Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA
Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, New Jersey, USA.
Antimicrob Agents Chemother. 2017 Nov 22;61(12). doi: 10.1128/AAC.01412-17. Print 2017 Dec.
species are a part of the human microbiome and can cause systemic infection upon immune suppression. infections are increasing and have greater rates of antifungal resistance than other species. Here, we present a gastrointestinal (GI) colonization model to explore whether colonized yeast exposed to caspofungin, an echinocandin antifungal, develop characteristic resistance mutations and, upon immunosuppression, breakthrough causing systemic infection. Daily therapeutic dosing (5 mg/kg of body weight) of caspofungin resulted in no reduction in fecal burdens, organ breakthrough rates similar to control groups, and resistance rates (0 to 10%) similar to those reported clinically. Treatment with 20 mg/kg caspofungin initially reduced burdens, but a rebound following 5 to 9 days of treatment was accompanied by high levels of resistance (/ mutants). Although breakthrough rates decreased in this group, the same mutants were recovered from organs. In an attempt to negate drug tolerance that is critical for resistance development, we cotreated mice with daily caspofungin and the chitin synthase inhibitor nikkomycin Z. The largest reduction (3 log) in GI burdens was obtained within 3 to 5 days of 20 mg/kg caspofungin plus nikkomycin treatment. Yet, echinocandin resistance, characterized by a novel Fks1-L630R substitution, was identified following 5 to 7 days of treatment. Therapeutic caspofungin plus nikkomycin treatment left GI burdens unchanged but significantly reduced organ breakthrough rates (20%; < 0.05). Single-dose pharmacokinetics demonstrated low levels of drug penetration into the GI lumen posttreatment with caspofungin. Overall, we show that echinocandin resistance can arise within the GI tract and that resistant mutants can readily disseminate upon immunosuppression.
物种是人类微生物组的一部分，在免疫抑制时会引起全身感染。真菌感染正在增加，并且比其他物种具有更高的抗真菌耐药率。在这里，我们提出了一种胃肠道（GI）定植模型，以探索暴露于棘白菌素类抗真菌药卡泊芬净的定植酵母是否会产生特征性耐药突变，并且在免疫抑制时突破定植引发全身感染。每日治疗剂量（5mg/kg 体重）的卡泊芬净并未降低粪便负荷，器官突破率与对照组相似，耐药率（0 至 10%）与临床报告相似。用 20mg/kg 的卡泊芬净治疗最初降低了负荷，但在治疗 5 至 9 天后出现反弹，同时伴有高水平的耐药性（/突变体）。尽管该组的突破率下降，但相同的突变体从器官中恢复。为了消除对耐药性发展至关重要的药物耐受性，我们用卡泊芬净和几丁质合成抑制剂 nikkomycin Z 对小鼠进行了联合治疗。在 20mg/kg 卡泊芬净加 nikkomycin 治疗的 3 至 5 天内，GI 负荷最大减少（3 对数）。然而，在治疗 5 至 7 天后，发现了棘白菌素类耐药性，其特征是新型 Fks1-L630R 取代。用卡泊芬净加 nikkomycin 进行治疗性治疗后，GI 负荷保持不变，但显著降低了器官突破率（20%；<0.05）。单次剂量药代动力学显示，卡泊芬净治疗后药物在胃肠道腔中的渗透水平较低。总体而言，我们表明棘白菌素类耐药性可以在胃肠道内产生，并且耐药突变体在免疫抑制时很容易传播。
