Pharmacokinetics of meropenem in patients with intra-abdominal infections

Bedikian, Annet; Okamoto, Mark P.; Nakahiro, Randall K.; Farino, J.; Heseltine, Peter N. R.; Appleman, Maria D.; Yellin, Albert E.; Berne, Thomas V.; Gill, Mark A.

doi:10.1128/aac.38.1.151

Cited by 65 publications

(41 citation statements)

References 18 publications

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“…This study demonstrates significant higher values of the Vd of both betalactam antibiotics given to the ICU patients if compared with data reported for healthy volunteers or less seriously ill patients [25][26][27][28] . The impact of age and decreasing Cl cr (ref.…”

Section: Discussionsupporting

confidence: 48%

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Kaška¹,

Havel²,

Selke-Krulichova³

et al. 2018

BIOMED PAP

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Aims. Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble timedependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates -creatinine clearance (Cl cr ) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/ tazobactam (PIP/TZB). Methods. In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry. Results. The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Cl cr ≥130 mL/min/1.73m 2 . Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vd me =70.3 L (41.9-101.5), Vd pip = 46.8 L (39.7-60.0). 100%fT me >MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFB pip with Vd pip (P=0.021). Conclusion. Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vd pip across subjects at each and every time point.

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Section: Discussionsupporting

confidence: 48%

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Kaška¹,

Havel²,

Selke-Krulichova³

et al. 2018

BIOMED PAP

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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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“…Major changes of these parameters will affect antibiotic concentrations and therefore bacterial killing. Changes in distribution through volume expansion may cause a dilution effect to hydrophilic antibiotics, thereby necessitating larger doses, as shown in those PK studies involved patients with IAI; higher V d values were noted than in healthy volunteers [86,87,95]. There is a lack of data on the presence and effect of impaired penetration and possible antibiotic clearance through surgical drains, suggesting that further studies be should be conducted.…”

Section: Approaches To Dosing Antibiotic In Iaimentioning

confidence: 99%

“…The increment of V d , was twice as high for both meropenem [86,87] and piperacillin [95] and 20% higher for ceftazidime [97]. Despite these PK differences in healthy volunteers, because of the high susceptibility of the majority of pathogens causing IAI, a loading dose in response to this increased V d would be required only on suspicion of a less susceptible bacterium (e.g.…”

Section: Summary Of Pk Datamentioning

confidence: 99%

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Improving antimicrobial use in critically ill patients

Adnan¹

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Pharmacokinetics of meropenem in patients with intra-abdominal infections

Cited by 65 publications

References 18 publications

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

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

Improving antimicrobial use in critically ill patients

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