Apotransferrin in Combination with Ciprofloxacin Slows Bacterial Replication, Prevents Resistance Amplification, and Increases Antimicrobial Regimen Effect
Apotransferrin in Combination with Ciprofloxacin Slows Bacterial Replication, Prevents Resistance Amplification, and Increases Antimicrobial Regimen Effect
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DOI：
10.1128/aac.00112-19
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发表时间：
2019-05-01
影响因子：
4.9
通讯作者：
Spellberg, Brad
中科院分区：
文献类型：
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作者：
Ambrose, Paul G.;VanScoy, Brian D.;Spellberg, Brad
人们对将传统小分子抗菌剂与非传统疗法相结合以增强抗菌效果重新产生了兴趣。载脂蛋白就是这样一种方法，它会降低微生物对铁的可获得性。采用体外一室感染模型，探讨载脂蛋白对环丙沙星杀菌活性的影响。挑战小组包括环丙沙星MIC值在0.08至32毫克/升之间的四株肺炎克雷伯菌。每个挑战分离株接受无效的环丙沙星单一疗法暴露(24小时浓度-时间曲线下的自由药物面积除以MIC[AUC/MIC比率]，范围从0.19到96.6)，有无载脂转铁蛋白。正如预期的那样，未处理的和载脂蛋白控制臂显示出未改变的典型对数细菌生长。我们确定了单独使用环丙沙星(R-2=0.64)和环丙沙星与载脂蛋白联合使用(R-2=0.84)的暴露与细菌密度变化之间的关系。在环丙沙星中加入载脂蛋白可显著降低环丙沙星暴露范围内的细菌密度。例如，在环丙沙星AUC/MIC比值为20时，环丙沙星单独治疗导致细菌密度增加近2log(10)cfu，而载铁蛋白和环丙沙星联合治疗导致细菌密度减少2log(10)cfu。此外，与单一治疗相比，添加载脂蛋白显著减少了环丙沙星耐药亚群的出现。这些数据表明，用载脂蛋白降低细菌复制率，并结合抗菌治疗，可以增加杀菌效果的幅度，抑制耐药亚群的增长速度。
There has been renewed interest in combining traditional small-molecule antimicrobial agents with nontraditional therapies to potentiate antimicrobial effects. Apotransferrin, which decreases iron availability to microbes, is one such approach. We conducted a 48-h one-compartment in vitro infection model to explore the impact of apotransferrin on the bactericidal activity of ciprofloxacin. The challenge panel included four Klebsiella pneumoniae isolates with ciprofloxacin MIC values ranging from 0.08 to 32 mg/liter. Each challenge isolate was subjected to an ineffective ciprofloxacin monotherapy exposure (free-drug area under the concentrationtime curve over 24 h divided by the MIC [AUC/MIC ratio] ranging from 0.19 to 96.6) with and without apotransferrin. As expected, the no-treatment and apotransferrin control arms showed unaltered prototypical logarithmic bacterial growth. We identified relationships between exposure and change in bacterial density for ciprofloxacin alone (R-2 = 0.64) and ciprofloxacin in combination with apotransferrin (R-2 = 0.84). Addition of apotransferrin to ciprofloxacin enabled a remarkable reduction in bacterial density across a wide range of ciprofloxacin exposures. For instance, at a ciprofloxacin AUC/MIC ratio of 20, ciprofloxacin monotherapy resulted in nearly 2 log(10) CFU increase in bacterial density, while the combination of apotransferrin and ciprofloxacin resulted in 2 log(10) CFU reduction in bacterial density. Furthermore, addition of apotransferrin significantly reduced the emergence of ciprofloxacin-resistant subpopulations compared to monotherapy. These data demonstrate that decreasing the rate of bacterial replication with apotransferrin in combination with antimicrobial therapy represents an opportunity to increase the magnitude of the bactericidal effect and to suppress the growth rate of drug-resistant subpopulations.