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.

Roberta Migliavacca,Cristina Lagatolla,Raffaela Bressan,Carola Mauri,Francesco Comandatore,Francesco Luzzaro,Simona Fioriti,Gloria D’Achille,Aurora Piazza,Oscar Cirioni,Gianluca Morroni,Marina Mingoia,Stefano Di Bella,Luigi Principe

doi:10.3390/antibiotics10111341

Abstract

Metallo-β-lactamases (MBLs) are among the most challenging bacterial enzymes to overcome. Aztreonam (ATM) is the only β-lactam not hydrolyzed by MBLs but is often inactivated by co-produced extended-spectrum β-lactamases (ESBL). We assessed the activity of the combination of ATM with old and new β-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates. Six Enterobacterales and three non-fermenting bacilli co-producing MBL and ESBL determinants were selected as difficult-to-treat pathogens. ESBLs and MBLs genes were characterized by PCR and sequencing. The activity of ATM in combination with seven different BLIs (clavulanate, sulbactam, tazobactam, vaborbactam, avibactam, relebactam, zidebactam) was assessed by microdilution assay and time–kill curve. ATM plus avibactam was the most effective combination, able to restore ATM susceptibility in four out of nine tested isolates, reaching in some cases a 128-fold reduction of the MIC of ATM. In addition, relebactam and zidebactam showed to be effective, but with lesser reduction of the MIC of ATM. E. meningoseptica and C. indologenes were not inhibited by any ATM–BLI combination. ATM–BLI combinations demonstrated to be promising against MBL and ESBL co-producers, hence providing multiple options for treatment of related infections. However, no effective combination was found for some non-fermentative bacilli, suggesting the presence of additional resistance mechanisms that complicate the choice of an active therapy.

Highlights

Infections sustained by metallo-β-lactamases (MBLs)-producing bacteria pose a global challenge due to the paucity of effective antibiotic options
The aim of the present work was to assess the activity of ATM in association with both old and new (AVI, REL, VAB, ZID) by currently available β-lactams inhibitors (BLIs), to understand the antimicrobial activity of these combinations against different MBL- and ESBL-producers
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]

Summary

Introduction

Infections sustained by metallo-β-lactamases (MBLs)-producing bacteria pose a global challenge due to the paucity of effective antibiotic options. From serine-β-lactamases, MBLs are Zn-dependent metalloproteinases which are non-susceptible to inactivation by currently available β-lactams inhibitors (BLIs), including vaborbactam (VAB), a cyclic boronate, and avibactam (AVI), a diazabicyclooctanone (DBO) derivative [3]. 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]. Due to the common association of MBL with other β-lactamases (especially ESBL and AmpC), a novel combination including ATM and AVI has been proposed but is not yet commercially available. AVI is a non-BLI that blocks β-lactamases through a reversible bond and is currently approved in association with ceftazidime for the treatment of complicated urinary tract infections (cUTI), intra-abdominal infections (IAI), pneumonia, and other infections sustained by Gram-negative bacteria [8]. Recent studies demonstrated a good efficacy of ATM–AVI combinations against Enterobacterales, including MBL-producers [9,10]

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