Carbapenem-resistant organisms (CROs) have become a global epidemic problem for many years. The reported rate of carbapenem resistance in non-fermenters, such as Pseudomonas aeruginosa and Acinetobacter baumanii, was higher than that in Enterobacterales (Chamieh et al., 2020). It is of note that the carbapenem resistance rates among the different bacterial isolation sites showed differences, such as the rates for carbapenem-resistant P. aeruginosa (CR-Pae) and carbapenem-resistant A. baumannii in bloodstream infections (BSIs) that were lower than those in respiratory infections (Cai et al., 2017). In China, the proportions of Escherichia coli (9.8%–13.6%) and Klebsiella pneumoniae (5.3%–10.4%) in BSIs increased significantly from 2010 to 2019, while the proportion of P. aeruginosa decreased significantly from 4.0% to 2.4% (Cui et al., 2021). Current evidence revealed that carbapenemase and β-lactamases combined with mutations that decrease permeability were associated with carbapenem resistance (Queenan and Bush, 2007).

Patients with bloodstream infections caused by carbapenem-resistant organisms (BSIs-CROs) suffer from a high risk of mortality, emphasizing the need for novel and rational therapies (Lemos et al., 2014; Martin et al., 2018). Several novel β-lactam/β-lactamase inhibitor combinations have been developed against various CROs, such as ceftazidime–avibactam (CZA), aztreonam–avibactam (AZA), meropenem–vaborbactam, and imipenem/cilastatin–relebactam (Papp-Wallace, 2019). Avibactam, as a bridged diazabicyclo[3.2.1]octanone (DBO) non-β-lactam inhibitor, provides excellent inhibition of class A, class C, and some of the class D β-lactamases (Bush and Bradford, 2019). Recently, CZA represented an important advance in the treatment of infections caused by CR-Pae and carbapenem-resistant Enterobacteriaceae (CRE) (Onorato et al., 2019). However, the activity of CZA against metallo-β-lactamases (MBLs) was limited (Bush and Bradford, 2019). Notably, AZA has been shown to be a potential treatment to inhibit MBLs (Biagi et al., 2019). Therefore, this study aimed to compare the in vitro activity of these two avibactam combinations (CZA and AZA) against BSIs-CROs.

CROs have been implicated in poorer clinical outcomes than are non-CROs (Lemos et al., 2014; Martin et al., 2018). The approval of new β-lactam/β-lactamase inhibitor combinations against CROs has expanded the options for novel therapeutics (Papp-Wallace, 2019). In our study, AZA showed a much higher antibacterial activity against CRE than did CZA. However, the in vitro antibacterial activity of CZA against CR-Pea was superior to that of AZA. In addition, increased concentration of avibactam enhanced the susceptibility of CZA and AZA to CZA-resistant CROs, especially for CRE.

In the present study, CZA showed a higher antibacterial activity against CR-Kpn (87.4%) than against CR-Eco (25.0%) and CR-Pae (81.5%). The susceptibility rate to CZA of CRE was in keeping with the results of a previous study (Yin et al., 2019). However, the susceptibility rate of CR-Pae was higher than that found in a previous study (81.5% vs. 68.0%). This may be due to the different sources of isolates. Carbapenemase genes revealed that bla _NDM was common in CZA-resistant CRE, which was also consistent with other studies (Sader et al., 2017; Yin et al., 2019). In addition, 35% of the CZA-resistant CR-Kpn harbored bla _KPC. Current evidence suggests that the overexpression of bla _KPC played an important role in CZA resistance (Shen et al., 2017). Interestingly, increased concentration of avibactam improved the in vitro activity of CZA against CRE. These results indicated that CZA with avibactam at 4 mg/L had better activity against K. pneumoniae carbapenemase (KPC)-producing CRE, but not against bla _NDM-positive isolates, while CZA with avibactam at 8 and 16 mg/L was active against both bla _KPC-positive and bla _NDM-positive isolates. However, current studies have demonstrated that avibactam did not present in vitro activity against MBL-producing isolates (Yahav et al., 2020). There are few related studies to explain this phenomenon. Therefore, further investigations are needed to evaluate the mechanism of CZA against New Delhi metallo-β-lactamase (NDM)-producing CRE isolates.

The novel combination AZA is known to be relatively stable against both serine carbapenemases and MBL hydrolysis (Cornely et al., 2020). In our study, the MIC₉₀ values of AZA against CR-Eco and CR-Kpn were 2/4 and 1/4 mg/L, respectively, which are similar to the results of a previous study (Sader et al., 2021). Likewise, a better in vitro antibacterial activity of AZA against CRE, especially for CR-Eco, was observed as the concentration of avibactam increased. However, the susceptibility rate of CR-Pae to AZA was lower than that to CZA in this study. Comparable susceptibility results have been reported as well (Wang et al., 2014; Karlowsky et al., 2017). Seven (58.3%) CZA-resistant CR-Pae isolates were negative for the tested carbapenemase genes. A previous study demonstrated that an upregulation of the efflux systems could result in resistance as well (Masuda et al., 2000). Thus, other mechanisms may have resulted in the high-level MIC of AZA. Fortunately, CZA was still active against 62.5% of CR-Pae with a high-level MIC of AZA. In addition, a further test confirmed that the in vitro antibacterial activity of CZA against CR-Pae with a high-level MIC of AZA was improved with increased concentration of avibactam. Therefore, employing the correlation of the clinical outcomes in different dosing regimens with resistance genotypes in BSIs by CR-Pae should be considered.

This study provides an insight into the activity of CZA and AZA against BSIs-CROs. However, there are also several limitations. Firstly, the isolates were only collected from China, especially in EC, which may be different from the rest of the world. Secondly, the majority of the isolates were CR-Kpn. Thirdly, the surveillance data were for 1 year, so it could not comprehensively reflect the dynamic trends of CROs.

In conclusion, both CZA and AZA showed good in vitro antibacterial activity against BSIs-CROs in China. In addition, CZA showed a higher susceptibility to CR-Kpn and CR-Pae, while AZA was highly active against CRE. Furthermore, the in vitro activity of CZA and AZA was improved against CROs with the increase of avibactam concentration. Rational strategies need to be confirmed in further prospective studies.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

In our study, we did not perform any experiments with animals or higher invertebrates, nor performed experiments on humans or the use of human tissue samples.

WY and YX developed the concept. WY and LX designed the experiments. JJ, CY, and ZL performed the laboratory measurements. WY and QL analyzed the data. YC and YX gave conceptual advice. WY and YX wrote the paper. All authors discussed the results and implications and commented on the manuscript at all stages. All authors contributed to the article and approved the submitted version.

This study was funded by the Key Research and Development Program of Zhejiang Province (no. 2021C03068) and the Youth Program of National Natural Science Foundation of China (no. 81803589). The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.