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.