Public Health Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ, USA.
Manchester Academic Health Science Centre, University of Manchester and University Hospital of South Manchester, Wythenshawe Hospital, Manchester, UK.
Lancet Infect Dis. 2017 Dec;17(12):e383-e392. doi: 10.1016/S1473-3099(17)30316-X. Epub 2017 Jul 31.
All serious fungal infections need appropriate antifungal therapy for successful patient outcome. Only a few classes of antifungal drugs are available, so the emergence of resistance to single drug classes and now multidrug resistance greatly hampers patient management. Azole resistance among Candida and Aspergillus species is one of the greatest challenges to clinical success, followed by echinocandin and multidrug resistance among some Candida species, especially Candida glabrata. The spread of agriculturally derived azole-resistant Aspergillus fumigatus and emerging threats such as multidrug resistant Candida auris are also alarming. The molecular mechanisms that cause drug resistance are naturally occurring in less susceptible species and are acquired in strains of susceptible organisms. Drug resistance mechanisms include altered drug-target interactions, reduced cellular drug concentrations mediated by drug efflux transporters, and permeability barriers associated with biofilms. Although C auris is inherently multidrug resistant, other strains typically develop resistance through stepwise selection of multiple drug-resistance mechanisms. Cellular stress induced by drug treatment promotes adaptation, which contributes to breakthrough resistance. Drug exposure also drives the emergence of resistance. An effective antifungal stewardship programme is essential to control drug resistance, and should incorporate rapid fungal diagnostics, therapeutic drug monitoring, and clinical intervention teams. The development of better diagnostic tools and strategies that allow targeted use of antifungals is essential to preserve drug effectiveness.
所有严重的真菌感染都需要适当的抗真菌治疗才能获得成功的治疗效果。只有少数几类抗真菌药物可用，因此单一药物类别的耐药性的出现，以及现在的多药耐药性，极大地阻碍了患者的治疗管理。念珠菌和曲霉属物种中的唑类耐药性是临床成功的最大挑战之一，其次是棘白菌素类和某些念珠菌物种（尤其是光滑念珠菌）的多药耐药性。农业衍生的唑类耐药性烟曲霉的传播以及多药耐药性耳念珠菌等新出现的威胁也令人震惊。导致耐药性的分子机制在耐药性较低的物种中是自然存在的，并且在敏感生物的菌株中获得。耐药机制包括改变药物靶点相互作用、药物外排转运蛋白介导的细胞内药物浓度降低以及与生物膜相关的通透性屏障。虽然耳念珠菌本身具有多药耐药性，但其他菌株通常通过逐步选择多种耐药机制来产生耐药性。药物治疗引起的细胞应激促进了适应性，这有助于突破耐药性。药物暴露也会导致耐药性的出现。有效的抗真菌管理计划对于控制耐药性至关重要，应包括快速的真菌诊断、治疗药物监测和临床干预团队。开发更好的诊断工具和策略，以允许有针对性地使用抗真菌药物对于保持药物有效性至关重要。
