Antibiotic Selection Pressure Determination through Sequence-Based Metagenomics
Antibiotic Selection Pressure Determination through Sequence-Based Metagenomics
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DOI：
10.1128/aac.01504-15
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发表时间：
2015-12-01
影响因子：
4.9
通讯作者：
Peter, Silke
中科院分区：
文献类型：
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作者：
Willmann, Matthias;El-Hadidi, Mohamed;Peter, Silke
人类肠道形成了抗生素抗性基因（ARG）的动态库。抗菌药物治疗对肠道耐药组具有显着影响，并导致耐药性的水平转移和选择增强。我们通过使用基于测序的宏基因组学和不同的 ARG 定量方法，监测了两名健康个体在为期 6 天的环丙沙星 (Cp) 治疗过程中肠道 ARG 的发展。应用固定效应和随机效应模型来确定每个定义的每日 Cp 剂量的 ARG 丰度变化，作为相应选择压力的表达。在肠道抵抗组组成的各种变化中，我们发现在一个个体中对 D 类 β-内酰胺酶有强烈的正选择，该酶部分位于可移动遗传元件上。此外，A 类 β-内酰胺酶观察到负选择趋势（每百万样本读数 -2.66 次点击/规定的每日剂量；P = 0.06）。治疗结束后 4 周，两个受试者的 ARG 成分恢复到初始状态，但程度不同。我们在此提出了一种用于确定抗生素选择压力的新颖分析算法，该算法可应用于临床环境中，以比较治疗方案对肠道抵抗组的影响。这一信息对于临床医生选择对患者肠道 ARG 选择性较低的抗菌药物至关重要，可能会减少耐药性的传播，并减轻医院获得性多重耐药病原体感染的负担。
The human gut forms a dynamic reservoir of antibiotic resistance genes (ARGs). Treatment with antimicrobial agents has a significant impact on the intestinal resistome and leads to enhanced horizontal transfer and selection of resistance. We have monitored the development of intestinal ARGs over a 6-day course of ciprofloxacin (Cp) treatment in two healthy individuals by using sequenced-based metagenomics and different ARG quantification methods. Fixed-and random-effect models were applied to determine the change in ARG abundance per defined daily dose of Cp as an expression of the respective selection pressure. Among various shifts in the composition of the intestinal resistome, we found in one individual a strong positive selection for class D beta-lactamases which were partly located on a mobile genetic element. Furthermore, a trend to a negative selection has been observed with class A beta-lactamases (-2.66 hits per million sample reads/defined daily dose; P = 0.06). By 4 weeks after the end of treatment, the composition of ARGs returned toward their initial state but to a different degree in both subjects. We present here a novel analysis algorithm for the determination of antibiotic selection pressure which can be applied in clinical settings to compare therapeutic regimens regarding their effect on the intestinal resistome. This information is of critical importance for clinicians to choose antimicrobial agents with a low selective force on their patients' intestinal ARGs, likely resulting in a diminished spread of resistance and a reduced burden of hospital-acquired infections with multidrug-resistant pathogens.