Sulbactam, a β-lactamase inhibitor, is commonly used in combination with β-lactam antibiotics to enhance their efficacy against drug-resistant bacteria[1]. One of the reasons for the development of bacterial resistance to β-lactam antibiotics is the production of β-lactamases[2]. Sulbactam irreversibly binds to bacterial β-lactamases, preventing these enzymes from hydrolyzing β-lactam antibiotics[3], thereby preserving the ability of β-lactam antibiotics to inhibit bacterial cell wall formation[4].
In vitro, when Sulbactam (0.5, 1, 2, 4, 8mg/L) is combined with β-lactam antibiotics (ampicillin, cefoperazone, imipenem) at various ratios (2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3) to treat Acinetobacter baumannii, Sulbactam significantly enhances the bactericidal activity of the antibiotics against A. baumannii [5]. Zidebactam (4mg/L) combined with Sulbactam (0.12–512mg/L) significantly restores the susceptibility of carbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates to Sulbactam. Among 43 CRAB strains, 84% showed a ≥2-fold decrease in MIC of Sulbactam when tested in combination with Zidebactam [6].
In vivo, Sulbactam (10.0mg/kg) was administered via intracerebroventricular injection to prevent ischemic injury in a rat model of cerebral ischemia. The administration began 5 days before the occurrence of ischemia, once daily for a total of 5 consecutive days. Sulbactam pretreatment significantly improved the binding characteristics of glutamate transporter-1 (GLT-1) and inhibited the increase in extracellular glutamate concentration in the CA1 region of the hippocampus in ischemic rats. Sulbactam also protected neurons in the CA1 region and alleviated ischemia-induced delayed neuronal death[7]. Sulbactam (400, 1000, and 2000mg/kg/d) was administered via intraperitoneal injection to induce epilepsy in a chronic renal failure (CRF) mouse model, starting immediately after the CRF model was established. Sulbactam at all three doses significantly induced epileptic seizures in a dose-dependent manner in CRF mice, leading to death. In particular, the high dose (2000mg/kg/d) of Sulbactam caused seizures in CRF mice as early as 3 days after administration[8].
References:
[1] Noguchi JK, Gill MA. Sulbactam: a beta-lactamase inhibitor. Clin Pharm. 1988 Jan;7(1):37-51.
[2] Tooke CL, Hinchliffe P, Bragginton EC, et al. β-Lactamases and β-Lactamase Inhibitors in the 21st Century. J Mol Biol. 2019 Aug 23;431(18):3472-3500.
[3] Akova M. Sulbactam-containing beta-lactamase inhibitor combinations. Clin Microbiol Infect. 2008 Jan;14 Suppl 1:185-8.
[4] Fu Y, Asempa TE, Kuti JL. Unraveling sulbactam-durlobactam: insights into its role in combating infections caused by Acinetobacter baumannii. Expert Rev Anti Infect Ther. 2025 Jan;23(1):67-78.
[5] Wang L, Chen Y, Han R, et al. Sulbactam Enhances in vitro Activity of β-Lactam Antibiotics Against Acinetobacter baumannii. Infect Drug Resist. 2021 Sep 28;14:3971-3977.
[6] Cedano J, Baez M, Pasteran F, et al. Zidebactam restores sulbactam susceptibility against carbapenem-resistant Acinetobacter baumannii isolates. Front Cell Infect Microbiol. 2022 Jul 8;12:918868.
[7] Gu WW, Cui X, Liu LZ, et al. Sulbactam improves binding property and uptake capacity of glutamate transporter-1 and decreases glutamate concentration in the CA1 region of hippocampus of global brain ischemic rats. Amino Acids. 2021 Nov;53(11):1649-1661.
[8] Wu Y, Gu D, Li J, et al. Role of the gut microbiota in cefoperazone/sulbactam-induced epilepsy in mice with chronic renal failure. Ren Fail. 2024 Dec;46(2):2371551.
Sulbactam一种β-内酰胺酶抑制剂，常与β-内酰胺类抗生素联合使用，以增强其对抗耐药菌的效力[1]。细菌产生β-内酰胺类抗生素能力原因之一是β-内酰胺酶的出现[2]，而Sulbactam通过不可逆地结合到细菌的β-内酰胺酶上，阻止这些酶分解β-内酰胺类抗生素[3]，从而保护β-内酰胺类抗生素对细菌细胞壁形成的抑制能力[4]。
在体外，当Sulbactam（0.5、1、2、4、8mg/L）与β-内酰胺类抗生素（氨苄西林、头孢哌酮、亚胺培南）以不同比例（2:1、1:1、1:1.5、1:2、1:2.5、1:3）联合处理鲍曼不动杆菌，显著增强了抗生素对鲍曼不动杆菌的杀菌活性[5]。Zidebactam（4mg/L）联合Sulbactam（0.12–512mg/L）处理耐碳青霉烯类鲍曼不动杆菌（CRAB）临床菌株，显著恢复了CRAB对Sulbactam的敏感性。在43株CRAB菌株中，84%的菌株在联合Zidebactam后对Sulbactam的MIC降低≥2倍稀释度[6]。
在体内，Sulbactam（10.0mg/kg）通过侧脑室注射给药，用于预防脑缺血大鼠模型中的缺血性损伤，给药时间为缺血发生前5天开始，每天一次，连续给药5天。Sulbactam预处理能够显著改善谷氨酸转运体-1（GLT-1）的结合特性，并抑制缺血大鼠海马CA1区细胞外谷氨酸浓度的升高，保护CA1区神经元，减轻缺血引起的迟发性神经元死亡 [7]。Sulbactam（400、1000和2000mg/kg/d）通过腹腔注射给药，以建立慢性肾衰竭（CRF）小鼠模型的癫痫，给药时间为CRF模型建立后立即进行。Sulbactam在所有三个剂量下均能以剂量依赖性方式显著诱导CRF小鼠发生癫痫发作，并导致死亡。特别是高剂量（2000mg/kg/d）的Sulbactam使CRF小鼠在给药后3天内即发生癫痫发作[8]。