Differential Activity of the Combination of Vancomycin and Amikacin on Planktonic vs. Biofilm-Growing Staphylococcus aureus Bacteria in a Hollow Fiber Infection Model
Differential Activity of the Combination of Vancomycin and Amikacin on Planktonic vs. Biofilm-Growing Staphylococcus aureus Bacteria in a Hollow Fiber Infection Model
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DOI：
10.3389/fmicb.2018.00572
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发表时间：
2018-03-27
影响因子：
5.2
通讯作者：
Ferran, Aude A.
中科院分区：
文献类型：
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作者：
Broussou, Diane C.;Lacroix, Marlene Z.;Ferran, Aude A.
结合目前可用的抗生素来优化其使用是一种很有前途的策略，可以减少针对生物膜相关感染的治疗失败。然而，这种组合的大多数试验都是在体外对浮游细菌进行的，这些细菌暴露在恒定浓度的抗生素中仅24小时，在这些条件下获得的协同效应并不一定能预测与生物膜相关的慢性临床感染的行为。为了提高体外联合检测细菌生物膜的预测性，我们首先采用了先前描述的中空纤维（HF）感染模型，允许金黄色葡萄球菌在药物暴露前形成生物膜。然后，我们模拟了阿米卡星和万古霉素的不同浓度曲线，类似于每天治疗5天以上的患者的游离血浆浓度曲线。我们评估了这两种药物单独或联合使用的能力，以减少浮游和生物膜嵌入的细菌种群，并防止这些种群中选择耐药性。虽然阿米卡星和万古霉素在单药治疗中对金黄色葡萄球菌没有任何杀菌活性，但联合用药具有协同作用，可显著减少浮游细菌数量3.0 ~ 6.0 log(10) CFU/mL。与此同时，与单独使用阿米卡星相比，该组合在生物膜包埋细菌上没有明显的优势，万古霉素与阿米卡星的结合仅能进一步最大减少0.3 log(10) CFU/mL。未发现万古霉素耐药，治疗前系统检出少量对阿米卡星不敏感的细菌。这些耐药菌在生物膜菌群中可以维持在较低水平，在浮游菌群中也可以通过添加万古霉素来抑制。总之，通过调整HF模型，我们能够证明万古霉素和阿米卡星联合对浮游和生物膜嵌入细菌种群的不同杀菌活性，这表明，对于生物膜相关感染，这种联合治疗的效果不会比阿米卡星单一治疗大得多。然而，添加万古霉素可以减少对阿米卡星的可能耐药性，并为防止治疗过程中抗生素耐药菌的选择提供相关策略。
Combining currently available antibiotics to optimize their use is a promising strategy to reduce treatment failures against biofilm-associated infections. Nevertheless, most assays of such combinations have been performed in vitro on planktonic bacteria exposed to constant concentrations of antibiotics over only 24 h and the synergistic effects obtained under these conditions do not necessarily predict the behavior of chronic clinical infections associated with biofilms. To improve the predictivity of in vitro combination assays for bacterial biofilms, we first adapted a previously described Hollow-fiber (HF) infection model by allowing a Staphylococcus aureus biofilm to form before drug exposure. We then mimicked different concentration profiles of amikacin and vancomycin, similar to the free plasma concentration profiles that would be observed in patients treated daily over 5 days. We assessed the ability of the two drugs, alone or in combination, to reduce planktonic and biofilm-embedded bacterial populations, and to prevent the selection of resistance within these populations. Although neither amikacin nor vancomycin exhibited any bactericidal activity on S. aureus in monotherapy, the combination had a synergistic effect and significantly reduced the planktonic bacterial population by 3.0 to 6.0 log(10) CFU/mL. In parallel, no obvious advantage of the combination, as compared to amikacin alone, was demonstrated on biofilm-embedded bacteria for which the addition of vancomycin to amikacin only conferred a further maximum reduction of 0.3 log(10) CFU/mL. No resistance to vancomycin was ever found whereas a few bacteria less-susceptible to amikacin were systematically detected before treatment. These resistant bacteria, which were rapidly amplified by exposure to amikacin alone, could be maintained at a low level in the biofilm population and even suppressed in the planktonic population by adding vancomycin. In conclusion, by adapting the HF model, we were able to demonstrate the different bactericidal activities of the vancomycin and amikacin combination on planktonic and biofilm-embedded bacterial populations, suggesting that, for biofilm-associated infections, the efficacy of this combination would not be much greater than with amikacin monotherapy. However, adding vancomycin could reduce possible resistance to amikacin and provide a relevant strategy to prevent the selection of antibiotic-resistant bacteria during treatments.