Avibactam (sodium salt) (NXL104, AVE1330A) is a covalent, reversible inhibitor of non-β-lactam β-lactamases. It effectively inhibits β-lactamase TEM-1 and CTX-M-15 with IC50 values of 8 nM and 5 nM, respectively. Avibactam is active against Ambler class A and C β-lactamases and also shows activity against certain Ambler class D enzymes. The mechanism of action of Avibactam is the formation of stable, irreversible covalent bonds at the active site of class A or class C beta-lactamases, resulting in permanent inactivation of the enzyme[1-3].
Avibactam (sodium salt) at a fixed concentration of 4 μg/ml dramatically improves the activities of cephalosporins against Enterobacteriaceae resistant to these agents by means of ESBL and AmpC β-lactamases[4-5].
Avibactam (sodium salt) and ceftazidime had bactericidal effects in infected with ceftazidime resistant Pseudomonas aeruginosa mice[6]. The addition of the beta-lactamase inhibitor avibactam (2-256 mg/kg; s.c; twice a day for five days) to ceftazidime restored the efficacy of ceftazidime in a mouse model of acute fatal septicemia in mice[7].
References:
[1]. Ehmann DE, Jahić H, et,al. Avibactam is a covalent, reversible, non-β-lactam β-lactamase inhibitor. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11663-8. doi: 10.1073/pnas.1205073109. Epub 2012 Jul 2. PMID: 22753474; PMCID: PMC3406822.
[2]. Bhattacharya S, Bonnet A, et,al. inventors; Novexel SA and Forest laboratories holdings, assignees. Polymorphic and pseudopolymorphic forms of a pharmaceutical compound. International patent WO 042560 A2. 2011 April 14.
[3]. Stachyra T, Péchereau MC, et,al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-beta-lactam beta-lactamase inhibitor. Antimicrob Agents Chemother. 2010 Dec;54(12):5132-8. doi: 10.1128/AAC.00568-10. Epub 2010 Oct 4. PMID: 20921316; PMCID: PMC2981269.
[4]. Lagacé-Wiens PR, Tailor F, et,al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C beta-lactamases. Antimicrob Agents Chemother. 2011 May;55(5):2434-7. doi: 10.1128/AAC.01722-10. Epub 2011 Feb 28. PMID: 21357295; PMCID: PMC3088241.
[5]. Sader HS, Castanheira M, et,al. Antimicrobial activity of ceftazidime-avibactam against Gram-negative organisms collected from U.S. medical centers in 2012. Antimicrob Agents Chemother. 2014;58(3):1684-92. doi: 10.1128/AAC.02429-13. Epub 2013 Dec 30. PMID: 24379201; PMCID: PMC3957905.
[6]. Berkhout J, Melchers MJ, et,al. Pharmacokinetics and penetration of ceftazidime and avibactam into epithelial lining fluid in thigh- and lung-infected mice. Antimicrob Agents Chemother. 2015 Apr;59(4):2299-304. doi: 10.1128/AAC.04627-14. Epub 2015 Feb 2. PMID: 25645843; PMCID: PMC4356781.
[7]. Endimiani A, Hujer KM, et,al. Evaluation of ceftazidime and NXL104 in two murine models of infection due to KPC-producing Klebsiella pneumoniae. Antimicrob Agents Chemother. 2011 Jan;55(1):82-5. doi: 10.1128/AAC.01198-10. Epub 2010 Nov 1. PMID: 21041503; PMCID: PMC3019638.
Avibactam (sodium salt)(NXL104, AVE1330A)是一种共价且可逆的非β-内酰胺类β-内酰胺酶抑制剂，有效抑制β-内酰胺酶TEM-1和CTX-M-15，IC50值分别为8 nM和5 nM。Avibactam对Ambler A类和C类β-内酰胺酶具有活性，并对某些Ambler D类酶也具有一定的活性。Avibactam的作用机制是在A类或C类β-内酰胺酶的活性位点形成稳定的、不可逆的共价键，导致酶永久失活[1-3]。
固定浓度4 μg/ml的Avibactam可通过ESBL和AmpC β-内酰胺酶显著提高头孢菌素对耐药肠杆菌科细菌的活性[4-5]。Avibactam和ceftazidime对耐ceftazidime的铜绿假单胞菌感染小鼠有杀菌作用[6]。在小鼠急性致死性败血症小鼠模型中，加入ceftazidime (2-256 mg/kg; s.c; twice a day for five days)可恢复ceftazidime的疗效[7]。