g ⅐ h/ml for healthy subjects. The mean sieving coefficients and saturation coefficients were >0.67 for both doripenem and doripenem-M-1. During CVVH and CVVHDF, respectively, the percentages of administered doripenem dose removed were 38% and 29%, and clearances of doripenem were 22 and 25 ml/min. Both CVVH and CVVHDF efficiently removed doripenem and doripenem-M-1. Despite significant removal of drug by CVVH and CVVHDF, a single 1-hour, 500-mg doripenem infusion produced significantly higher plasma concentrations of doripenem, higher systemic exposure (area under the plasma concentration-time curve from time zero to 12 h after the start of infusion [AUC 0-12 ]), and longer half-life (t 1/2 ) in subjects receiving CVVH or CVVHDF than in healthy volunteers. The recovery of drug in ultrafiltrate and ultrafiltrate/dialysate and the enhanced rate of reduction of plasma concentrations indicate that CVVH and CVVHDF significantly augmented residual total body clearance of doripenem in subjects receiving CRRT. Doripenem dosage regimens for patients receiving CRRT thus need to be adjusted.

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Section: Discussionsupporting

confidence: 75%

“…The clearances of imipenem by CVVH ranged from 6.5 to 13.3 ml/min in the 1990s and have increased to 22.9 to 36.0 ml/min during the last decade (9,10,21). This increase is in part due to the utilization of larger-surface-area hemofilters and higher ultrafiltration rates.…”

Section: Discussionmentioning

confidence: 96%

Influence of Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodiafiltration on the Disposition of Doripenem

Cirillo

Vaccaro

Balis

et al. 2011

Antimicrob Agents Chemother

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“…The sieving coefficients observed in our study differed dramatically from those reported by Cirillo et al A possible explanation for the difference between prefilter/ postfilter clearance and sieving coefficient-dependent clearance could be adsorption of doripenem to the filter membrane. The prefilter/postfilter clearance values found in our trial are within the range of values reported previously for imipenem (36 Ϯ 13 ml/min with CVVH and 57 Ϯ 32 ml/min with CVVHDF) and meropenem (49 Ϯ 8.3 ml/min with CVVH), although the membrane sizes in our trial were considerably larger than those in the previous studies (12,13). Our data show an uncharacteristically low clearance for CVVHDF patients, which may be attributed to the larger membrane size and higher membrane k UF employed for the CVVHF and CVVHD groups.…”

Section: Resultscontrasting

confidence: 48%

Doripenem Treatment during Continuous Renal Replacement Therapy

Vossen

Wenisch

Maier‐Salamon

et al. 2016

Antimicrob Agents Chemother

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dDoripenem is a broad-spectrum parenteral carbapenem with enhanced activity against Pseudomonas aeruginosa. While the initial dosing recommendation for renally competent patients and patients undergoing continuous renal replacement therapy (cRRT) was 500 mg every 8 h (q8h), the dose for renally competent patients was updated to 1 g q8h in June 2012. There are no updated data for the dosing of patients on continuous renal replacement therapy. The original dosing regimen for cRRT patients was based on nonseptic patients, while newer publications chose comparatively low target concentrations for a carbapenem. Thus, there is an urgent need for updated recommendations for dosing during cRRT. In the trial presented here, we included 13 oliguric septic patients undergoing cRRT in an intensive care setting. Five patients each were treated with hemodiafiltration or hemodialysis, while three patients received hemofiltration treatment. All patients received 1 g doripenem every 8 h. Doripenem concentrations in the plasma and ultrafiltrate were measured over 48 h. The mean hemofilter clearance was 36.53 ml/min, and the mean volume of distribution was 59.26 liters. The steady-state trough levels were found at 8.5 mg/liter, with no considerable accumulation. Based on pharmacokinetic and pharmacodynamic considerations, we propose a regimen of 1 g q8h, which may be combined with a loading dose of 1.5 to 2 g for critically ill patients. (This study has been registered with EudraCT under registration no. 2009-018010-18 and at ClinicalTrials.gov under registration no. NCT02018939.)

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“…Given that sampling was not performed during the distribution phase, standard first-order equations were used to calculate the pharmacokinetic (PK) parameters of interest. The percent of time that the free piperacillin plasma level was above the minimum inhibitory concentration (MIC) during the dosing interval (%T.MIC) was calculated for MIC of 16 and 64 mcg/ml using previously reported methods (8,9). A pharmacodynamic (PD) target for piperacillin of .50%T.MIC64 mcg/ml was selected as the parameter of interest based on prior publications and proportion with target achievement calculated (10).…”

Section: Pharmacokinetic and Pharmacodynamic Calculationsmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

Bauer¹,

Salem

Connor

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Current recommendations for piperacillin-tazobactam dosing in patients receiving continuous renal replacement therapy originate from studies with relatively few patients and lower continuous renal replacement therapy doses than commonly used today. This study measured the pharmacokinetic and pharmacodynamic characteristics of piperacillin-tazobactam in patients treated with continuous renal replacement therapy using contemporary equipment and prescriptions.Design, setting, participants, & measurements A multicenter prospective observational study in the intensive care units of two academic medical centers was performed, enrolling patients with AKI or ESRD receiving piperacillin-tazobactam while being treated with continuous renal replacement therapy. Pregnant women, children, and patients with end stage liver disease were excluded from enrollment. Plasma and continuous renal replacement therapy effluent samples were analyzed for piperacillin and tazobactam levels using HPLC. Pharmacokinetic and pharmacodynamic parameters were calculated using standard equations. Multivariate analyses were used to examine the association of patient and continuous renal replacement therapy characteristics with piperacillin pharmacokinetic parameters.Results Forty-two of fifty-five subjects enrolled had complete sampling. Volume of distribution (median=0.38 L/kg, intraquartile range=0.20 L/kg) and elimination rate constants (median=0.104 h 21 , intraquartile range=0.052 h 21 ) were highly variable, and clinical parameters could explain only a small fraction of the large variability in pharmacokinetic parameters. Probability of target attainment for piperacillin was 83% for total drug but only 77% when the unbound fraction was considered.Conclusions There is significant patient to patient variability in pharmacokinetic/pharmacodynamic parameters in patients receiving continuous renal replacement therapy. Many patients did not achieve pharmacodynamic targets, suggesting that therapeutic drug monitoring might optimize therapy.

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Pharmacokinetics and Pharmacodynamics of Imipenem during Continuous Renal Replacement Therapy in Critically Ill Patients

Cited by 67 publications

References 43 publications

Influence of Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodiafiltration on the Disposition of Doripenem

Influence of Continuous Venovenous Hemofiltration and Continuous Venovenous Hemodiafiltration on the Disposition of Doripenem

Doripenem Treatment during Continuous Renal Replacement Therapy

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

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