Andes D, Craig W A
University of Wisconsin, Madison, Wisconsin, USA.
Antimicrob Agents Chemother. 1998 Sep;42(9):2375-9. doi: 10.1128/AAC.42.9.2375.
The in vivo activities of amoxicillin and amoxicillin-clavulanate against 17 strains of Streptococcus pneumoniae with penicillin MICs of 0.12-8.0 mg/liter were assessed in a cyclophosphamide-induced neutropenic murine thigh infection model. Renal impairment was produced by administration of uranyl nitrate to prolong the amoxicillin half-life in the mice from 21 to 65 min, simulating human pharmacokinetics. Two hours after thigh infection with 10(5) to 10(6) CFU, groups of mice were treated with 7 mg of amoxicillin per kg of body weight alone or combined with clavulanate (ratio, 4:1) every 8 h for 1 and 4 days. There was an excellent correlation between the MIC of amoxicillin (0.03 to 5.6 mg/liter) and (i) the change in log10 CFU/thigh at 24 h and (ii) survival after 4 days of therapy. Organisms for which MICs were 2 mg/liter or less were killed at 1.4 to 4.2 and 1.6 to 4.1 log10 CFU/thigh at 24 h by amoxicillin and amoxicillin-clavulanate, respectively. The four strains for which MICs were >4 mg/liter grew 0.2 to 2.6 and 0.6 to 2. 3 logs at 24 h despite therapy with amoxicillin and amoxicillin-clavulanate, respectively. Infection was uniformly fatal by 72 h in untreated mice. Amoxicillin therapy resulted in no mortality with organisms for which MICs were 1 mg/liter or less, 20 to 40% mortality with organisms for which MICs were 2 mg/liter, and 80 to 100% mortality with organisms for which MICs were 4.0-5.6 mg/liter. Lower and higher doses (0.5, 2, and 20 mg/kg) of amoxicillin were studied against organisms for which MICs were near the breakpoint. These studies demonstrate that a reduction of 1 log10 or greater in CFU/thigh at 24 h is consistently observed when amoxicillin levels exceed the MIC for 25 to 30% of the dosing interval. These studies would support amoxicillin (and amoxicillin-clavulanate) MIC breakpoints of 1 mg/liter for susceptible, 2 mg/liter for intermediate, and 4 mg/liter for resistant strains of S. pneumoniae.
在环磷酰胺诱导的中性粒细胞减少小鼠大腿感染模型中，评估了阿莫西林和阿莫西林 - 克拉维酸盐对17株青霉素MIC为0.12 - 8.0mg/L的肺炎链球菌的体内活性。通过给予硝酸铀酰造成肾功能损害，将小鼠体内阿莫西林的半衰期从21分钟延长至65分钟，以模拟人体药代动力学。用10(5)至10(6)CFU感染大腿两小时后，每组小鼠每8小时接受7mg/kg体重的阿莫西林单独治疗或与克拉维酸盐联合治疗（比例为4:1），持续1天和4天。阿莫西林的MIC（0.03至5.6mg/L）与（i）24小时时大腿中每克CFU的log10变化以及（ii）治疗4天后的生存率之间存在极好的相关性。MIC为2mg/L或更低的菌株在24小时时分别被阿莫西林和阿莫西林 - 克拉维酸盐在大腿中杀死至1.4至4.2和1.6至4.1 log10 CFU/克。MIC>4mg/L的四株菌株尽管分别用阿莫西林和阿莫西林 - 克拉维酸盐治疗，但在24小时时仍生长0.2至2.6和0.6至2.3个对数。未治疗的小鼠在72小时内感染均致死。对于MIC为1mg/L或更低的菌株，阿莫西林治疗无死亡率；对于MIC为2mg/L的菌株，死亡率为20%至40%；对于MIC为4.0 - 5.6mg/L的菌株，死亡率为80%至100%。研究了较低和较高剂量（0.5、2和20mg/kg）的阿莫西林对MIC接近断点的菌株的作用。这些研究表明，当阿莫西林水平在给药间隔的25%至30%超过MIC时，在24小时时大腿中CFU/克持续观察到减少1 log10或更多。这些研究将支持肺炎链球菌敏感菌株的阿莫西林（和阿莫西林 - 克拉维酸盐）MIC断点为1mg/L，中介菌株为2mg/L，耐药菌株为4mg/L。
