侵袭性真菌病来袭,我们该如何应对?
医疗技术的进步使得重症ICU、肿瘤、严重免疫功能低下等患者有了更多的治疗选择,同时也增加了这些患者IFD的发生风险[1];新型免疫抑制剂的应用、靶向治疗时代的发展使缺乏传统危险因素的患者也成为了IFD的高危人群[2-3]。近年来随着高危患者的增多,IFD发病率呈显著上升趋势[4]。此外,IFD的致病菌构成正在不断改变:
①唑类药物大量应用导致念珠菌由白念珠菌的流行转向克柔念珠菌、光滑念珠菌等非白念珠菌的流行[5];
②COVID-19疫情使毛霉菌等罕见真菌被全球广泛关注,且研究发现少见真菌(如毛霉菌、镰刀菌、弯孢菌、赛多孢菌属等)的发病率正不断增加[6-7];
③耐药真菌的出现成为全球性的挑战[8]。面对日益严峻及不断变化的IFD,目前临床常用检测方法均存在一定的局限性,诊断IFD的敏感性和特异性不足;因此,IFD患者预后差,病死率高。
针对当前IFD的挑战,新型诊断技术的探讨、适当的预防或经验治疗策略、有效的辅助管理等是改善预后的重要措施;其中,全面开展抗真菌药物管理计划,提高抗真菌药物的合理应用是关键环节。
多烯类、三唑类、棘白菌素类是目前临床治疗IFD的主要抗真菌药物,但各类药物均存在一定的不足与局限性:
①棘白菌素类药物无法覆盖新型隐球菌、毛霉菌、镰刀菌等少见真菌[9];
②对三唑类和棘白菌素类耐药的念珠菌/曲霉病检出率不断增加[10-12];
③传统多烯类药物存在显著的肾毒性和输液反应,三唑类药物的肝毒性较为常见;
④三唑类药物与CYP450酶间复杂的关系导致其与化疗药、靶向药、免疫抑制剂等多种药物存在显著的药物间相互作用[13]等。
因此,临床处方时应用依据不同药物的药理学特点,同时结合感染特点、患者基础情况,选择适当的抗真菌药物,以提高治疗有效率、降低不良反应发生率。与此同时,上述现有抗真菌药物的局限性也促进了新型抗真菌药物的研发及新型的抗真菌疗法的出现[14]。
参考文献:(可上下滑动查看)
1.Firacative C. Invasive fungal disease in humans: are we aware of the real impact [J]. Mem Inst Oswaldo Cruz . 2020 Oct 9;115:e200430
2.Vehreschild JJ, Koehler P, Lamoth F et al. Future challenges and chances in the diagnosis and management of invasive mould infections in cancer patients[J]. Medical Mycology, 2021, 59, 93–101
3.孙于谦, 黄晓军. 靶向治疗时代血液肿瘤患者侵袭性真菌病诊治的挑战与机遇. 中华内科杂志. 2020;59(10):745-748
4.Webb BJ, Ferraro JP, Rea S et al. Epidemiology and Clinical Features of Invasive Fungal Infection in a US Health Care Network[J]. Open Forum Infect Dis. 2018 Jul 31;5(8):ofy187
5.Nguyen S, Truong JQ and Bruning JB. Targeting Unconventional Pathways in Pursuit of Novel Antifungals[J]. Front Mol Biosci . 2021 Jan 12;7:621366
6.Ghosh A, Sarkar A, Paul P et al. The rise in cases of mucormycosis, candidiasis and aspergillosis amidst COVID19[J]. Fungal Biol Rev. 2021 Sep 17.
7.Salmanton-García J, Koehler P, Kindo A et al. Needles in a haystack: Extremely rare invasive fungal infections reported in FungiScope R —Global Registry for Emerging Fungal Infections[J]. J Infect . 2020 Nov;81(5):802-815
8.McCarty TP and Pappas PG. Antifungal Pipeline[J]. Front Cell Infect Microbiol . 2021 Sep 6;11:732223
9.Nett JE and Andes DR. Antifungal Agents Spectrum of Activity, Pharmacology, and Clinical Indications[J]. Infect Dis Clin North Am. 2016 Mar;30(1):51-83.
10.Perlin DS, Rautemaa-Richardson R and Alastruey-Izquierdo A. The global problem of antifungal resistance: prevalence, mechanisms, and management[J]. Lancet Infect Dis 2017; 17: e383–92
11.Lestrade PPA, Meis JF, Melchers WJG et al. Triazole resistance in Aspergillus fumigatus: recent insights and challenges for patient management[J]. Clin Microbiol Infect. 2019;25(7):799-806
12.Yassin Z, Lotfali E, Khourgami MR et al. Caspofungin resistance in clinical Aspergillus Flavus isolates[J]. Journal of Medical Mycology. 2021;31:101166
13.Nivoix Y, Ledoux MP and Herbrecht R. Antifungal Therapy: New and Evolving Therapies[J]. Semin Respir Crit Care Med . 2020 Feb;41(1):158-174
14.Wei Du, Yiru Gao, Li Liu et al. Striking Back against Fungal Infections: The Utilization of Nanosystems for Antifungal Strategies[J]. Int J Mol Sci. 2021 Sep 18;22(18):10104.