Vol.57 No.4 July 2009
Pharmacokinetic-pharmacodynamic (PK-PD) analysis of anti-MRSA drugs based on their human plasma concentration profiles and penetration into the ELF in a mouse model of MRSA lung infection
1)Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka, Kohoku-ku, Yokohama, Kanagawa, Japan
2)Product Management & Promotion Dept., Meiji Seika Kaisha, Ltd.
3)Agricultural & Veterinary Division, Meiji Seika Kaisha, Ltd.
4)Fukuoka University Chikushi Hospital
Abstract
We evaluated the efficacy of arbekacin(ABK), vancomycin(VCM), and teicoplanin(TEIC) in a mouse model of MRSA lung infection in which a drug concentration profile was produced to mimick that in humans (ABK 200 mg q.d., ABK 100 mg q.d., VCM 1 g q.d., and TEIC 400 mg q.d.).
Two types of MRSA, MSC03154 and MSC15761, isolated from clinical sources were used. ABK, VCM, and TEIC MICs were 0.5, 1, and 1 μg/mL for MSC03154 and 1, 1, and 1 μg/mL for MSC15761, respectively.
The viable bacterial count of MSC03154 in the lung tissues was significantly decreased in the ABK 200 mg q.d. group compared to that in the VCM 1 g q.d. group or TEIC 400 mg q.d. group.
The reduction rates of MSC15761 were significantly higher in the groups of ABK 200 mg q.d., ABK 100 mg q.d., and VCM 1 g q.d. than in the TEIC 400 mg q.d. group.
Dynamic PK-PD analysis based on drug concentrations in the epithelial lining fluid(ELF) and the time-kill curves demonstrated different drug efficacy as described in the above in vivo results.
In conclusion, we produced a similar anti-MRSA drug concentration profile in the mouse model of MRSA lung infection to that in humans, and evaluated the efficacy of ABK, VCM, and TEIC, each of which has different pharmacokinetics and mechanism of action. Our results suggested that dynamic PK-PD analysis based on drug concentration in the ELF and the time-kill curves are a useful tool in predicting anti-MRSA drug efficacy.
Key word
MRSA, animal model, arbekacin, epithelial lining fluid, PK-PD
Received
December 16, 2008
Accepted
May 20, 2009
Jpn. J. Chemother. 57 (4): 295-303, 2009
