Echinocandin Resistance in Candida Species: Mechanisms of Reduced Susceptibility and Therapeutic Approaches
Echinocandin Resistance in Candida Species: Mechanisms of Reduced Susceptibility and Therapeutic Approaches
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DOI：
10.1345/aph.1r020
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发表时间：
2012-07-01
影响因子：
2.9
通讯作者：
Garey, Kevin W.
中科院分区：
文献类型：
--
作者：
Beyda, Nicholas D.;Lewis, Russell E.;Garey, Kevin W.
目的：总结已发表的关于念珠菌属棘白菌素敏感性降低机制的数据，棘白菌素抗性对念珠菌属分离株的适应性和毒力的影响，以及当前和未来的治疗方法.数据来源：检索MEDLINE数据库（1966- 2011年9月）.研究选择和数据提取：使用术语棘白菌素、抗性和念珠菌属检索数据库。资料综合：棘白菌素类化合物在体外对大多数念珠菌有抑制作用。并且是治疗念珠菌血症的一线药物。然而，已经发表了描述由于耐药分离株导致棘白菌素治疗失败的病例报告。棘白菌素敏感性的降低已显示通过3种主要机制发生：（1）适应性应激反应，其在超最小抑制浓度（MIC）下导致细胞壁几丁质含量升高和体外反常生长;（2）获得性FKS突变，其赋予葡聚糖合酶敏感性降低、MIC升高，并与临床失败相关;和（3）固有的FKS突变，其是C. parapsilosis和C. Guilliermondii突变，其与获得性FKS突变相比赋予升高的MIC水平但降低的葡聚糖合酶敏感性的较低水平。一些FKS突变体已被证明与野生型分离株相比具有显著降低的适应性和毒力，并且可能导致在大型监测研究中报告的棘白菌素抗性的低发生率。评价FKS突变体的治疗策略包括棘白菌素剂量递增和与钙调磷酸酶抑制剂、HSP 90抑制剂和几丁质合成酶抑制剂等药物联合治疗。低，它可以提出一个重大的治疗挑战，特别是在多重耐药念珠菌分离株。剂量递增不太可能有效治疗FKS突变分离株，并且显著的不良反应限制了评价为联合治疗的药物的临床使用。棘白菌素治疗无效的感染患者应接受药敏测试，并在可能的情况下使用替代抗真菌剂进行治疗。
OBJECTIVE: To summarize published data regarding mechanisms of reduced echinocandin susceptibility in Candida spp., the impact of echinocandin resistance on the fitness and virulence of Candida isolates, and current and future treatment approaches.DATA SOURCES: A search of MEDLINE databases (1966-September 2011) was conducted.STUDY SELECTION AND DATA EXTRACTION: Databases were searched using the terms echinocandin, resistance, and Candida. Citations from publications were reviewed for additional references.DATA SYNTHESIS: Echinocandins have in vitro activity against most Candida spp. and are first-line agents in the treatment of candidemia. However, case reports describing echinocandin treatment failure due to resistant isolates have been published. Reduced echinocandin susceptibility has been shown to occur via 3 main mechanisms: (1) adaptive stress responses, which result in elevated cell wall chitin content and paradoxical growth in vitro at supra minimum inhibitory concentrations (MICs); (2) acquired FKS mutations, which confer reduced glucan synthase sensitivity, elevated MICs, and are associated with clinical failure; and (3) intrinsic FKS mutations, which are naturally occurring mutations in C. parapsilosis and C. guilliermondii, which confer elevated MIC levels but a lower level of reduced glucan synthase sensitivity compared with acquired FKS mutations. Some FKS mutants have been shown to have significantly reduced fitness and virulence versus wild type isolates and may contribute to the low incidence of echinocandin resistance reported in large surveillance studies. Treatment strategies evaluated for FKS mutants include echinocandin dose escalation and combination with agents such as calcineurin inhibitors, HSP90 inhibitors, and chitin synthase inhibitors.CONCLUSIONS: While the incidence of echinocandin resistance in Candida spp. is low, it can present a significant therapeutic challenge, especially in multidrug-resistant Candida isolates. Dose escalation is unlikely to be effective in treating FKS mutant isolates, and significant adverse effects limit the clinical use of agents evaluated as combination therapy. Patients with infections failing to respond to echinocandin therapy should undergo susceptibility testing and be treated with an alternative antifungal agent if possible.