3rd Department of Pediatrics, Hippokration Hospital, Konstantinoupoleos 49, GR-546 42 Thessaloniki, Greece.
Antimicrob Agents Chemother. 2011 Dec;55(12):5923-9. doi: 10.1128/AAC.00548-11. Epub 2011 Sep 12.
Aspergillus is damaged by polymorphonuclear neutrophils (PMNs) by means of nonoxidative and oxidative mechanisms, which may be affected by antifungal and antibacterial agents that patients with invasive pulmonary aspergillosis often receive. The pharmacodynamic interactions among deoxycholate amphotericin B (AMB), ciprofloxacin (CIP), and human PMNs against Aspergillus fumigatus growth are unknown. We therefore studied the interactions between 0.032 to 2.0 μg/ml of AMB, 0.1 to 50 μg/ml of CIP at a fixed AMB/CIP ratio of 1:3.125, and PMNs from six donors at an effector-to-target (E:T) ratio of 400:1 against a clinical A. fumigatus isolate using an XTT metabolic assay and the Bliss independence pharmacodynamic-interaction model. CIP exhibited no antifungal activity alone or in combination with PMNs. Synergy was found between AMB and PMNs, with interaction indices (II) of 0.06 to 0.21; the highest interaction of 21% ± 3.6% was observed at 0.22 ± 0.09 μg/ml of AMB. The AMB and CIP (AMB+CIP) combination was synergistic (II = 0.39) at low AMB concentrations and antagonistic (II = 1.39) at high AMB concentrations, with a maximal synergistic interaction of 16% ± 3.7% observed at 0.16 ± 0.08 μg/ml of AMB. The triple combination AMB+CIP+PMNs was synergistic, with interaction indices of 0.05 to 0.20, and a maximal synergistic interaction of 24% ± 4% was observed at 0.20 ± 0.07 μg/ml of AMB. The increased percentage of Bliss synergy of the triple combination AMB+CIP+PMNs (24% ± 4%) was the product of those of the constituent double combinations AMB+PMNs (21% ± 3.6%) and AMB+CIP (16% ± 3.7%). Thus, the antifungal activity of AMB, at clinically relevant concentrations, was enhanced in combination with PMNs and CIP against A. fumigatus growth in a concentration-dependent manner.
曲霉属被多形核中性粒细胞（PMN）通过非氧化和氧化机制所破坏，这一过程可能受到侵袭性肺曲霉病患者常接受的抗真菌和抗菌药物的影响。脱氧胆酸盐两性霉素 B（AMB）、环丙沙星（CIP）和人 PMN 对烟曲霉生长的药效学相互作用尚不清楚。因此，我们研究了 0.032 至 2.0μg/ml 的 AMB、0.1 至 50μg/ml 的 CIP 在固定 AMB/CIP 比为 1:3.125 以及 6 位供体的 PMN 与临床烟曲霉分离株的效应器与靶标（E:T）比为 400:1 时的相互作用，使用 XTT 代谢测定法和 Bliss 独立性药效学相互作用模型。CIP 单独或与 PMN 联合使用时均无抗真菌活性。AMB 和 PMN 之间存在协同作用，相互作用指数（II）为 0.06 至 0.21；在 0.22±0.09μg/ml 的 AMB 时观察到最高的 21%±3.6%的相互作用。AMB 和 CIP（AMB+CIP）组合在低 AMB 浓度时协同（II=0.39），在高 AMB 浓度时拮抗（II=1.39），在 0.16±0.08μg/ml 的 AMB 时观察到最大协同作用 16%±3.7%。AMB+CIP+PMN 的三联组合具有协同作用，相互作用指数为 0.05 至 0.20，在 0.20±0.07μg/ml 的 AMB 时观察到最大协同作用 24%±4%。三联组合 AMB+CIP+PMN 的 Bliss 协同作用增加百分比（24%±4%）是其组成的双重组合 AMB+PMN（21%±3.6%）和 AMB+CIP（16%±3.7%）的产物。因此，在临床相关浓度下，AMB 的抗真菌活性与 PMN 和 CIP 联合使用时，以浓度依赖性方式增强了对烟曲霉生长的抑制作用。
