van de Sande Wendy W J, Mathot Ron A A, ten Kate Marian T, van Vianen Wim, Tavakol Mehri, Rijnders Bart J A, Bakker-Woudenberg Irma A J M
Erasmus MC, University Medical Center Rotterdam, Department of Medical Microbiology and Infectious Diseases, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
Antimicrob Agents Chemother. 2009 May;53(5):2005-13. doi: 10.1128/AAC.01556-08. Epub 2009 Feb 23.
At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.
目前，伏立康唑（VOR）是治疗侵袭性肺曲霉病（IPA）的首选药物。然而，特别是在疾病的晚期阶段以及严重免疫功能低下的宿主中，死亡率仍然很高。VOR与棘白菌素联合使用可能会改善治疗效果。我们在此研究在短暂性中性粒细胞减少的大鼠晚期IPA中联合使用VOR和阿尼芬净（ANI）是否会产生更高的治疗效果。由于VOR在啮齿动物体内的代谢速度比在人类体内更快，因此需要调整VOR的剂量，以在啮齿动物体内获得与人类相当的血浆浓度-时间曲线下面积（AUC）。在本研究中，阐明了大鼠体内VOR和ANI的药代动力学，并应用了产生与人相似AUC的给药方案。所制定的给药方案大鼠耐受性良好，对肾和肝功能无影响。VOR在早期IPA中显示出优异的疗效（大鼠存活率100%）。在晚期IPA中，VOR的疗效较差（大鼠存活率50%），而存活大鼠的肺和血清中半乳甘露聚糖浓度显著降低。在晚期IPA中给予ANI导致大鼠存活率为22%，真菌半乳甘露聚糖的血清浓度略有下降但不显著。在晚期IPA中，VOR联合ANI并未导致治疗效果显著提高，大鼠存活率为67%，血清中半乳甘露聚糖浓度显著降低。总之，VOR单药治疗对晚期IPA的治疗有效，且优于使用ANI。联合使用这两种药物并不能显著改善治疗效果。
