College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA.
Microbiol Spectr. 2024 Oct 3;12(10):e0387623. doi: 10.1128/spectrum.03876-23. Epub 2024 Aug 20.
Metallo-beta-lactamase (MBL)-producing carbapenem-resistant (CRE) infections continue to pose a serious threat to healthcare. Due to their unique active site, MBLs evade the activity of many novel beta-lactam/beta-lactamase inhibitor combinations, which have been specifically targeted toward those carbapenemases with serine active sites. Furthermore, resistance to most, if not all, other clinically relevant antimicrobial classes leaves few reliable therapeutic options. Combination therapy has thus played a vital role in the treatment of MBL-producing CRE infections. In this study, we utilized the static time-kill assay to investigate clinically relevant concentrations of cefepime, piperacillin-tazobactam, and meropenem alone and in combination with either amikacin or the novel plazomicin to determine if combinations of routinely used beta-lactam therapy with an aminoglycoside would achieve bactericidal activity against eight clinically isolated Verona integron-encoded MBL (VIM)-producing CRE. Furthermore, we compared this activity to the combination of aztreonam/avibactam, which has shown potent activity against MBL-producing CRE. Both aztreonam/avibactam and meropenem with either aminoglycoside were rapidly bactericidal within 4 hours and remained bactericidal through 24 hours against all isolates with few exceptions. Combinations including cefepime and piperacillin-tazobactam were also rapidly bactericidal, but activity after 24 hours was inconsistent depending upon the partner aminoglycoside and isolate. Further investigation is warranted to elucidate optimal antibiotic exposures against MBL-producing CRE, including novel agents in the pipeline.IMPORTANCECarbapenem-resistant (CRE) are one of the most pressing antimicrobial-resistant threats at present. In addition to exhibiting resistance to many, if not all, commonly used antimicrobial agents, CRE achieves these resistant phenotypes through a variety of mechanisms, each of which can uniquely affect available treatment options. The present study is an investigation of several Verona integron-encoded metallo-beta-lactamase (VIM)-producing CRE isolated from patients at our academic medical center. Because metallo-beta-lactamases (MBLs) are inherently resistant to many of the novel treatments designed to treat CRE due to their different active site composition, we tested several antimicrobial combinations containing routinely utilized broad-spectrum beta-lactams and aminoglycosides. Our results further our understanding of combination therapy options against VIM-producing CRE, including with non-carbapenem-beta-lactams cefepime and piperacillin. By optimizing combinations of existing antimicrobial agents, we hope to expand the available armamentarium against these resistant pathogens.
金属β-内酰胺酶（MBL）产生的碳青霉烯类耐药（CRE）感染继续对医疗保健构成严重威胁。由于其独特的活性部位，MBL 逃避了许多新型β-内酰胺/β-内酰胺酶抑制剂组合的活性，这些抑制剂专门针对那些具有丝氨酸活性部位的碳青霉烯酶。此外，对大多数（如果不是全部）其他临床相关抗菌药物类别的耐药性使得可靠的治疗选择有限。因此，联合治疗在治疗 MBL 产生的 CRE 感染中发挥了至关重要的作用。在这项研究中，我们使用静态时间杀伤测定法来研究头孢吡肟、哌拉西林他唑巴坦和亚胺培南单独使用以及与阿米卡星或新型普拉佐米星联合使用的临床相关浓度，以确定常规使用的β-内酰胺治疗与氨基糖苷类药物联合使用是否会对 8 种临床分离的 Verona 整合子编码的 MBL（VIM）产生的 CRE 产生杀菌活性。此外，我们将这种活性与已经显示出对 MBL 产生的 CRE 具有强大活性的阿佐米星/阿维巴坦进行了比较。阿佐米星/阿维巴坦和亚胺培南与氨基糖苷类药物联合使用在 4 小时内迅速杀菌，并在 24 小时内保持对所有分离株的杀菌活性，除了少数例外。包括头孢吡肟和哌拉西林他唑巴坦在内的组合也迅速杀菌，但在 24 小时后的活性因伴用的氨基糖苷类药物和分离株而异。需要进一步研究以阐明针对 MBL 产生的 CRE 的最佳抗生素暴露，包括新的管道药物。
意义：
碳青霉烯类耐药（CRE）是目前最紧迫的抗菌药物耐药威胁之一。除了对许多（如果不是全部）常用抗菌药物表现出耐药性外，CRE 通过多种机制获得这些耐药表型，每种机制都可能独特地影响可用的治疗选择。本研究是对我们学术医疗中心的患者分离的几种 Verona 整合子编码的金属β-内酰胺酶（VIM）产生的 CRE 进行的研究。由于金属β-内酰胺酶（MBL）由于其不同的活性部位组成而对许多旨在治疗 CRE 的新型治疗药物固有耐药，因此我们测试了几种包含常规使用的广谱β-内酰胺类和氨基糖苷类药物的抗菌药物组合。我们的结果进一步了解了针对 VIM 产生的 CRE 的联合治疗选择，包括非碳青霉烯类β-内酰胺类药物头孢吡肟和哌拉西林。通过优化现有抗菌药物组合，我们希望扩大针对这些耐药病原体的可用武器库。
