2017. Daptomycin loading dose, one of the advantageous procedures in a neutropenic murine thigh infection model
Session: Poster Abstract Session: Antimicrobial Resistant Infections: Treatment
Saturday, October 29, 2016
Room: Poster Hall
  • IDweek2016 No.2017.pdf (1.0 MB)
  • Background: Daptomycin (DAP) has been an important option for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). The ratio of the area under the unbound concentration-time curve to the MIC (fAUC/MIC) has been shown to be the best predicts bacterial killing by DAP. Previous clinical study showed DAP blood concentration took 2 days to reach steady state, suggesting the benefits of the treatment initiation with a loading dose, while few previous study have evaluated the antimicrobial benefit of DAP loading dose. Herein, we evaluated the efficacy of DAP loading dose against infections caused by clinically isolated MRSA.

    Methods: Three MRSA isolates (DAP MIC: 0.5, 1 and 2 mg/L) were tested in neutropenic thigh infection model. Based on the pharmacokinetic study results, DAP was administered 40 to 100 mg/kg with single dosage, four DAP regimens simulated human concentration-time profiles (i) day1: 8 mg/kg q24h and day2: 6 mg/kg q24h, (ii) day1and 2: 6 mg/kg q24h (without loading dose), (iii) day1: 8 mg/kg q24h and day2: 4 mg/kg q24h, (iv) day1 and 2: 4 mg/kg q24h (without loading dose) were administered to mice. Efficacy was evaluated after 72 h from DAP treatment started as the change in bacterial density in treated animals as compared with the 0 h control animals.

    Results: The pharmacokinetic studies demonstrated an AUC range of 441.5 to 2508.8 mg*h/L and half-lives of 1.4 h. The numbers of organisms recovered from the thighs of infected animals serving as 0 h controls ranged from 7.36 to 7.68 log10 colony formation unit (CFU). The bacterial densities of control mice at 72 h ranged from 7.85 to 8.86 log10 CFU. DAP loading dose regimen (iii) showed the greater antimicrobial activity against MRSA (DAP MIC 1 mg/L ) than that of the other loading regimen (iv) (-3.10 ± 0.63 log10 CFU vs -0.71 ± 0.34, p < 0.05). DAP loading dose regimen (iii) achieved greater log10 CFU changes than that of non-loading dose regimen (ii), while total DAP dosage for two days were same (-3.10 ± 0.63 vs -1.46 ± 0.48, p < 0.05). Additionally, antimicrobial susceptibility getting worth, the antimicrobial activity of DAP reduced.

    Conclusion: These data suggested that DAP loading dose regimen would be one of the advantageous procedures for patients infected with MRSA.

    Hideo Kato, MS1, Mao Hagihara, PhD1, Jun Hirai, MD2, Naoya Nishiyama, MD1, Yuusuke Koizumi, MD, PhD1, Hiroyuki Suematsu, MS1, Yuka Yamagishi, MD, PhD1 and Hiroshige Mikamo, MD, PhD1, (1)Aichi Medical University, Aichi, Japan, (2)University of the Ryukyus, Okinawa, Japan


    H. Kato, None

    M. Hagihara, None

    J. Hirai, None

    N. Nishiyama, None

    Y. Koizumi, None

    H. Suematsu, None

    Y. Yamagishi, None

    H. Mikamo, None

    Findings in the abstracts are embargoed until 12:01 a.m. CDT, Wednesday Oct. 26th with the exception of research findings presented at the IDWeek press conferences.