Meropenem and Continuous Renal Replacement Therapy: In Vitro Permeability of 2 Continuous Renal Replacement Therapy Membranes and Influence of Patient Renal Function on the Pharmacokinetics in Critically Ill Patients

Isla, Arantxazu; Maynar, Javier; Sánchez-Izquierdo, José Ángel; Rodríguez-Gascón, Alicia; Arzuaga, Alazne; Corral, Esther; Pedraz, José Luís

doi:10.1177/0091270005280583

Cited by 51 publications

(46 citation statements)

References 38 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: 83%

“…The total body clearances reported by the nine investigative teams which have assessed the influence of CVVH and/or CVVHDF vary widely (52 to 1,064 ml/min) and thus are relatively noninformative in terms of application of the data to prospective patient care situations. Focusing on those studies in patients with CL CR less than 70 ml/min dramatically reduces the variability in CL, to 52 to 143 ml/min (13,17,21). The mean nonrenal clearances from a subgroup of 5 investigations of 38 patients ranged from 35 to 59 ml/min and are comparable to the values observed in individuals with normal renal function ( Table 2).…”

Section: Discussionmentioning

confidence: 90%

“…The disposition of meropenem has been evaluated extensively in critically ill patients with creatinine clearances ranging from 0 to 118 ml/min (13,15,17,21). The total body clearances reported by the nine investigative teams which have assessed the influence of CVVH and/or CVVHDF vary widely (52 to 1,064 ml/min) and thus are relatively noninformative in terms of application of the data to prospective patient care situations.…”

Section: Discussionmentioning

confidence: 99%

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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: 83%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…19,20 Data suggest extracorporeal removal of meropenem ranging from 23% to 56% in adults receiving CRRT; however, there are no estimates in children receiving CRRT. [21][22][23][24][25][26][27] The standard meropenem dose in a patient this age is 20 mg/kg per dose IV every 8 to 12 hours. Further, Nehus et al 28 conducted clinical trial simulations to determine dosing regimens in children that would provide for a target attainment of 40% and 75% time above the MIC.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Continuous Infusion Meropenem With Concurrent Extracorporeal Life Support and Continuous Renal Replacement Therapy: A Case Report

Cies

Moore²,

Conley

et al. 2016

The Journal of Pediatric Pharmacology and Therapeutics

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Pharmacokinetic parameters can be significantly altered for both extracorporeal life support (ECLS) and continuous renal replacement therapy (CRRT). This case report describes the pharmacokinetics of continuousinfusion meropenem in a patient on ECLS with concurrent CRRT. A 2.8-kg, 10-day-old, full-term neonate born via spontaneous vaginal delivery presented with hypothermia, lethargy, and a ~500-g weight loss from birth. She progressed to respiratory failure on hospital day 2 (HD 2) and developed sepsis, disseminated intravascular coagulation, and liver failure as a result of disseminated adenoviral infection. By HD 6, acute kidney injury was evident, with progressive fluid overload >1500 mL (+) for the admission. On HD 6 venoarterial ECLS was instituted for lung protection and fluid removal. On HD 7 she was initiated on CRRT. On HD 12, a blood culture returned positive and subsequently grew Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) for meropenem of 0.25 mg/L. She was started on vancomycin, meropenem, and amikacin. A meropenem bolus of 40 mg/kg was given, followed by a continuous infusion of 10 mg/kg/hr (240 mg/kg/day). On HD 15 (ECLS day 9) a meropenem serum concentration of 21 mcg/mL was obtained, corresponding to a clearance of 7.9 mL/kg/min. Repeat cultures from HDs 13 to 15 (ECLS days 7-9) were sterile. This meropenem regimen was successful in providing a target attainment of 100% for serum concentrations above the MIC for ≥40% of the dosing interval and was associated with a sterilization of blood in this complex patient on concurrent ECLS and CRRT circuits.

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“…However, this population is subject to conditions that may significantly influence meropenem pharmacokinetics (PKs) and, consequently, modify the dosing requirements, such as hypoproteinemia, variable urine output, or diverse CRRT settings (6). It follows that while several studies have described meropenem PKs in critically ill patients with continuous venovenous hemofiltration (CVVHF) and continuous venovenous hemodiafiltration (CVVHDF) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19), empirical dosing at the bedside is still challenging in this scenario.…”

mentioning

confidence: 99%

Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

Ulldemolins

Soy

Llauradó-Serra

et al. 2015

Antimicrob Agents Chemother

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n Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL ‫؍‬ 3.68 ؉ 0.22 · (residual diuresis/100) and V ‫؍‬ 33.00 · (weight/73) 2.07 , where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (f u ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ u T >MIC ), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ u T >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population. Meropenem is a broad-spectrum carbapenem with high levels of activity against Gram-positive and Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter spp., and anaerobes (1), and is one of the most prescribed antibiotics for the empirical treatment of severe infections (2). It exhibits optimal killing activity when the concentrations of the unbound fraction (f u ) of drug in plasma are maintained above the MIC of the bacteria for a certain percentage of dosing interval T (referred to as the percentage of the ƒ u T ϾMIC ), which in in vitro and in vivo animal studies has been defined to be about 40% (3). However, some clinical data suggest that critically ill patients may require a higher percentage of the ƒ u T ϾMIC , even 100% (4, 5).Meropenem is a hydrophilic, small molecule with a low volume of distribution (V; 0.3 liter/kg) and a very low level of protein binding (Ͻ2%). These characteristics make meropenem a drug...

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Meropenem and Continuous Renal Replacement Therapy: In Vitro Permeability of 2 Continuous Renal Replacement Therapy Membranes and Influence of Patient Renal Function on the Pharmacokinetics in Critically Ill Patients

Cited by 51 publications

References 38 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

Pharmacokinetics of Continuous Infusion Meropenem With Concurrent Extracorporeal Life Support and Continuous Renal Replacement Therapy: A Case Report

Meropenem Population Pharmacokinetics in Critically Ill Patients with Septic Shock and Continuous Renal Replacement Therapy: Influence of Residual Diuresis on Dose Requirements

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