Department of Medical Sciences, Section of Infectious Diseases, Uppsala University Hospital, SE-751 85 Uppsala, Sweden.
Antimicrob Agents Chemother. 2011 Apr;55(4):1629-37. doi: 10.1128/AAC.00791-10. Epub 2011 Jan 31.
An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole-resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as Candida glabrata and Candida krusei strains with differences in their degrees of susceptibility to voriconazole were exposed to voriconazole or amphotericin B alone, to both drugs simultaneously, or to voriconazole followed by amphotericin B in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced (median reduction, 61%; range, 9 to 94%). Levels of voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but were not correlated with the MIC values (correlation coefficient, -0.19; P = 0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole-resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.
先前已经证明，在对伏立康唑敏感的白色念珠菌菌株中，伏立康唑对两性霉素 B 序贯剂量的杀菌活性具有拮抗作用。由于预计在由耐药菌株引起的感染中，治疗失败和需要转为其他抗真菌药物的情况会更常见，因此研究在对伏立康唑敏感性降低的念珠菌菌株中是否仍然存在这种拮抗作用是很有意义的。假设拮抗作用不会发生在伏立康唑耐药菌株中，因此我们用具有已知伏立康唑耐药机制的白色念珠菌菌株，以及对伏立康唑敏感性不同的光滑念珠菌和克柔念珠菌菌株，在体外动力学模型中单独暴露于伏立康唑或两性霉素 B、同时暴露于两种药物，或先用伏立康唑后用两性霉素 B。单独给予两性霉素 B 或与伏立康唑同时给予两性霉素 B 均可产生杀菌活性。当两性霉素 B 在伏立康唑之后给予时，其活性降低（中位数降低 61%；范围 9%至 94%）。伏立康唑对两性霉素 B 活性的抑制程度在不同菌株之间存在显著差异，但与 MIC 值无关（相关系数 -0.19；P=0.65）。在 CDR1 和 CDR2 表达增加的白色念珠菌菌株中发现了抑制作用，但在 MDR1 表达增加的菌株中没有发现。总之，对伏立康唑的敏感性降低不会消除伏立康唑对耐药性念珠菌菌株中两性霉素 B 的杀菌活性的伏立康唑依赖性抑制作用。单独通过 MIC 值无法预测相互作用的程度。
