Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation

Eguchi, Ken; Kanazawa, Katsunori; Shimizudani, Takeshi; Kanemitsu, Keiji; Kaku, Mitsuo

doi:10.1007/s10156-009-0001-8

Cited by 14 publications

(18 citation statements)

References 18 publications

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“…Indeed, this approach is unfavorable for highly resistant bacterial isolates because it reduces the initial bactericidal effects due to both the decrease in meropenem peak concentration and the delay in its peak time, as demonstrated by Eguchi et al (2010). It is therefore difficult for meropenem to achieve the MIC of highly resistant bacterial isolates, even at a high dose.…”

Section: Discussionmentioning

confidence: 99%

Is Meropenem as a Monotherapy Truly Incompetent for Meropenem-Nonsusceptible Bacterial Strains? A Pharmacokinetic/Pharmacodynamic Modeling With Monte Carlo Simulation

Song

Cao

et al. 2019

Front. Microbiol.

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Infections due to meropenem-nonsusceptible bacterial strains (MNBSs) with meropenem minimum inhibitory concentrations (MICs) ≥ 16 mg/L have become an urgent problem. Currently, the optimal treatment strategy for these cases remains uncertain due to some limitations of currently available mono- and combination therapy regimens. Meropenem monotherapy using a high dose of 2 g every 8 h (q 8 h) and a 3-h traditional simple prolonged-infusion (TSPI) has proven to be helpful for the treatment of infections due to MNBSs with MICs of 4–8 mg/L but is limited for cases with higher MICs of ≥16 mg/L. This study demonstrated that optimized two-step-administration therapy (OTAT, i.e., a new administration model of i.v. bolus plus prolonged infusion) for meropenem, even in monotherapy, can resolve this problem and was thus an important approach of suppressing such highly resistant bacterial isolates. Herein, a pharmacokinetic (PK)/pharmacodynamic (PD) modeling with Monte Carlo simulation was performed to calculate the probabilities of target attainment (PTAs) and the cumulative fractions of response (CFRs) provided by dosage regimens and 39 OTAT regimens in five dosing models targeting eight highly resistant bacterial species with meropenem MICs ≥ 16 mg/L, including Acinetobacter baumannii, Acinetobacter spp., Enterococcus faecalis, Enterococcus faecium, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus haemolyticus, and Stenotrophomonas maltophilia, were designed and evaluated. The data indicated that meropenem monotherapy administered at a high dose of 2 g q 8 h and as an OTAT achieved a PTA of ≥90% for isolates with an MIC of up to 128 mg/L and a CFR of ≥90% for all of the targeted pathogen populations when 50% f T > MIC (50% of the dosing interval during which free drug concentrations remain above the MIC) is chosen as the PD target, with Enterococcus faecalis being the sole exception. Even though 50% f T > 5 × MIC is chosen as the PD target, the aforementioned dosage regimen still reached a PTA of ≥90% for isolates with an MIC of up to 32 mg/L and a CFR of ≥90% for Acinetobacter spp., Pseudomonas aeruginosa, and Klebsiella pneumoniae populations. In conclusion, meropenem monotherapy displays potential competency for infections due to such highly resistant bacterial isolates provided that it is administered as a reasonable OTAT but not as the currently widely recommended TSPI.

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Section: Discussionmentioning

confidence: 99%

Is Meropenem as a Monotherapy Truly Incompetent for Meropenem-Nonsusceptible Bacterial Strains? A Pharmacokinetic/Pharmacodynamic Modeling With Monte Carlo Simulation

Song

Cao

et al. 2019

Front. Microbiol.

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“…Despite acquisition of target AUC 0−24 /MIC by OTSI method, we were unable to demonstrate a microbiological or clinical superiority of these recommended VAN OTSI regimens based on MCSs as little data are currently available, either in vivo or in vitro experiments. However, in a study of in vitro pharmacodynamic model and MCSs (Eguchi et al, 2010), experimental verification of the efficacy of optimized two-step infusion therapy (OTIT), for meropenem but not for VAN, was performed. Surprisingly, the in vitro bactericidal effect of the optimal meropenem OTIT regimens is consistent with the bactericidal effect predicted by their respective PTA of these regimens derived from MCSs, especially for Pseudomonas aeruginosa isolates with meropenem MIC of ≤4 mg/L, which partly indicated the feasibility of MCSs method in predicting the efficacy of the regimens although the research object of this study was meropenem rather than VAN.…”

Section: Discussionmentioning

confidence: 99%

Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling

Song

Zeng

et al. 2021

Front. Microbiol.

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The increasing emergence of bacterial strains with high VAN MICs (BSH–VAN–M), such as Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus bovis, results in growing concern that VAN is not effective against these isolates. Due to the limited data on VAN against BSH–VAN–M and the application limits of drugs currently considered to be effective for BSH–VAN–M, exploration of “new usages for old drugs” is reasonable to improve and maximize the efficacy of existing antibiotics. This study aimed to construct a novel dosing strategy to mine the competence of VAN in the management of BSH–VAN–M infections. Herein, we optimized the traditional intermittent i.v. infusion (TIII) method to create an optimal two-step infusion (OTSI). With pharmacokinetic (PK)/pharmacodynamic (PD) modeling at the targeted ratio of the daily area under the concentration-time curve (AUC0–24) to the minimum inhibitory concentration (MIC) (AUC0–24/MIC) of 400, we used Monte Carlo simulations to evaluate the efficacy of 25 VAN regimens (including 15 OTSI regimens and 10 TIII regimens with daily doses of up to 6 g) to treat pneumonia, meningitis, sternal osteomyelitis, mastitis, pleuritis, bacteremia, and bacterial pericarditis resulting from isolates with MICs of ≤64 mg/L and to the current E. faecalis, E. faecium, S. aureus, S. epidermidis, and S. bovis populations with a pooled MIC distribution. Our data indicated that 4 g/day VAN, with an OTSI but not a TIII, for mastitis, pleuritis, bacteremia, and bacterial pericarditis due to isolates with MICs of ≤4 mg/L or to the current E. faecalis, S. aureus, S. epidermidis, and S. bovis populations achieved the desired PK/PD exposure at the AUC0–24/MIC target of 400. This study suggests the superiority and feasibility of OTSI relative to TIII for the competence mining of VAN against BSH–VAN–M from the perspective of PK/PD and provides a new resource for understanding how PK/PD modeling shapes the performance of VAN to meet the growing challenges of BSH–VAN–M infections.

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“…The delay of onset of antibacterial activity compared with intermittent administration can be circumvented by administration of an initial loading dose before continuous or prolonged infusion 54,57 .…”

Section: Pharmacokinetic/pharmacodynamic Conceptmentioning

confidence: 99%

“…Prolonged infusion allows 4 hours between each 8 hours dosing interval, when other agents could be administered through the same intravenous line. The duration of infusion (3-4 hours) approximates the duration of coverage of the dosing interval with free drug in excess of the MIC that provides the maximal microbiological effect [52][53][54] . According to the literature, the prolonged infusion of piperacillin-tazobactam resulted in cost savings by reducing the dosing frequency from every 6 hours to every 8 hours.…”

Section: Pharmacokinetic/pharmacodynamic Conceptmentioning

confidence: 99%

Beta-lactam antibiotics use in intensive care units - the pathophysiological, pharmacokinetic, pharmacodynamic and pharmacoeconomic approach

et al. 2015

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Experimental verification of the efficacy of optimized two-step infusion therapy with meropenem using an in vitro pharmacodynamic model and Monte Carlo simulation

Cited by 14 publications

References 18 publications

Is Meropenem as a Monotherapy Truly Incompetent for Meropenem-Nonsusceptible Bacterial Strains? A Pharmacokinetic/Pharmacodynamic Modeling With Monte Carlo Simulation

Is Meropenem as a Monotherapy Truly Incompetent for Meropenem-Nonsusceptible Bacterial Strains? A Pharmacokinetic/Pharmacodynamic Modeling With Monte Carlo Simulation

Competence Mining of Vancomycin (VAN) in the Management of Infections Due to Bacterial Strains With High VAN Minimum Inhibitory Concentrations (MICs): A Novel Dosing Strategy Based on Pharmacokinetic/Pharmacodynamic Modeling

Beta-lactam antibiotics use in intensive care units - the pathophysiological, pharmacokinetic, pharmacodynamic and pharmacoeconomic approach

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