1887

Abstract

VIM-producing isolates are usually associated with high MICs to carbapenems. Preclinical studies investigating the pharmacokinetic–pharmacodynamic (PK-PD) characteristics of carbapenems against these isolates are lacking. The antibacterial activity of meropenem against one WT and three VIM-producing clinical isolates (median MICs 0.031, 8, 16 and 128 mg l) was studied in a dialysis-diffusion PK-PD model and verified in a thigh infection neutropenic animal model by testing selected strains and exposures. The PK-PD target associated with bactericidal activity was estimated and the target attainment for different dosing regimens was calculated with Monte Carlo analysis. The model was correlated with the data, with logCFU/ml reduction of < 1 for the VIM-producing (MIC 16 mg l) and >2 for the WT (MIC 0.031 mg l) isolates, with % T >MIC 25 and 100 %, respectively. The bactericidal activity for all isolates was associated with 40 %  T>MIC and attained in >90 % of cases with the standard 1 g q8 0.5 h infusion dosing regimen only for isolates with MICs up to 1 mg l. For isolates with MICs of 2–8 mg l, prolonged infusion regimens (4 h infusion q8 or 2 h infusion q4) of standard (1 g) and higher (2 g) doses or continuous infusion regimens (3–6 g) are required. For isolates with a MIC of 16 mg l the unconventional dosing regimen of 2 g as 2 h infusion q4 or 12 g continuous infusion will be required. Prolonged and continuous infusion regimens of meropenem may increase efficacy against VIM-producing isolates.

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2016-03-01
2019-10-15
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