Lamaris Gregory A, Ben-Ami Ronen, Lewis Russell E, Chamilos Georgios, Samonis George, Kontoyiannis Dimitrios P
Department of Infectious Diseases, Infection Control and Employee Health, University of Texas MD Anderson Cancer Center, University of Houston, Houston, TX 77030, USA.
J Infect Dis. 2009 May 1;199(9):1399-406. doi: 10.1086/597615.
Breakthrough zygomycosis is increasingly observed among patients at high risk for fungal infection who are receiving voriconazole, reflecting either selective pressure or voriconazole-associated alterations in Zygomycetes virulence. We tested the latter hypothesis, using 2 phylogenetically disparate zygomycosis models.
Three Zygomycetes strains were exposed to voriconazole by serial passages on voriconazole-containing medium. The virulence of voriconazole-exposed Zygomycetes strains was compared with that of voriconazole-nonexposed strains in Drosophila and murine models of zygomycosis by assessment of survival curves, pulmonary fungal burdens, and expression of inflammation-associated genes.
Among Toll-deficient (Tl(-/-)) and wild-type fruit flies, infection with Zygomycetes isolates that had been exposed to voriconazole yielded significantly lower survival rates than infection with Zygomycetes strains grown in drug-free media. In contrast, exposure of Rhizopus oryzae to itraconazole, amphotericin B, or caspofungin and exposure of Aspergillus fumigatus to voriconazole did not alter the virulence of these isolates in fruit flies. In the murine model, infection with a R. oryzae strain preexposed to voriconazole was associated with decreased survival rates and increased pulmonary fungal burdens, compared with infection with a voriconazole-nonexposed R. oryzae strain. In addition, enhanced angioinvasion, inflammation, and expression of genes involved in stress response and tissue repair were found in mouse lungs infected with voriconazole-exposed R. oryzae.
Exposure of Zygomycetes organisms to voriconazole selectively enhanced their virulence. The mechanisms underlying these phenotypic changes should be studied further.
在接受伏立康唑治疗的真菌感染高危患者中，突破性接合菌病越来越常见，这反映了选择性压力或伏立康唑相关的接合菌毒力改变。我们使用两种系统发育不同的接合菌病模型来检验后一种假设。
通过在含伏立康唑的培养基上连续传代，使三种接合菌菌株接触伏立康唑。通过评估生存曲线、肺部真菌负荷以及炎症相关基因的表达，在果蝇和小鼠接合菌病模型中比较接触伏立康唑的接合菌菌株与未接触伏立康唑的菌株的毒力。
在 Toll 缺陷（Tl(-/-)）和野生型果蝇中，感染接触过伏立康唑的接合菌分离株后的存活率显著低于感染在无药培养基中生长的接合菌菌株后的存活率。相比之下，米根霉接触伊曲康唑、两性霉素 B 或卡泊芬净以及烟曲霉接触伏立康唑并未改变这些分离株在果蝇中的毒力。在小鼠模型中，与感染未接触伏立康唑的米根霉菌株相比，感染预先接触过伏立康唑的米根霉菌株与存活率降低和肺部真菌负荷增加有关。此外，在感染接触过伏立康唑的米根霉的小鼠肺中发现血管侵袭增强、炎症以及参与应激反应和组织修复的基因表达增加。
接合菌生物体接触伏立康唑会选择性增强其毒力。这些表型变化的潜在机制应进一步研究。
