Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA.
Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Center for Evolutionary Biology and Medicine, Pittsburgh, PA, USA.
Lancet Microbe. 2021 Oct;2(10):e545-e554. doi: 10.1016/s2666-5247(21)00118-x. Epub 2021 Jul 23.
Some antibiotic pairs display a property known as collateral sensitivity in which the evolution of resistance to one antibiotic increases sensitivity to the other. Alternating between collaterally sensitive antibiotics has been proposed as a sustainable solution to the problem of antibiotic resistance. We aimed to identify antibiotic pairs that could be considered for treatment strategies based on alternating antibiotics.
We did a retrospective analysis of 448 563 antimicrobial susceptibility test results acquired over a 4-year period (Jan 1, 2015, to Dec 31, 2018) from 23 hospitals in the University of Pittsburgh Medical Center (Pittsburgh, PA, USA) hospital system. We used a score based on mutual information to identify pairs of antibiotics displaying disjoint resistance, wherein resistance to one antibiotic is commonly associated with susceptibility to the other and vice versa. We applied this approach to the six most frequently isolated bacterial pathogens (, and ) and subpopulations of each created by conditioning on resistance to individual antibiotics. To identify higher-order antibiotic interactions, we predicted rates of multidrug resistance for triplets of antibiotics using Markov random fields and compared these to the observed rates.
We identified 69 antibiotic pairs displaying varying degrees of disjoint resistance for subpopulations of the six bacterial species. However, disjoint resistance was rarely conserved at the species level, with only 6 (0·7%) of 875 antibiotic pairs showing evidence of disjoint resistance. Instead, more than half of antibiotic pairs (465 [53·1%] of 875) exhibited signatures of concurrent resistance, whereby resistance to one antibiotic is associated with resistance to another. We found concurrent resistance to extend to more than two antibiotics, with observed rates of resistance to three antibiotics being higher than predicted from pairwise information alone.
The high frequency of concurrent resistance shows that bacteria have means of counteracting multiple antibiotics at a time. The almost complete absence of disjoint resistance at the species level implies that treatment strategies based on alternating between antibiotics might require subspecies level pathogen identification and be limited to a few antibiotic pairings.
US National Institutes of Health.
一些抗生素对显示出一种称为“协同敏感性”的特性，即对一种抗生素的耐药性的进化会增加对另一种抗生素的敏感性。交替使用协同敏感的抗生素被提议作为解决抗生素耐药性问题的可持续解决方案。我们旨在确定可以根据交替使用抗生素来考虑的抗生素对。
我们对来自美国匹兹堡大学医学中心（匹兹堡，宾夕法尼亚州）医院系统的 23 家医院在 4 年期间（2015 年 1 月 1 日至 2018 年 12 月 31 日）获得的 448563 次抗菌药物敏感性测试结果进行了回顾性分析。我们使用基于互信息的分数来识别显示不相交耐药性的抗生素对，其中一种抗生素的耐药性通常与另一种抗生素的敏感性相关，反之亦然。我们将这种方法应用于六种最常分离的细菌病原体（、和）以及通过 Conditioning 于单个抗生素的耐药性来创建的每种病原体的亚群。为了识别更高阶的抗生素相互作用，我们使用马尔可夫随机场预测了三抗生素三联体的多药耐药率，并将这些预测值与观察到的耐药率进行了比较。
我们确定了 69 种抗生素对，这些抗生素对六种细菌物种的亚群表现出不同程度的不相交耐药性。然而，在种水平上，不相交的耐药性很少被保守，只有 6（0.7%）对 875 对抗生素对显示出不相交耐药性的证据。相反，超过一半的抗生素对（465[53.1%]对 875）表现出并发耐药的特征，即一种抗生素的耐药性与另一种抗生素的耐药性相关。我们发现并发耐药性扩展到三种以上抗生素，观察到的三种抗生素耐药率高于仅从两两信息预测的耐药率。
并发耐药性的高频表明细菌具有同时对抗多种抗生素的手段。在种水平上几乎完全不存在不相交的耐药性意味着基于抗生素交替的治疗策略可能需要亚种水平的病原体鉴定，并限于少数抗生素配对。
美国国立卫生研究院。
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