Optimizing the Dosing Regimens of Daptomycin Based on the Susceptible Dose-Dependent Breakpoint against Vancomycin-Resistant Enterococci Infection

Wichai Santimaleeworagun; Dhitiwat Changpradub; Sudaluck Thunyaharn; Jatapat Hemapanpairoa

doi:10.3390/antibiotics8040245

Optimizing the Dosing Regimens of Daptomycin Based on the Susceptible Dose-Dependent Breakpoint against Vancomycin-Resistant Enterococci Infection

Antibiotics (Basel). 2019 Nov 29;8(4):245. doi: 10.3390/antibiotics8040245.

Authors

Wichai Santimaleeworagun^{1

2}, Dhitiwat Changpradub³, Sudaluck Thunyaharn⁴, Jatapat Hemapanpairoa⁵

Affiliations

¹ Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakorn Pathom 73000, Thailand.
² Pharmaceutical Initiative for Resistant Bacteria and Infectious Diseases Working Group (PIRBIG), Nakorn Pathom 73000, Thailand.
³ Division of Infectious Disease, Department of Medicine, Phramongkutklao Hospital, Bangkok 10400, Thailand.
⁴ Faculty of Medical Technology, Nakhonratchasima College, Nakhon Ratchasima, 30000, Thailand.
⁵ Department of Pharmacy Practice and Pharmaceutical Care, Faculty of Pharmaceutical Sciences, Burapha University, Chonburi 20131, Thailand.

Abstract

Daptomycin, a lipopeptide antibiotic, is one of the therapeutic options used for the treatment of vancomycin-resistant enterococci (VRE). Recently, the Clinical and Laboratory Standards Institute (CLSI) M100 30th edition has removed the susceptibility (S) breakpoint for Enterococcus faecium and replaced it with a susceptible dose-dependent (SDD) breakpoint of ≤4 μg/mL, with a suggested dosage of 8-12 mg/kg/day. Herein, we aimed to determine the minimum inhibitory concentration (MIC) values of daptomycin against clinical VRE isolates and to study the appropriate daptomycin dosing regimens among critically ill patients based on the new susceptibility CLSI breakpoint. The MIC determination of daptomycin was performed using E-test strips among clinical VRE strains isolated from patients at the Phramongkutklao Hospital. We used Monte Carlo simulation to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of the ratio of the free area under the curve to MIC (fAUC₀_-₂₄/MIC) > 27.4 and fAUC_0-24/MIC > 20 for survival and microbiological response, respectively, at the first day and steady state. Further, we determined that the simulated daptomycin dosing regimen met the minimum concentration (Cmin) requirements for safety of being below 24.3 mg/L. All of the 48 VRE isolates were E. faecium strains, and the percentiles at the 50th and 90th MIC of daptomycin were 1 and 1.5 μg/mL, respectively. At MIC ≤ 2 μg/mL, a daptomycin dosage of 12 mg/kg/day achieved the PTA target of survival and microbiological response at the first 24 h time point and steady state. For a MIC of 4 μg/mL, none of the dosage regimens achieved the PTA target. For CFR, a dosage of 8-12 mg/kg/day could achieve the 90% CFR target at the first day and steady state. All dosing regimens had a low probability of Cmin being greater than 24.3 mg/L. In conclusion, the MIC of VRE against daptomycin is quite low, and loading and maintenance doses with 8 mg/kg/day were determined to be optimal and safe.

Keywords: Enterococcus faecium; MIC; Monte Carlo simulation; VRE; daptomycin.