Fantin B, Leggett J, Ebert S, Craig W A
Medical Service, William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin 53705.
Antimicrob Agents Chemother. 1991 Jul;35(7):1413-22. doi: 10.1128/AAC.35.7.1413.
We studied the relationship between in vitro susceptibility tests (MICs, MBCs) and in vivo activity of tobramycin, pefloxacin, ceftazidime, and imipenem against 15 gram-negative bacilli from five different species in a murine thigh infection model. Complete dose-response curves were determined for each antimicrobial agent against each strain, and three parameters of in vivo activity were defined: maximal attainable antimicrobial effect (i.e., reduction in log10 CFU per thigh compared with untreated controls) at 24 h (Emax), total dose required to reach 50% of maximal effect (P50), and total dose required to achieve a bacteriostatic effect (static dose). Pefloxacin demonstrated the greatest Emax (P less than 0.05). Tobramycin was the most potent antimicrobial agent, as indicated by its having the lowest static dose/MIC ratio (P less than 0.002). Log10 P50s and static doses correlated significantly with log10 MICs or MBCs for the 15 strains of each antibiotic (P less than 0.01) except imipenem (P greater than 0.50). The greater potency of imipenem against the three Pseudomonas aeruginosa strains than against strains of the family Enterobacteriaceae (P less than 0.01) explained this lack of correlation. A longer duration of postantibiotic effect for imipenem against P. aeruginosa (P = 0.02) contributed to its increased potency against these strains. We conclude that in vitro susceptibility tests correlated well with in vivo activity in this animal model and that variations in potency among the four antimicrobial agents could be explained by differences in pharmacokinetics or pharmacodynamic activity.
我们在小鼠大腿感染模型中研究了妥布霉素、培氟沙星、头孢他啶和亚胺培南对来自五个不同菌种的15株革兰氏阴性杆菌的体外药敏试验（MIC、MBC）与体内活性之间的关系。针对每种抗菌药物和每个菌株测定了完整的剂量反应曲线，并定义了体内活性的三个参数：24小时时的最大可达到抗菌效果（即与未治疗对照组相比，每只大腿log10 CFU的减少量）（Emax）、达到最大效果50%所需的总剂量（P50）以及达到抑菌效果所需的总剂量（静态剂量）。培氟沙星显示出最大的Emax（P<0.05）。妥布霉素是最有效的抗菌药物，其静态剂量/MIC比值最低即表明了这一点（P<0.002）。除亚胺培南外（P>0.50），每种抗生素的15个菌株的log10 P50和静态剂量与log10 MIC或MBC显著相关（P<0.01）。亚胺培南对三株铜绿假单胞菌菌株的效力高于对肠杆菌科菌株的效力（P<0.01），这解释了这种缺乏相关性的情况。亚胺培南对铜绿假单胞菌的抗生素后效应持续时间更长（P = 0.02），这导致其对这些菌株的效力增加。我们得出结论，在该动物模型中体外药敏试验与体内活性相关性良好，并且这四种抗菌药物之间效力的差异可以通过药代动力学或药效学活性的差异来解释。
