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Drug Combinations to Prevent Antimicrobial Resistance: Various Correlations and Laws, and Their Verifications, Thus Proposing Some Principles and a Preliminary Scheme
Antibiotics ( IF 4.8 ) Pub Date : 2022-09-20 , DOI: 10.3390/antibiotics11101279
Houqin Yi 1, 2 , Ganjun Yuan 1, 2 , Shimin Li 1, 2 , Xuejie Xu 1 , Yingying Guan 1, 2 , Li Zhang 2 , Yu Yan 2
Affiliation  

Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy for fighting the resistance. However, the abuse of drug combinations conversely accelerates the spread of AMR. In our previous work, we concluded that the mutant selection indexes (SIs) of one agent against a specific bacterial strain are closely related to the proportions of two agents in a drug combination. To discover probable correlations, predictors and laws for further proposing feasible principles and schemes guiding the AMR-preventing practice, here, three aspects were further explored. First, the power function (y = axb, a > 0) correlation between the SI (y) of one agent and the ratio (x) of two agents in a drug combination was further established based on the mathematical and statistical analyses for those experimental data, and two rules a1 × MIC1 = a2 × MIC2 and b1 + b2 = −1 were discovered from both equations of y = a1xb1 and y = a2xb2 respectively for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations showed greater potency for narrowing itself MSW and preventing the resistance. Second, a new concept, mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combination; a positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using 181 data pairs reported. These results together for the above three aspects indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and while the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, the former conclusion was further verified and improved via antibiotic exposure to 43 groups designed as different drug concentrations and various proportions. The results further proposed that the C/MPC for the agent with larger proportion in drug combinations can be considered as a predictor and is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Based on these above correlations, laws, and their verification experiments, some principles were proposed, and a diagram of the mutation-preventing effects and the resistant trajectories for drug combinations with different concentrations and ratios of two agents was presented. Simultaneously, the reciprocal of MPC alone (1/MPC), proposed as the stress factors of two agents in drug combinations, together with their SI in combination, is the key to predict the mutation-preventing potency and control the trajectories of collateral sensitivity. Finally, a preliminary scheme for antimicrobial combinations preventing AMR was further proposed for subsequent improvement research and clinic popularization, based on the above analyses and discussion. Moreover, some similar conclusions were speculated for triple or multiple drug combinations.

中文翻译:

预防抗生素耐药性的药物组合:各种相关性和规律及其验证,从而提出一些原则和初步方案

抗菌素耐药性(AMR)一直严重威胁着人类健康,联合疗法被证明是一种经济有效的对抗耐药性的策略。然而,药物组合的滥用反而加速了 AMR 的传播。在我们之前的工作中,我们得出结论,一种药物针对特定细菌菌株的突变选择指数 (SI) 与药物组合中两种药物的比例密切相关。为了发现可能的相关性、预测因素和规律,以进一步提出指导 AMR 预防实践的可行原则和方案,这里进一步探讨了三个方面。首先,一个代理人的SI ( y ) 与比率(基于这些实验数据的数学和统计分析,进一步建立了药物组合中两种药物的x ),并发现了两个规则 a 1 × MIC 1 = a 2 × MIC 2和 b 1 + b 2 = −1 y = a 1 x b1y = a 2 x b2的两个方程分别为药物组合中的两种药物。同时,发现单独使用具有较大 MPC 的药物组合药物显示出缩小自身 MSW 和预防耐药性的更大效力。其次,提出了一个新的概念——突变预防选择指数(MPSI),用于评价联合用药中两种药物的突变预防效力差异;随后建立了 MPSI 与突变预防浓度 (MPC) 或最小抑制浓度 (MIC) 之间的正相关关系。受此启发,使用报告的 181 个数据对建立了 MIC 与抗菌剂对致病菌的相应 MPC 之间的显着正相关,这与之前的报道相反。以上三个方面的结果共同表明,单独和联合使用的 MPC 是药物组合预测突变预防效果和侧支敏感轨迹的非常重要的指标,而药物的 MPC 可以从其粗略计算相应的麦克风。随后,通过设计为不同药物浓度和不同比例的43组抗生素暴露,进一步验证和完善了前一结论。结果进一步提出,药物组合中比例较大的药物的C/MPC可作为预测因子,是判断两种药物是否发生耐药和侧支敏感性的关键。基于以上这些相关性、规律及其验证实验,提出了一些原则,并给出了两种药物不同浓度和比例的药物组合的突变预防效果和耐药轨迹图。同时,单独 MPC 的倒数 (1/MPC) 被提议作为药物组合中两种药物的应激因子,连同它们的 SI 组合,是预测突变预防效力和控制侧支敏感性轨迹的关键。最后,在上述分析和讨论的基础上,进一步提出了抗菌组合预防AMR的初步方案,以供后续改进研究和临床推广。此外,一些类似的结论被推测用于三联或多联药物。
更新日期:2022-09-20
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