Data_Sheet_1_Pulse Dosing of Antibiotic Enhances Killing of a Staphylococcus aureus Biofilm.pdf

Biofilms are highly tolerant to antibiotics and underlie the recalcitrance of many chronic infections. We demonstrate that mature Staphylococcus aureus biofilms can be substantially sensitized to the treatment by pulse dosing of an antibiotic – in this case, oxacillin. Pulse (periodic) dosing was compared to continuous application of antibiotic and was studied in a novel in vitro flow system which allowed for robust biofilm growth and tractable pharmacokinetics of dosing regimens. Our results highlight that a subpopulation of the biofilm survives antibiotic without becoming resistant, a population we refer to as persister bacteria. When oxacillin was continuously present the persister level did not decline, but, importantly, providing correctly timed periodic breaks decreased the surviving population. We found that the length of the periodic break impacted efficacy, and there was an optimal length that sensitized the biofilm to repeat treatment without allowing resistance expansion. Periodic dosing provides a potential simple solution to a complicated problem.

生物膜（Biofilms）对抗生素具有高度耐受性，是诸多慢性感染难以根治的核心诱因。本研究证实，采用抗生素脉冲给药（pulse dosing）的方式，可大幅增强成熟金黄色葡萄球菌（Staphylococcus aureus）生物膜对治疗的敏感性，本研究中选用的抗生素为苯唑西林（oxacillin）。研究将脉冲（周期性）给药与抗生素持续给药方案进行对比，并依托一种新型体外（in vitro）流动系统开展实验——该系统可实现稳定的生物膜生长，同时能精准调控给药方案的药代动力学（pharmacokinetics）参数。研究结果显示，生物膜中存在一类亚群可在抗生素暴露下存活且不产生耐药性，我们将这类菌群命名为持留菌（persister bacteria）。当苯唑西林持续存在时，持留菌的种群数量并未出现下降；但值得注意的是，施加时序合理的周期性给药间歇，可有效降低存活菌群的数量。研究发现，周期性间歇的时长会对治疗效果产生影响，存在一个最优间歇时长，可在避免耐药性扩散的同时，使生物膜对后续重复治疗更为敏感。脉冲给药为这一复杂临床难题提供了一种潜在的简易解决方案。