Grossman Nina T, Casadevall Arturo
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
Antimicrob Agents Chemother. 2017 Feb 23;61(3). doi: 10.1128/AAC.02108-16. Print 2017 Mar.
is an environmentally ubiquitous fungal pathogen that primarily causes disease in people with compromised immune systems, particularly those with advanced AIDS. There are estimated to be almost 1 million cases per year of cryptococcal meningitis in patients infected with human immunodeficiency virus, leading to over 600,000 annual deaths, with a particular burden in sub-Saharan Africa. Amphotericin B (AMB) and fluconazole (FLC) are key components of cryptococcal meningitis treatment: AMB is used for induction, and FLC is for consolidation, maintenance and, for occasional individuals, prophylaxis. However, the results of standard antifungal susceptibility testing (AFST) for AMB and FLC do not correlate well with therapeutic outcomes and, consequently, no clinical breakpoints have been established. While a number of explanations for this absence of correlation have been proffered, one potential reason that has not been adequately explored is the possibility that the physiological differences between the infection environment and the AFST environment lead to disparate drug susceptibilities. These susceptibility-influencing factors include melanization, which does not occur during AFST, the size of the polysaccharide capsule, which is larger in infecting cells than in those grown under normal laboratory conditions, and the presence of large polyploid "titan cells," which rarely occur under laboratory conditions. Understanding whether and how differentially expresses mechanisms of resistance to AMB and FLC in the AFST environment compared to the environment could enhance our ability to interpret AFST results and possibly lead to the development of more applicable testing methods.
是一种在环境中普遍存在的真菌病原体，主要导致免疫系统受损的人患病，尤其是晚期艾滋病患者。据估计，每年感染人类免疫缺陷病毒的患者中发生近100万例隐球菌性脑膜炎病例，导致每年超过60万人死亡，撒哈拉以南非洲负担尤为沉重。两性霉素B（AMB）和氟康唑（FLC）是隐球菌性脑膜炎治疗的关键组成部分：AMB用于诱导治疗，FLC用于巩固、维持治疗，偶尔也用于预防。然而，AMB和FLC的标准抗真菌药敏试验（AFST）结果与治疗结果相关性不佳，因此尚未确定临床断点。虽然已经提出了许多关于这种缺乏相关性的解释，但一个尚未得到充分探讨的潜在原因是，感染环境与AFST环境之间的生理差异可能导致不同的药物敏感性。这些影响敏感性的因素包括黑色素化（AFST过程中不会发生）、多糖荚膜的大小（感染细胞中的多糖荚膜比正常实验室条件下生长的细胞中的更大）以及大型多倍体“巨细胞”的存在（在实验室条件下很少出现）。了解在AFST环境中与感染环境相比是否以及如何差异表达对AMB和FLC的耐药机制，可能会增强我们解释AFST结果的能力，并可能导致开发更适用的检测方法。
