University of Iowa, Iowa City, United States.
Drug Resist Updat. 2011 Jun;14(3):164-76. doi: 10.1016/j.drup.2011.01.004. Epub 2011 Feb 24.
The CLSI established clinical breakpoints (CBPs) for caspofungin (CSF), micafungin (MCF) and anidulafungin (ANF) versus Candida. The same CBP (susceptible (S): MIC ≤ 2 mcg/ml; non-S: MIC > 2 mcg/ml) was applied to all echinocandins and species. More data now allow reassessment of these CBPs. We examined cases of echinocandin failure where both MICs and fks mutations were assessed; wild type (WT) MICs and epidemiological cutoff values (ECVs) for a large Candida collection; molecular analysis of fks hotspots for Candida with known MICs; and pharmacokinetic and pharmacodynamic (PK/PD) data. We applied these findings to propose new species-specific CBPs for echinocandins and Candida. Of 18 candidiasis cases refractory to echinocandins and with fks mutations, 28% (CSF), 58% (ANF) and 66% (MCF) had MICs in the S category using CBP of ≤ 2 mcg/ml, while 0-8% would be S using CBP of ≤ 0.25 mcg/ml. WT MIC distributions revealed ECV ranges of 0.03-0.25 mcg/ml for all major species except C. parapsilosis (1-4 mcg/ml) and C. guilliermondii (4-16 mcg/ml). Among Candida tested for fks mutations, only 15.7-45.1% of 51 mutants were detected using the CBP for NS of >2 mcg/ml. In contrast, a cutoff of >0.25 mcg/ml for C. albicans, C. tropicalis, C. krusei, and C. dubliniensis detected 85.6% (MCF) to 95.2% (CSF) of 21 mutant strains. Likewise, a cutoff of >0.12 mcg/ml for ANF and CSF and of >0.06 mcg/ml for MCF detected 93% (ANF) to 97% (CSF, MCF) of 30 mutant strains of C. glabrata. These data, combined with PK/PD considerations, support CBPs of ≤ 0.25 mcg/ml (S), 0.5 mcg/ml (I), ≥ 1 (R) for CSF/MCF/ANF and C. albicans, C. tropicalis and C. krusei and ≤ 2 mcg/ml (S), 4 mcg/ml (I), and ≥ 8 mcg/ml (R) for these agents and C. parapsilosis. The CBPs for ANF and CSF and C. glabrata are ≤ 0.12 mcg/ml (S), 0.25 mcg/ml (I), and ≥ 0.5 mcg/ml (R), whereas those for MCF are ≤ 0.06 mcg/ml (S), 0.12 mcg/ml (I), and ≥ 0.25 mcg/ml (R). New, species-specific CBPs for Candida and the echinocandins are more sensitive to detect emerging resistance associated with fks mutations, and better able to predict risk for clinical failure.
CLSI 为卡泊芬净（CSF）、米卡芬净（MCF）和阿尼芬净（ANF）制定了针对念珠菌的临床折点（CBPs）。相同的 CBP（敏感（S）：MIC≤2 mcg/ml；非 S：MIC＞2 mcg/ml）适用于所有棘白菌素和物种。现在有更多的数据可以重新评估这些 CBPs。我们检查了棘白菌素治疗失败的病例，这些病例都评估了 MIC 和 fks 突变；对大量念珠菌进行了野生型（WT）MIC 和流行病学截断值（ECV）评估；对已知 MIC 的念珠菌进行了 fks 热点的分子分析；以及药代动力学和药效学（PK/PD）数据。我们将这些发现应用于提出棘白菌素和念珠菌的新种特异性 CBPs。在对棘白菌素耐药且有 fks 突变的 18 例念珠菌病病例中，28%（CSF）、58%（ANF）和 66%（MCF）的 MIC 处于 S 类别，使用≤2 mcg/ml 的 CBP，而使用≤0.25 mcg/ml 的 CBP 则为 0-8%。WT MIC 分布显示，除了近平滑念珠菌（1-4 mcg/ml）和季也蒙念珠菌（4-16 mcg/ml）外，所有主要念珠菌物种的 ECV 范围为 0.03-0.25 mcg/ml。在检测 fks 突变的念珠菌中，仅 15.7-45.1%的 51 个突变体使用＞2 mcg/ml 的 NS CBP 被检测到。相比之下，＞0.25 mcg/ml 的 cutoff 可检测到 85.6%（MCF）至 95.2%（CSF）的 21 个突变株。同样，＞0.12 mcg/ml 的 cutoff 可检测到 CSF、MCF 和 ANF 中的 93%（ANF）至 97%（CSF、MCF）的 30 株光滑念珠菌突变株。这些数据，结合 PK/PD 考虑因素，支持 CSF/MCF/ANF 和 C. albicans、C. tropicalis 和 C. krusei 的≤0.25 mcg/ml（S）、0.5 mcg/ml（I）、≥1（R）和≤2 mcg/ml（S）、4 mcg/ml（I）、和≥8 mcg/ml（R）的 CBPs。ANF 和 CSF 以及 C. glabrata 的 CBPs 为≤0.12 mcg/ml（S）、0.25 mcg/ml（I）和≥0.5 mcg/ml（R），而 MCF 的 CBPs 为≤0.06 mcg/ml（S）、0.12 mcg/ml（I）和≥0.25 mcg/ml（R）。针对念珠菌和棘白菌素的新种特异性 CBPs 更能检测到与 fks 突变相关的新出现的耐药性，并能更好地预测临床失败的风险。
