With the widespread use of carbapenem antibiotics in recent years, the isolation rate of carbapenem-resistant gram-negative bacilli (CR-GNB), primarily carbapenem-resistant Enterobacteriaceae (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA) and carbapenem-resistant Acinetobacter baumannii (CRAB), has increased (Doi, 2019). Kidney transplant (KT) recipients are particularly vulnerable to CR-GNB infection due to factors such as severe surgical trauma and compromised immune function. These infections are often associated with high clinical failure, morbidity, and mortality due to limited treatment options (Bodro et al., 2015; Zhang et al., 2021). In China, the main antibiotics used to treat infections caused by these refractory isolates are aminoglycosides, polymyxin and tigecycline. However, concerns about their clinical efficacy, safety, and emerging resistance have limited their clinical use (Nang et al., 2021; Yahav et al., 2021). Especially most of the above drugs are nephrotoxic, and considering the protection of transplanted kidney function, the use of these drugs is further limited in KT recipients. Clinically, the treatment options for CR-GNB infection following kidney transplantation are minimal, and new therapeutic approaches against these refractory pathogens are urgently needed.

Ceftazidime-avibactam (CAZ-AVI), a novel β-lactam/β-lactamase inhibitor, was approved by the China National Medical Products Administration on May 21, 2019, for the treatment of complicated abdominal and urinary tract infections, hospital-acquired, ventilator-associated pneumonia, and infections caused by aerobic gram-negative bacteria in adult patients with limited treatment options (van Duin and Bonomo, 2016; Torres et al., 2018). Avibactam is a novel synthetic β-lactamase inhibitor with activity against Ambler class A [extended-spectrum β-lactamases (ESBLs), Klebsiella pneumoniae carbapenemases (KPCs)], class C (AmpC), and some class D [oxacillinases (OXA) β-lactamases]. However, CAZ/AVI is inactive against class B metallo-β-lactamases (MBLs), such as New Delhi metallo-β-lactamase (NDM), Imipenemase (IMP), and Verona integron-encoded metallo-β-lactamase (VIM) (Falcone and Paterson, 2016).

Although some studies have indicated that CAZ-AVI treatment for CR-GNB infections is more effective than polymyxins and tigecycline (van Duin et al., 2018; Fang et al., 2021; Shi et al., 2021), the risk factors associated with treatment failure of CAZ-AVI remain unclear, especially in this special population of KT recipients. Additionally, previous in vitro studies have demonstrated that CAZ-AVI, when used in combination with other drugs, exhibits high synergistic activity against CR-GNB (Gaibani et al., 2017; Wang et al., 2021; Zhang et al., 2024). However, it is unclear whether this combination is beneficial. Therefore, we conducted a retrospective study to assess the risk factors for clinical failure and death in CR-GNB-infected KT recipients treated with CAZ-AVI, as well as the effect of combination therapy.

According to the electronic medical records, 654 kidney transplants were performed in our center between June 2019 and December 2023, and 88 CR-GNB-infected recipients received CAZ-AVI treatment, of which four CR-GNB-infected recipients received CAZ-AVI for < 72 h and three CR-GNB-infected recipients aged < 18 years were excluded from the study. Finally, 81 recipients were included in the study.

This is the largest single-center study reported to date focused on KT recipients receiving CAZ-AVI for CR-GNB infection to explore the risk factors associated with clinical failure and 30-day mortality, as well as the effectiveness of combination therapy. The results showed that CAZ-AVI was administered to 81 CR-GNB-infected recipients, including 61 CRKP-infected recipients, 16 CRPA-infected recipients, and 4 CRAB-infected recipients. The 30-day mortality, clinical cure, and microbiological cure rates were 22.2%, 72.8%, and 66.7%, respectively, indicating that CAZ-AVI is effective in the treatment of CR-GNB infection after kidney transplantation.

The reported 30-day mortality of 22.2% in this study is consistent with the 30-day mortality reported in a recently published study involving 210 solid organ transplant recipients with bloodstream CRKP infection at 14 transplant centers in four countries, and they reported a 30-day mortality of 13.25% in recipients treated with CAZ-AVI (Pérez-Nadales et al., 2023). Another multicenter retrospective study from 2015 to 2019 at six medical centers in the United States included 203 CREs (n = 117) and CRPAs (n = 63) isolated from culture specimens, and the 30-day mortality in patients treated with CAZ-AVI was 17.2% (Jorgensen et al., 2019). However, Chen et al (Chen et al., 2021). reported 38.1% 30-day mortality in the liver transplant population, which was significantly higher than the 30-day mortality in our study (19.4%), which could be attributed to the difference in patient severity between studies. Our study revealed that 30-day mortality was associated with higher APACHE II scores, consistent with previous reports (Zhang et al., 2024). A meta-analysis conducted by Qian et al (Qian et al., 2021). reported that the average APACHE II score in nonsurviving patients was significantly higher than that in surviving patients at the time of diagnosis of CRKP infection, indicating that the APACHE II score is a critical and useful scoring system for clinicians to assess disease severity and predict the prognosis of patients with CR-GNB infection.

In addition, the clinical and microbiological cure rates in the present study were 72.8% and 66.7%, respectively, which were consistent with previous reports. Temkin et al (Temkin et al., 2017). reported a single-center case study in which 38 patients with CRE (89% CRKP) infection were treated with CAZ-AVI, with clinical and microbiological cure rates of 68.4% and 63.1%, respectively. In a multicenter study by King et al (King et al., 2017), which evaluated the clinical outcomes of 60 CRE (83% CRKP)-infected patients treated with CAZ-AVI, 65% and 53% achieved microbiological cure and clinical cure, respectively, at the end of CAZ-AVI treatment. The present study revealed that clinical failure was associated with higher APACHE II scores and failure to administer CAZ-AVI within 48 hours of infection onset, consistent with previous reports (Yu et al., 2023; Xu et al., 2024). A multicenter retrospective cohort study by Jorgensen et al (Jorgensen et al., 2019). demonstrated that CAZ-AVI initiation within 48 h of infection onset was associated with a lower clinical failure rate in patients with CR-GNB infection. Additionally, several studies have shown that the treatment of severe infections is time-sensitive, and delays in appropriate treatment have negative consequences (Seymour et al., 2017; Bonine et al., 2019), emphasizing the importance of rapid diagnostic testing in early pathogen identification and susceptibility testing. Continuous renal replacement therapy (CRRT) has previously been reported to be associated with clinical failure of CAZ-AVI treatment (Shields et al., 2018; Jorgensen et al., 2019); however, this association was not observed in our study, which may be attributed to our small sample size.

In the pre-CAZ-AVI era, combinations of two or more active antimicrobial agents were widely considered superior to single-agent regimens for treating CR-GNB, particularly for CRE infections associated with high mortality scores (Gutiérrez-Gutiérrez et al., 2017; Giannella et al., 2018). The role of CAZ-AVI as a combination therapy is still debated. A recent meta-analysis of 17 studies and 1435 patients (837 treated with CAZ-AVI combination therapy and 598 treated with CAZ-AVI monotherapy) treated with CAZ-AVI for CR-GNB infection revealed no significant difference in mortality, clinical cure rate, or microbiological cure rate between CAZ-AVI combination therapy and monotherapy, but monotherapy was more likely to present a trend toward posttreatment resistance than combination therapy (Li et al., 2021). Several studies have shown that CAZ-AVI combination therapy can reduce mortality compared with monotherapy, particularly in critically ill patients (Tumbarello et al., 2015; Zheng et al., 2021). In contrast, a small number of studies have reported the opposite results. Corbella et al (Corbella et al., 2022). reported an inverse correlation between combination therapy and clinical cure in 61 CRPA patients treated with CAZ-AVI. Karaiskos et al (Karaiskos et al., 2021). revealed that CAZ-AVI combination therapy was an independent risk factor for death in a multicenter prospective observational study, and this difference may be explained by the inclusion of patients with more severe infections in the combination group. In the present study, combination therapy showed no clear improvement in terms of 30-day mortality or clinical cure compared to monotherapy, consistent with the findings of most previous studies (Temkin et al., 2017; Li et al., 2021), indicating that CAZ-AVI is effective when administered alone. Compared with combination therapy, CAZ-AVI monotherapy may reduce the incidence of adverse events, particularly acute kidney injury, on the basis of the characteristics of combination therapy with aminoglycosides or colistin (Shields et al., 2016; King et al., 2017). No acute kidney injury events were observed in this study, which could be attributed to the fact that most CAZ-AVI combination antimicrobials used in the present study were carbapenems.

The recurrence rate within 90 days after onset in the present study was 4.9% (4/81), which was lower than the 11.7% to 21% reported in previous studies (Shields et al., 2016, 2018), and all four recurrent recipients were cured by CAZ-AVI retreatment. CAZ-AVI resistance was not detected in the present study, which is consistent with the findings of previous studies (Vena et al., 2020; Corbella et al., 2022). However, there is mounting evidence that resistance develops during CAZ-AVI exposure. Shields et al (Shields et al., 2016). reported that 10% (8/77) of CRE-infected patients developed resistance after receiving CAZ-AVI treatment for a median of 15 days (IQR, 7–31). Another study reported that 3.5% (20/577) of CRKP-infected patients had persistently positive cultures after CAZ-AVI initiation and eventually developed resistance to CAZ-AVI (Tumbarello et al., 2021). The most common cause of CAZ-AVI resistance is a point mutation in the bla_KPC gene, which can restore susceptibility to carbapenems, so some authors encourage clinicians to combine CAZ-AVI with carbapenems or other antibiotics to prevent resistance (Liu et al., 2022). The present study revealed CAZ-AVI to be safe, with an incidence of treatment-related adverse reactions similar to that previously reported (Balandín et al., 2022; Corbella et al., 2022), and no severe adverse drug reactions occurred.

This study has many limitations. First, because this was a single-center, retrospective study, the generalizability of our findings is limited. Second, since CAZ-AVI was introduced in China in 2019, our sample size was relatively small, which may have prevented us from identifying important risk factors for 30-day mortality and clinical failure, and larger randomized controlled trials are required to address this issue. Third, carbapenemase detection assays were not performed in this study due to the lack of necessary clinical laboratory equipment and reagents.

This study identified the risk factors for clinical failure and 30-day mortality in CR-GNB-infected KT recipients treated with CAZ-AVI, and our study suggested that CAZ-AVI provides clinical benefit in terms of survival and clinical response in CR-GNB-infected KT recipients, even as a monotherapy. Higher APACHE II scores were associated with 30-day mortality and clinical failure, and timely administration of CAZ-AVI within 48 hours of infection onset was positively associated with a clinical cure. These findings may help clinicians optimize treatment strategies for KT recipients with CR-GNB infections using CAZ-AVI and reduce mortality in the future.

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

The studies involving humans were approved by the ethics committee of The First Affiliated Hospital of Anhui Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because this study is a retrospective study. The animal study was approved by the ethics committee of The First Affiliated Hospital of Anhui Medical University. The study was conducted in accordance with the local legislation and institutional requirements.

FZ: Conceptualization, Formal analysis, Investigation, Writing – original draft. PL: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft. JZ: Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft. HD: Data curation, Formal analysis, Methodology, Software, Writing – original draft. GL: Conceptualization, Formal analysis, Writing – review & editing. CL: Conceptualization, Validation, Writing – review & editing.