avibactam

Avibactam is a non–beta-lactam beta-lactamase inhibitor in the diazabicyclooctane class. It is used in combination with certain beta-lactam antibiotics to extend activity against beta-lactamase–producing bacteria. The most widely used formulation is ceftazidime–avibactam, sold as Avycaz in the United States and Zavicefta in Europe. Avibactam inhibits many serine beta-lactamases, including class A enzymes such as KPC, class C cephalosporinases, and many class D enzymes like OXA-48–like enzymes, thereby restoring the activity of ceftazidime against these organisms. It does not inhibit metallo-beta-lactamases (NDM, VIM, IMP) or all other beta-lactamases, and resistance can occur.

Mechanism: Avibactam binds reversibly to the active-site serine of beta-lactamases, forming a reversible acyl-enzyme complex that protects co-administered beta-lactams from hydrolysis.

Clinical use: Ceftazidime–avibactam is approved for complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia including ventilator-associated pneumonia.

Pharmacokinetics and administration: Administered intravenously; primarily renally excreted with dose adjustments in renal impairment. A common adult dose is 2.5 g given every 8 hours (ceftazidime 2 g with avibactam 0.5 g) infused over about 2 hours.

Safety and resistance: Adverse events resemble those of cephalosporins (diarrhea, nausea, vomiting, headache); hypersensitivity and C. difficile risk exist. Because avibactam does not inhibit metallo-beta-lactamases, pathogens producing these enzymes may be resistant; aztreonam–avibactam is being explored to address some of these cases.

Regulatory status: FDA approved ceftazidime–avibactam in 2015; EMA approvals followed; indicated for complicated intra-abdominal infections, complicated urinary tract infections, and hospital-acquired pneumonia including ventilator-associated pneumonia.