Alexander B D, Perfect J R
Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina, USA.
Drugs. 1997 Nov;54(5):657-78. doi: 10.2165/00003495-199754050-00002.
Medical advances have led to increased numbers of immunocompromised patients living longer. Coinciding with this increase in the immunocompromised patient population is an increase in the number of clinically significant fungal infections. Unfortunately, widespread use of the limited numbers of antifungal agents to treat these infections has led to the development of drug resistance. Thus, in an attempt to sort out the mechanisms of resistance for each of the systemically useful antifungal agents, a comprehensive review of the literature has been carried out. The most common mechanisms for the development of resistance involve changes in the enzymatic pathways which serve as the drug targets. For instance, changes in enzymes responsible for the biosynthesis of ergosterol, the target of azole activity, lead to azole resistance. Another common mechanism used by fungi to avoid drug toxicity includes reduced intracellular accumulation of the drug through both decreased permeability and energy-dependent efflux pumps. Using our current understanding of the mechanisms of drug resistance as a template, several strategies to overcome resistance have been identified. These include improvement of host immune function, the use of adjuvant surgery, the development of new drug delivery systems for currently available drugs and the development of new classes of antifungal agents. Also, clinical trials to establish appropriate drug doses and duration of therapy are needed, as well as the benefits of antifungal prophylaxis explored and the use of combination therapies entertained. The war against drug resistant fungi has been identified as we approach the year 2000. With careful and cogent investigations, we do have the tools to fight back against these opportunists. Of all the strategies reviewed, however, in our opinion, the development of new antifungal drugs is likely to have the most significant future impact on our management of drug resistance in fungal infections.
医学进步使免疫功能低下的患者数量增加且寿命延长。与此同时，免疫功能低下患者群体数量的增加伴随着具有临床意义的真菌感染数量的上升。不幸的是，用于治疗这些感染的有限数量抗真菌药物的广泛使用导致了耐药性的产生。因此，为了梳理出每种全身性有效抗真菌药物的耐药机制，我们对文献进行了全面综述。耐药性产生的最常见机制涉及作为药物靶点的酶促途径的变化。例如，负责麦角固醇生物合成的酶发生变化，而麦角固醇是唑类药物的作用靶点，这会导致对唑类药物产生耐药性。真菌用于避免药物毒性的另一种常见机制包括通过降低通透性和能量依赖性外排泵减少药物在细胞内的积累。以我们目前对抗耐药机制的理解为模板，已确定了几种克服耐药性的策略。这些策略包括改善宿主免疫功能、采用辅助手术、开发针对现有药物的新给药系统以及开发新型抗真菌药物。此外，还需要进行临床试验以确定合适的药物剂量和治疗持续时间，探索抗真菌预防的益处并考虑联合治疗的使用。随着我们迈向2000年，与耐药真菌的斗争已经打响。通过认真且有说服力的研究，我们确实拥有反击这些机会致病菌的工具。然而，在所有综述的策略中，我们认为，开发新型抗真菌药物可能会对我们管理真菌感染中的耐药性产生最重大的未来影响。
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