Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.
Department of Statistics, Uppsala University, SE-75105 Uppsala, Sweden.
EBioMedicine. 2017 Sep;23:111-118. doi: 10.1016/j.ebiom.2017.08.021. Epub 2017 Aug 24.
Mecillinam (amdinocillin) is a β-lactam antibiotic used to treat uncomplicated urinary tract infections (UTIs). We have previously shown that inactivation of the Escherichia coli cysB gene is the major cause of mecillinam resistance (Mec) in clinical isolates. In this study, we used different E. coli strains (laboratory and clinical isolates) that were Mec due to cysB mutations to determine how mecillinam susceptibility was affected during growth in urine compared to growth in the commonly used growth medium Mueller Hinton (MHB). We also examined mecillinam susceptibility when bacteria were grown in urine obtained from 48 different healthy volunteers. Metabolome analysis was done on the urine samples and the association between the mecillinam susceptibility patterns of the bacteria and urine metabolite levels was studied. Two major findings with clinical significance are reported. First, MecE. coli cysB mutant strains (both laboratory and clinical isolates) were always more susceptible to mecillinam when grown in urine as compared to laboratory medium, with many strains showing complete phenotypic susceptibility in urine. Second, the degree of reversion to susceptibility varied between urine samples obtained from different individuals. This difference was correlated with osmolality such that in urine with low osmolality the Mec mutants were more susceptible to mecillinam than in urine with high osmolality. This is the first example describing conditional resistance where a genetically stable antibiotic resistance can be phenotypically reverted to susceptibility by metabolites present in urine. These findings have several important clinical implications regarding the use of mecillinam to treat UTIs. First, they suggest that mecillinam can be used to treat also those clinical strains that are identified as Mec in standard laboratory tests. Second, the results suggest that testing of mecillinam susceptibility in the laboratory ought to be performed in media that mimics urine to obtain clinically relevant susceptibility testing results. Third, these findings imply that changes in patient behavior, such as increased water intake or use of diuretics to reduce urine osmolality and increased intake of cysteine, might induce antibiotic susceptibility in an infecting MecE. coli strain and thereby increase treatment efficiency.
美西林（氨曲南）是一种用于治疗单纯性尿路感染（UTI）的β-内酰胺类抗生素。我们之前已经表明，大肠埃希菌 cysB 基因突变是临床分离株中美西林耐药（Mec）的主要原因。在这项研究中，我们使用了不同的大肠埃希菌菌株（实验室和临床分离株），这些菌株由于 cysB 突变而对美西林产生耐药性，以确定与在常用生长培养基 Mueller Hinton（MHB）中生长相比，在尿液中生长时美西林的敏感性如何受到影响。我们还检查了在从 48 名不同健康志愿者获得的尿液中生长的细菌时的美西林敏感性。对尿液样本进行了代谢组学分析，并研究了细菌的美西林敏感性模式与尿液代谢物水平之间的关系。报告了两个具有重要临床意义的主要发现。首先，与实验室培养基相比，当在尿液中生长时，MecE. coli cysB 突变株（包括实验室和临床分离株）对美西林的敏感性总是更高，许多菌株在尿液中表现出完全的表型敏感性。其次，在从不同个体获得的尿液样本之间，回复敏感性的程度有所不同。这种差异与渗透压相关，即尿液渗透压较低时，Mec 突变体对美西林的敏感性高于尿液渗透压较高时。这是第一个描述条件性耐药的例子，其中遗传稳定的抗生素耐药性可以通过尿液中存在的代谢物表型逆转为敏感性。这些发现对使用美西林治疗尿路感染具有重要的临床意义。首先，它们表明美西林可用于治疗在标准实验室测试中被鉴定为 Mec 的临床菌株。其次，结果表明，为了获得临床相关的药敏测试结果，应在模拟尿液的培养基中进行美西林药敏测试。第三，这些发现意味着患者行为的改变，例如增加饮水量或使用利尿剂降低尿液渗透压和增加半胱氨酸的摄入，可能会使感染的 MecE. coli 菌株产生抗生素敏感性，从而提高治疗效果。
