Pfaller M A, Diekema D J, Sheehan D J
Department of Pathology, Medical Microbiology Division, C606 GH, University of Iowa College of Medicine, Iowa City, 52242, USA.
Clin Microbiol Rev. 2006 Apr;19(2):435-47. doi: 10.1128/CMR.19.2.435-447.2006.
Developing interpretive breakpoints for any given organism-drug combination requires integration of the MIC distribution, pharmacokinetic and pharmacodynamic parameters, and the relationship between in vitro activity and outcome from both in vivo and clinical studies. Previously, the Subcommittee for Antifungal Testing of the Clinical and Laboratory Standards Institute (CLSI [formerly National Committee for Clinical Laboratory Standards]) proposed MIC interpretive breakpoints for fluconazole and Candida spp. These breakpoints were considered to be somewhat weak, because the clinical data supporting them came largely from mucosal infections and there were very few infections involving strains with elevated fluconazole MICs. We readdress the issue of fluconazole breakpoints for Candida by using published clinical and microbiologic data to provide further validation of the breakpoints proposed by the CLSI in 1997. We also address interpretive breakpoints for agar disk diffusion testing of fluconazole. The MIC distribution for fluconazole was determined with a collection of 13,338 clinical isolates. The overall MIC at which 90% of the isolates were inhibited was 8 microg/ml: 91% were susceptible (S) at a MIC of <or=8 microg/ml and 3% were resistant (R) (MIC >or= 64 microg/ml). Similar results were obtained for 2,190 isolates from randomized clinical trials. Analysis of available data for 1,295 patient-episode-isolate events (692 represented mucosal infections and 603 represented invasive infections) from 12 published clinical studies demonstrated an overall success rate of 77%, including 85% for those episodes in which the fluconazole MIC was <or=8 microg/ml, 67% for those episodes in which the MIC was 16 to 32 microg/ml, and 42% for those episodes with resistant (MIC >or= 64 microg/ml) isolates. Pharmacodynamic analysis demonstrated a strong relationship between MIC, fluconazole dose, and outcome. A dose/MIC ratio of approximately 25 was supportive of the following susceptibility breakpoints for fluconazole and Candida spp.: S, MIC <or= 8 microg/ml; susceptible-dose dependent (SDD), MIC = 16 to 32 microg/ml; R, MIC >or= 64 microg/ml. The corresponding disk test breakpoints are as follows: S, >or=19 mm; SDD, 15 to 18 mm; R, <or=14 mm.
为任何特定的微生物 - 药物组合制定解释性断点需要整合最低抑菌浓度（MIC）分布、药代动力学和药效学参数，以及体外活性与体内和临床研究结果之间的关系。此前，临床和实验室标准协会（CLSI，前身为国家临床实验室标准委员会）的抗真菌检测小组委员会提出了氟康唑和念珠菌属的MIC解释性断点。这些断点被认为有些薄弱，因为支持它们的临床数据主要来自黏膜感染，涉及氟康唑MIC升高菌株的感染非常少。我们通过使用已发表的临床和微生物学数据重新探讨念珠菌属氟康唑断点问题，以进一步验证CLSI在1997年提出的断点。我们还探讨了氟康唑琼脂纸片扩散试验的解释性断点。用13338株临床分离株的集合确定了氟康唑的MIC分布。90%的分离株被抑制时的总体MIC为8μg/ml：MIC≤8μg/ml时91%为敏感（S），3%为耐药（R）（MIC≥64μg/ml）。从随机临床试验的2190株分离株中获得了类似结果。对12项已发表临床研究中1295例患者 - 感染事件 - 分离株数据（692例代表黏膜感染，603例代表侵袭性感染）的分析表明总体成功率为77%，其中氟康唑MIC≤8μg/ml的感染事件成功率为85%，MIC为16至32μg/ml的感染事件成功率为67%，分离株耐药（MIC≥64μg/ml）的感染事件成功率为42%。药效学分析表明MIC、氟康唑剂量和结果之间存在密切关系。剂量/MIC比值约为25支持以下氟康唑和念珠菌属的敏感性断点：S，MIC≤8μg/ml；剂量依赖性敏感（SDD），MIC = 16至32μg/ml；R，MIC≥64μg/ml。相应的纸片试验断点如下：S，≥19mm；SDD，15至18mm；R，≤14mm。
