JMI Laboratories , North Liberty, Iowa, USA.
mSphere. 2023 Oct 24;8(5):e0016223. doi: 10.1128/msphere.00162-23. Epub 2023 Sep 28.
To evaluate the resistance mechanisms among clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome sequencing were performed. Results were analyzed for strain typing, acquired β-lactamases, and mutations in chromosomal genes; gene expression was measured for known β-lactam resistance contributors. Results were compared to a control group of 10 . isolates displaying MIC values at 8 mg/L for meropenem ± vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM > MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of , , , and was significantly greater among a higher percentage of the MEM > MEV isolates. Furthermore, the association of and overexpression was detected in 17/33 MEM > MEV isolates and only 1/10 MEM = MEV isolate. In addition, the -derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM > MEV, and none of the isolates displayed MEM = MEV. Other resistance mechanisms were not observed or were equally observed in both groups. In rare cases, vaborbactam plays a role in lowering the meropenem MIC values in clinical isolates likely due to the inhibition of the AmpC gene that was overexpressed in the presence of upregulation of MexXY with or without alterations in the AmpC gene. IMPORTANCE isolates are intrinsically resistant to multiple antimicrobial agents and meropenem is an important therapeutic option to treat infections caused by this organism. Meropenem-vaborbactam activity is similar to that of meropenem alone against isolates. Isolates belonging to this species that display lower meropenem-vaborbactam compared to meropenem are rare. We initiated this study to understand the resistance mechanisms that could lead to lower meropenem-vaborbactam MIC values when compared to meropenem alone. We documented that isolates displaying lower meropenem-vaborbactam exhibited overexpression of MexXY and AmpC. In addition, isolates displaying the R79Q PDC (AmpC) mutation were more likely to display lower meropenem-vaborbactam when compared to isolates displaying the same MIC values for these agents.
为了评估表现出美罗培南（MEM）MIC 值高于美罗培南-沃巴坦（MEV）的临床分离株的耐药机制。对 2014 年至 2019 年在美国医院收集的临床分离株进行了药敏试验。进行了全基因组和转录组测序。对菌株分型、获得性β-内酰胺酶和染色体基因突变进行了分析；测量了已知β-内酰胺耐药贡献者的基因表达。将结果与 10 株 MIC 值为 8mg/L 的美罗培南±沃巴坦的对照 株进行了比较。在 88 株显示 MEM > MEV 的分离株中，33 株（37.5%）当重新测试时，对美罗培南-沃巴坦的 MIC 值较美罗培南有可重复的降低。在较高比例的 MEM > MEV 分离株中， 、 、 和 的表达显著增加。此外，在 17/33 MEM > MEV 分离株中检测到 和 的过表达，而在 1/10 MEM = MEV 分离株中仅检测到 1 株。此外，在 33.3%的 MEM > MEV 分离株中检测到由 衍生的头孢菌素酶氨基酸取代 R79Q，而在 MEM = MEV 分离株中均未检测到。在两组中均未观察到或同样观察到其他耐药机制。在极少数情况下，沃巴坦在降低临床分离株的美罗培南 MIC 值方面发挥作用，这可能是由于在 MexXY 上调的情况下抑制了 AmpC 基因，而 AmpC 基因的改变或不改变。重要性 分离株对多种抗菌药物固有耐药，美罗培南是治疗该病原体引起的感染的重要治疗选择。美罗培南-沃巴坦的活性与单独使用美罗培南相似，对 分离株。与单独使用美罗培南相比，显示出较低美罗培南-沃巴坦 MIC 值的属于该种的分离株很少见。我们开始这项研究是为了了解可能导致与单独使用美罗培南相比美罗培南-沃巴坦 MIC 值降低的耐药机制。我们记录到显示出较低美罗培南-沃巴坦 MIC 值的分离株表现出 MexXY 和 AmpC 的过表达。此外，与显示相同 MIC 值的分离株相比，显示 R79Q PDC（AmpC）突变的分离株更有可能显示出较低的美罗培南-沃巴坦 MIC 值。
