Penicillin-Binding Proteins and Alternative Dual-Beta-Lactam Combinations for Serious Enterococcus faecalis Infections with Elevated Penicillin MICs.
Penicillin-Binding Proteins and Alternative Dual-Beta-Lactam Combinations for Serious Enterococcus faecalis Infections with Elevated Penicillin MICs.
复制标题
青霉素结合蛋白和替代双 β-内酰胺组合治疗青霉素 MIC 升高的严重粪肠球菌感染。
DOI：
10.1128/aac.00871-22
复制
发表时间：
2023
影响因子：
4.9
通讯作者：
García-Solache,Mónica
中科院分区：
文献类型：
--
作者：
Cusumano,JaclynA;Daffinee,KathrynE;Ugalde-Silva,Paul;Peti,Wolfgang;Arthur,Michel;Desbonnet,Charlene;Rice,LouisB;LaPlante,KerryL;García-Solache,Mónica
氨苄西林-头孢曲松已成为粪肠球菌心内膜炎的一线治疗药物。我们对不同的大肠杆菌的青霉素结合蛋白（PBP）谱进行了表征。粪肠球菌菌株，并测试协同作用，以更好地告知β-内酰胺治疗E.粪便感染我们评估了来自MIC升高的菌株E的PBP 2B的亲和力。我们还表征了PBP 4和PBP 2B的结构以及PBP 4和PBP 2B的表达，并使用缺失和互补研究来评估PBP 2B对抗性水平的影响。对青霉素敏感和耐药的大肠杆菌进行了检测。在24小时时间-杀灭研究中，粪肠球菌分离株对头孢曲松或头孢洛林与其他β-内酰胺类药物组合的耐受性。两株青霉素敏感株（JH 2 -2和L2052）具有相同的pBP序列和相似的PBP表达水平。其中一株青霉素敏感性降低的菌株（L2068）的pbp序列与敏感菌株相同，但表达更多的PBP 4。第二个青霉素敏感性降低的菌株（LS 4828）在PBP 4和PBP 2B中具有氨基酸取代，并且表达增加的两种蛋白质的量。PBP 2B似乎对β-内酰胺MIC的升高没有显著贡献。对具有突变的PBPs和增加的表达的菌株（L2068和LS 4828）没有证实协同作用。美罗培南+头孢曲松或厄他培南+头孢曲松显示出最一致的协同活性。菌株LS 4828的PBP 2B对降低青霉素敏感性没有显著贡献。当在静态亚抑制浓度下测试时，MIC和PBP表达水平都与所鉴定的协同组合不直接相关。
Ampicillin-ceftriaxone has become a first-line therapy for Enterococcus faecalis endocarditis. We characterized the penicillin-binding protein (PBP) profiles of various E. faecalis strains and tested for synergy to better inform beta-lactam options for the treatment of E. faecalis infections. We assessed the affinity of PBP2B from elevated-MIC strain E. faecalis LS4828 compared to type strain JH2-2 using the fluorescent beta-lactam Bocillin FL. We also characterizedpbp4andpbpAstructures and PBP4 and PBP2B expression and used deletion and complementation studies to assess the impact of PBP2B on the levels of resistance. We tested penicillin-susceptible and -resistant E. faecalis isolates against ceftriaxone or ceftaroline combinations with other beta-lactams in 24-h time-kill studies. Two penicillin-susceptible strains (JH2-2 and L2052) had identicalpbpsequences and similar PBP expression levels. One reduced-penicillin-susceptibility strain (L2068) hadpbpsequences identical to those of the susceptible strains but expressed more PBP4. The second decreased-penicillin-susceptibility strain (LS4828) had amino acid substitutions in both PBP4 and PBP2B and expressed increased quantities of both proteins. PBP2B did not appear to contribute significantly to the elevated beta-lactam MICs. No synergy was demonstrable against the strains with both mutated PBPs and increased expression (L2068 and LS4828). Meropenem plus ceftriaxone or ertapenem plus ceftriaxone demonstrated the most consistent synergistic activity. PBP2B of strain LS4828 does not contribute significantly to reduced penicillin susceptibility. Neither the MIC nor the level of PBP expression correlated directly with the identified synergistic combinations when tested at static subinhibitory concentrations.