Some Gram-negative pathogens have accumulated enough resistance mechanisms to render them virtually untreatable by modern antibacterial chemotherapy. A mainstay for the treatment of Gram-negative infections is the β-lactam classes of drugs. The most common form of resistance to β-lactam antibiotics is the expression of various β-lactamase enzymes capable of hydrolyzing the β-lactam ring of β-lactam drugs, rendering them ineffective. In efforts to restore the efficacy of β-lactam antibiotics, β-lactamases have also been targeted with a variety of inhibitors. However, the three inhibitors, Clavulanic acid, Tazobactam, and Sulbactam, contain a β-lactam core. In this study, Avibactam is a member of a class of inhibitors. It is a covalent, reversible, non-β-lactam β-lactamase inhibitor. More importantly, Avibactam does not contain a β-lactam core but maintains the capacity to covalently acylate its β-lactamase targets. In addition, Ceftazidime-avibactam is a combination of the third-generation cephalosporin ceftazidime and the non-β-lactam β-lactamase inhibitor avibactam.
Avibactam inhibits β-lactamase TEM-1 and CTX-M-15 with IC50s of 8 nM and 5 nM, respectively. Avibactam also inhibits class A, C, and some class D β-lactamases. Furthermore, Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor combination for the treatment of serious infections caused by resistant gram-negative pathogens. Ceftazidime/avibactam is also a beta-lactam/beta-lactamase combination antibiotic. It has the potential for the treatment of complicated urinary tract infections, complicated intra-abdominal infections, and for hospital-acquired/ventilator-associated pneumonia. In addition, Aztreonam/avibactam is under development for treatment of serious infections.
In summary, Avibactam is a covalent, slowly reversible inhibitor. It is a unique mechanism of inhibition among β-lactamase inhibitors. Avibactam can combine with β-lactam partners, has the potential for the treatment of bacterial infections comprising gram-negative organisms.
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