Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999-2015
Changes in In Vitro Susceptibility Patterns of Aspergillus to Triazoles and Correlation With Aspergillosis Outcome in a Tertiary Care Cancer Center, 1999-2015
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DOI：
10.1093/cid/cix297
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发表时间：
2017-07-15
影响因子：
11.8
通讯作者：
Kontoyiannis, Dimitrios P.
中科院分区：
文献类型：
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作者：
Heo, Sang Taek;Tatara, Alexander M.;Kontoyiannis, Dimitrios P.
背景资料。在血液系统恶性肿瘤或造血干细胞移植(HSCT)的高危患者中，氮唑耐药曲霉病是一个值得关注的问题。我们在MD Anderson癌症中心检测了1999-2002年(引入曲霉菌强效三唑类药物伏立康唑和泊沙康唑之前)和2003-2015年间从呼吸道来源分离的290株曲霉菌的三氮唑最小抑菌浓度(MIC)随时间的变化。我们还检测了从这两个时期分离的37株具有非野生型(WT)MIC的烟曲霉的麦角固醇生物合成基因(cyp51a、erg3C、erg1)的多态性。对于107例血液癌和/或HSCT合并侵袭性肺曲霉菌病的患者，我们在体外的易感性与42天的死亡率相关。37株(13%)未检出非WT的MIC值，且均为低水平(MIC值为8 mg/L)。高三氮唑的MIC在第二个时期更常见，而且是曲霉属特有的，只在烟曲霉中出现。未检测到cyp51a、erg3C、erg1基因的多态性。体外最低抑菌浓度与侵袭性肺曲霉菌病患者42天死亡率之间没有相关性，与抗真菌治疗无关。亚洲种族(优势比(OR)2 0.9；95%可信区间[CI]2.5~173.5；P=.0.0 5)和前3个月的唑类暴露(OR 9.6；95%CI，1.9~4 8.5；P=.0.0 6)与唑类耐药有关。曲霉菌中非WT的唑类最低抑菌浓度正在增加，这与血液病或造血干细胞移植患者既往的唑类暴露有关。然而，在我们的患者队列中，没有发现MIC与曲霉病的预后相关。
Background. Azole-resistant aspergillosis in high-risk patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) is a cause of concern.Methods. We examined changes over time in triazole minimum inhibitory concentrations (MICs) of 290 sequential Aspergillus isolates recovered from respiratory sources during 1999-2002 (before introduction of the Aspergillus-potent triazoles voriconazole and posaconazole) and 2003-2015 at MD Anderson Cancer Center. We also tested for polymorphisms in ergosterol biosynthetic genes (cyp51A, erg3C, erg1) in the 37 Aspergillus fumigatus isolates isolated from both periods that had non-wild-type (WT) MICs. For the 107 patients with hematologic cancer and/or HSCT with invasive pulmonary aspergillosis, we correlated in vitro susceptibility with 42-day mortality.Results. Non-WT MICs were found in 37 (13%) isolates and was only low level (MIC < 8 mg/L) in all isolates. Higher-triazole MICs were more frequent in the second period and were Aspergillus-species specific, and only encountered in A. fumigatus. No polymorphisms in cyp51A, erg3C, erg1 genes were identified. There was no correlation between in vitro MICs with 42-day mortality in patients with invasive pulmonary aspergillosis, irrespective of antifungal treatment. Asian race (odds ratio [OR], 20.9; 95% confidence interval [CI], 2.5-173.5; P=.005) and azole exposure in the prior 3 months (OR, 9.6; 95% CI, 1.9-48.5; P=.006) were associated with azole resistance.Conclusions. Non-WT azole MICs in Aspergillus are increasing and this is associated with prior azole exposure in patients with hematologic cancer or HSCT. However, no correlation of MIC with outcome of aspergillosis was found in our patient cohort.