Aztreonam plus clavulanate, tazobactam or avibactam for the treatment of metallo-β-lactamase-producing-Gram negative related infections

Abstract

Metallo-β-lactamase (MBL)-producing Gram negatives are often extremely-resistant, leading to real therapeutic dead-end. Here, we evaluated the in vitro and in vivo efficacy of aztreonam in combination with ceftazidime-avibactam, ceftolozane-tazobactam or amoxicillin-clavulanate for the treatment of infections caused by MBL-producing Enterobacteriaceae, MBL-producing P. aeruginosa and extremely drug-resistant S. maltophilia. First, we report two clinical cases: a urinary tract infection caused by NDM-5-producing E. coli isolate and a pulmonary infection caused by S. maltophilia efficiently treated with association of aztreonam/ceftazidime-avibactam and aztreonam/amoxicillin-clavulanate, respectively. Then, a total of 50 MBL-producing Enterobacteriaceae, 3 MBL-producing P. aeruginosa and 5 extremely drug-resistant S. maltophila isolates were used to test aztreonam susceptibility in combination with ceftolozane-tazobactam, ceftazidime-avibactam or amoxicillin-clavulanate. Etest® strip superposition method was used to determine the MICs of the aztreonam/inhibitor combinations. According to CLSI breakpoints, aztreonam susceptibility was fully restored for 86%, 20% and 50% of the MBL-producing Enterobacteriaceae when combined with ceftazidime-avibactam, ceftolozane-tazobactam and amoxicillin-clavulanate, respectively. In P. aeruginosa, the aztreonam/ceftazidime-avibactam combination was the most potent, even though reduction in MICs was at most two-fold. With the 5 S. maltophilia isolates aztreonam/ceftazidime-avibactam and aztreonam/amoxicillin-clavulanate were found to be equal (100% susceptibility). Overall, Aztreonam/ceftazidime-avibactam was the most potent combination to treat infections caused by MBL producers compared to aztreonam/amoxillin-clavulanate and aztreonam/ceftolozane-tazobactam. However, in many cases aztreonam/amoxillin-clavulanate was found to be as efficient as aztreonam/ceftazidime-avibactam, offering the main advantage to be markedly cheaper. We also confirmed the validity of Etest® superpositions as a very simple method to determine MICs of aztreonam combinations.