Exploring Aztreonam in Combination with Ceftazidime-Avibactam or Meropenem-Vaborbactam as Potential Treatments for Metallo- and Serine-β-Lactamase-Producing Enterobacteriaceae

Abstract

Metallo-β-lactamase (MBL)-producing Enterobacteriaceae, particularly those that coharbor serine β-lactamases, are a serious emerging public health threat given their rapid dissemination and the limited number of treatment options. Preclinical and anecdotal clinical data support the use of aztreonam in combination with ceftazidime-avibactam against these pathogens, but other aztreonam-based combinations have not been explored. The objective of this study was to evaluate the in vitro activity and compare synergy between aztreonam in combination with ceftazidime-avibactam and meropenem-vaborbactam against serine and MBL-producing Enterobacteriaceae via time-kill analyses. Eight clinical Enterobacteriaceae strains (4 Escherichia coli and 4 Klebsiella pneumoniae) coproducing NDM and at least one serine β-lactamase were used for all experiments. Drugs were tested alone, in dual β-lactam combinations, and in triple-drug combinations against all strains. All strains were resistant to ceftazidime-avibactam and meropenem-vaborbactam and 7/8 (87.5%) strains were resistant to aztreonam. Aztreonam combined with ceftazidime-avibactam was synergistic against all 7 aztreonam-resistant strains. Aztreonam combined with meropenem-vaborbactam was synergistic against all aztreonam-resistant strains with the exception of an OXA-232-producing K. pneumoniae strain. Neither triple combination was synergistic against the aztreonam-susceptible strain. These data suggest that aztreonam plus meropenem-vaborbactam has similar activity to aztreonam plus ceftazidime-avibactam against Enterobacteriaceae producing NDM and other non-OXA-48-like serine β-lactamases. Confirmation of these findings in future in vitro and in vivo models is warranted.

Therapeutic Options for Metallo-β-Lactamase-Producing Enterobacterales

“…44 Thus, a combination between ATM and a β-lactam/β-lactamase inhibitor such as ceftazidime-avibactam (CAZ-AVI) has become an attractive combination with synergistic in vitro activity, even against pathogens co-producing metallo-and serine βlactamases. [45][46][47][48][49][50] This in vitro synergy has also been observed against NDM producing K. pneumoniae in the murine neutropenic thigh infection model. 46 Avibactam's spectrum of activity includes Class A, C, and some D β-lactamases, including clinically important…”

Dissemination of Carbapenemases (KPC, NDM, OXA-48, IMP, and VIM) Among Carbapenem-Resistant Enterobacteriaceae Isolated From Adult and Children Patients in China

“…These findings limited the utility of ceftazidime-avibactam and polymyxin B and prompted the development of novel or combinational therapies to combat CRE strains. For example, aztreonam plus meropenem-vaborbactam and aztreonam plus ceftazidimeavibactam showed good antibacterial activity against NDMand non-OXA-48-like producing Enterobacteriaceae (Biagi et al, 2019). The combination of colistin and amikacin showed consistently bactericidal against NDM-5-bearing mcr-1-positive E. coli, which might be an alternative therapeutic option for the treatment of lethal infections (Zhou et al, 2017).…”

Microbiology of Meropenem-Vaborbactam: A Novel Carbapenem Beta-Lactamase Inhibitor Combination for Carbapenem-Resistant Enterobacterales Infections

“…In an effort to explore optimal combinations of antimicrobial agents with activity against serine and MBL-producing CROs, the activity of aztreonam plus ceftazidime-avibactam and aztreonam plus meropenem-vaborbactam against clinical E. coli and K. pneumoniae strains coproducing NDM and one or more serine β-lactamases was evaluated and compared in a recent in vitro study [ 6 ]. The addition of aztreonam with each of these combination agents resulted in synergistic activity against enterobacteriaceae strains that co-produce NDM and at least one serine β-lactamase, with the anticipated exception of aztreonam plus meropenem-vaborbactam having no activity against OXA-48-like-producing enterobacteriaceae strains.…”

“…These combinations maintain the efficacy of the β-lactam class of antibiotics and expand the spectrum of activity against gram-negative pathogens [ 4 , 5 ]. However, these β-lactam inhibitors are only active against some Class A, SHV, TEM, Klebsiella pneumoniae carbapenemase (KPC) enzymes; none of these β-lactamase inhibitors have activity against the emerging and more resistant Class B (NDM IMP, VIM), C (not true carbapenemase), or D (OXAs) enzymes [ 6 ].…”