Cortegiani Andrea, Russotto Vincenzo, Maggiore Alessandra, Attanasio Massimo, Naro Alessandro R, Raineri Santi Maurizio, Giarratano Antonino
Department of Biopathology and Medical Biotechnologies (DIBIMED), Section of Anaesthesia, Analgesia, Intensive Care and Emergency, University Hospital P. Giaccone, University of Palermo, Via del Vespro 129, Palermo, Italy.
Cochrane Database Syst Rev. 2016 Jan 16;2016(1):CD004920. doi: 10.1002/14651858.CD004920.pub3.
Invasive fungal infections are important causes of morbidity and mortality among critically ill patients. Early institution of antifungal therapy is pivotal for mortality reduction. Starting a targeted antifungal therapy after culture positivity and fungi identification requires a long time. Therefore, alternative strategies (globally defined as 'untargeted antifungal treatments') for antifungal therapy institution in patients without proven microbiological evidence of fungal infections have been discussed by international guidelines. This review was originally published in 2006 and updated in 2016. This updated review provides additional evidence for the clinician dealing with suspicion of fungal infection in critically ill, non-neutropenic patients, taking into account recent findings in this field.
To assess the effects of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) compared to placebo or no antifungal or any other antifungal drug (either systemic or nonabsorbable) in non-neutropenic, critically ill adults and children. We assessed effectiveness in terms of total (all-cause) mortality and incidence of proven invasive fungal infections as primary outcomes.
We searched the following databases to February 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), and EMBASE (OVID). We also searched reference lists of identified studies and major reviews, abstracts of conference proceedings, scientific meetings and clinical trials registries. We contacted experts in the field, study authors and pharmaceutical companies as part of the search strategy.
We included randomized controlled trials (RCTs) (irrespective of language or publication status) comparing the use of untargeted treatment with any antifungal drug (either systemic or nonabsorbable) to placebo, no antifungal, or another antifungal agent in non-neutropenic critically ill participants.
Three authors independently applied selection criteria, extracted data and assessed the risk of bias. We resolved any discrepancies by discussion. We synthesized data using the random-effects model and expressed the results as risk ratios (RR) with 95% confidence intervals. We assessed overall evidence quality using the GRADE approach.
We included 22 studies (total of 2761 participants). Of those 22 studies, 12 were included in the original published review and 10 were newly identified. Eleven trials compared the use of fluconazole to placebo or no antifungal treatment. Three trials compared ketoconazole versus placebo. One trial compared anidulafungin with placebo. One trial compared caspofungin to placebo. Two trials compared micafungin to placebo. One trial compared amphotericin B to placebo. Two trials compared nystatin to placebo and one trial compared the effect of clotrimazole, ketoconazole, nystatin and no treatment. We found two new ongoing studies and four new studies awaiting classification. The RCTs included participants of both genders with wide age range, severity of critical illness and clinical characteristics. Funding sources from pharmaceutical companies were reported in 11 trials and one trial reported funding from a government agency. Most of the studies had an overall unclear risk of bias for key domains of this review (random sequence generation, allocation concealment, incomplete outcome data). Two studies had a high risk of bias for key domains. Regarding the other domains (blinding of participants and personnel, outcome assessment, selective reporting, other bias), most of the studies had a low or unclear risk but four studies had a high risk of bias.There was moderate grade evidence that untargeted antifungal treatment did not significantly reduce or increase total (all-cause) mortality (RR 0.93, 95% CI 0.79 to 1.09, P value = 0.36; participants = 2374; studies = 19). With regard to the outcome of proven invasive fungal infection, there was low grade evidence that untargeted antifungal treatment significantly reduced the risk (RR 0.57, 95% CI 0.39 to 0.83, P value = 0.0001; participants = 2024; studies = 17). The risk of fungal colonization was significantly reduced (RR 0.71, 95% CI 0.52 to 0.97, P value = 0.03; participants = 1030; studies = 12) but the quality of evidence was low. There was no difference in the risk of developing superficial fungal infection (RR 0.69, 95% CI 0.37 to 1.29, P value = 0.24; participants = 662; studies = 5; low grade of evidence) or in adverse events requiring cessation of treatment between the untargeted treatment group and the other group (RR 0.89, 95% CI 0.62 to 1.27, P value = 0.51; participants = 1691; studies = 11; low quality of evidence). The quality of evidence for the outcome of total (all-cause) mortality was moderate due to limitations in study design. The quality of evidence for the outcome of invasive fungal infection, superficial fungal infection, fungal colonization and adverse events requiring cessation of therapy was low due to limitations in study design, non-optimal total population size, risk of publication bias, and heterogeneity across studies.
AUTHORS' CONCLUSIONS: There is moderate quality evidence that the use of untargeted antifungal treatment is not associated with a significant reduction in total (all-cause) mortality among critically ill, non-neutropenic adults and children compared to no antifungal treatment or placebo. The untargeted antifungal treatment may be associated with a reduction of invasive fungal infections but the quality of evidence is low, and both the heterogeneity and risk of publication bias is high.Further high-quality RCTs are needed to improve the strength of the evidence, especially for more recent and less studied drugs (e.g. echinocandins). Future trials should adopt standardized definitions for microbiological outcomes (e.g. invasive fungal infection, colonization) to reduce heterogeneity. Emergence of resistance to antifungal drugs should be considered as outcome in studies investigating the effects of untargeted antifungal treatment to balance risks and benefit.
侵袭性真菌感染是重症患者发病和死亡的重要原因。尽早开始抗真菌治疗对于降低死亡率至关重要。在培养结果呈阳性且鉴定出真菌后开始进行靶向抗真菌治疗需要很长时间。因此，国际指南已讨论了在没有真菌感染的微生物学证据的患者中开始抗真菌治疗的替代策略（全球定义为“非靶向抗真菌治疗”）。本综述最初发表于2006年，并于2016年更新。本次更新后的综述为临床医生处理重症非中性粒细胞减少患者的疑似真菌感染提供了更多证据，同时考虑了该领域的最新研究结果。
评估在非中性粒细胞减少的重症成人和儿童中，与安慰剂、不使用抗真菌药物或任何其他抗真菌药物（全身性或非吸收性）相比，使用任何抗真菌药物（全身性或非吸收性）进行非靶向治疗的效果。我们将总（全因）死亡率和确诊的侵袭性真菌感染发生率作为主要结局来评估有效性。
我们检索了以下数据库至2015年2月：Cochrane对照试验中心注册库（CENTRAL）、MEDLINE（OVID）和EMBASE（OVID）。我们还检索了已识别研究的参考文献列表和主要综述、会议论文摘要、科学会议和临床试验注册库。作为检索策略的一部分，我们联系了该领域的专家、研究作者和制药公司。
我们纳入了随机对照试验（RCT）（无论语言或发表状态如何），这些试验比较了在非中性粒细胞减少的重症参与者中使用任何抗真菌药物（全身性或非吸收性）进行非靶向治疗与安慰剂、不使用抗真菌药物或另一种抗真菌药物的情况。
三位作者独立应用入选标准、提取数据并评估偏倚风险。我们通过讨论解决了任何差异。我们使用随机效应模型合成数据，并将结果表示为具有95%置信区间的风险比（RR）。我们使用GRADE方法评估总体证据质量。
我们纳入了22项研究（共2761名参与者）。在这22项研究中，12项被纳入最初发表的综述，10项是新识别的。11项试验比较了氟康唑与安慰剂或不使用抗真菌治疗的情况。3项试验比较了酮康唑与安慰剂。1项试验比较了阿尼芬净与安慰剂。1项试验比较了卡泊芬净与安慰剂。2项试验比较了米卡芬净与安慰剂。1项试验比较了两性霉素B与安慰剂。2项试验比较了制霉菌素与安慰剂，1项试验比较了克霉唑、酮康唑、制霉菌素和不治疗的效果。我们发现了两项正在进行的新研究和四项等待分类的新研究。RCT纳入了年龄范围广泛、重症程度和临床特征各异的男女参与者。11项试验报告了来自制药公司的资金来源，1项试验报告了来自政府机构的资金。大多数研究在本综述的关键领域（随机序列生成、分配隐藏、不完整的结局数据）总体偏倚风险不明确。两项研究在关键领域存在高偏倚风险。关于其他领域（参与者和人员的盲法、结局评估、选择性报告、其他偏倚），大多数研究的偏倚风险较低或不明确，但四项研究存在高偏倚风险。有中等质量的证据表明，非靶向抗真菌治疗并未显著降低或增加总（全因）死亡率（RR 0.93，95% CI 0.79至1.09，P值 = 0.36；参与者 = 2374；研究 = 19）。关于确诊的侵袭性真菌感染的结局，有低质量的证据表明非靶向抗真菌治疗显著降低了风险（RR 0.57，95% CI 0.39至0.83，P值 = 0.0001；参与者 = 2024；研究 = 17）。真菌定植的风险显著降低（RR 0.71，95% CI 0.52至0.97，P值 = 0.03；参与者 = 1030；研究 = 12），但证据质量较低。在非靶向治疗组和其他组之间，发生浅表真菌感染的风险没有差异（RR 0.69，95% CI 0.37至1.29，P值 =
