Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.
Antifungal tolerance is a subpopulation effect distinct from resistance and is associated with persistent candidemia.
复制标题
DOI：
10.1038/s41467-018-04926-x
复制
发表时间：
2018-06-25
影响因子：
16.6
通讯作者：
Berman J
中科院分区：
文献类型：
--
作者：
Rosenberg A;Ene IV;Bibi M;Zakin S;Segal ES;Ziv N;Dahan AM;Colombo AL;Bennett RJ;Berman J
对高于最低抑菌浓度（MIC）的抗真菌药物浓度的耐受性很少被量化，目前的临床建议建议应被忽略。在这里，我们量化的抗真菌药物耐药性在白色念珠菌分离株的MIC以上的增长的分数，并发现它是从敏感性/耐药性不同。相反，耐受性是由于细胞亚群的缓慢生长，这些亚群比其余群体更有效地克服药物应激，并且与细胞内药物积累呈负相关。许多辅助药物与广泛使用的真菌抑制药物氟康唑联合使用，可降低耐受性而不影响耐药性。因此，在无脊椎动物感染模型中，辅助联合治疗在治疗高耐受性分离株感染方面比氟康唑更有效，并且不影响低耐受性分离株感染。此外，从具有持续性念珠菌血症的免疫功能正常患者中回收的分离株显示出比容易被氟康唑清除的分离株更高的耐受性。因此，耐受性与患者对氟康唑治疗的反应相关，并可能有助于预测患者对氟康唑治疗的反应。作者表明，抗真菌耐受性（定义为真菌病原体生长超过最小抑菌浓度的分数）是由于克服药物应激的细胞亚群生长缓慢，并且高耐受性通常与持续感染有关。
Tolerance to antifungal drug concentrations above the minimal inhibitory concentration (MIC) is rarely quantified, and current clinical recommendations suggest it should be ignored. Here, we quantify antifungal tolerance in Candida albicans isolates as the fraction of growth above the MIC, and find that it is distinct from susceptibility/resistance. Instead, tolerance is due to the slow growth of subpopulations of cells that overcome drug stress more efficiently than the rest of the population, and correlates inversely with intracellular drug accumulation. Many adjuvant drugs used in combination with fluconazole, a widely used fungistatic drug, reduce tolerance without affecting resistance. Accordingly, in an invertebrate infection model, adjuvant combination therapy is more effective than fluconazole in treating infections with highly tolerant isolates and does not affect infections with low tolerance isolates. Furthermore, isolates recovered from immunocompetent patients with persistent candidemia display higher tolerance than isolates readily cleared by fluconazole. Thus, tolerance correlates with, and may help predict, patient responses to fluconazole therapy. The authors show that antifungal tolerance, defined as the fraction of growth of a fungal pathogen above the minimal inhibitory concentration, is due to the slow growth of subpopulations of cells that overcome drug stress, and that high tolerance is often associated with persistent infections.
登录
查看更多内容
影响因子：
4.5
作者：
Diezmann S;Michaut M;Shapiro RS;Bader GD;Cowen LE
通讯作者：
Cowen LE
影响因子：
14.2
作者：
Coenye, T.;De Vos, M.;Nelis, H.
通讯作者：
Nelis, H.
影响因子：
38.9
作者：
Colombo, Arnaldo L.;Guimares, Thais;Sukienik, Teresa;Pasqualotto, Alessandro C.;Andreotti, Ricardo;Queiroz-Telles, Flavio;Nouer, Simone A.;Nucci, Marcio
通讯作者：
Nucci, Marcio
影响因子：
2.8
作者：
Gerstein, Aleeza C.;Rosenberg, Alexander;Berman, Judith
通讯作者：
Berman, Judith
影响因子：
2.9
作者：
Da Matta, Daniel A.;Melo, Analy S.;Colombo, Arnaldo L.
通讯作者：
Colombo, Arnaldo L.