Jitmuang Anupop, Tiengrim Surapee, Thamlikitkul Visanu, Koomanachai Pornpan
Division of Infectious Diseases and Tropical Medicine, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Microbiol Spectr. 2025 Sep 2;13(9):e0137925. doi: 10.1128/spectrum.01379-25. Epub 2025 Aug 12.
Extensively drug-resistant (XDR) infection has significant challenges due to limited treatment options. Although sulbactam (SUL) shows effectiveness against XDR , the efficacy of SUL-based combinations remains unclear. This investigation aimed to delineate the activity of SUL combined with various antimicrobial agents against XDR . Sixty-two clinical isolates of XDR were tested for minimal inhibitory concentrations (MICs) of SUL, amikacin (AMI), ciprofloxacin, colistin (COL), fosfomycin (FOS), gentamicin, meropenem (MER), rifampicin (RIF), sitafloxacin (SIT), and tigecycline (TIG) using broth microdilution. The checkerboard method, employing the fractional inhibitory concentration index, assessed synergy between the SUL-based combination. Time-kill analyses of selected isolates were conducted to measure log colony-forming unit per milliliter growth changes over 24 hours between individual and combined agents. The SUL MICs ranged from <4 to 256 mg/L, with an MIC of 64 mg/L. MIC ranges were lower for TIG (0.12-4.0 mg/L) and COL (0.5-2.0 mg/L), but higher for FOS (64->512 mg/L). Synergism was evident in the combinations of SUL/FOS (41.9%), SUL/AMI (19.3%), SUL/MER (17.7%), SUL/RIF (14.5%), SUL/TIG (12.9%), SUL/COL (6.5%), and SUL/SIT (4.8%). Only 1.6%-3.2% of the combinations exhibited antagonism. In the time-kill assays, a combination of SUL/FOS/AMI/MER exhibited sustained bactericidal activity at 24 hours against the two isolates, whereas two- and three-agent combinations showed varying degrees of synergism. Combining SUL with available antimicrobial agents had varying degrees of synergistic effect against XDR . Notably, the clinical utility of SUL-based combination therapy for XDR infections requires further exploration.IMPORTANCEThis study evaluated the effectiveness of SUL combined with other antibiotics against XDR . Sixty-two clinical isolates were tested using broth microdilution and checkerboard methods. The SUL MIC was 64 mg/L, with tigecycline and colistin showing lower MIC ranges and higher fosfomycin. Synergistic activity was most notable with SUL/fosfomycin (41.9%), followed by SUL/amikacin (19.3%) and SUL/meropenem (17.7%). Antagonism was rare (1.6%-3.2%). Time-kill assays showed that the four-drug combination of SUL/fosfomycin/amikacin/meropenem had sustained bactericidal activity over 24 hours. While SUL-based combinations showed variable synergy, further studies are needed to determine their clinical potential.
广泛耐药（XDR）感染由于治疗选择有限而面临重大挑战。尽管舒巴坦（SUL）对XDR感染显示出有效性，但基于舒巴坦的联合用药疗效仍不明确。本研究旨在描述舒巴坦与多种抗菌药物联合对XDR感染的活性。采用肉汤微量稀释法对62株XDR临床分离株进行舒巴坦、阿米卡星（AMI）、环丙沙星、黏菌素（COL）、磷霉素（FOS）、庆大霉素、美罗培南（MER）、利福平（RIF）、司他夫沙星（SIT）和替加环素（TIG）的最低抑菌浓度（MIC）检测。采用棋盘法并通过部分抑菌浓度指数评估基于舒巴坦的联合用药之间的协同作用。对选定的分离株进行时间杀菌分析，以测量个体药物和联合用药在24小时内每毫升对数集落形成单位的生长变化。舒巴坦的MIC范围为<4至256mg/L，MIC为64mg/L。替加环素（0.12 - 4.0mg/L）和黏菌素（0.5 - 2.0mg/L）的MIC范围较低，而磷霉素（64 -> 512mg/L）的MIC范围较高。舒巴坦/磷霉素（41.9%）、舒巴坦/阿米卡星（19.3%）、舒巴坦/美罗培南（17.7%）、舒巴坦/利福平（14.5%）、舒巴坦/替加环素（12.9%）、舒巴坦/黏菌素（6.5%）和舒巴坦/司他夫沙星（4.8%）联合用药表现出明显的协同作用。只有1.6% - 3.2%的联合用药表现出拮抗作用。在时间杀菌试验中，舒巴坦/磷霉素/阿米卡星/美罗培南联合用药对两株分离株在24小时时表现出持续的杀菌活性，而两药和三药联合用药表现出不同程度的协同作用。舒巴坦与现有抗菌药物联合对XDR感染有不同程度的协同作用。值得注意的是，基于舒巴坦的联合治疗对XDR感染的临床实用性需要进一步探索。
重要性
本研究评估了舒巴坦与其他抗生素联合对XDR感染的有效性。采用肉汤微量稀释法和棋盘法对62株临床分离株进行检测。舒巴坦的MIC为64mg/L，替加环素和黏菌素的MIC范围较低，磷霉素的MIC范围较高。舒巴坦/磷霉素（41.9%）的协同活性最为显著，其次是舒巴坦/阿米卡星（19.3%）和舒巴坦/美罗培南（17.7%）。拮抗作用罕见（1.6% - 3.2%）。时间杀菌试验表明，舒巴坦/磷霉素/阿米卡星/美罗培南四联用药在24小时内具有持续的杀菌活性。虽然基于舒巴坦的联合用药表现出不同程度协同作用，但仍需要进一步研究以确定其临床潜力。
