Playford E Geoffrey, Webster Angela C, Sorrell Tania C, Craig Jonathan C
Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
J Antimicrob Chemother. 2006 Apr;57(4):628-38. doi: 10.1093/jac/dki491. Epub 2006 Feb 3.
This study aims to systematically identify and summarize the effects of antifungal prophylaxis in non-neutropenic critically ill adult patients on all-cause mortality and the incidence of invasive fungal infections.
Systematic review and meta-analysis of randomized controlled trials in all languages comparing the prophylactic use of any antifungal agent or regimen with placebo, no antifungal or another antifungal agent or regimen in non-neutropenic critically ill adult patients. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2005), MEDLINE (1966 to 2 September 2005) and EMBASE (1980 to week 36, 2005). We also hand-searched reference lists, abstracts of conference proceedings and scientific meetings (1998-2004) and contacted authors of included studies and pharmaceutical manufacturers. The primary outcomes assessed were all-cause mortality and proven invasive fungal infections. Two reviewers independently applied selection criteria, performed quality assessment and extracted data using an intention-to-treat approach. Data were synthesized using the random effects model and expressed as relative risk with 95% confidence intervals.
Twelve unique trials (eight comparing fluconazole and four ketoconazole with no antifungal or a non-absorbable agent) involving 1606 randomized patients were included. For both outcomes of total mortality and invasive fungal infections, almost all trials of fluconazole and ketoconazole separately showed a non-significant risk reduction with prophylaxis. When combined, fluconazole/ketoconazole reduced total mortality by one-quarter (relative risk 0.76, 95% confidence interval 0.59-0.97) and invasive fungal infections by about one-half (relative risk 0.46, 95% confidence interval 0.31-0.68). No significant increase in the incidence of infection or colonization with the azole-resistant fungal pathogens Candida glabrata or Candida krusei was demonstrated, although the confidence intervals of the summary effect measures were wide. Adverse effects requiring treatment discontinuation were not more common amongst patients receiving prophylaxis. Results across all trials were homogeneous despite considerable heterogeneity in clinical and methodological characteristics.
Prophylaxis with fluconazole or ketoconazole in critically ill patients reduces invasive fungal infections by one-half and total mortality by one-quarter. Although no significant increase in azole-resistant Candida species associated with prophylaxis was demonstrated, trials were not powered to exclude such an effect. In patients at increased risk of invasive fungal infections, antifungal prophylaxis with fluconazole should be considered.
本研究旨在系统地识别和总结抗真菌预防措施对非中性粒细胞减少的成年危重症患者全因死亡率和侵袭性真菌感染发生率的影响。
对所有语言的随机对照试验进行系统评价和荟萃分析，比较在非中性粒细胞减少的成年危重症患者中使用任何抗真菌药物或方案进行预防与使用安慰剂、不使用抗真菌药物或使用其他抗真菌药物或方案的效果。我们检索了Cochrane对照试验中心注册库（CENTRAL，Cochrane图书馆，2005年第3期）、MEDLINE（1966年至2005年9月2日）和EMBASE（1980年至2005年第36周）。我们还手工检索了参考文献列表、会议论文摘要和科学会议（1998 - 2004年），并联系了纳入研究的作者和制药厂商。评估的主要结局是全因死亡率和确诊的侵袭性真菌感染。两名评价者独立应用选择标准、进行质量评估并采用意向性分析方法提取数据。数据采用随机效应模型进行合并，并以相对风险及95%置信区间表示。
纳入了12项独特的试验（8项比较氟康唑，4项比较酮康唑与不使用抗真菌药物或非吸收性药物），涉及1606例随机分组的患者。对于总死亡率和侵袭性真菌感染这两个结局，几乎所有单独使用氟康唑和酮康唑的试验均显示预防措施可使风险有非显著性降低。合并分析时，氟康唑/酮康唑使总死亡率降低了四分之一（相对风险0.76，95%置信区间0.59 - 0.97），侵袭性真菌感染降低了约二分之一（相对风险0.46，95%置信区间0.31 - 0.68）。尽管汇总效应量的置信区间较宽，但未显示对唑类耐药真菌病原体光滑念珠菌或克柔念珠菌的感染或定植发生率有显著增加。需要停药治疗的不良反应在接受预防治疗的患者中并不更常见。尽管临床和方法学特征存在相当大的异质性，但所有试验的结果具有同质性。
在危重症患者中使用氟康唑或酮康唑进行预防可使侵袭性真菌感染降低一半，总死亡率降低四分之一。尽管未显示预防措施与唑类耐药念珠菌属的显著增加有关，但这些试验的效能不足以排除这种影响。对于侵袭性真菌感染风险增加的患者，应考虑使用氟康唑进行抗真菌预防。
