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. 2026 Sep 22;15(1):2732702. doi: 10.1080/22221751.2026.2732702

Breaking the deadlock of metallo-β-lactamases: evidence and prospects for Aztreonam/Avibactam

Junxin Zhou a,b,c, Rui Weng a,b, Yining Ye a,b, Xinhong Han d, Huangdu Hu e, Wenzeng Xu a,b, Qiucheng Shi f, Yinping Wang a,b, Weiyi Huang a,b, Jingjing Quan a,b, Ping Zhang a,b, Ying Fu g, Jintao He h, Zhihui Zhou a,b, Xiaoxing Du a,b, Dongdong Zhao a,b,CONTACT, Yan Jiang a,b,✉, Yunsong Yu a,b,✉
PMCID: PMC13618160  PMID: 42773792

ABSTRACT

Multidrug-resistant Gram-negative bacteria pose a significant threat to global public health, with resistance mediated by metallo-β-lactamases being particularly prominent. Aztreonam/avibactam (AZA), a novel β-lactam/β-lactamase inhibitor combination, had been approved in China and the European Union for treating complicated intra-abdominal infections and hospital-acquired pneumonia (including ventilator-associated pneumonia) in adults. The combination exhibits broad-spectrum antimicrobial activity against carbapenemase-producing Enterobacterales. It inhibits KPC and OXA-48, and importantly, aztreonam (ATM) is stable against metallo-β-lactamases. Current in vitro activity studies strongly support the use of AZA against MBL-producing Enterobacterales, while its activity against non-fermenting bacteria appears to vary depending on the species and isolate, requiring further clinical confirmation. As a prime example of “repurposing existing drugs,” its pharmacokinetics and pharmacodynamics have been thoroughly studied, and phase III studies have provided supportive safety and efficacy data, but the clinical evidence specifically concerning microbiologically confirmed MBL-producing infections remains limited and exploratory because of very small subgroup sizes. It is important to note that the combination of ceftazidime/avibactam (CZA) with ATM differs significantly from AZA in pharmacokinetic properties. Therefore, CZA plus ATM (CZA + ATM) cannot be considered an equivalent substitute for AZA. Currently, the resistance rate for AZA is low, with most cases being isolated events. The primary mechanisms of resistance involve mutations in the PBP3 gene, mutations and overexpression of β-lactamases, reduced outer membrane permeability, and overexpression of efflux pumps. Available data suggest that AZA is an important treatment option for severe infections caused by multidrug-resistant Enterobacterales, including MBL-producing strains, although pharmacoeconomic conclusions remain context-dependent.

KEYWORDS: MBLs, BLBLIs, Aztreonam/avibactam, PK/PD, PBP3 insertion

Introduction

Since the advent of antimicrobial agents, antimicrobial resistance (AMR) has posed a global public health challenge. Between 1990 and 2019, deaths directly attributable to AMR increased from 1.06 million to 1.20 million, with projections reaching 1.91 million by 2050 [1]. Carbapenem resistance has risen most rapidly, with deaths increasing by 70% from 1990 to 2021 [1]. Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major contributor to this mortality. In 2024, the World Health Organization continued to list carbapenem-resistant Enterobacterales (CRE) as a serious threat [2, 3]. In China, imipenem resistance among Enterobacterales rose from 3.1% in 2005–11.1% in 2024, remaining above 10% for seven years. Carbapenem-resistant Escherichia coli (CREC) and CRKP account for 80–90% of CRE [4, 5]. The primary resistance mechanism is carbapenemases production, with species and geographic variation. Globally, KPC is the most common in CRKP (e.g. 94% CRKP strains carried blaKPC-2 in China), while NDM predominates in CREC, especially the NDM-5 subtype [6, 7].

Recent novel β-lactam/β-lactamase inhibitor combinations (BLBLIs) are facing rising resistance. In China, the proportion of CRKP isolates resistant to CZA increased from 6.9% in 2021 to 7.6% in 2024. CZA resistance mainly arises from KPC mutations and metallo β-lactamases (MBLs), with the MBLs conferring broader resistance (including to carbapenems and most novel BLBLIs)[8]. The proportion of CRKP co-producing KPC and NDM (KN-CRKP) has risen globally from 0.03% in 2014 to 3.10% in 2023, often causing local outbreaks [9].

Certain populations show a significantly higher MBL carriage among CRKP: 5–10% in routine intensive care units, 24% in bloodstream infections among hematological malignancy patients, 16.4% in their intestinal colonizers, and as high as 60–70% in pediatric patients [10–13.] In China, other Enterobacterales (e.g. Enterobacter cloacae complex and Citrobacter species) also exhibit high MBL carriage rates in China [14].

Aztreonam (ATM) is the only clinically available monobactam. However, ATM alone is generally ineffective against MBL-producing CRE [15]. Biochemical studies suggest that ATM is spared from MBL-mediated hydrolysis because it binds MBLs in a nonproductive orientation: its sulfonate group interacts with the zinc centre, while the β-lactam ring is positioned away from the zinc-activated nucleophile required for hydrolysis [16, 17]. In contrast, serine enzymes readily hydrolyze ATM, rendering it inactive. Although MBLs do not hydrolyze ATM, most MBL-producing strains co-carry other serine β-lactamases, such as extended-spectrum β-lactamases (ESBLs), AmpC, or even serine carbapenemases like KPC. Avibactam is a non-β-lactam β-lactamase inhibitor that reversibly inhibits serine β-lactamases (ESBLs, AmpC, KPC, OXA-48) and is not hydrolyzed by MBLs. When combined, ATM is protected by avibactam from hydrolysis by co-produced serine enzymes, while the MBLs remain unaffected but cannot destroy ATM. This combination has been validated in animal models to overcome MBL-mediated resistance, making it the current theoretical optimal regimen for otherwise untreatable MBL-producing CRE infections [18]. This review aims to systematically summarize the pharmacodynamics, pharmacokinetics, clinical efficacy, safety profile, and resistance mechanisms of aztreonam/avibactam (AZA), thereby providing guidance for its rational clinical application.

Literature search strategy

A literature search was conducted in PubMed for studies published from January 2010 to December 2025. The main search terms included “aztreonam-avibactam,” “aztreonam/avibactam,” “ATM-AVI,” “metallo-β-lactamase,” “MBL,” “carbapenem-resistant Enterobacterales,” “CRE,” “minimum inhibitory concentration,” “MIC,” “pharmacokinetics,” “pharmacodynamics,” “clinical trial,” and “ceftazidime-avibactam plus aztreonam.” Additional relevant articles were identified from drug instructions and regulatory documents. Eligible studies included in vitro susceptibility studies, surveillance studies, PK/PD analyses, clinical trials, observational studies, case series, safety studies, and pharmacoeconomic analyses related to AZA or CZA plus aztreonam.

Development strategy for AZA

MBLs are classified into B1, B2, and B3 based on zinc-coordinating ligands and the number of metal ions in the active site: B1 and B3 typically contain two zinc ions, while B2 contains one [19]. Zinc ions are central to MBL function because they participate directly in substrate binding and β-lactam hydrolysis, including activation of the nucleophilic water/hydroxide required for ring opening [17]. However, sequence similarity is very low across subclasses (<20%), and even within B1 it is relatively low (∼30%), with few highly conserved residues beyond the zinc ligands [19]. These inherent characteristics fundamentally increase the difficulty of designing broad-spectrum inhibitors. At the same time, MBLs share structural similarities with certain human enzymes; inhibitors must effectively bind to the zinc ion in the active site of MBLs while avoiding inhibition of other metalloproteases or cysteine proteases in the human body to prevent off-target toxicity [20]. The importance of zinc extends beyond catalysis. During infection, host nutritional immunity restricts zinc availability, which can reduce MBL activity and destabilize non-metallated apo-MBLs in the periplasm [21]. Furthermore, in a zinc-limited infection microenvironment, bacteria can evolve MBLs with enhanced apo-form stability and higher zinc-binding affinity, thereby diminishing the efficacy of inhibitors [22]. Clinically successful enzymes such as NDM-1 have evolved strategies to overcome this pressure, including membrane anchoring, improved in-cell stability, and variants with enhanced zinc affinity or mono-zinc activity [23, 24]. Thus, zinc availability, zinc binding, enzyme stability, and catalytic activity are tightly linked, collectively representing major challenges in MBL inhibitor research and development.

Given the current critical situation regarding MBL-producing strains and the ongoing development of MBL inhibitors, therapeutic options for treating infections caused by MBL-producing strains remain severely limited. Studies testing the in vitro activity of ATM combined with avibactam were conducted as early as 2011, demonstrating potent bactericidal activity against CRE (including those producing MBLs). However, the commercialized AZA was not approved by the European Union until April 2024 for the treatment of patients with complicated intra-abdominal infections (cIAIs), hospital-acquired pneumonia (HAP), and complicated urinary tract infections (cUTIs). CZA received FDA approval for use in 2015. Therefore, during periods when AZA was unavailable, CZA + ATM became an alternative treatment option.

In 2017, it was first reported that combining CZA + ATM effectively overcame resistance of Enterobacteriaceae producing MBLs[25]. This regimen is based on the stability of ATM against MBLs, and the protection that CZA provides against hydrolysis of ESBLs and AmpC. Furthermore, the combination of the two drugs may produce a synergistic effect by simultaneously inhibiting multiple penicillin-binding proteins.

In vitro antimicrobial activity of AZA

From 2011 to December 2025, 51 studies have confirmed the efficacy of AZA against Enterobacterales, with an overall 50% minimum inhibitory concentration (MIC50) value of ≤0.03–0.12 mg/L and a 90% minimum inhibitory concentration (MIC90) value of 0.12–2 mg/L. For CRE strains, MIC50 and MIC90 values ranged from 0.12–1 mg/L and 0.5–4 mg/L, respectively (Table 1). Notably, AZA exhibits favourable in vitro activity against CRE strains producing various carbapenemases, particularly against those producing MBLs. Specifically, for KPC-producing CRE, the MIC50 ranged from 0.12 to 0.5 mg/L, with MIC90 values between 0.25 and 2 mg/L; for OXA-48-like-producing CRE, the MIC50 ranged from 0.12 to 0.25 mg/L, MIC90 was 0.25–1 mg/L; for MBL-producing CRE (involving 31 studies), MIC50 was ≤0.03–1 mg/L, with MIC90 ranging from 0.25 to 1 mg/L. Furthermore, CRE strains lacking carbapenemases (such as those with porin deficiency combined with high AmpC/ESBLs production) also exhibit sensitivity, though their overall susceptibility was lower than that of carbapenemase-producing strains. Their MIC50 values ranged from ≤0.12–0.5 mg/L, while MIC90 values fell between 0.5 and 16 mg/L. It is noteworthy that two studies reported MIC90 values as high as 16 and 8 mg/L respectively, significantly exceeding those reported in other investigations [26, 27]. Kim et al. reported that the MIC₉₀ of AZA against non-CP-CRE strains (8 mg/L) was higher than that against CP-CRE strains (1 mg/L), though the underlying mechanism in non-CP-CRE remains unknown due to a lack of genomic analysis [27]. In contrast, Mushtaq et al. performed whole-genome sequencing on seven E. coli isolates with MICs ≥ 8 mg/L and identified ftsI insertion mutations (YRIN or YRIK after Pro333) in six strains, all of which also carried acquired AmpC (CMY-42 in five and CMY-146 in one) [26].

Table 1.

In vitro activity of aztreonam/avibactam against Enterobacterales.

PubMed PMID Region Collection time Strains Total Carbapenem-resistant strains KPC strains MBL strains OXA-48-like strains None-carbapenemase-producing strains
24342639 China 2011-2012 Enterobacteriaceae MIC50/MIC90, ≤0.06/0.12 (n = 291) / / / / /
30249690 INFORM Global 2012-2015 Enterobacteriaceae MIC50/MIC90, 0.06/0.12 (n = 45872) / / / MIC50/MIC90, 0.25/0.5 (n = 265) /
25963984 Global 2012-2013 Enterobacterales MIC50/MIC90, 0.06/0.12 (n = 23,516) MIC50/MIC90, 0.25/1 (n = 577) / MIC50/MIC90, 0.12/1 (n = 91) / /
27161636 Global 2012-2014 Enterobacteriaceae MIC50/MIC90, 0.03/0.12 (n = 38266) / MIC50/MIC90, 0.25/0.5 (n = 557) / / /
28630192 Global 2012-2015 Enterobacteriaceae MIC50/MIC90, 0.06/0.12 (n = 51,352) MIC50/MIC90, 0.25/1 (n = 1498) / MIC50/MIC90, 0.12/1 (n = 267) / /
39672348 China 2014-2020 NDM-Enterobacterales / / / MIC50/MIC90, 0.12/1 (n = 204) / /
38154750 ATLAS Global 2016-2020 Enterobacterales MIC50/MIC90, 0.06/0.25 (n = 82,775) / / MIC50/MIC90, 0.12/1 (n = 1628) / /
37998793 ATLAS Global 2016-2020 Enterobacterales MIC90, 0.12-0.25 (n = 116,602) MIC90, 1 (n = 5576) / MIC90, 1 (n = 1877) / /
32841721 Latin America, Africa/Middle East, Asia, and Eurasia 2016-2017 K. pneumoniae / MIC50/MIC90, 0.25/0.5 (n = 583) / MIC50/MIC90, 0.12/0.25 (n = 114) / /
29061754 America 2016 Enterobacteriaceae MIC50/MIC90, ≤0.03/0.12 (n = 10451) MIC50/MIC90, 0.12/0.5 (n = 120) MIC50/MIC90, 0.25/0.5 (n = 102) MIC50/MIC90, 0.12/0.5 (n = 59) MIC50/MIC90, 0.25/0.25 (n = 57) MIC50/MIC90, 0.25/4 (n = 12)
35510161 China 2016-2017 CRE / MIC50/MIC90, ≤0.12/0.5 (n = 312) MIC50/MIC90, 0.25/0.5 (n = 147) MIC50/MIC90, ≤0.12/0.5 (n = 118) / MIC50/MIC90, ≤0.12/0.5 (n = 24)
37154758 Taiwan, China 2016-2021 CPE / MIC50/MIC90, 0.25/1 (n = 195) MIC50/MIC90, 0.5/1 (n = 38) MIC50/MIC90, 0.25/1 (n = 143) MIC50/MIC90, 0.25/1 (n = 14) /
40365080 America 2017-2022 CRE / MIC50/MIC90, 0.25/1 (n = 511) / MIC50/MIC90, 0.25/1 (n = 50) / MIC50/MIC90, 0.25/4 (n = 89)
40711423 Span 2017-2024 CPE MIC50/MIC90, 0.12/0.5 (n = 300) / MIC50/MIC90, 0.12/0.25 (n = 100) MIC50/MIC90, 0.12/0.25 (n = 100) MIC50/MIC90, 0.12/0.25 (n = 100) /
36736925 Span 2018 MBL-E / / / MIC50/MIC90, ≤1/≤1 (n = 55) / /
33116675 China 2018-2019 CRE / MIC50/MIC90, ≤0.12/1 (n = 120) / / / /
40225828 America 2018-2020 Enterobacterales MIC50/MIC90, ≤0.03/0.12 (n = 45497) / / MIC50/MIC90,0.25/0.5 (n = 50) / /
35481835 China 2018-2019 CRE / MIC50/MIC90,0.25/1 (n = 1158) MIC50/MIC90,0.5/1 (n = 569) MIC50/MIC90,0.12/1 (n = 400) / /
35760303 ATLAS Global 2019 Enterobacterales MIC50/MIC90, 0.03/0.25 (n = 18713) MIC90, 0.5 (n = 1607) / MIC50/MIC90, 0.12/0.5 (n = 462) / /
35041100 SENTRY Global 2019-2020 Enterobacterales MIC50/MIC90, ≤0.03/0.12 (n = 8786) MIC50/MIC90, 0.25/0.5 (n = 424) / / / /
37526796 Latin America, Africa/Middle East, Asia and Eurasia 2019-2021 Enterobacterales MIC90, 0.25 (n = 24937) MIC90, 1 (n = 3289) MIC90, 0.5 (n = 705) MIC90, 2 (n = 1610) MIC90, 0.5 (n = 831) /
36846612 America 2019-2021 Enterobacterales MIC50/MIC90, ≤0.03/0.12 (n = 27834) MIC50/MIC90, 0.25/0.5 (n = 261) MIC50/MIC90, 0.12/1 (n = 171) MIC50/MIC90, 0.25/0.5 (n = 33) MIC50/MIC90, 0.25/0.5 (n = 12) MIC50/MIC90, 0.5/2 (n = 44)
40521716 Europe 2019-2023 Enterobacterales MIC50/MIC90, ≤0.03/0.12 (n = 8074) MIC50/MIC90, 0.25/0.5 (n = 757) / / / /
33276387 Europe, Asia, Latin America 2019 Enterobacterales MIC50/MIC90, ≤0.03/0.12 (n = 8787) MIC50/MIC90, 0.25/0.5 (n = 396) MIC50/MIC90, 0.25/0.5 (n = 138) MIC50/MIC90, 0.12/0.5 (n = 110) MIC50/MIC90, 0.25/0.5 (n = 87) MIC50/MIC90, 0.5/2 (n = 39)
34900759 China 2019 CRE / MIC50/MIC90, 0.5/2 (n = 374) / / / /
37184411 China 2019 Enterobacterales MIC50/MIC90, ≤1/≤1 (n = 1202) MIC50/MIC90, ≤1/4 (n = 119) / MIC50/MIC90, ≤1/4 (n = 43) / /
34970142 China 2019 CRKP / MIC50/MIC90, 1/4 (n = 318) / / / /
38354826 Europe, Latin America and the Asia-Pacific region 2020-2022 CRE / MIC50/MIC90, 0.25/0.5 (n = 1016) MIC50/MIC90, 0.25/0.5 (n = 430) MIC50/MIC90, 0.12/0.5 (n = 356) MIC50/MIC90, 0.25/0.5 (n = 126) MIC50/MIC90, 0.5/2 (n = 103)
38904361 Europe 2020 Enterobacterales MIC90, ≤1 (n = 1909) / / / / /
39183351 ARTEMIS Europe 2020 K. pneumoniae MIC50/MIC90, 1/2 (n = 187) MIC50/MIC90, 1/2 (n = 104) / / / /
39183351 ARTEMIS Europe 2020 E. coli MIC50/MIC90, 0.25/1 (n = 93) / / / / /
39304121 China 2021 CRE / MIC50/MIC90, 1/1 (n = 332) / / / /
41132366 America 2021-2023 Enterobacterales MIC90,0.12 (n = 10574) MIC90,0.5 (n = 81) / / / /
33334045 South Korea 2014Jan.-2018 Oct. CRE / / MIC50/MIC90, 0.25/1 (n = 17) MIC50/MIC90, 0.25/1 (n = 11) / MIC50/MIC90, 0.5/8 (n = 46)
32387260 China 2018 Jan.-2019 Jun. CRE / / MIC50/MIC90, 0.25/2 (n = 60) MIC50/MIC90, 0.12/2 (n = 26) / /
37982631 China 2018 Aug.-2022 Jun. CRKP / MIC50/MIC90, 1/4 (n = 114) / / / /
34060895 America 2019 Mar.-2020 Dec. MBL-E / / / MIC50/MIC90, 0.5/8 (n = 64) / /
40207055 China 2021 Jan.-2024 Jun. CRKP / MIC50/MIC90, 0.12/0.25 (n = 363) / MIC50/MIC90, 0.12/0.25 (n = 240) / /
32473388 China 2016 Oct.-2017 Sept. MBL-Enterobacteriaceae / / / MIC50/MIC90,<0.12/1 (n = 161) / /
38176458 England 2019-2020 CRE / / / / / MIC50/MIC90, 0.5/16 (n = 51)
36968952 Europe, Asia, Latin America 2019-2021 CRE / MIC50/MIC90, 0.25/0.5 (n = 1098) MIC50/MIC90, 0.25/0.5 (n = 473) MIC50/MIC90, 0.12/0.5 (n = 347) MIC50/MIC90, 0.25/0.5 (n = 205) MIC50/MIC90, 0.5/2 (n = 126)
40298548 America 2019-2023 C. freundii MIC50/MIC90, 0.06/0.25 (n = 1374) MIC50/MIC90, 0.12/0.5 (n = 12) / / / /
40298548 America 2019-2023 E. cloacae MIC50/MIC90, 0.06/0.5 (n = 3732) MIC50/MIC90, 0.25/1 (n = 52) / MIC50/MIC90, 0.12/0.25 (n = 12) / /
40499756 America 2020-2021 Enterobacterales MIC50/MIC90, 0.12/0.5 (n = 157) / MIC50/MIC90, 0.12/0.5 (n = 115) MIC50/MIC90, 0.25/0.5 (n = 30) / /
38927230 America 2020-2022 Enterobacterales MIC50/MIC90, 0.25/1 (n = 210) / / / / /
39856702 America 2020-2022 Enterobacterales MIC50/MIC90, 0.06/0.25 (n = 3911) MIC50/MIC90, 0.25/1 (n = 104) / / / /
39501203 America 2020-2022 Enterobacterales MIC50/MIC90, ≤0.03/0.12 (n = 4802) MIC50/MIC90, 0.25/1 (n = 49) / MIC50/MIC90, ≤0.03/0.5 (n = 8) / /
40108737 France / Enterobacterales MIC50/MIC90, 0.12/0.75 (n = 127) / / MIC50/MIC90, 0.12/0.75 (n = 32) / /
40683213 France / CRE / MIC50/MIC90, 0.12/1 (n = 414) / MIC50/MIC90, 0.12/0.75 (n = 82) / MIC50/MIC90, 0.5/4 (n = 122)
26392487 America, Singapore / Enterobacteriaceae / / MIC50/MIC90, 0.12/0.5 (n = 108) MIC50/MIC90, 0.12/1 (n = 55) / /
36308322 Switzerland / MBL-E / / / MIC50/MIC90, 1/16 (n = 64) / /
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CPE: carbapenemase-producing Enterobacterales; MBL-E: metallo β-lactamase-producing Enterobacterales; /: indicates that no relevant data were reported in the literature.

In vitro activity studies of AZA had also focused on Pseudomonas aeruginosa (P. aeruginosa) and Stenotrophomonas maltophilia (S. maltophilia). The carbapenemases carried by the former are primarily MBLs, such as VIM, IMP, and NDM. Whereas S. maltophilia naturally carries two inducible β-lactamases: L1, a subclass B3 MBL, and L2, a class A serine β-lactamase. This distinction is central to the rationale for AZA activity, because aztreonam is relatively stable to L1-mediated hydrolysis, while avibactam inhibits L2. Nine existing studies indicated that AZA exhibited an overall MIC50 of 8–16 mg/L and an MIC90 of 16–>256 mg/L against P. aeruginosa (Table 2). One US study reported significantly lower values, with MIC50 and MIC90 of 0.25 and 1 mg/L respectively (n = 2130) [28]. A recent comparative study further showed that, among 38 MDR P. aeruginosa isolates, CZA + ATM had lower MICs than AZA in 25 isolates, suggesting greater in vitro activity in some strains [29]. However, this does not imply that CZA + ATM offers any clinical advantage over multidrug-resistant Pseudomonas aeruginosa isolates. In comparison, S. maltophilia showed slightly better susceptibility to AZA, with an MIC50 of 2–4 mg/L and an MIC90 of 4–8 mg/L. This data covered nearly 3,500 clinical isolates worldwide. A recent study by Kunz Coyne et al. compared AZA with CZA + ATM against 23 S. maltophilia complex isolates[30]. The two regimens showed comparable overall in vitro activity, with no uniform advantage of either regimen. Semi-mechanistic pharmacodynamic modelling suggested that AZA performed better in strains with dominant L2 β-lactamase expression, whereas CZA + ATM was favoured in settings of L1 or SmeABC efflux pump dominance [30]. These modelling findings highlight that population averages may not capture genotype-dependent differences in dynamic activity. However, the MICs of AZA against both Acinetobacter baumannii (A. baumannii) and anaerobic bacteria were > 32 mg/L, indicating a lack of in vitro activity [31, 32].

Table 2.

In vitro activity of aztreonam/avibactam against Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

Ref Region Collection time Strains Total Carbapenem.resistant.strains MBL strains
24342639 China 2011-2012 P. aeruginosa MIC50/MIC90, 16/>64(n = 25) / /
28630192 Global 2012-2015 P. aeruginosa MIC50/MIC90, 8/64(n = 11842) / MIC50/MIC90, 16/64(n = 452)
34900759 China 2019 CRPA / MIC50/MIC90, 16/64(n = 65) /
38304722 Taiwan,China 2019-2021 CRPA / MIC50/MIC90, 16/>32(n = 110) /
39856702 America 2020–2022 P. aeruginosa MIC50/MIC90, 0.25/1(n = 2130) / /
39304121 China 2021 CRPA / MIC50/MIC90, 8/32(n = 152) /
33086177 / 2022-2024 P. aeruginosa MIC50/MIC90, 8/16(n = 30) / /
40108737 France / P. aeruginosa MIC50/MIC90, 16/>256(n = 53) / /
36308322 Switzerland / MBL-P. aeruginosa / / MIC50/MIC90, 16/>128(n = 39)
38483164 European / P. aeruginosa MIC90, 32(n = 950) / /
32928733 SENTRY 2008-2018 S. maltophilia MIC50/MIC90, 4/4(n = 47) / /
40084947 Japan 2012-2024 S. maltophilia MIC50/MIC90, 4/8(n = 53) / /
33618662 China 2014-2018 S. maltophilia MIC50/MIC90, 2/8(n = 76) / /
33086177 / 2022-2024 S. maltophilia MIC50/MIC90, 2/8(n = 24) / /
32900683 America 2019-2023 S. maltophilia MIC50/MIC90, 2/4(n = 1400) / /
32900683 Global / S. maltophilia MIC50/MIC90, 4/4(n = 1839) / /
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CRPA, carbapenem-resistant Pseudomonas aeruginosa; /, indicates that no relevant data are reported in the literature.

Consequently, AZA showed variable in vitro activity against P. aeruginosa and S. maltophilia, with MIC distributions that should be interpreted cautiously because clinical breakpoints for these organisms are not established. These data do not support a general conclusion of reliable clinical activity against non-fermenters, particularly P. aeruginosa. In contrast, AZA lacked meaningful in vitro activity against A. baumannii and anaerobic bacteria (MICs >32 mg/L). Overall, the spectrum of AZA is best supported for MBL-producing Enterobacterales, whereas its potential role against non-fermenters remains organism- and isolate-dependent and requires further clinical validation.

Comparative in vitro activity of novel BLBLIs against MBL-producing strains

In vitro activity of AZA against MBLs-producing Gram-negative bacteria differs markedly from that of novel BLBLIs such as cefepime/taniborbactam and cefepime/zidebactam. In a study of 490 MBL-producing Enterobacterales from 27 countries, AZA demonstrated the most consistent and broad-spectrum activity, with all isolates being susceptible (MIC₅₀/MIC₉₀, 0.12/0.5 mg/L) regardless of the presence of other β-lactamases, porin mutations or efflux pump overexpression [33]. In the same collection, cefiderocol showed only 66.7% susceptibility by EUCAST breakpoints, whereas cefepime/taniborbactam inhibited only 36.7% of isolates when applying cefepime breakpoints [33]. In another evaluation using 190 isogenic E. coli strains each overproducing a single β-lactamase, cefepime/taniborbactam displayed an overall inhibition spectrum comparable to AZA (MIC₅₀/MIC₉₀, 0.25/8 mg/L versus 0.5/4 mg/L), but lacked activity against certain MBL variants such as IMP-1, VIM-89 and NDM-9 [34]. Le Terrier et al. further demonstrated that cefepime/zidebactam, cefepime/taniborbactam, and meropenem/nacubactam were the most effective combinations in E. coli, whereas AZA demonstrated a minor shortcoming, with reduced activity specifically observed against strains producing PER-type and CMY-type β-lactamases [35]. A shared weakness of AZA and cefepime/taniborbactam became particularly evident in NDM-producing E. coli strains harbouring YRIN or YRIK insertions in penicillin-binding protein 3 (PBP3). In a collection of 28 such clinical isolates co-producing CMY-42, all strains were fully resistant to both combinations, whereas cefepime/zidebactam retained very low MICs (MIC₅₀/MIC₉₀, 0.25/0.25 mg/L), its intrinsic antibacterial and PBP2-enhancing effect remaining unaffected by PBP3 alterations [36].

In P. aeruginosa, the antimicrobial activity spectra of BLBLIs differed substantially. AZA remained consistently active against MBLs, while cefepime/zidebactam offered broad coverage but could be affected by certain class A and C β-lactamases. Cefepime/taniborbactam showed gaps against both IMP-type MBLs and various serine β-lactamases. The narrowest spectra belonged to meropenem/nacubactam (ineffective against nearly all MBLs and OXA-23) and cefepime/enmetazobactam (deficient against β-lactamases from all four Ambler classes) [35]. Cefepime/taniborbactam MICs were readily compromised by efflux pump overexpression. When NDM-1 production coexisted with MexAB-OprM overexpression and OprD deficiency, nearly all tested BLBLIs lost activity [37]. In this setting, AZA and cefepime/zidebactam still provided the broadest coverage against mutants expressing various acquired β-lactamases [37].

In summary, among Enterobacterales, AZA provides the highest coverage against MBL producers. Cefepime/taniborbactam offers similarly broad inhibition but has gaps for certain MBL subtypes. Both are inferior to cefepime/zidebactam in the presence of PBP3 insertions. In P. aeruginosa, drug choice must be guided by the specific combination of resistance mechanisms, with AZA remaining the most reliable option against MBL producers [35, 37].

Pharmacokinetics/Pharmacodynamics (PK/PD) of AZA

PK/PD of aztreonam and avibactam

ATM has extremely low oral bioavailability (<1%), requiring intravenous (IV), intramuscular (IM), nebulization, or intraperitoneal (IP) administration, with regimens ranging from 0.5 g twice daily to 2 g four times daily depending on patient condition and infection severity.

Its PK follows a two-compartment open model, with a rapid distribution phase and an elimination half-life of about 2 h, a steady-state volume of distribution of 0.18 L/kg (similar to extracellular fluid volume), and a protein binding rate of around 56%. ATM penetrates widely into tissues and body fluids, including synovial fluid (83.0 mg/L after 2 h), bone (16.0 mg/L), bronchial secretions (0.5–18.7 mg/L) and cerebrospinal fluid (CSF) [38, 39]. CSF penetration is markedly enhanced in meningitis, with concentrations ranging from 0.76 to 16.6 mg/L and reaching 39–62 mg/L after multiple doses [40, 41]. It also distributes widely to abdominal organs: after a single 2 g dose in surgical patients, concentrations range from 12 to 33 µg/g in endometrium, fallopian tubes and ovaries, and reach 65.4 mg/L in liver and 9.2 mg/L in muscle [42,43]. ATM is minimally metabolized, with approximately two-thirds excreted unchanged in urine, and only 3.1%–6.9% as its primary metabolite SQ26992 [44]. Clearance correlates directly with creatinine clearance, requiring dose adjustment in renal impairment.

In terms of PD, ATM exhibits time-dependent killing. The duration during which the free drug concentration exceeds the MIC (%ƒT > MIC) has been identified as a key pharmacokinetic parameter. For Enterobacterales, the target %ƒT > MIC is 45–70% [45], whereas for P. aeruginosa it is 50–60% [46]. Monte Carlo simulations supported that 1 g every 8 h achieves high probability of target attainment against Enterobacterales, whereas 1 g every 6 h or 2 g every 8 h is needed for P. aeruginosa. Therefore, the dose or frequency of administration should be increased when treating or managing suspected P. aeruginosa infections.

Avibactam also has low oral bioavailability and must be given intravenously. Its volume of distribution is approximately 22 L (confined to extracellular space), with low plasma protein binding (around 8%) [47]. It exhibits linear PK and good tissue penetration. Concentrations in bronchial epithelial lining fluid reach approximately 30% of plasma level, and during meningeal inflammation CSF exposure can reach 38% of plasma AUC [48]. In patients with complicated intra-abdominal infections and urinary tract infections, the central volume of distribution was 32.9% and 43.4% higher, respectively, than in healthy volunteers [49].

Avibactam is minimally metabolized and has no significant inhibitory or inducing effect on cytochrome P450, and is primarily eliminated unchanged by the kidneys. Its renal clearance (about 158 mL/min) exceeds glomerular filtration rate, suggesting active tubular secretion [50]. The elimination half-life is approximately 2 h, and exposure increases approximately 3.8-fold and 7-fold in moderate and severe renal impairment, respectively, necessitating dose adjustment [48].

Regarding PD, avibactam acts by fully inhibiting β-lactamases, so the activity of AZA is determined by the PK/PD characteristics of ATM alone. The threshold concentration (CT) is the minimum concentration required to restore ATM activity. For Enterobacterales, a CT of 2.5 mg/L is recommended when combined with ATM, and free avibactam must exceed t CT for ≥ 50% of the dosing interval [51]. However, when combined with ceftazidime, the required concentration is only at least 0.5 mg/L [52]. Therefore, the PD target of avibactam is higher for the AZA than CZA. For P. aeruginosa, the optimal CT is 1 mg/L [53].

PK/PD and dose adjustments in special populations

The PK of ATM varies significantly in specific patient populations, which is a key factor in determining clinical dose adjustments. In patients with renal impairment, its clearance correlates with creatinine clearance: when creatinine clearance is below 10 mL/min, serum clearance decreases to 29 mL/min and the half-life is prolonged to approximately 6-8 h [54]. Accordingly, for patients with creatinine clearance of 30–80, 10–29, and less than 10 ml/min or anuria, the recommended dose should be adjusted to 75%, 50% and 25% of the standard dose, respectively [54]. The reduced clearance rate in elderly patients is primarily due to age-related renal impairment. In pediatric patients, PK was age-dependent: in infants less than seven days old and weighing less than 2.5 kg, the half-life was as long as 5.71 h and the clearance was only 0.94 mL/min/kg. Therefore, dosing every 12 h was recommended. In children aged one month to two years, the half-life was approximately 1.7 h and dosing every six to eight hours was recommended [55]. Critically ill patients may require higher doses due to an increased volume of distribution, reduced protein binding, and increased clearance. The pharmacokinetic variability of avibactam is primarily related to its renal clearance, with renal function being a key factor in influencing exposure [49]. Hemodialysis effectively removes ATM and avibactam, so administration should be scheduled to take place afterwards. Avibactam is not significantly metabolized by the liver, no dose adjustment was required for patients with mild to moderate hepatic impairment.

The dosage adjustment regimen for AZA in adults based on renal function is shown in Table 3. As the population PK of this drug in pediatric patients has not yet been established, it is not approved for use in pediatrics.

Table 3.

Dosage adjustment regimens for AZA and CZA based on renal function [50, 81].

Renal Function Classification (Based on CrCl) AZA CZA
Mild impairment (CrCl > 50 mL/min) Load dose: 2 g/0.67 g; maintenance dose: 1.5 g/0.5 g, q6h 2 g/0.5 g, q8h
Moderate impairment (CrCl 30–50 mL/min) Load dose: 2 g/0.67 g Maintenance dose: 0.75 g/0.25  g, q6h 1 g/0.25 g, q8h
Severe impairment (CrCl 15–30 mL/min) Load dose: 1.35 g/0.45 g Maintenance dose: 0.675 g/0.225  g, q8h 0.75 g/0.1875g, q12h
End-stage renal disease (CrCl ≤ 15 mL/min) and haemodialysis Load dose: 1 g/0.33 g; maintenance dose: 0.675 g/0.225 g, q12h 0.75 g/0.1875g, q48h
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Use the Cockcroft-Gault formula to estimate creatinine clearance (CrCl). q6h: once every 6 h; q8h: once every 8 h; q12h: once every 12 h; q48h: once every 48 h.

To further characterize the PK profile of AZA, a population PK analysis was conducted, including a total of 4,914 plasma samples of ATM (from 431 subjects) and 18,222 plasma samples of avibactam (from 2,635 subjects) [56]. Body weight and time-dependent creatinine clearance were key covariates influencing the clearance of both compounds. The type of infection also significantly affected clearance and volume of distribution. Exposure was lowest in patients with cIAIs, whilst exposure and median ƒT > CT were generally higher in patients with HAP and cUTIs compared with those with cIAIs.

The pharmacodynamic target for AZA is the simultaneous achievement of 60% ƒT > MIC (8 mg/L) for ATM and 50% ƒT > CT (2.5 mg/L) for avibactam. The simulation results show that, for patients with varying degrees of renal function and different types of infection, the fixed-dose combination regimen achieves a steady-state probability of pharmacodynamic target attainment (PTA) ranging from 89% to over 99% [56].

PK/PD non-interchangeability of AZA and CZA + ATM

Where AZA is unavailable, the Infectious Diseases Society of America (IDSA) guidelines have recommended an alternative regimen of CZA 2.5 g every 8 h combined with ATM 2 g every 8 h administered as a 3-hour infusion [57]. This regimen essentially consists of a temporary combination of two separate drugs. To understand the gap between this alternative and AZA, it is necessary to clarify the advantages of AZA. AZA uses an optimized fixed 3:1 ratio (ATM 1.5 g and avibactam 0.5 g), with its loading and maintenance doses selected based on large-scale population PK modelling and phase III clinical trial validation. It can simultaneously achieve the respective PD targets of ATM and avibactam across different renal function and infection types, with a joint PTA of 89% to >99% [56]. However, CZA + ATM has a fundamental flaw—the fixed ratio of ceftazidime to avibactam was designed to protect ceftazidime. When ATM is added to the combination, the dose of avibactam is not increased accordingly, disrupting the balance between the antibiotic and the protective agent. Population PK simulation confirmed that the steady-state exposure to avibactam in the combination regimen was approximately 25% lower than that in the fixed-dose AZA combination regimen, which directly resulted in the PD target of 50% ƒT > 2.5 mg/L not being reliably achieved, ultimately causing the combined PTA to fall below 85% [56]. Moreover, a therapeutic drug monitoring study in critically ill patients showed that even with prolonged (3-hour) infusion regimen of CZA with aztreonam, avibactam achieved 50% ƒT > 1 mg/L (a threshold far lower than 2.5 mg/L) in only 74% of patients, and attainment of 100% ƒT > MIC fell to 35% [58].

More critically, CZA + ATM also exhibits an incompletely recognized drug interaction and higher PK variability. A healthy volunteer study (the COMBINE study) found that when co-administered with CZA, the total clearance of ATM was unexpectedly reduced by approximately 16%, leading to increased ATM exposure and a potential risk of elevated liver enzymes [59]. In real-world complex patient populations (e.g. the elderly, burn patients, septic shock), the apparent volumes of distribution of ceftazidime, avibactam and ATM are significantly increased, while clearance is reduced by about 50% compared to typical values, with estimated glomerular filtration rate being the only stable covariate [60]. This high variability makes drug exposure unpredictable with the temporary combination, undermining the reliability of its PD targets. In contrast, the AZA PK model, based on data from over 2,600 subjects, includes clear, quantified adjustments for key covariates such as renal function, resulting in a more robust exposure–response relationship.

Taken together, AZA and CZA + ATM differ substantially in formulation, exposure predictability, and PK/PD target attainment. AZA is a fixed-dose formulation that delivers aztreonam and avibactam in a synchronized and standardized manner, supporting predictable co-exposure and joint PTA across renal function strata [61]. In contrast, CZA + ATM is a co-administration strategy using two separately prepared products. Although simultaneous or Y-site infusion can improve overlap between ATM and avibactam exposure, this regimen remains more vulnerable to infusion timing, renal function, and patient-specific PK variability [61]. Therefore, CZA + ATM should be regarded as an important practical alternative when AZA is unavailable, but not as a pharmacokinetically interchangeable substitute for fixed-dose AZA.

Mechanisms of resistance to AZA

Since 2020, there have been a series of reports on AZA resistant strains. Due to the limited antimicrobial spectrum of AZA, certain anaerobic bacteria, Acinetobacter baumannii and Gram-positive bacteria are naturally resistant to it. This section focuses on reviewing the mechanisms of resistance to AZA in Enterobacterales.

Several studies have shown that a four-amino-acid insertion (YRIN or YRIK) following proline at position 333 of the PBP3 protein is commonly observed in Escherichia coli strains exhibiting reduced susceptibility to AZA [26]. These strains are predominantly NDM-producing or carbapenem-resistant strains, and frequently harbour multiple β-lactamases, including CMY-type AmpC, TEM and CTX-M [62]. A global genomic analysis (n = 159,341) found that 2.01% of E. coli strains carried PBP3 insertion variants, of which 94.75% were amino acid repeats at positions 334-337 (YRIN accounted for 65.92% and YRIK for 28.83%), followed by PYRI repeats at positions 333-336 (4.16%)[63]. These variant strains were distributed across 62 countries on six continents, primarily concentrated in high-risk clones ST410, ST167 and ST405, with 83.32% carrying NDM. MBL-producing CREC strains often have insertional mutations in PBP3. This is a significant resistance mechanism, but it needs to work together with other β-lactames, like AmpC, because it is not enough on its own to cause resistance.

This mode of synergy is congruent with the resistance mechanisms of CZA, wherein β-lactamase mutations and overexpression play a significant role in resistance to AZA. Ma et al. reported that the presence of both KPC-21 (a Trp105Arg mutation in KPC-2) and a YRIN insertion in PBP3 led to high-level resistance to AZA (MIC = 512/4 mg/L) in E. coli, while susceptibility to CZA remained [64]. Cloning experiments demonstrated that KPC-21 alone conferred only a slight increase in MIC, but significantly enhanced resistance in combination with the PBP3 insertion. Xiang et al. identified a KPC-2 Ser109Pro mutation in CRKP that reduced affinity for avibactam and ATM [65]. Ser109Pro significantly increased resistance in the presence of an OmpK36 deletion and high-level KPC expression.

When PBP3 harbours a YRIN or YRIK insertion, certain CTX-M-type ESBLs capable of efficiently hydrolyzing ATM can also mediate resistance. For example, CTX-M-15 and its variant CTX-M-199 can lead to resistance to AZA in this context, with MIC exceeding 16 mg/L [66]. In contrast, CTX-M-14 only causes a slight reduction in susceptibility, with an MIC of 4 mg/L [66]. This disparity stems from a difference in the amino acid at position 240: CTX-M-15 features glycine, whereas CTX-M-14 features aspartate [66]. In Enterobacter mori, the Arg244Gly mutation in SHV-12 can mediate resistance to AZA, raising the MIC from 0.5/4 mg/L to 4/4 mg/L [67]. This mutation disrupts the arginine salt bridge within the avibactam binding pocket, resulting in an increase in binding energy from −5.24 kcal/mol to −4.32 kcal/mol, as well as an increase in the inhibition constant from 143.96 μM to 677.37 μM, which indicates a decline in inhibitory efficiency of avibactam [67]. However, this mutation is also associated with reduced resistance to cephalosporins.

CMY-type AmpC is another important class of resistance gene. Specific mutations in CMY-16, such as Tyr150Ser and Asn346His, can directly reduce the effectiveness of avibactam [68]. Conversely, the synergistic interplay between CMY-42 and PBP3 insertion mutations is a more frequently observed phenomenon. CMY-42 has potent hydrolytic activity against ATM, and its presence alongside PBP3 insertions creates a solid basis for AZA resistance [69, 70]. Furthermore, bacteria can enhance their resistance levels by modulating the gene dosage of resistance determinants. For example, Inc mutations located on IncI1/IncL plasmids can increase plasmid copy numbers [71]. Alternatively, the insertion sequence IS1294 can generate tandem repeats via rolling-circle replication or facilitate the translocation of resistance elements onto naturally high-copy, small plasmids [72]. These strategies enable exceptionally high levels of drug resistance to be mediated at a relatively minimal fitness cost.

In addition to β-lactamase and PBP3 mutations, reduced outer membrane permeability and overactive efflux pumps also contribute to AZA resistance. In Klebsiella pneumoniae, truncation mutations in the OmpK36 pore protein (e.g. Y310*) hinder drug entry into the periplasmic space, but reintroducing the wild-type gene restores susceptibility [65]. Concurrently, upregulation of the AcrAB-TolC efflux pump exacerbates resistance, while the addition of the PAβN inhibitor significantly reduces the MIC [62]. These findings suggest that reduced membrane permeability resulting from pore protein deficiency is a more prevalent resistance mechanism than efflux pump activation, and that the two often interact synergistically with β-lactamase mutations to form complex resistance networks.

Clinical applications and efficacy evaluation

Two Phase III trials, REVISIT and ASSEMBLE, were conducted to evaluate the efficacy and safety of AZA in the treatment of severe infections.

The REVISIT study was a prospective, multinational, randomized, open-label but centre-blinded trial enrolling patients with cIAIs and HAP, including ventilator-associated pneumonia (VAP). Patients were randomized in a 2:1 ratio to receive AZA (1.5 g/0.5 g every 6 h, with metronidazole for cIAIs) or meropenem (1 g every 8 h) [73]. In the intention-to-treat analysis of 422 patients, the clinical cure rate was 68.4% in the AZA group and 65.7% in the meropenem group. Subgroup analysis showed similar efficacy between the two groups in cIAIs (76.4% vs 74.0%), whereas in HAP/VAP, the AZA group had a cure rate of 45.9% vs 41.7% [73]. The 28-day all-cause mortality rate was lower in the AZA group (overall 4.3% vs 7.1%; 10.8% vs 19.4% in the HAP/VAP subgroup) [73]. However, the interpretation of REVISIT for MBL-producing infections should be cautious, because only 10 patients had MBL-positive baseline pathogens, and only 7 received AZA [74].

The ASSEMBLE study specifically targeted severe infections caused by MBL-positive Gram-negative bacteria. Although the study was terminated early due to recruitment difficulties, among the 15 patients enrolled, clinical cure was observed in 42% of patients receiving AZA compared with 0% in the best-available-therapy group [75]. The 28-day mortality rate in the AZA group was lower than that in the control group (8% vs 33%) [75]. However, the very small sample size precludes any definitive conclusion regarding superiority.

Fixed-dose AZA and CZA + ATM are pharmacologically related but not identical regimens. AZA provides synchronized exposure of aztreonam and avibactam in a fixed-dose formulation, whereas CZA + ATM requires separate preparation and infusion, making administration more complex and increasing the risk of ATM-AVI exposure mismatch, even with Y-site co-infusion [61, 74]. However, current evidence does not establish categorical clinical superiority of AZA over CZA + ATM, because direct comparative trials are lacking [61, 74].

Although CZA + ATM does not effectively achieve the pharmacodynamic targets of AZA, multiple case reports have demonstrated that this regimen is effective in treating infections caused by MBL-producing Enterobacteriaceae (Table 4). Despite potential biases, this combination remains crucial when AZA is not readily available. The prospective observational study by Falcone et al. provides the strongest evidence: compared with other active treatments, this combination regimen significantly reduced 30-day all-cause mortality in patients with MBL-producing Enterobacteriaceae bloodstream infections (19.2% vs. 44%), with a hazard ratio of 0.17 in multivariate Cox regression, representing an 83% reduction in the risk of death, and a propensity score-adjusted hazard ratio of 0.37 [76]. Regarding secondary endpoints, the risk of clinical failure at 14 days was reduced by 70%, and hospital stay was significantly shortened [76]. A study by Bavaro et al. in patients with COVID-19 complicated by bloodstream infections further supports this regimen. KPC-producing strains were treated with CZA, while those producing NDM received the combination regimen [77]. Results showed similar 14-day mortality rates (26% vs. 38%) and 28-day mortality rates (35% vs. 48%) between the two groups [77]. The 14-day mortality rate was only 7% for patients who initiated appropriate treatment early, but rose to 64% when treatment was delayed beyond 72 h [77]. However, Meini et al. observed that among elderly patients with multiple comorbidities, the 30-day mortality rate remained as high as 46.7% even when all patients received this combination therapy, highlighting the significant impact of patients' baseline conditions on prognosis [78].

Table 4.

Case reports of treatment with CZA combined with aztreonam.152

PubMed PMID Number of patients receiving CZA + ATM Sex, age MBL-producing Enterobacterales pathogen(s) Infection site Clinical outcome
28167541 1 Female, 72 years Enterobacter cloacae (NDM-1) Skin and soft tissue Clinical cure
30021742 1 Male, 42 years K. pneumoniae (NDM-1, OXA-181, CTX-M-15) Bone Clinical cure
30530600 1 Female, 3 years Morganella morganii (NDM-1, CMY-4) Bloodstream Clinical cure
30282120 1 Mae, 61 years E. cloacae (NDM-1) Skin and soft tissue Clinical cure
31704216 1 Female, 67 years K. pneumoniae (NDM-1) Bloodstream Clinical cure of index infection, urinary tract infection with same organism at day 30
  1 Female, 44 years K. pneumoniae (NDM-1) Respiratory Clinical cure of index infection, respiratory with same organism at day 20
31802119 1 Male, 4 years Enterobacter hormaechei (KPC-4, NDM-1) Bloodstream Clinical cure
33217119 1 Male, 73 years E. cloacae (IMP-4) Bloodstream Clinical cure
  1 Male, 50 years E. cloacae (IMP-4) Bone Clinical cure
  1 Male, 64 years E. cloacae (IMP-4) Bloodstream Clinical cure of index infection, pyelonephritis due to the same organism at 4 months
  1 Male, 49 years E. cloacae (IMP-4) Skin and soft tissue Clinical cure
33924769 1 Male, 57 years K. pneumoniae (NDM-1) Bloodstream Clinical cure
33958683 1 Female, 40 years K. pneumoniae (NDM-1) Endocarditis Clinical cure
34888479 1 Female, 45 years E. cloacae (IMP-4) Bloodstream Clinical cure
34716170 1 Female, 30 years K. pneumoniae (VIM) Bone Clinical cure
36225496 1 Male, 39 years Citrobacter sedlakii (NDM) Bone Clinical cure
36371600 1 Male, 62 years K. pneumoniae (NDM) Bloodstream Clinical cure
37601796 1 Female, 70 years K. pneumoniae (NDM) Bone Clinical cure
  1 Male, 71 years E. cloacae (NDM, OXA-48) Bone Clinical cure
38376188 1 Male, 30 years K. pneumoniae (VIM), Serratia marcescens (VIM) Bloodstream Clinical cure
  1 Male, 30 years K. pneumoniae (VIM). Skin and soft tissue Clinical cure
  1 Male, 81 years S. marcescens (VIM) Skin and soft tissue Clinical cure of index infection and bacteremia from S. marcescens at day 21
  1 Male, 19 years S. marcescens (VIM), K. pneumoniae Skin and soft tissue Clinical cure
38646598 1 Female, 33 years E. cloacae, E. coli Urinary tract Clinical cure
38289725 1 Male, 12 years E. coli (NDM-1) Bloodstream Clinical cure of index infection, bacteremia from E. coli at day 36 leading to death
38885998 1 Male, 40 years K. pneumoniae (MBL producer) Central nervous system Clinical cure
39050862 1 Male, 70 years K. pneumoniae (NDM, OXA-48) Skin and soft tissue infection Clinical cure
39494754 1 Male, 50 years E. coli (NDM, OXA-48), M. morganii Biliary tract infection Clinical cure
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In this context, therapeutic drug monitoring (TDM) is particularly critical for this temporary combination regimen. Clinical case reports have demonstrated that TDM can identify insufficient exposure and guide individualized dose adjustments. For example, TDM successfully helped achieve bactericidal targets in a child with bloodstream infection caused by an Enterobacter sp. carrying KPC and NDM [79]. In a cystic fibrosis patient, TDM revealed inadequate target attainment with intermittent infusion, and only after switching to continuous infusion was 100% ƒT > MIC achieved [80]. Therefore, although CZA + ATM may be used as a temporary option when AZA is unavailable, TDM and synergy testing should be performed.

Overall, AZA is an effective treatment option for infections caused by MBL-producing Enterobacterales. Its mechanistic rationale, synchronized PK/PD exposure, standardized susceptibility testing, and supporting prospective Phase III data make it a practical preferred option when available [61]. CZA + ATM remains a clinically relevant and mature alternative, especially when AZA is unavailable, with encouraging observational outcomes. However, this regimen requires more complex administration, may be affected by AZA exposure mismatch, and lacks standardized susceptibility testing [61]. Therefore, in the absence of definitive clinical evidence demonstrating the superiority of AZA, regimen selection should move beyond a binary “equivalent versus non-equivalent” framework and consider drug availability, laboratory capacity, organ function, administration feasibility, pathogen species, resistance mechanisms, drug exposure, timing of therapy, age, comorbidities, and infection severity.

Safety assessment

In the REVISIT trial, 412 patients received at least one dose of the study drug, with 275 receiving AZA and 137 receiving meropenem [73]. The incidence of treatment-related adverse events of any grade was 64% in both groups, while the incidence of serious adverse events was 19% and 18%, respectively [73]. No treatment-related serious adverse events were reported in the AZA group, whereas one case of abnormal liver function was reported in the meropenem group [73].

Common laboratory abnormalities associated with AZA include anaemia (7%), elevated ALT (7%), elevated AST (5%) and diarrhea (6%) [73]. Other events occurring in at least 3% of patients include hypokalemia (6%), fever (5%), abnormal liver function tests (4%), nausea (4%) and vomiting (4%) [73]. Hypersensitivity or allergic reactions occurred in 13% of patients, with no cases classified as severe [73]. Liver dysfunction occurred in 18% of patients, with no cases meeting the Hays criteria. And Clostridioides difficile diarrhea occurred in 8% of patients (4% in the meropenem group) [73].

In addition, AZA may cause uncommon reactions such as eosinophilia, leukocytosis, dizziness, hypotension and rash [81]. Rare, serious adverse reactions include pancytopenia, neutropenia, seizures, hepatitis and severe skin reactions [82]. In patients with renal impairment, reduced drug clearance may increase the risk of neurological events if the dose is too high [82]. Overall, AZA is well tolerated and has a favourable benefit-risk profile.

Summary and outlook

AZA is currently the only BLBLIs effective against Enterobacterales producing MBLs. Although European and American guidelines recommend cefiderocol, which is not yet available in China and is already facing a problem of resistance [83, 84]. Therefore, AZA holds greater promise.

Two pharmacoeconomic studies published in 2025 demonstrated its superior cost-effectiveness. Compared to meropenem combined with colistin, although AZA has a higher pharmaceutical cost, the model estimated a higher clinical cure rate, lower mortality, shorter hospital stays, and reduced risk of nephrotoxicity. Consequently, it was associated with a per-patient savings of €534 in cIAIs, while in HAP and VAP, the incremental cost-effectiveness ratio is €1,552 per quality-adjusted life year, below the willingness-to-pay threshold [85]. A Spanish dynamic transmission model predicted that introducing this drug as a first-line treatment could prevent nearly 20,000 infections, save over 4,600 lives, and reduce healthcare costs by around €40.5 million over 10 years, resulting in a net monetary benefit of €1.22 billion [86]. However, these findings are derived from country-specific economic analyses and model assumptions, and their generalizability to other healthcare systems remains uncertain. Despite its high procurement cost, AZA may represent a cost-effective strategic option in settings where model assumptions, local epidemiology, drug pricing, and healthcare costs are comparable.

In summary, AZA is a valuable addition to the therapeutic arsenal for treating severe, multidrug-resistant Enterobacterales infections in adults, particularly in regions where MBLs are prevalent. CZA + ATM remains an important and clinically relevant alternative, particularly in settings where AZA is not available. To prevent resistance from emerging, precise prescribing guided by rapid molecular diagnostics is essential. While current resistance rates remain low, continuous surveillance is warranted. Given the suboptimal in vitro activity against P. aeruginosa, combination therapy represents a promising avenue for future development. Furthermore, additional clinical data regarding pediatric patients and specific patient populations is required.

Funding Statement

This work was supported by a grant from the National Natural Science Foundation of China [grant numbers 82272373 and 82402666] and Zhejiang Provincial Natural Science Foundation [grant number LQN25H200002].

Disclosure statement

No potential conflict of interest was reported by the author(s).

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