Antibacterial activity of tigemonam dicholate (SQ 30836) and interaction with beta-lactamases of gram-negative bacteria

Abstract

SQ 30836 is an orally absorbed salt of tigemonam, a new monobactam similar to aztreonam in structure and microbiologic properties. When assayed against 400 clinical isolates, tigemonam's activity was similar to that of aztreonam and carumonam. It was highly effective against Enterobacteriaceae but showed poor activity against gram-positive organisms. It inhibited 90% of Escherichia coli, Klebsiella, Shigella, Yersinia, Proteus, Providencia, and Morganella strains at 0.5 micrograms/mL or less, and all Salmonella and Hafnia strains at 1 micrograms/mL or less. Citrobacter, Enterobacter, and Serratia strains were less susceptible (minimum inhibitory concentrations [MIC30] of 2, 32, and 8 micrograms/mL respectively). The activity of the new compound against Enterobacteriaceae is comparable with and often higher than that of third-generation cephalosporins and oral comparison compounds. In contrast to aztreonam, tigemonam had minimal activity against Pseudomonas sp and glucose nonfermenting gram-negative bacteria. Data suggest that poor penetration through the outer membranes of Pseudomonas sp may be responsible for this failure. Tigemonam was stable to hydrolysis by plasmid-mediated and chromosomal beta-lactamases. It was more stable than aztreonam to hydrolysis by the Kl enzyme of Klebsiella and by the Proteus vulgaris beta-lactamase. Also, measurement of the IC50 (concentration of inhibitor able to reduce the activity of the enzyme by 59%) showed that tigemonam has less affinity than aztreonam for class I cephalosporinases. However, only levels of beta-lactamase, not hydrolysis rates or affinity, correlated to MICs of the two monobactams for the resistant Enterobacter and Citrobacter strains.