SESSION II Discovery and Development of the Monobactams

A novel procedure designed to detect naturally occurring (3-lactam-containing molecules led to isolation of the monobactams- structurally unique, bacterially produced, monocyclic (3-lactam antibiotics. Although none of these monobactams exhibited im-pressive antimicrobial activity, side-chain variation- as with the penicillins and cephalosporins- resulted in potently active compounds. Aztreonam was chosen from hundreds of compounds for extended laboratory studies. In addition to a unique chemi-cal structure, aztreonam has biologic properties that are unique in comparison with those of the classical penicillins and cephalosporins. Aztreonam is relatively inactive against gram-positive bacteria and anaerobes but is extremely effective against aerobic gram-negative bacteria, including Pseudomonas aeruginosa. The drug is highly resistant to en-zymatic hydrolysis by (3-lactamases, particularly those known to be mediated by R plas-mids, and is a poor inducer of chromosomal (3-lactamases. In the majority of drug com-binations tested, aztreonam exhibits additive or synergistic activity. In a series of animal-model infections, the drug showed a high degree of efficacy that was consistent with findings in studies in vitro. In a hamster model for Clostridium difficile-induce