Samir Agrawal：聚焦造血干细胞移植领域内抗真菌药物预防性应用

摘要：由中国医疗保健国际交流促进会血液学分会主办，北京大学人民医院血液病研究所承办的2025北京国际造血干细胞移植学术会议于2025年4月25-26日在北京正式举办。本次会议将“移植的艺术（ART OF TRANSPLANT）”为主题，汇集全球领先的血液学专家，探索

编者按：由中国医疗保健国际交流促进会血液学分会主办，北京大学人民医院血液病研究所承办的2025北京国际造血干细胞移植学术会议于2025年4月25-26日在北京正式举办。本次会议将“移植的艺术（ART OF TRANSPLANT）”为主题，汇集全球领先的血液学专家，探索造血干细胞移植的技术创新和未来趋势，着力破解基础研究向临床应用转化的关键技术瓶颈，为血液系统疾病治疗开辟新维度。《肿瘤瞭望-血液时讯》现场特邀伦敦玛丽女王大学Samir Agrawal教授，系统梳理血液肿瘤患者侵袭性真菌病（IFD）的防治策略，深入剖析预防性用药与精准诊断的协同机制。

《肿瘤瞭望-血液时讯》：基于您在侵袭性真菌病（IFD）预防领域的经验，如何在HSCT患者中平衡抗菌药物耐药风险与预防性抗真菌治疗的必要性？

Samir Agrawal：这实质上是一个需要权衡的临床问题：抗真菌药物预防性应用与耐药性风险管控之间的平衡具有现实重要性。过去十余年的临床研究数据清晰表明，预防性治疗策略已发生显著转变——从最初以氟康唑为代表的单一药物应用，逐步过渡为以唑类抗真菌药物，如泊沙康唑为核心的抗霉菌活性预防方案。

但值得注意的是，多项研究结果显示其临床获益并未完全达到预期，且流行病学特征呈现新变化：曲霉病发病率呈现下降趋势，而包括毛霉目在内的罕见或既往罕见霉菌感染病例有所增加。这种变化使得在感染防控与耐药性控制之间形成新的挑战。

本中心采取的策略是联合应用非广谱抗真菌预防方案与早期诊断体系，这主要基于预防性用药与精准诊断之间存在的固有矛盾——当实施广谱抗霉菌预防时，后续病原学诊断的敏感性必然受到影响。因此我们选择构建以生物标志物监测、胸部影像学评估为核心的早期诊断体系，并以此指导抗真菌药物的靶向治疗。

尽管我们充分认可特定临床场景下经验性治疗的必要性，但始终遵循"先诊断后治疗"的原则，在启动经验性治疗的同时完善病原学检测，待获得明确检测结果后再行治疗方案的系统性评估与调整。

Oncology Frontier-Hematology Frontier：Given your expertise in IFD prevention, how do you balance the risks of antimicrobial resistance with the necessity of prophylactic antifungal therapy in HSCT recipients?

Samir Agrawal：So it's a balance. So the balance between prevention, so antifungal prophylaxis use of drugs versus concerns about resistance is a real one. I think it's clear from clinical studies over the last 10 to 15 years, that we have seen a change in the use of prophylaxis. So we've gone from fluconazole has being used primarily to mould-active prophylaxis with these azole drugs, such as particularly posaconazole. But it the outcomes we've seen from studies is perhaps not quite what we would have expected. And we are seeing a changing epidemiology with apparently less aspergillosis and more rare moulds, or previously rare mould, such as Mucorales. So to my mind, there's a challenge then between trying to prevent increasing resistance. In our center, our approach has been to a combined non-mould active prophylaxis with a diagnostic strategy. Really, the two are not compatible. So if you use mould-active prophylaxis, you have to accept that diagnosis becomes more challenging. We've gone the other way, which is to use early diagnosis using biomarkers, using imaging, particularly of the chest and the base treatment with antifungal drugs. On the results of those studies, I completely accept that empirical treatment is warranted in some patients. And we will do that. But we will still perform the diagnostic studies and then review empirical treatment once we have the results of those studies.

《肿瘤瞭望-血液时讯》：近年来，HSCT 受者感染的流行病学特征有何变化？针对这些新兴或耐药病原体，感染管理的核心原则和治疗方案需要哪些创新？

Samir Agrawal：近10-15年间，侵袭性真菌病流行病学的显著变迁引发了临床关注，抗真菌药物耐药性发生率上升导致治疗难度显著增加已成为不争事实。循证医学数据明确显示，耐药菌株感染患者的临床预后显著劣于敏感菌株感染者。

针对这一严峻挑战，临床决策的核心在于审慎权衡预防性用药策略的利弊：是否实施预防、能否实现有效预防以及所需付出的综合代价。此处的"代价"不仅涵盖耐药性发展的生物学成本，还包括长期用药的经济负担、潜在不良反应风险等综合因素。特别是在造血干细胞移植（HSCT）受者群体中，抗真菌药物与其他治疗药物间的相互作用构成显著临床挑战。

在预防性治疗与诊断导向策略之间的抉择，本质上需基于各医疗机构的实际诊疗路径进行个体化决策。因此，制定普适于所有医疗机构的全球性临床指南既不可行亦不科学。本中心采取的临床路径为：在建立侵袭性霉菌感染，尤其是曲霉病早期诊断体系的基础上，实施非广谱抗真菌预防用药策略，通过生物标志物动态监测及影像学评估实现精准化干预。

Oncology Frontier-Hematology Frontier：In recent years, how have the epidemiological characteristics of infections changed in HSCT recipients? What innovations are needed in core management principles and treatment regimens for these emerging or drug-resistant pathogens?

Samir Agrawal：Certainly, the changing epidemiology in the last 10 to 15 years is of concern, because seeing more antifungal resistance is really very challenging to treat. And the data suggests that if patients have resistant organisms, then outcomes are poorer. How can we address that? So I think , the core aspect of how we manage patients is in many ways, what I've just said is to make a decision around whether we are trying to prevent and can we do that successfully? And at what cost—that's to say, increasing resistance, not to mention other costs such as financial cost of drugs, but also costs in terms of potential side effects. And particularly in the HSCT setting, drug interactions are really a potential major headache. And to balance that , are we trying to diagnose? And that's really a decision that we base on your approach at your center. So it's impossible to come up with global guidelines that they're going to advise you what to do in your center. And our approach, as I've said, is to try and use non-mold-active prophylaxis in the context of diagnostics aimed at early detection of invasive mold infection, specifically aspergillosis.

《肿瘤瞭望-血液时讯》：近年来，随着新型抗感染药物和治疗技术的出现，它们在HSCT 患者感染管理中发挥了怎样的作用？有没有一些具体的研究成果或案例可以分享？

Samir Agrawal：在造血干细胞移植领域，新型抗真菌药物对临床结局的改善效应已得到明确验证。新一代唑类药物的问世具有划时代意义，其兼具抗霉菌活性与口服生物利用度的特性，从根本上改变了侵袭性真菌病的治疗范式。

随机对照研究数据证实，相较于30年前侵袭性真菌病（以曲霉病和侵袭性念珠菌病为代表）近乎无法有效治疗的困境，当前治疗体系已实现革命性突破。然而临床实践中仍面临严峻挑战，包括唑类耐药烟曲霉感染率上升、固有多重耐药的罕见霉菌感染病例增加，以及耳念珠菌等新兴病原体的流行。值得关注的是，尽管存在这些障碍，抗真菌药物研发管线仍展现出令人鼓舞的发展前景。

从临床转化角度，亟须建立新型药物引入的支撑体系。鉴于多数创新药物由中小型制药企业开发，其开展随机对照研究面临特殊挑战——包括研究资金、患者入组及终点设计等复杂问题。若不能及时优化临床试验指导原则，可能导致患者错失应用新型作用机制药物的治疗机会。值得强调的是，当前抗真菌领域正处于关键发展期，若能突破转化医学瓶颈，将这些实验室成果有效转化为临床实践，必将开启精准抗真菌治疗的新纪元。

Oncology Frontier-Hematology Frontier：In recent years, with the emergence of new anti - infectious drugs and therapeutic technologies, what role have they played in the management of infections in HSCT patients? Are there any specific research results or cases to share?

Samir Agrawal：So in terms of how the newer drugs that we have available impacted on HSCT outcomes were clearly in the antifungal arena, the emergence of the newer generation azole drugs with mold activity, bioavailable orally have been practice-changing. The randomized controlled studies in this area have really been transformational, because if we go back 30 years, then invasive fungal disease, particularly at that time aspergillosis, but also invasive candidiasis, were basically nearly impossible to successfully treat. So in that context has been a revolution. However, we still find ourselves faced with now drug-resistant, particularly azole-resistant Aspergillus fumigatus and rare mold infections, some of which are inherently multidrug-resistant, the rise of Candida auris, for example. And so we still have many challenges, but equally the antifungal pipeline is quite promising. I think clinically, we have to see how we can support the introduction of these new drugs, because it's very challenging. These drugs are often made by relatively small pharmaceutical companies that are trying to investigate these drugs in randomized controlled studies, which are extremely challenging. And we may find, if we don't adapt our clinical study rules, that we will miss out, and our patients will miss out on the potential benefits of a significant number of new drugs with novel mechanisms of action. And in that sense, it's actually very exciting.The area is quite exciting if we can get these drugs into clinical practice.