Past, present, and future perspectives on aztreonam and avibactam

Aztreonam is a monobactam antibiotic approved in 1986 to treat infections caused by aerobic Gram-negative bacteria, but, together with cephalosporins, lost clinical utility due to the emergence of extended-spectrum β-lactamases (ESBLs) and novel (serine) carbapenemases. Avibactam was the first in a novel non-β-lactam β-lactamase inhibitor class to effectively inhibit these enzymes. It has been approved in combination with ceftazidime to treat Gram-negative infections caused by bacteria that produce AmpC, ESBLs and serine carbapenemases, and with aztreonam to treat patients infected with metallo-β-lactamase-producing enteric bacteria. Combinations of avibactam with ceftazidime and/or aztreonam have been used successfully to treat enteric pathogens producing multiple classes of β-lactamases.

Development of aztreonam, avibactam, and avibactam combinations are placed into a historical perspective, based on both preclinical and clinical data. A search of MEDLINE (Ovid) was used to identify relevant literature.

Avibactam combined with ceftazidime and aztreonam in either dual or triple combinations provides the opportunity to treat previously untreatable Gram-negative infections that produce multiple β-lactamases. Aztreonam combinations should be particularly attractive, due to stability to metallo-β-lactamase hydrolysis and its safety advantage in treating penicillin-allergic patients. Other inhibitor combinations in development may challenge these combinations.