Lignell Anders, Löwdin Elisabeth, Cars Otto, Sjölin Jan
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden.
J Antimicrob Chemother. 2008 Jul;62(1):142-8. doi: 10.1093/jac/dkn154. Epub 2008 Apr 12.
The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B.
Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole.
Voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure.
Voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.
本研究旨在探讨伏立康唑对两性霉素B杀菌活性的影响并进行特性描述。
在体外动力学模型中，将4株对伏立康唑敏感的白色念珠菌菌株分别单独、同时或序贯暴露于伏立康唑和两性霉素B。分别给予能使伏立康唑和两性霉素B浓度达到0.005 - 5mg/L和2.5mg/L的大剂量药物。使用蠕动泵去除含抗真菌药物的RPMI 1640培养基，并用新鲜培养基替代，调节流速以获得所需的半衰期。在测试两种药物时，计算机控制的定量泵可补偿消除率的差异。采用静态时间杀菌方法，将一株白色念珠菌暴露于5mg/L伏立康唑不同时间，然后在三次反复冲洗伏立康唑后，再暴露于2.5mg/L两性霉素B。
单独使用伏立康唑和两性霉素B分别产生抑菌和杀菌活性。同时给予伏立康唑和两性霉素B产生杀菌活性，而在伏立康唑给药24 - 96小时后序贯给予重复剂量的两性霉素B时，仅观察到抑菌活性。伏立康唑对两性霉素B杀菌活性的抑制呈剂量依赖性，但一旦伏立康唑浓度降至最低抑菌浓度（MIC）以下，似乎可以恢复。无论伏立康唑预先暴露的持续时间如何，去除伏立康唑后杀菌活性迅速恢复。
伏立康唑以浓度和时间依赖性方式抑制序贯给药的两性霉素B的杀菌作用；其临床意义有待进一步研究。
