The Revival of Aztreonam in Combination with Avibactam against Metallo-β-Lactamase-Producing Gram-Negatives: A Systematic Review of In Vitro Studies and Clinical Cases

Abstract

Infections caused by metallo-β-lactamase (MBL)-producing Enterobacterales and Pseudomonas are increasingly reported worldwide and are usually associated with high mortality rates (>30%). Neither standard therapy nor consensus for the management of these infections exist. Aztreonam, an old β-lactam antibiotic, is not hydrolyzed by MBLs. However, since many MBL-producing strains co-produce enzymes that could hydrolyze aztreonam (e.g., AmpC, ESBL), a robust β-lactamase inhibitor such as avibactam could be given as a partner drug. We performed a systematic review including 35 in vitro and 18 in vivo studies on the combination aztreonam + avibactam for infections sustained by MBL-producing Gram-negatives. In vitro data on 2209 Gram-negatives were available, showing the high antimicrobial activity of aztreonam (MIC ≤ 4 mg/L when combined with avibactam) in 80% of MBL-producing Enterobacterales, 85% of Stenotrophomonas and 6% of MBL-producing Pseudomonas. Clinical data were available for 94 patients: 83% of them had bloodstream infections. Clinical resolution within 30 days was reported in 80% of infected patients. Analyzing only patients with bloodstream infections (64 patients), death occurred in 19% of patients treated with aztreonam + ceftazidime/avibactam. The combination aztreonam + avibactam appears to be a promising option against MBL-producing bacteria (especially Enterobacterales, much less for Pseudomonas) while waiting for new antimicrobials.

Antimicrobial Activity of Aztreonam in Combination with Old and New β-Lactamase Inhibitors against MBL and ESBL Co-Producing Gram-Negative Clinical Isolates: Possible Options for the Treatment of Complicated Infections

“…Pending the development of new molecules, combinations of ATM with different BLIs are being investigated for the treatment of infections sustained by Enterobacterales expressing both serine-ß-lactamases and MBLs [ 22 , 23 ]. The combination of ATM with AVI was one of the most promising and has also been used in clinical settings with relatively good results [ 7 ]. Our data showed that, against MBL-producers, DBO derivatives were the most active BLIs when combined with ATM.…”

“…The only β-lactam effective, because it is not hydrolyzed, against MBL-producers is ATM, a monobactam approved in 1986 but currently infrequently used due to the spread of extended-spectrum β-lactamases (ESBLs) [ 7 ]. ATM is effective against MBL-producer infections as long as these isolates are ESBL-negative.…”

“…Indeed, recent studies demonstrated a good efficacy of ATM–AVI combinations against Enterobacterales , including MBL-producers [ 9 , 10 ]. This association has been also used in the clinical settings with most of the cases showing a favorable outcome [ 7 ].…”

Treatment of Severe Infections Due to Metallo-Betalactamases Enterobacterales in Critically Ill Patients

“…Indeed, CZA is active against Ambler A, C and D beta-lactamases including extended spectrum beta-lactamases such as CTX-M, AmpC and OXA-48. In a systematic review of in vitro data, MIC values ≤ 4 mg/L for ATM in combination with CZA have been described in 79.6% of the MBL-producing Enterobacterales [ 26 ].…”

“…The association was tested as a last-resort therapy and reported in a growing number of case-reports and cohorts [ 26 ]. In a multicenter cohort of 102 patients with BSI due to MBL-producing Enterobacterales (NDM n = 82, VIM n = 20), Falcone et al compared the activity of CZA/ATM with other various combination therapies [ 27 ].…”