In vitro synergistic activity of aztreonam (AZT) plus novel and old β-lactamase inhibitor combinations against metallo-β-lactamase-producing AZT-resistant Enterobacterales

Abstract

The emergence of metallo-β-lactamase (MBL)-producing Enterobacterales , mainly New Delhi metallo-β-lactamase (NDM), represents a clinical threat due to the limited therapeutic alternatives. Aztreonam (AZT) is stable to MBLs, but most MBL-producing Enterobacterales isolates usually co-harbour other β-lactamases that confer resistance to AZT and, consequently, its use is restricted in these isolates. We compared the ability of sulbactam (SUL), tazobactam (TAZ), clavulanic acid (CLA) and avibactam (AVI) to restore the AZT activity in MBL-producing AZT-resistant Enterobacterales isolates. A collection of 64 NDM-producing AZT-resistant Enterobacterales from five hospitals in Buenos Aires city, Argentina, were studied during the period July–December 2020. MICs were determined using the agar dilution method with Mueller–Hinton agar according to Clinical and Laboratory Standards Institute (CLSI) recommendations. AVI, SUL and TAZ were used at a fixed concentration of 4 mg l−1, whereas CLA was used at a fixed concentration of 2 mg l−1. A screening method based on disc diffusion to evaluate this synergy was also conducted. Detection of bla KPC, bla OXA, bla NDM, bla VIM, bla CTXM-1, bla PER-2 and bla CIT was performed by PCR. The AZT-AVI combination restored the AZT activity in 98.4 % of AZT-resistant strains, whereas CLA, TAZ and SUL did so in 70.3, 15.6 and 12.5 %, respectively, in isolates co-harbouring extended-spectrum β-lactamases, but were inactive in isolates harbouring AmpC-type enzymes and/or KPC. The synergy screening test showed an excellent negative predictive value to confirm the absence of synergy, but positive results should be confirmed by a quantitative method. The excellent in vitro performance of the AZT-CLA combination represents a much more economical alternative to AZT-AVI, which could be of use in the treatment of MBL-producing, AZT-resistant Enterobacterales .

Drug development concerning metallo-β-lactamases in gram-negative bacteria

“…Thus, MBLs are capable of inactivating almost all β-lactams, with the exception of aztreonam. Nevertheless, the use of aztreonam was also limited by the fact that MBL-producing strains carried SBLs, which requires broad-spectrum inhibitors (Cervino et al, 2021 ). Therefore, the development of new drugs against MBL or MBL +SBL producers has become a global biomedical research hotspot.…”

“…A series of in vitro studies on the combined effects of aztreonam+AVI against MBLs have been carried out. Aztreonam+AVI (≤0.015–4+4 μg/ml) has strong antibacterial activity on Enterobacteriaceae producing MBLs alone or both MBLs and SBLs (Karlowsky et al, 2017 ; Biagi et al, 2019 ; Niu et al, 2020 ; Zhang et al, 2020 ; Bhatnagar et al, 2021 ; Cervino et al, 2021 ; Feng et al, 2021 ). Karlowsky et al found that aztreonam+AVI (4 μg/ml+4 μg/ml) also has a good inhibitory effect on a small portion of MBL- P. aeruginosa isolates (63/452) (Karlowsky et al, 2017 ).…”

“…Aztreonam was approved by the FDA in 1986 and is the only clinically available monocyclic lactam antibiotic against MBLs due to its structural stability in the presence of MBLs (Ramsey and MacGowan, 2016 ). However, the majority of MBL-carrying isolates coproduce one or more SBLs, which limits its usefulness as a monotherapy (Cervino et al, 2021 ). CAZ-AVI is a drug in phase 3 clinical trials and has been recommended by the Infectious Diseases Society of America in combination with aztreonam for the treatment of severe infections caused by MBL-carrying Enterobacteriaceae (Tamma et al, 2021 ).…”

Pharmacokinetic/Pharmacodynamic Evaluation of Aztreonam/Amoxicillin/Clavulanate Combination against New Delhi Metallo-β-Lactamase and Serine-β-Lactamase Co-Producing Escherichia coli and Klebsiella pneumoniae

“…Aztreonam/avibactam is currently being investigated as a treatment option against MBL-producing Gram-negative bacteria [ 12 ]. Even though aztreonam is impervious to MBL, the concerted expressions of extended-spectrum β-lactamases (ESBL) in MDR bacteria can hydrolyze aztreonam [ 13 ]. Aztreonam combined with old and new β-lactamase inhibitors is being evaluated against MBL and ESBL co-producing Gram-negative clinical isolates as a possible option for the treatment of complicated infections [ 14 ].…”