Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration

Tegeder, Irmgard; Neumann, Frank; Bremer, Frank; Brune, Kay; Lötsch, Jörn; Geißlinger, Gerd

doi:10.1016/s0009-9236(99)70121-9

Cited by 78 publications

(71 citation statements)

References 41 publications

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“…Enhanced Cl may occur with highly protein bound antimicrobial agents, such as flucloxacillin and ceftriaxone, as a result of hypoalbuminaemia (Burkhardt et al 2007;Ulldemolins et al 2010). Renal replacement therapy is an effective Cl mechanism for antimicrobial agents but marked variability in performance of Cl by renal replacement therapy has been described (Tegeder et al 1999;Krueger et al 2003;Lipman et al 2003;Arzuaga et al 2005;Dagenais and Keller 2009;Bilgrami et al 2010). Hepatic dysfunction in critically ill patients also affects elimination of drugs, such as ciprofloxacin, moxifloxacin and ceftriaxone, which are metabolised by the liver or undergo transintestinal Cl (Heinemeyer et al 1990;Jones et al 1997;Stass et al 2002).…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?

Felton

Hope

Roberts

2014

Diagnostic Microbiology and Infectious Disease

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Section: Accepted M Manuscriptmentioning

confidence: 99%

How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?

Felton

Hope

Roberts

2014

Diagnostic Microbiology and Infectious Disease

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“…An adaptive-grid nonparametric approach to the pharmacokinetic and pharmacodynamic models (Proceedings of the 14th IEEE Symposium on Computer-Based Medical Systems, IEEE Computer Society, Bethesda, Md., 2001, p. 389-394) was used. Because of prior data relating to meropenem pharmacokinetic modeling (1,14,33,42), a two-compartment open model with a time-delimited zero-order input (intermittent administration) or a short (5-min [see above]) intravenous infusion followed by a continuous drug infusion was used. In both instances, first-order elimination was used in the model.…”

Section: Subjectsmentioning

confidence: 99%

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

Krueger

Bulitta

Kinzig‐Schippers

et al. 2005

Antimicrob Agents Chemother

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Meropenem is a broad-spectrum carbapenem antibacterial agent. In order to optimize levels in plasma relative to the MICs, the ideal dose level and dosage regimen need to be determined. The pharmacokinetics of meropenem were studied in two groups, each comprising eight healthy volunteers who received the following doses: 500 mg as an intravenous infusion over 30 min three times a day (t.i.d.) versus a 250-mg loading dose followed by a 1,500 mg continuous infusion over 24 h for group A and 1,000 mg as an intravenous infusion over 30 min t.i.d. versus a 500-mg loading dose followed by a 3,000-mg continuous infusion over 24 h for group B. Meropenem concentrations in plasma and urine were determined by liquid chromatography-mass spectrometry/mass spectrometry and high-performance liquid chromatography with UV detection, respectively. Pharmacokinetic calculations were done by use of a two-compartment open model, and the data were extrapolated by Monte Carlo simulations for 10,000 simulated subjects for pharmacodynamic evaluation. There were no significant differences in total clearance and renal clearance between group A and group B or between the intermittent treatment and the continuous infusion. The analyses of the probability of target attainment by MIC for the high-and low-dose continuous infusions were robust up to MICs of 4 mg/liter and 2 mg/liter, respectively. The corresponding values for intermittent infusions were only 0.5 mg/liter and 0.25 mg/liter. When these observations were correlated with MICs obtained from the MYSTIC database, intermittent infusion results in adequate activity against two of the most common nosocomially acquired pathogens, Klebsiella pneumoniae and Enterobacter cloacae. However, against Pseudomonas aeruginosa, the evaluation shows a clear advantage of high-dose therapy administered as a continuous infusion. We believe that in the empirical therapy situation, the continuous-infusion mode of administration is most worth the extra efforts. We conclude that clinical trials for evaluation of the continuous infusions of meropenem in critically ill patients are warranted.Considerable evidence demonstrates that the amount of time that free drug concentrations exceed the MIC is the measure of drug exposure most closely linked to the ability of a regimen of ␤-lactam antibiotics to kill the target organisms (9,17,19,48). This linkage is likely due to the fact that the rate of organism killing is maximized rapidly with the concentration and maximal killing is attained at drug concentrations of four to six times the MIC (6). Among the ␤-lactam agents, there are differences in the fraction of the dosing interval in which the drug concentration needs to be in excess of the MIC to attain organism stasis or to attain maximal killing of the organism population. Generally, ␤-lactams have some postantibiotic effects against gram-positive cocci but only limited postantibiotic effects against gram-negative rods (4,8,18,22,48). This means that the duration of plasma levels above the MIC is the most critica...

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“…A number of published studies have evaluated the pharmacokinetics of imipenem and cilastatin in critically ill patients with severe acute renal failure undergoing continuous renal replacement therapies (CRRT) (14,19,25,32,38,43). However, there are important questions regarding the applicability of these previous studies to current clinical practice.…”

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confidence: 99%

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

Fish

Teitelbaum

Abraham

2005

Antimicrob Agents Chemother

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The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n ‫؍‬ 6 patients) or hemodiafiltration (CVVHDF; n ‫؍‬ 6 patients). Patients (mean ؎ standard deviation age, 50.9 ؎ 15.9 years; weight, 98.5 ؎ 15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre-and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL S ) and elimination half-life (t 1/2 ) of imipenem were 145 ؎ 18 ml/min and 2.7 ؎ 1.3 h during CVVH versus 178 ؎ 18 ml/min and 2.6 ؎ 1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL S , respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 g/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC ‫؍‬ 4 to 8 g/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.

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Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration

Cited by 78 publications

References 41 publications

How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?

How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?

Evaluation by Monte Carlo Simulation of the Pharmacokinetics of Two Doses of Meropenem Administered Intermittently or as a Continuous Infusion in Healthy Volunteers

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

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