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KMID : 1144320110430030251
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감염과 화학요법
2011 Volume.43 No. 3 p.251 ~ p.257
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Efficacy of Vancomycin against Staphylococcus aureus according to Inoculum Size in a Neutropenic Mouse Infection Model
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Shin Hyun-ho
Hang Seung-Hoon
Yim Dong-Seok
Lee Dong-Gun
Park Chul-Min
Kim Si-Hyun
Kwon Jae-Cheol
Hong Kyung-wook
Park Sun-Hee
Choi Su-Mi
Choi Jung-Hyun
Yoo Jin-Hong
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Abstract
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Background: Staphylococcus aureus is one of the most important gram-positive pathogens in many clinical situations. Use of vancomycin against methicillin resistant S. aureus (MRSA) has been anecdotally associated with treatment failure, which could be attributable to an inoculum effect (IE). Using a neutropenic mouse thigh infection model, we tried to evaluate the in vivo IE of vancomycin against S. aureus.
Materials and Methods : Twenty strains of S. aureus were used. Minimum inhibitory concentrations (MICs) were determined by the Clinical and Laboratory Standards Institute guideline. Six-week-old specific-pathogen-free, female CD-1 mice weighing 23-27 grams were used. The neutropenic mice received inoculations of 5.02-5.74 log10 CFU/thigh in one thigh (low inoculum, LI), and 7.22-7.73 log10 CFU/thigh in the other thigh (high inoculum, HI) before therapy. The mice were treated with 6 hourly subcutaneous doses of vancomycin (3.125-100 mg/kg) for 24 h. Single-dose serum pharmacokinetics of vancomycin was determined. Dose-response data were analyzed by an Emax model using non-linear regression. Static doses and area under the curve (AUC)/MIC for bacteriostatic effect at each inoculum were calculated and compared. The ratio of static dose and AUC/MIC between HI and LI (IE index) provided the magnitude of IE for each organism.
Materials and Methods : Five methicillin-susceptible S. aureus (MSSA) strains and 15 MRSA strains were used. Vancomycin MICs of the 20 strains varied by 4-fold (0.5-2 mg/L). The AUC/MIC ratio was the major parameter determining the efficacy of vancomycin against S. aureus . Mean (range) static dose on LI and HI was 20.7 (11.8-35.1) and 136.7 (32.1-314), respectively. The mean IE index of static dose between them was 7.39. Mean (range) of AUC/MIC on LI and HI was 27.0 (6.61-66.6) and 152.3 (46.2-344), respectively, which produced a mean IE index of AUC/MIC of 7.47. The IE indices of the MSSA strains were significantly higher than those of the MRSA strains (11.3 vs. 6.1 on static dose [P=0.018], 11.4 vs. 6.2 on AUC/MIC [P=0.034]).
Conclusions: With a 100-fold inoculum increment of S. aureus , at least a 7-fold dose of vancomycin would be required to show the same bacteriostatic effect. Thus, IE as well as MICs is an important parameter in selecting and adjusting a dose and dosage interval along with the resistance profile in the treatment of S. aureus infections. IE to vancomycin observed in the in vivo neutropenic mouse model was more evident for MSSA strains than for MRSA strains.
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KEYWORD
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Staphylococcus aureus , Vancomycin, Inoculum effect, In vivo
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