中国抗真菌药物管理专家共识(2024版)
Highlight box
Key recommendations
• The principles of antifungal stewardship (AFS) can be summarized as the 3Rs, namely: the right patient, the right time, and the right use of antifungal drugs.
What was recommended and what is new?
• Eight right use metrics are referred to the international Delphi survey published in J Antimicrob Chemother including four of the drug choice metrics (i.e., appropriate indications, refer to the antimicrobial spectra, follow evidence-based guidelines, and discuss with the appropriate management team), one of the drug dosage metrics (i.e., select appropriate loading and maintenance doses), and all of the drug de-escalation and drug consumption metrics.
• This consensus proposes for the first time a set of AFS metrics suitable for China, two-thirds of which were modified or newly added from the results of the international Delphi survey, including all the right patient metrics, the right time metrics, and all the drug duration metrics in the right use, as well as the remaining four drug choice metrics and three drug dosage metrics.
What is the implication, and what should change now?
• The proposal of these 24 metrics may provide a reference basis for the management and monitoring of invasive fungal disease (IFD) in medical and healthcare institutions, improve the standard of clinical diagnosis and treatment of IFD, promote the rational use of antifungals and improve patient prognosis. Medical and healthcare institutions should select the right patient (via early diagnosis of IFD), at the right treatment time (via stratified diagnosis of IFD), and ensure the right use of antifungal drugs, including choosing the right drug with the right dosage, with appropriate drug duration, drug de-escalation and drug consumption monitoring.
引言
背景
抗真菌药物管理(antifungal stewardship,AFS)是一种旨在改善侵袭性真菌病(invasive fungal disease,IFD)患者抗真菌药物使用质量的干预措施,包括三方面含义:①完善诊断及监测标准,根据准确的评估合理选择恰当的抗真菌药物、给药时间及治疗剂量;②根据患者个体情况、药物的毒副反应等尽可能降低不良事件的发生;③指导医疗保健系统实施整体规划,降低医疗成本。AFS的原则可以概括为3R,即:恰当的患者(right patient,通过IFD的早期诊断,选择恰当的患者)、恰当的时机(right time,通过IFD的分层诊断,选择恰当的治疗时机)、抗真菌药物恰当的使用(right use,包括选择恰当的药物、剂量及疗程,恰当的药物降阶梯和监测药物的消耗,实现抗真菌药物的恰当使用)。研究显示,我国IFD的发病率逐年增高,临床漏诊/误诊率(86.1%)[1]及病死率(52.5%~100%)高,加之抗真菌不合理使用率(44%)[2]、治疗相关不良事件发生率(29.0%)[3]、药物间相互作用发生风险率(88%)[4]均较高,导致该类患者平均住院时间长,重症监护室入住率、再入院率及医疗成本高,救治成功率低,疾病负担沉重[5]。因此,IFD已成为威胁我国乃至全球健康的重大感染性疾病。
理论与知识空白
国家卫生健康委分别于2019年及2022年印发《关于建立全国真菌病监测网的通知》及《遏制微生物耐药国家行动计划(2022—2025年)》,旨在加强真菌病监测网的建设,提高我国规范诊治IFD的能力及抗真菌药物临床应用的管理水平[6,7]。同期世界卫生组织(World Health Organization,WHO)针对IFD发布了全球第一份真菌重点病原体清单(fungal priority pathogens list,FPPL),共列出了19种致病真菌,并根据其年发病率、耐药特点、死亡率、并发症及后遗症等因素,将其分为严重、高度、中度三个优先等级,其中中国常见的新生隐球菌、烟曲霉及白念珠菌均被纳入严重优先等级[8]。该清单强调了加强公共卫生干预措施、规范临床诊治、提高全球真菌感染及病原体耐药的监测能力、研发诊断方法及治疗药物的重要性。此外,COVID-19相关侵袭性真菌病的发病率约12.6%,已成为新型冠状病毒感染的主要并发症之一,这对抗真菌药物管理的复杂性和迫切性提出了新的挑战[9-13]。目前许多国家已尝试探寻AFS方案并制定相关指南,以解决IFD患者管理及诊治中遇到的问题,结果证实AFS的使用及推广可在一定程度上提高临床救治水平[14,15]。由于IFD的易感人群、各类真菌病的发病率、耐药特点及诊治在不同国家及地区存在显著差异,直接参考国外AFS指南并不完全适用于中国国情。因此,制定符合我国国情的AFS专家共识迫在眉睫。
目的
基于目前我国对AFS认识尚浅且存在迫切需求,由钟南山院士和廖万清院士牵头,广州医科大学附属第一医院国家呼吸医学中心、国家呼吸系统疾病临床医学研究中心、肺部真菌病诊治协作组,在参考国外AFS共识指标的基础上,结合中国国情及各领域权威专家的诊治经验,拟定AFS指标列表。随后,邀请国内IFD诊治相关领域的权威专家,应用德尔菲(Delphi)法对拟定的AFS指标进行调研及讨论,最终形成本共识,以期为临床规范诊治、改善患者预后和控制医疗成本提供参考依据。
方法
《共识》制定小组成员
在钟南山院士与廖万清院士的牵头及组织下,共有44名权威专家参与本次问卷的填写(两位院士未参与)。参与本次调研问卷的学科及44名专家数量组成如下:呼吸与危重症医学科(24位)、血液科(7位)、重症医学科(2位)、检验科(3位)、皮肤科(3位)、感染科(2位)及药学部(3位)的权威专家组成。此外,还包含1位统计师,负责统计相关的工作。
指标拟定
本共识基于国外2021年发表的《建立医院抗真菌药物管理的基本指标:一项国际德尔菲法调查结果》[16],参考国家卫建委颁布的《抗菌药物临床应用指导原则(2015年版)》[17]和《抗菌药物临床应用管理评价指标及要求》[18],并结合中国国情及国内权威专家的诊治经验,初步拟定一组AFS指标。将所有指标归纳整理后分为恰当的患者、恰当的时机、抗真菌药物恰当的使用三个方面,其中抗真菌药物恰当的使用又进一步分为:药物选择(drug choice)、药物剂量(drug dosage)、药物降阶梯(drug de-escalation)、疗程(drug duration)和药物消耗(drug consumption)五个层面。
德尔菲法
本共识应用德尔菲法,于2022年9月至2023年2月间,将初步拟定的AFS指标问卷以电子邮件的形式发送给44位专家组成员进行匿名调研[19],该问卷中详细介绍了本共识制定的背景、目的及方法,专家可在意见栏中提出修改意见及新增其他指标。
统计分析方法
采用李克特(Likert)5级评分法对各指标进行评级(1=非常同意、2=同意、3=保持中立或不确定、4=不同意、5=非常不同意)[20]。通过投票同意率统计每项指标的调查结果,同意率定义为选择“非常同意”或“同意”的专家百分比[16]。目前尚无公认的德尔菲法共识比例,其取值范围一般介于51%~80%[21]。本共识将同意率≥80%视为达成共识。
结果
专家组成员调研问卷完成情况
本共识共发出调研问卷44份,收回44份,应答率为100%,专家组总体积极性高。参与问卷调查专家的人口统计学特征详见表1。
Full table
候选指标列表
本共识基于国外AFS指标[16]和中国临床实际情况初步拟定43个指标,经44名专家调研及讨论修正后,保留8个指标(指标3.1.1~3.1.3,3.1.8,3.2.3,3.3.1,3.5.1和3.5.2)、修改后保留3个指标(指标1.2,3.1.5和3.2.4)、新增13个指标,最终获得指标共24个(详见表2)。这一组AFS指标分别为:恰当的患者4个、恰当的时机3个、抗真菌药物恰当的使用17个;其中22个指标的同意率≥80%,达成共识。
Full table
恰当的患者(Right patient)
在纳入本次调研的24个指标中,涉及“恰当的患者”的4个指标均达成共识,但部分专家对其中一些指标提出了不同意见。针对指标1.1,有4位专家(呼吸与危重症医学科,2;血液科,1;皮肤科,1)对应用PCR、mNGS/tNGS、纳米孔测序等技术对真菌核酸进行检测持谨慎态度,原因在于这些技术尚未标准化、缺乏PCR商品化检测试剂盒、NGS和纳米孔测序的价格昂贵且临床价值仍有待验证。针对指标1.2“IFD患者在接受经验性治疗的同时,应完善影像学、病原学、血清学(如G实验、GM实验、念珠菌抗原、隐球菌荚膜多糖抗原等)等检查,结合临床反应综合评估疗效后,再对抗真菌治疗方案进行相应调整”,由于调研时的初拟指标未考虑“治疗效果”的评估,有一位呼吸与危重症医学科的专家选择“不同意”,该专家建议根据患者对经验性治疗后的临床反应进行综合评估,如患者一般情况、临床症状(发热、呼吸困难)及体征是否好转、影像学病灶的吸收情况等指标进行综合判断,因此,我们对该指标进行了相应的完善。针对指标1.3“IFD低危及中危患者经广谱抗生素治疗3~5天无效,并出现持续发热等临床症状,应尽快应完善影像学、病原学、血清学(如G实验、GM实验、念珠菌抗原、隐球菌荚膜多糖抗原等)、组织病理学等检查,同时低危和中危患者可开始诊断驱动治疗”,对于该指标,有1位呼吸与危重症医学科和1位药学部专家不建议纳入低危患者,但未说明具体原因,有2位呼吸与危重症医学科专家建议中、低危患者明确诊断再启动治疗。
恰当的时机(Right time)
本共识中“恰当的时机”3个指标中,指标2.1“IFD高危患者预防性抗真菌治疗可显著获益,建议对高危患者进行预防性抗真菌治疗”未达成共识,10位专家(呼吸与危重症医学科,6;感染科,2;药学部,2)对该指标持“中立或不确定”态度,同意率仅为75.61%。专家认为,初拟指标问卷中IFD高危患者的定义不够明确,不能仅靠单个危险因素决定是否启动预防性抗真菌治疗,应结合患者的免疫状态、临床表现、影像学及血清学结果、感染部位、疾病严重程度等综合判断,此外,应重视结构性肺病及重症病毒性肺炎患者合并或继发IFD的危害,强调此类患者预防性、抢先/诊断驱动抗真菌治疗的临床价值。而关于初始调研指标2.3“侵袭性毛霉病(invasive mucormycosis,IM)为罕见真菌感染,不建议常规进行毛霉病的预防性抗真菌治疗”,有2位呼吸与危重症医学科专家提出:越来越多的研究表明IM并非罕见真菌病,尤其是在血液系统恶性肿瘤患者中;此外,由于IM的病情进展迅速、病死率极高,1位皮肤科专家建议在有比较明确的高危因素下积极明确病原学诊断,必要时可采用广谱抗真菌药物进行预防治疗。目前该指标已针对专家意见进行相应修改及补充。
恰当的药物使用(Right drug)
药物选择
在17个“恰当的使用”指标中,其中8个指标涉及“药物选择”,均达成共识,其中3.1.7 “IFD治疗中如对抗真菌药物不耐受或出现其他药物相关不良反应,建议改用安全性、耐受性更好的抗真菌药物”这一指标的同意率达100%。
针对3.1.4“出现突破性IFD提示预后不佳,抗真菌治疗建议选择耐受性好、广谱、强效的药物”这一指标,有1位药学部专家“不同意”,认为应在明确病原菌后进行目标治疗;其他3位专家(呼吸与危重症医学科,1;感染科,1;药学部,1)则建议应根据临床疾病变化、病原微生物检测结果、明确突破原因,同时兼顾药物的安全性及疗效,综合选择耐受性更好、广谱、强效的抗真菌药物。
对于指标3.1.5“IFD治疗的同时应积极治疗原发疾病,在保证抗真菌治疗效果的情况下,选择与原发病治疗药物相互作用较少的抗真菌药物”,有1位感染科专家选择“保持中立/不确定”,建议根据病情、真菌类型等具体分析,同时有1位药学部专家建议增加“在同等的疗效情况下”这一前提条件。目前该指标已针对专家意见进行相应修改及补充。
药物剂量
4个“药物剂量”指标均达成共识,其中“根据抗真菌药物的药效学/药代动力学(pharmacokinetics/ pharmacodynamics,PK/PD)特点,选择适当的负荷剂量和维持剂量”和“如条件允许,建议进行治疗药物浓度监测(therapeutic drug monitoring ,TDM)指导三唑类抗真菌药物的剂量优化”这2个指标同意率均为100%。
针对“予三唑类药物对IFD高危患者进行预防性抗真菌治疗时,需达到有效的血药浓度,保证其效果,必要时进行TDM,避免出现突破性IFD”这一指标,有2位呼吸与危重症医学科专家选择“保持中立/不确定”,1位药学部专家选择“不同意”。他们认为,在进行经验性或预防性抗真菌治疗时,应重视真菌病原学检测及相关实验室指标的评估,严格控制适应症,避免药物滥用;预防用药与治疗用药不同,疗程与剂量难以掌控;此外,不同基础疾病患者预防用药的选择也存在差异,如侵袭性曲霉病(invasive aspergillosis,IA)风险高的患者不推荐使用氟康唑进行预防。
药物降阶梯
本共识仅涉及1个“药物降阶梯”的指标,即“根据药敏结果和/或临床治疗反应及疗效,从广谱药物降到窄谱药物”,该指标的同意率超过90%,但仍有4位专家(呼吸与危重症医学科,2;皮肤科,1,药学部,1)选择“保持中立/不确定”及“不同意”。他们认为:药敏结果与治疗效果不一定完全一致,如现有治疗方案有效,则无需更换及调整。
药物疗程
与“药物疗程”有关的指标共2个,同意率均超过90%。关于“IFD治疗过程中,应定期复查影像学、血清学指标(如G实验、GM实验、念珠菌抗原、隐球菌荚膜多糖抗原等)和真菌耐药情况,评估抗真菌的疗效,判定疾病转归,适当调整疗程”这一指标,有1位呼吸与危重症医学科的专家提出同时应关注临床症状改善与否,并在判定疾病转归时注意区分复发及再感染。
药物消耗
共有2个指标涉及药物消耗,其中“根据床位使用情况调整的限定日剂量(defined daily dose,DDD)”这一指标同意率仅为73.17%,未达成共识。原因在于IFD复杂多样,不同地区和医院病种、发病率存在差异,且抗真菌治疗需个体化,疗程因人而异,需确保治疗充分、足量、个体化,因此仅凭DDD这一指标评估用药疗程并不合理。“治疗时长(length of therapy,LOT)”这一指标虽已达成共识,但仍有3位呼吸与危重症医学科的专家选择“保持中立/不确定”,2位专家(呼吸与危重症医学科,1;药学部,1)选择“不同意”或“非常不同意”。原因在于,患者的个体免疫状态、感染的真菌类型及临床分型等不同,导致抗真菌治疗的时间存在显著差异,例如人工心瓣膜的隐球菌感染需终身治疗。因此,应遵循个体化原则治疗,且抗真菌药物的疗程大多较长,将LOT作为AFS疗程评估指标欠妥。
讨论
本共识制定小组由来自不同领域的专家组成,其中大部分为呼吸与危重症医学科专家,这是因为在中国,呼吸与危重症医学科专家主要负责治疗肺部感染性疾病,而感染科专家主要负责治疗肝病和结核病。
近年来,多项研究提示规范实施AFS可明显改善IFD的诊疗水平、患者预后及降低医疗成本[27-29]。选择恰当的患者进行相应的抗真菌治疗(如预防性、诊断驱动性、经验性及目标治疗)是规范实施AFS的重要前提。此外,多项研究证实:根据AFS指标进行干预后,不仅可明显提高由经验性或发热驱动治疗转换为基于影像学、微生物学及血清学的诊断驱动治疗患者的比例,而且依据诊断结果进行抗真菌管理的患者比例也随之增加[27,30,31]。与经验性治疗相比较,诊断驱动治疗在选择恰当患者的同时,可显著降低临床治疗成本,且不影响总体生存率[32,33]。本共识中关于“恰当的患者”的4个指标均达成共识。绝大多数的专家建议对疑似IFD的患者,需尽快完善影像学、病原学、血清学(如G实验、GM实验、念珠菌抗原、隐球菌荚膜多糖抗原等)和组织病理学等检查以明确病原学诊断。如条件允许,建议应用PCR、mNGS/tNGS等技术对真菌核酸进行检测以提高诊断率[34,35]。
随着免疫抑制宿主比例及种类的增多,AFS的另一关键措施则是强调在恰当的时机及时启动抗真菌治疗对于改善患者预后至关重要。本共识中与“恰当的抗真菌治疗时机”相关的指标共3个,其中“IFD高危患者预防性抗真菌治疗可显著获益,建议对高危患者进行预防性抗真菌治疗”这一指标未达成共识。中国一项多中心研究根据IFD的独立危险因素将接受化疗的血液系统恶性肿瘤患者分为高危(危险评分>15)、中危(危险评分11~15)和低危(危险评分0~10)三组,结果发现高/中危组患者预防性抗真菌治疗获益,IFD发生率分别从23.3%/6.6%降低至8.4%/2.1%(P=0.007),而低危组患者IFD的发生率并未降低,甚至从0.6%增加至2%(P=0.004)[36]。尽管目前中国和国际相关指南均建议对IA的高危人群(如中性粒细胞持续减少的同种异体造血干细胞移植、重度移植物抗宿主病、接受诱导或再诱导治疗的急性髓性白血病等)进行预防性抗真菌治疗[32,37,38],但本共识中仍有24.39%的专家对此观点“保持中立/不确定”。他们认为,不同指南关于IFD高危患者的定义存在差异,不能仅凭某一危险因素决定是否启动预防性抗真菌治疗,应结合患者的免疫状态、临床表现、影像学及血清学结果、感染部位、疾病严重程度等进行综合判断。与IA相比,IM在临床较为少见,目前尚无循证医学证据支持针对IM进行预防,因此,本共识不建议常规对毛霉进行预防性治疗。
本共识的第三个重要组成部分是抗真菌药物的恰当使用,包括:选择恰当的药物、治疗剂量、疗程、从广谱降阶至窄谱药物的时机、药物消耗等。本共识建议,抗真菌药物的选择需结合患者原发病、肝肾功能及并发症,在综合考量抗真菌药物的适应证、禁忌证、抗菌谱、菌株的耐药情况、耐受性、药物间相互作用、临床疗效、药物剂量调整原则等方面后,确保在同等的疗效情况下,选择药物相互作用较少、兼顾安全性及疗效的抗真菌药物[39-45]。
在抗真菌药物暴露期间发生的任何IFD,包括药物的抗真菌谱未能覆盖的致病真菌感染,均称之为突破性IFD。突破性IFD发生的危险因素众多,主要包括宿主、真菌和医源性三个方面,例如,宿主使用免疫抑制剂、抗真菌药物出现耐药、选用不恰当的抗真菌药物或血药浓度未达标等。值得注意的是,抗真菌药物的吸收、分布、代谢和清除易受到宿主免疫状态、基础疾病、合并用药、耐药真菌的感染或治疗期间获得性感染、抗真菌耐药性等多种因素的影响[46],且突破性IFD普遍预后不佳。因此,本共识推荐选择耐受性更好、广谱、强效的抗真菌药物进行治疗。
TDM是保证疗效的重要手段,既可有效避免过度药物暴露、减少药物相关不良反应,也可避免因剂量不足导致的治疗失败,已证明可以优化IFD的管理,特别是对于具有显著暴露-反应关系和不可预测的PK/PD特征或药物治疗指数狭窄的特定抗真菌药物[47]。因此,本共识推荐在采用三唑类药物对IFD患者进行抗真菌治疗时,采用TDM优化药物剂量,以确保药物迅速达到目标血药浓度,保证其疗效,同时减少抗真菌药物的不良反应,最终达到优化临床疗效并将毒性降至最低的目的[31,48,49]。
LOT目前主要用于评价抗生素治疗的持续时间,但该指标并未结合药物的使用剂量进行综合评价。虽然本文中LOT作为药物消耗指标已达成共识,但由于真菌感染复杂多样,各级医院病种和发病率、不同免疫状态和感染类型的治疗疗程均存在显著差异,因此建议IFD抗真菌治疗应遵循个体化原则,不能将LOT作为AFS消耗评估的唯一指标。DDD是目前国外常用的AFS指标之一,是指某一特定药物用于治疗主要适应证的成人平均日剂量[50,51]。由于DDD值可从药房配药记录中直接获取,在依赖纸质记录的医疗机构中具有一定优势,目前多数研究仅用来记录、监测、比较或评估医疗机构间抗真菌药物使用量的情况[24,31,39,40,48,49,52-57]。然而,IFD患者通常需长期治疗,难以获得完整的院外治疗记录,无法准确评估患者的治疗时长,加之真菌感染的治疗复杂,需根据患者的病情决定疗程,且各级医院IFD的病种和发病率均存在明显差异,DDD值因地区或种族而异。因此,将DDD作为AFS的治疗消耗指标存在明显的局限性。
结论
本共识针对AFS指标进行了全面的文献综述,并采用德尔菲法进行匿名投票,避免了专家之间的相互影响[58]。这是亚洲首个AFS共识,确立了中国AFS的标准。其优势在于受访专家具有广泛代表性和权威性,涉及呼吸与危重症医学、血液学、重症医学、感染病学、药学、皮肤病学和统计学等多个领域;所调研的指标充分考虑了中国临床的实际情况,有22个(22/24,91.7%)达成了共识,涵盖了恰当的患者、恰当的时机和恰当的抗真菌药物使用三个方面。这将为医疗卫生机构干预和监测IFD提供参考和依据,有利于进一步提升临床的诊治水平、促进抗真菌药物的合理使用及改善患者预后。
Acknowledgments
Funding: This work was supported by
Footnote
Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-13/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-13/coif). Nanshan Zhong serves as Editor-in-Chief of Journal of Thoracic Disease. F.Y. reports that this work was supported by the National Natural Science Foundation of China (Nos. 82270007, 82202544), the Natural Science Foundation of Guangdong Province (No. 8227010505) and Horizontal Project (No. 75772451). The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the current work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
References
- Zhu K, Feng H, Xu Y, et al. An analysis of 60 years of autopsy data from Zhejiang university in Hangzhou, China. PLoS One 2014;9:e112500. [Crossref] [PubMed]
- Zeng X, Ye S, Liu M. Investigation of the usage of hospitalized patients using antifungal agents in the respiratory medicine department of a hospital. Chinese Journal of Antibiotics 2017;42:600-3.
- de Souza MC, Santos AG, Reis AM. Adverse Drug Reactions in Patients Receiving Systemic Antifungal Therapy at a High-Complexity Hospital. J Clin Pharmacol 2016;56:1507-15. [Crossref] [PubMed]
- Andes D, Azie N, Yang H, et al. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients. Antimicrob Agents Chemother 2016;60:3398-406. [Crossref] [PubMed]
- Ueno R, Nishimura S, Fujimoto G, et al. Healthcare resource utilization and economic burden of antifungal management in patients with hematologic malignancy in Japan: a retrospective database study. Curr Med Res Opin 2021;37:1121-34. [Crossref] [PubMed]
- General Office of the National Health Commission. Notice on the establishment of a national mycosis surveillance network (2019-05-28) [2023-3-30]. Available online: http://www.nhc.gov.cn/yzygj/s7659/201905/12ee85de594c4a4299927022cfd50dad.shtml
- National Health Commission, Ministry of Education, Ministry of Science and Technology, Ministry of Industry and Information Technology, etc. Notice on the issuance of the National Action Plan for the Containment of Microbial Resistance (2022-2025) (2022-10-28) [2023-3-30]. Available online: http://www.nhc.gov.cn/yzygj/s7659/202210//2875ad7e2b2e46a2a672240ed9ee750f.shtml
- WHO fungal priority pathogens list to guide research, development and public health action. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.
- Shen N, Liu B, He B. Co-infection in Coronavirus disease and progress in antibiotic therapy. Chin J Tuberc Respir Dis 2021;44:4-7. [PubMed]
- Feys S, Almyroudi MP, Braspenning R, et al. A Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (CAPA). J Fungi (Basel) 2021;7:1067. [Crossref] [PubMed]
- Machado M, Valerio M, Álvarez-Uría A, et al. Invasive pulmonary aspergillosis in the COVID-19 era: An expected new entity. Mycoses 2021;64:132-43. [Crossref] [PubMed]
- Chong WH, Neu KP. Incidence, diagnosis and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA): a systematic review. J Hosp Infect 2021;113:115-29. [Crossref] [PubMed]
- Kanj SS, Haddad SF, Meis JF, et al. The battle against fungi: lessons in antifungal stewardship from COVID 19 times. Int J Antimicrob Agents 2023;62:106846. [Crossref] [PubMed]
- Johnson MD, Lewis RE, Dodds Ashley ES, et al. Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium. J Infect Dis 2020;222:S175-98. [Crossref] [PubMed]
- Khanina A, Tio SY, Ananda-Rajah MR, et al. Consensus guidelines for antifungal stewardship, surveillance and infection prevention, 2021. Intern Med J 2021;51:18-36. [Crossref] [PubMed]
- Khanina A, Urbancic KF, Haeusler GM, et al. Establishing essential metrics for antifungal stewardship in hospitals: the results of an international Delphi survey. J Antimicrob Chemother 2021;76:253-62. [Crossref] [PubMed]
- General Office of the National Health and Family Planning Commission, Office of the State Administration of Traditional Chinese Medicine, Drug and Equipment Bureau of the General Logistics Department of the People's Liberation Army. Guiding Principles for Clinical Application of Antibiotics (2015 edition). National Health Office Medical Hair (2015) No. 43. Available online: https://www.hospital-nsmc.com.cn/public_ywgk/2021/negJNrdw.html
- Evaluation indexes and requirements for clinical application management of antibiotics. Available online: https://www.gov.cn/foot/2015-08/27/content_2920793.htm
- Drumm S, Bradley C, Moriarty F. 'More of an art than a science'? The development, design and mechanics of the Delphi Technique. Res Social Adm Pharm 2022;18:2230-6. [Crossref] [PubMed]
- Norman G. Likert scales, levels of measurement and the "laws" of statistics. Adv Health Sci Educ Theory Pract 2010;15:625-32. [Crossref] [PubMed]
- Hasson F, Keeney S, McKenna H. Research guidelines for the Delphi survey technique. J Adv Nurs 2000;32:1008-15. [Crossref] [PubMed]
- Teh BW, Yeoh DK, Haeusler GM, et al. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, 2021. Intern Med J 2021;51:67-88. [Crossref] [PubMed]
- Cornely OA, Hoenigl M, Lass-Flörl C, et al. Defining breakthrough invasive fungal infection-Position paper of the mycoses study group education and research consortium and the European Confederation of Medical Mycology. Mycoses 2019;62:716-29. [Crossref] [PubMed]
- Mondain V, Lieutier F, Hasseine L, et al. A 6-year antifungal stewardship programme in a teaching hospital. Infection 2013;41:621-8. [Crossref] [PubMed]
- Goemaere B, Lagrou K, Spriet I, et al. Systemic antifungal drug use in Belgium-One of the biggest antifungal consumers in Europe. Mycoses 2019;62:542-50. [Crossref] [PubMed]
- Prusakov P, Goff DA, Wozniak PS, et al. A global point prevalence survey of antimicrobial use in neonatal intensive care units: The no-more-antibiotics and resistance (NO-MAS-R) study. EClinicalMedicine 2021;32:100727. [Crossref] [PubMed]
- Markogiannakis A, Korantanis K, Gamaletsou MN, et al. Impact of a non-compulsory antifungal stewardship program on overuse and misuse of antifungal agents in a tertiary care hospital. Int J Antimicrob Agents 2021;57:106255. [Crossref] [PubMed]
- Gamarra F, Nucci M, Nouér SA. Evaluation of a stewardship program of antifungal use at a Brazilian tertiary care hospital. Braz J Infect Dis 2022;26:102333. [Crossref] [PubMed]
- Mularoni A, Adamoli L, Polidori P, et al. How can we optimise antifungal use in a solid organ transplant centre? Local epidemiology and antifungal stewardship implementation: A single-centre study. Mycoses 2020;63:746-54. [Crossref] [PubMed]
- Hare D, Coates C, Kelly M, et al. Antifungal stewardship in critical care: Implementing a diagnostics-driven care pathway in the management of invasive candidiasis. Infect Prev Pract 2020;2:100047. [Crossref] [PubMed]
- Whitney L, Al-Ghusein H, Glass S, et al. Effectiveness of an antifungal stewardship programme at a London teaching hospital 2010-16. J Antimicrob Chemother 2019;74:234-41. [Crossref] [PubMed]
- Chinese Association Hematologists, Chinese Invasive Fungal Infection Working Group. The Chinese guidelines for the diagnosis and treatment of invasive fungal disease in patients with hematological disorders and cancers (the 6th revision). Chin J Intern Med 2020;59:754-63. [PubMed]
- Cordonnier C, Pautas C, Maury S, et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis 2009;48:1042-51. [Crossref] [PubMed]
- White PL, Bretagne S, Caliendo AM, et al. Aspergillus Polymerase Chain Reaction-An Update on Technical Recommendations, Clinical Applications, and Justification for Inclusion in the Second Revision of the EORTC/MSGERC Definitions of Invasive Fungal Disease. Clin Infect Dis 2021;72:S95-S101. [Crossref] [PubMed]
- Editorial Board of Chinese Journal of Infectious Diseases. Clinical practice expert consensus for the application of metagenomic next generation sequencing. Chin J Infect Dis 2020;38:681-9.
- Wang L, Wang Y, Hu J, et al. Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study. Front Med 2019;13:365-77. [Crossref] [PubMed]
- Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1-e60. [Crossref] [PubMed]
- Maertens JA, Girmenia C, Brüggemann RJ, et al. European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia. J Antimicrob Chemother 2018;73:3221-30. [Crossref] [PubMed]
- Apisarnthanarak A, Yatrasert A, Mundy LM, et al. Impact of education and an antifungal stewardship program for candidiasis at a Thai tertiary care center. Infect Control Hosp Epidemiol 2010;31:722-7. [Crossref] [PubMed]
- Lachenmayr SJ, Strobach D, Berking S, et al. Improving quality of antifungal use through antifungal stewardship interventions. Infection 2019;47:603-10. [Crossref] [PubMed]
- de Souza MC, Dos Santos AG, Reis AM. Drug utilization study of systemic antifungal agents in a Brazilian tertiary care hospital. Int J Clin Pharm 2016;38:1398-406. [Crossref] [PubMed]
- Lachenmayr SJ, Berking S, Horns H, et al. Antifungal treatment in haematological and oncological patients: Need for quality assessment in routine care. Mycoses 2018;61:464-71. [Crossref] [PubMed]
- Dong WH, Zhang GZ, Li JX, et al. Development of indicators for evaluating the appropriate use of triazoles for invasive fungal disease: A Delphi panel survey. J Clin Pharm Ther 2017;42:720-32. [Crossref] [PubMed]
- Kara E, Metan G, Bayraktar-Ekincioglu A, et al. Implementation of Pharmacist-Driven Antifungal Stewardship Program in a Tertiary Care Hospital. Antimicrob Agents Chemother 2021;65:e0062921. [Crossref] [PubMed]
- Valladales-Restrepo LF, Ospina-Cano JA, Aristizábal-Carmona BS, et al. Study of Prescription-Indication of Outpatient Systemic Anti-Fungals in a Colombian Population. A Cross-Sectional Study. Antibiotics (Basel) 2022;11:1805. [Crossref] [PubMed]
- Lewis RE, Andes DR. Managing uncertainty in antifungal dosing: antibiograms, therapeutic drug monitoring and drug-drug interactions. Curr Opin Infect Dis 2021;34:288-96. [Crossref] [PubMed]
- John J, Loo A, Mazur S, et al. Therapeutic drug monitoring of systemic antifungal agents: a pragmatic approach for adult and pediatric patients. Expert Opin Drug Metab Toxicol 2019;15:881-95. [Crossref] [PubMed]
- Ananda-Rajah MR, Slavin MA, Thursky KT. The case for antifungal stewardship. Curr Opin Infect Dis 2012;25:107-15. [Crossref] [PubMed]
- Nwankwo L, Periselneris J, Cheong J, et al. A Prospective Real-World Study of the Impact of an Antifungal Stewardship Program in a Tertiary Respiratory-Medicine Setting. Antimicrob Agents Chemother 2018;62:e00402-18. [Crossref] [PubMed]
- Muñoz P, Bouza E. The current treatment landscape: the need for antifungal stewardship programmes. J Antimicrob Chemother 2016;71:ii5-ii12. [Crossref] [PubMed]
- Bienvenu AL, Argaud L, Aubrun F, et al. A systematic review of interventions and performance measures for antifungal stewardship programmes. J Antimicrob Chemother 2018;73:297-305. [Crossref] [PubMed]
- Valerio M, Muñoz P, Rodríguez CG, et al. Antifungal stewardship in a tertiary-care institution: a bedside intervention. Clin Microbiol Infect 2015;21:492.e1-9. [Crossref] [PubMed]
- Menichetti F, Bertolino G, Sozio E, et al. Impact of infectious diseases consultation as a part of an antifungal stewardship programme on candidemia outcome in an Italian tertiary-care, University hospital. J Chemother 2018;30:304-9. [Crossref] [PubMed]
- Rodríguez-Campos E, Guisado-Gil AB, Peñalva G, et al. Application of new indicators to assess the quality of antimicrobial use in intensive care units. Int J Antimicrob Agents 2023;62:106865. [Crossref] [PubMed]
- Rahme D, Ayoub M, Shaito K, et al. First trend analysis of antifungals consumption in Lebanon using the World Health Organization collaborating center for drug statistics methodology. BMC Infect Dis 2022;22:882. [Crossref] [PubMed]
- Grau S, Hernández S, Echeverría-Esnal D, et al. Antimicrobial Consumption among 66 Acute Care Hospitals in Catalonia: Impact of the COVID-19 Pandemic. Antibiotics (Basel) 2021;10:943. [Crossref] [PubMed]
- Morii D, Ichinose N, Yokozawa T, et al. Impact of an infectious disease specialist on antifungal use: an interrupted time-series analysis in a tertiary hospital in Tokyo. J Hosp Infect 2018;99:133-8. [Crossref] [PubMed]
- Sinha IP, Smyth RL, Williamson PR. Using the Delphi technique to determine which outcomes to measure in clinical trials: recommendations for the future based on a systematic review of existing studies. PLoS Med 2011;8:e1000393. [Crossref] [PubMed]