Candida biofilms: antifungal resistance and emerging therapeutic options.
Candida biofilms: antifungal resistance and emerging therapeutic options.
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发表时间：
2004-02
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通讯作者：
D. Kuhn;M. Ghannoum
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作者：
D. Kuhn;M. Ghannoum
血管内导管感染是住院患者发病和死亡的主要原因，占美国每年发生的 20 万例医院血流感染的大部分。在念珠菌培养呈阳性的静脉导管中，40% 实际上代表真菌血症，这通常需要全身治疗和移除导管才能实现治愈。直到最近，需要移除设备的原因尚不清楚。然而，我们的研究小组和其他人已经证明与生物膜相关的念珠菌对抗真菌药物几乎完全耐药。与细菌物种类似，念珠菌生物膜的形成经历早期、中期和成熟阶段。该过程与多糖细胞外基质（ECM）的生成相关。成熟的白色念珠菌生物膜在真菌细胞和 ECM 的分布方面具有异质结构，并表现出广泛的抗菌药物耐药性。人们开始了解造成如此严重的抗真菌耐药性的机制。最近的数据表明，耐药性是阶段特异性的和多因素的，涉及外排泵和甾醇合成（分别在早期和成熟生物膜阶段）。代谢静止和 ECM 似乎都没有显着贡献。药敏试验和共焦扫描激光显微镜证明唑类未能对成熟的念珠菌生物膜发挥活性。然而，伏立康唑的亚抑制浓度会损害生物膜的形成并导致细胞形态畸变。相比之下，脂质制剂两性霉素和棘白菌素表现出独特的针对成熟生物膜的活性。这种能力背后的机制尚不清楚。本综述讨论了其他药理学（例如导管涂层、抗菌肽和抗生素锁）和非药理学方法在预防和治疗装置相关生物膜中的作用。
Intravascular catheter infections are a major cause of morbidity and mortality in hospitalized patients, accounting for the majority of the 200,000 nosocomial bloodstream infections occurring in the US annually. Of the intravenous lines that are culture-positive for Candida, 40% actually represent fungemia, which generally necessitates systemic treatment and line removal to affect cure. Until recently, the reason for the need for device removal was unclear. However, our research group and others have demonstrated a near-total resistance to antifungals by biofilm-associated Candida. Similar to bacterial species, Candida biofilm formation proceeds through early, intermediate and maturation phases. This process is associated with the generation of a polysaccharide extracellular matrix (ECM). Mature C. albicans biofilms have a heterogeneous architecture, in terms of distribution of fungal cells and ECM, and exhibit broad antimicrobial resistance. The mechanisms causing such profound antifungal resistance are beginning to be understood. Recent data indicate that resistance is phase-specific and multifactorial, involving efflux pumps and sterol synthesis (at early and mature biofilm phases, respectively). Neither metabolic quiescence nor the ECM appear to contribute substantially. Susceptibility testing and confocal scanning laser microscopy demonstrated that azoles failed to exert activity against mature Candida biofilms. However, sub-inhibitory concentrations of voriconazole impaired biofilm formation and caused cell morphological aberrations. In contrast, lipid-formulation amphotericins and the echinocandins uniquely exhibited activity against mature biofilms. The mechanisms underlying this ability are unknown. The role of other pharmacological (eg, catheter coatings, antimicrobial peptides and antibiotic locks) and non-pharmacological methods in the prevention and treatment of device-related biofilms is discussed in this review.