Limited Ability of Posaconazole To Cure both Acute and Chronic Trypanosoma cruzi Infections Revealed by Highly Sensitive In Vivo Imaging
Limited Ability of Posaconazole To Cure both Acute and Chronic Trypanosoma cruzi Infections Revealed by Highly Sensitive In Vivo Imaging
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DOI：
10.1128/aac.00520-15
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发表时间：
2015-08-01
影响因子：
4.9
通讯作者：
Kelly, John M.
中科院分区：
文献类型：
--
作者：
Francisco, Amanda Fortes;Lewis, Michael D.;Kelly, John M.
抗真菌药物泊沙康唑在体外和实验小鼠模型中显示出对克氏锥虫的显着活性。尽管如此，在最近的一项临床试验中，它显示出有限的治疗潜力。在实验性恰加斯病中，药物测试是有问题的，因为很难证明无菌治疗，特别是在寄生虫负担极低和组织分布不明确的感染慢性阶段。为了更好地评估泊沙康唑对急性和慢性恰加斯病的疗效，我们开发了一种高度敏感的生物发光成像系统，该系统生成的数据比其他方法（包括基于PCR的方法）更准确。接种生物发光T.通过体内和离体成像评估Cruzi，使用环磷酰胺诱导的免疫抑制来增强复发的检测。泊沙康唑在治疗急性和慢性T。克鲁兹感染。而20天的治疗与苄硝唑是100%成功地实现无菌治愈，泊沙康唑失败，在几乎所有的情况下。然而，用泊沙康唑治疗慢性感染确实显著减少了感染引起的脾肿大，即使在没有寄生虫学治愈的情况下。基于成像的筛查系统还显示，脂肪组织是泊沙康唑治疗的小鼠在急性感染阶段复发的主要部位，而不是慢性感染阶段。这种查加斯病的体内筛选模型具有预测性，可重复性和适应性，可适应不同的治疗方案。它应该提供更大的保证，药物不会过早进入临床试验。
The antifungal drug posaconazole has shown significant activity against Trypanosoma cruzi in vitro and in experimental murine models. Despite this, in a recent clinical trial it displayed limited curative potential. Drug testing is problematic in experimental Chagas disease because of difficulties in demonstrating sterile cure, particularly during the chronic stage of infection when parasite burden is extremely low and tissue distribution is ill defined. To better assess posaconazole efficacy against acute and chronic Chagas disease, we have exploited a highly sensitive bioluminescence imaging system which generates data with greater accuracy than other methods, including PCR-based approaches. Mice inoculated with bioluminescent T. cruzi were assessed by in vivo and ex vivo imaging, with cyclophosphamide-induced immunosuppression used to enhance the detection of relapse. Posaconazole was found to be significantly inferior to benznidazole as a treatment for both acute and chronic T. cruzi infections. Whereas 20 days treatment with benznidazole was 100% successful in achieving sterile cure, posaconazole failed in almost all cases. Treatment of chronic infections with posaconazole did however significantly reduce infection-induced splenomegaly, even in the absence of parasitological cure. The imaging-based screening system also revealed that adipose tissue is a major site of recrudescence in mice treated with posaconazole in the acute, but not the chronic stage of infection. This in vivo screening model for Chagas disease is predictive, reproducible and adaptable to diverse treatment schedules. It should provide greater assurance that drugs are not advanced prematurely into clinical trial.