Extending the utility and durability of antifungal agents via innovative treatment regimens that minimise drug resistance

一种叫做念珠菌的真菌生活在人体内，有时会导致致命的感染，通常发生在遭受身体创伤或免疫力减弱的患者身上。当检测到念珠菌感染血液或其他通常无菌的身体部位（侵袭性念珠菌病）时，使用抗真菌药物进行快速治疗可能是挽救生命的措施。不幸的是，有效的药物数量有限，而且念珠菌对它们的耐药性越来越强。世界卫生组织（World Health organization）最近强调，这一困境是一场日益令人担忧的公共卫生危机。侵袭性念珠菌病是英国最常见的侵袭性真菌感染，估计每年有5000例。重症监护病房的危重病人尤其脆弱，估计所有感染中有30-40%发生在这一环境中。不幸的是，即使使用抗真菌药物，高达50%的患者将无法存活。治疗选择有限，只有四种抗真菌药物可用；唑类;echinocandins;多基因;核苷类似物。保持这些药物的有效性对于确保我们将来有可行的治疗方案来管理侵袭性念珠菌病至关重要。这是本研究的首要目标。有几种方法可以用来保持现有抗真菌药物的有效性。一是改变它们的使用方式，最好是减少使用频率或减少达到效果所需的药物量。另一种是结合不同的药物类别（称为联合治疗）。抗真菌药物使用的最佳修改将保持抗真菌活性，但降低耐药性的出现率。为了实现这一目标，我们需要彻底了解抗真菌耐药性（AFR）是如何发展的。AFR可以定义为真菌细胞在高浓度抗真菌药物存在下生长的能力。这种行为可以很容易地在实验室中研究，因为真菌细胞可以快速生长（一夜之间），我们有很多方法来观察它们对抗真菌药物的反应，比如显微镜和生长试验。在这项工作计划中，我们将连接利物浦、伦敦和埃克塞特的三个世界级研究中心，以发现新的药物和药物组合，防止真菌生长，并限制AFR。第一步将是在各种抗真菌药物和药物组合（包括即将上市的新型抗真菌药物）存在的情况下，测量五种不同念珠菌的生长情况。然后，最有效的药物治疗将在侵袭性念珠菌病的小鼠模型中进行研究。通过了解念珠菌在实验室环境、小鼠和危重患者中适应真菌药物的方式，我们可以开发新的测试，在感染期间早期识别AFR。作为一个由科学家和临床医生组成的团队，我们可以分享重要的知识，并根据当前的实践，开发更好的AFR测试。反过来，这将有助于临床医生在治疗期间发现AFR，并修改患者的治疗以获得更好的结果。

A type of fungus called Candida, that lives on and in the human body, can sometimes cause fatal infections in humans, usually in patients who have suffered from a physical trauma or have weakened immunity. When a Candida infection of the bloodstream or other normally sterile body site (invasive candidiasis) is detected, rapid treatment with antifungal drugs can be a lifesaving measure. Unfortunately, there are a limited number of effective drugs, and Candida species are becoming more resistant to them. This dilemma has recently been highlighted by the World Health Organisation as a public health crisis of growing concern.Invasive candidiasis is the most common invasive fungal infection in the UK, with an estimated 5,000 cases each year. Critically ill patients in intensive care units are particularly vulnerable, with an estimated 30-40% of all infections occurring in this setting. Unfortunately, even with the use of antifungal drugs, up to 50% of patients will not survive. Treatment options are limited with just four antifungal drug classes available; azoles; echinocandins; polyenes; nucleoside analogues. Preserving the effectiveness of these drugs is vital for ensuring we have viable treatment options to manage invasive candidiasis in the future. This is the overarching aim of this study.There are several approaches that can be used to preserve the effectiveness of available antifungal drugs. One is to change the way in which they are used, preferably by reducing the frequency of use or the amount of drug needed to achieve an effect. Another is to combine different drug classes (called combination therapy). The best modifications of antifungal use will maintain antifungal activity but reduce the rate of emergence of drug resistance. To achieve this, we need a thorough understanding of how antifungal resistance (AFR) develops. AFR can be defined as the ability of fungal cells to grow in the presence of high concentrations of antifungal drug. This behaviour can be readily studied in the lab since fungal cells can be grown very quickly (overnight) and we have many methods for observing their responses to antifungal drugs, such as microscopy and growth tests.In this programme of work, we will connect three world class research centres in Liverpool, London and Exeter to discover new drugs and drug combinations that prevent fungal growth, and limit AFR. The first step will be to measure the growth of five different Candida species in the presence of various antifungal drugs and drug combinations, including new antifungal drugs that will soon come to market. The most effective drug treatments will then be progressed to study their effectiveness in a mouse model of invasive candidiasis. By learning about the way that Candida species adapt to fungal drugs in the laboratory setting, in mice and in critically ill patients, we can develop new tests to recognise AFR early when this happens during an infection. By working as a team of scientists and clinicians we can share important knowledge and, informed by current practices, develop better tests for AFR. In turn this will help clinicians to detect AFR as it emerges during treatment, and to modify patients' treatment for a better outcome.