Sanati H, Ramos C F, Bayer A S, Ghannoum M A
Department of Internal Medicine, Harbor-UCLA Medical Center, Torrance, California 90509, USA.
Antimicrob Agents Chemother. 1997 Jun;41(6):1345-8. doi: 10.1128/AAC.41.6.1345.
Although there are an increasing number of new antifungal agents available, the morbidity and mortality due to invasive mycoses remain high. The high rates of polyene toxicities and the development of azole resistance have raised the issue of using antifungal agents of these classes in combination, despite theoretical concerns regarding antagonism between such agents. This study was designed to evaluate the in vivo efficacy of combined therapy with amphotericin B and fluconazole against Candida albicans. Two distinct animal models were used in this study: a neutropenic-mouse model of hematogenously disseminated candidiasis and the infective-endocarditis rabbit model. Treatment efficacy was assessed by determining reductions in mortality as well as decreases in tissue fungal densities. In the neutropenic-mouse model, amphotericin B, as well as combination therapy, significantly prolonged survival compared to untreated controls (P < 10(-5) and P = 0.001, respectively). The fungal densities in the kidneys of neutropenic mice were significantly reduced with either amphotericin B monotherapy or amphotericin B-fluconazole combined therapy compared to those of controls (P < 10(-6)). Fluconazole monotherapy also reduced fungal densities in the kidneys; however, this decrease was not statistically significant (P = 0.17). In contrast, treatment with either fluconazole alone or combined with amphotericin B (but not amphotericin B monotherapy) significantly decreased fungal densities in the brain (P = 0.025). In the rabbit endocarditis model, amphotericin B monotherapy or combined therapy significantly decreased fungal densities in cardiac vegetations (P < 0.01 versus the controls). Although no significant antagonism was seen when fluconazole was given in combination with amphotericin B, combination therapy did not augment the antifungal activity of amphotericin B.
尽管可用的新型抗真菌药物越来越多，但侵袭性真菌病导致的发病率和死亡率仍然很高。多烯类药物毒性发生率高以及唑类耐药性的出现，引发了联合使用这类抗真菌药物的问题，尽管理论上担心此类药物之间存在拮抗作用。本研究旨在评估两性霉素B和氟康唑联合治疗白色念珠菌的体内疗效。本研究使用了两种不同的动物模型：血液播散性念珠菌病的中性粒细胞减少小鼠模型和感染性心内膜炎兔模型。通过确定死亡率的降低以及组织真菌密度的减少来评估治疗效果。在中性粒细胞减少小鼠模型中，与未治疗的对照组相比，两性霉素B以及联合治疗均显著延长了生存期（分别为P < 10(-5)和P = 0.001）。与对照组相比，两性霉素B单药治疗或两性霉素B - 氟康唑联合治疗均显著降低了中性粒细胞减少小鼠肾脏中的真菌密度（P < 10(-6)）。氟康唑单药治疗也降低了肾脏中的真菌密度；然而，这种降低没有统计学意义（P = 0.17）。相比之下，单独使用氟康唑或与两性霉素B联合使用（但不包括两性霉素B单药治疗）均显著降低了脑中的真菌密度（P = 0.025）。在兔心内膜炎模型中，两性霉素B单药治疗或联合治疗均显著降低了心脏赘生物中的真菌密度（与对照组相比，P < 0.01）。尽管氟康唑与两性霉素B联合使用时未观察到明显的拮抗作用，但联合治疗并未增强两性霉素B的抗真菌活性。
