Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia, USA.
MD Anderson Cancer Center, Michale E. Keeling Center for Comparative Medicine and Research, Bastrop, Texas, USA.
Antimicrob Agents Chemother. 2023 May 17;67(5):e0013223. doi: 10.1128/aac.00132-23. Epub 2023 Apr 11.
Trypanosoma cruzi naturally infects a broad range of mammalian species and frequently results in the pathology that has been most extensively characterized in human Chagas disease. Currently employed treatment regimens fail to achieve parasitological cure of T. cruzi infection in the majority of cases. In this study, we have extended our previous investigations of more effective, higher dose, intermittent administration protocols using the FDA-approved drug benznidazole (BNZ), in experimentally infected mice and in naturally infected dogs and nonhuman primates (NHP). Collectively, these studies demonstrate that twice-weekly administration of BNZ for more than 4 months at doses that are ~2.5-fold that of previously used daily dosing protocols, provided the best chance to obtain parasitological cure. Dosing less frequently or for shorter time periods was less dependable in all species. Prior treatment using an ineffective dosing regimen in NHPs did not prevent the attainment of parasitological cure with an intensified BNZ dosing protocol. Furthermore, parasites isolated after a failed BNZ treatment showed nearly identical susceptibility to BNZ as those obtained prior to treatment, confirming the low risk of induction of drug resistance with BNZ and the ability to adjust the treatment protocol when an initial regimen fails. These results provide guidance for the use of BNZ as an effective treatment for T. cruzi infection and encourage its wider use, minimally in high value dogs and at-risk NHP, but also potentially in humans, until better options are available.
克氏锥虫自然感染范围广泛的哺乳动物物种，并经常导致在人类恰加斯病中得到最广泛描述的病理学。目前使用的治疗方案未能在大多数情况下实现对克氏锥虫感染的寄生虫学治愈。在这项研究中，我们扩展了之前使用 FDA 批准的药物苯硝唑（BNZ）对更有效、更高剂量、间歇性给药方案的研究，在实验感染的小鼠和自然感染的狗和非人灵长类动物（NHP）中进行了研究。这些研究表明，每周两次给药超过 4 个月，剂量是之前每日给药方案的 2.5 倍左右，为获得寄生虫学治愈提供了最好的机会。在所有物种中，频率较低或时间较短的剂量不太可靠。在 NHP 中使用无效剂量方案进行的先前治疗并不能阻止使用强化 BNZ 剂量方案获得寄生虫学治愈。此外，在 BNZ 治疗失败后分离的寄生虫对 BNZ 的敏感性与治疗前获得的寄生虫几乎相同，这证实了 BNZ 诱导耐药性的风险低，并且在初始方案失败时能够调整治疗方案。这些结果为 BNZ 作为克氏锥虫感染的有效治疗方法提供了指导，并鼓励更广泛地使用 BNZ，至少在高价值的狗和高危 NHP 中使用，也可能在人类中使用，直到有更好的选择。
