Efficacy and safety of ceftazidime-avibactam versus standard antibiotic therapy for resistant Gram-negative bacterial infections: a systematic review and meta-analysis

Introduction

The evolution of multi-drug resistance in Klebsiella pneumoniae (KP), an important opportunistic pathogen, constitutes a global public health crisis (1). The bacterium colonizes human mucosal surfaces for long periods of time through biofilm formation and virulence factors (e.g., capsular polysaccharides, siderophores) (2). Its carbapenem-resistant strain (CRKP) forms a continuous chain of transmission in healthcare facilities (3). Studies indicated that in 2019, KP exhibited an average resistance rate of 10.1% to carbapenem antibiotics, representing a 1.1% increase from 2017 (4,5). In addition, KP can cause a wide range of tissue and organ infections, including bloodstream infections, with high morbidity and mortality rates, particularly in the case of KP pneumonia, which has a mortality rate reaching as high as 50% (6). This highlights the serious challenge that “superbugs” pose to modern medicine (7).

The core of the resistance mechanism of CRKP lies in the expression of carbapenemases, especially class A (Klebsiella pneumoniae carbapenemase, KPC), class B (New Delhi Metallo-β-lactamase, NDM/Verona Integron-encoded Metallo-β-lactamase, VIM) and class D (OXA-48 carbapenemase) β-lactamases (8), These enzymes inactivate carbapenems by hydrolyzing the β-lactam ring, and Metallo-β-lactamases can mediate resistance to the latest drugs (9,10). This evolution has led to a surge in the failure rate of conventional treatment options. It is worth noting that the clinical threat posed by CRKP in critical care settings is becoming increasingly prominent: among orthopedic patients, the reoperation rate following CRKP infection reaches as high as 38% (11). In respiratory intensive care units, CRKP accounts for 39.9% of hospital-acquired pneumonia pathogens, forming a vicious cycle of antibiotic resistance with interventions such as mechanical ventilation (12). Particularly concerning are patients with sepsis, where CRKP infections result in a significantly higher mortality rate (41.2%) compared to infections caused by susceptible strains, and the window for effective treatment is less than one hour (13).

In February 2015, the Food and Drug Administration of the United States (FDA) approved ceftazidime-avibactam (CAZ-AVI), a combination of the third-generation cephalosporin ceftazidime and a novel β-lactamase inhibitor called avibactam, for treating complex urinary tract and abdominal infections caused by Gram-negative bacteria that are resistant to multiple or all antibiotics (7). Nevertheless, the effectiveness and safety of ceftazidime/avibactam in treating KP infections remain inconclusive, sparking ongoing debate (1,14,15). Further extensive clinical studies are required to verify its efficacy. Hence, a Meta-analysis was conducted to assess the efficacy and safety of CAZ-AVI in combating drug-resistant KP infections, aiming to furnish an evidence-based foundation for clinicians to select appropriate treatment strategies. We present this article in accordance with the PRISMA reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-386/rc).

Methods

Search strategy

The study involved conducting searches on various databases, including China National Knowledge Infrastructure (CNKI, https://www.cnki.net/), Wanfang Database (Wanfang, https://www.wanfangdata.com.cn/index.html), VIP Database for Chinese Technical Periodicals (VIP, https://www.cqvip.com/), Chinese Biomedical Literature Database (CBM, http://www.sinomed.ac.cn/index.jsp), PubMed (https://pubmed.ncbi.nlm.nih.gov/), Web of Science (https://access.clarivate.com/) and Cochrane Public Library (https://www.cochranepubliclibrary.ca/). The search period covers the period from the establishment of the database to February 2024. Chinese search terms used were “ceftazidime-avibactam”, “Klebsiella pneumoniae”, “therapeutic effect”, and “safety”. Synonyms such as “Ceftazidime-avibactam”, “Klebsiella pneumoniae”, “Efficacy”, and “Safety” were integrated as English keywords, interconnected with “AND”.

Literature inclusion and exclusion criteria

Inclusion criteria for the literature review are as follows: (I) Study type: randomized controlled trials, prospective or retrospective cohort studies; (II) language: Chinese or English; (III) patients diagnosed with pulmonary infection caused by CRKP; (IV) administration of CAZ-AVI either as a standalone treatment or in combination with other antibiotics, without restrictions on dosage or duration of treatment; (V) inclusion of standard antibiotic treatment groups treated with non-CAZ-AVI antibiotics, either as monotherapy or in combination, with no limitations on dosage or treatment duration, and no constraints on study design. (VI) Outcome indicators encompass measures of effectiveness such as clinical response, bacterial clearance rate, and C-reactive protein (CRP), procalcitonin (PCT) levels, and other relevant parameters, while safety outcomes include mortality rates and incidence of adverse reactions. (VII) In cases where data from the same author are duplicated, the study with the largest sample size or the most recent publication is prioritized. (VIII) Data collection is confined to studies published in databases until February 2024. Literature exclusion criteria involve: (I) redundant and irrelevant studies and reviews; (II) studies that are not randomized controlled trials; (III) studies conducted on animal subjects; (IV) discrepancies in the study outcomes; (V) absence of the CAZ-AVI group and/or the standard antibiotic treatment group in the study results; (VI) incomplete, missing, unusable data, or data with evident errors.

Literature screening and data extraction

Two researchers from the research team conducted a thorough literature review using established inclusion and exclusion criteria. They initially screened the titles and abstracts of the articles, and if necessary, proceeded to review the full texts. In cases of disagreement, they consulted with third-party experts for resolution. Data from the relevant documents that met the inclusion criteria were extracted based on a predetermined literature feature table. The extracted information included details on study design, total sample size, sample sizes of the CAZ-AVI and standard antibiotic treatment groups, and outcome variables, among others.

Literature quality evaluation

The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality. Scores ranged from 0 to 9, with ratings of 79, 46, and 4, corresponding to high (grade A), moderate (grade B), and low (grade C) methodological quality, respectively.

Statistical analysis

Literature management was conducted using NoteExpress 3.2 software, while Excel 2003 software was utilized to collect and extract data from the literature. For Meta analysis, Revman5.4.1 software was employed, with the heterogeneity of the data being analyzed using the Q test (P value) and evaluated using the I² value. In cases where P>0.10 or I²≤50%, indicating the absence of heterogeneity, the fixed effect model (FEM) analysis was applied; alternatively, the random effect model (REM) analysis was utilized. The data were described and analyzed using the odds ratio (OR) and its 95% confidence interval (CI), with a forest plot being generated. Sensitivity analysis was performed to assess the stability of the meta-analysis results, and publication bias was evaluated using a funnel plot. The significance level was set at α=0.05 (two-tailed).

Results

Literature retrieval results

Following the article retrieval strategy, a total of 2,203 relevant articles were initially queried from databases such as China Knowledge Network, Wanfang Database, VIP Chinese Sci-tech Journals Database, China Biomedical Database, PubMed, Web of Science, and Cochrane Library. Duplicate articles within each database were then removed. Subsequently, through the examination of titles, abstracts, and full texts, eight articles were ultimately selected (16-23) (Figure 1).

Figure 1 Flow chart of literature screening.

Study characteristics

The baseline information primarily consisted of gender, age, duration of illness, outcome parameters, and other relevant factors. The quality assessment of the 8 selected studies was conducted using the enhanced NOS (Table 1).

Meta-analysis of clinical data

A total of 7 studies compared the clinical effectiveness of patients between the CAZ-AVI group and the standard antibiotic treatment group. The CAZ-AVI group included 408 cases, while the standard antibiotic treatment group had 310 cases. A heterogeneity test was conducted on the collected studies, revealing no statistical heterogeneity among them. Therefore, a fixed-effects model was utilized to combine the data from these studies. The results of the meta-analysis indicated that the clinical effectiveness of the CAZ-AVI group was significantly superior to that of the standard antibiotic treatment group showing statistical significance (OR: 2.56, 95% CI: 1.84–3.58, P<0.00001) (Figure 2A). It means the clinical efficacy of ceftazidime/avibactam is superior to other treatments.

Figure 2 Forest map of meta-analysis for clinical data. (A) Comparison of clinical efficacy between the ceftazidime-avibactam group and the standard antibiotic treatment group. (B) Adverse reactions between the ceftazidime-avibactam group and the standard antibiotic treatment group. (C) Comparison of original mortality between the ceftazidime-avibactam group and the standard antibiotic treatment group. CI, confidence interval.

Five articles were included in the analysis to compare the adverse reactions in the CAZ-AVI and standard antibiotic treatment groups. The CAZ-AVI group consisted of 227 cases, while the standard antibiotic treatment group had 200 cases. Statistical heterogeneity was detected among the studies, prompting the utilization of the REM for data synthesis. The meta-analysis results indicated a statistically significant difference in adverse reactions between the CAZ-AVI and standard antibiotic treatment groups, with a lower occurrence in the CAZ-AVI group (95% CI: 0.11–0.88, P=0.03) (Figure 2B).

A total of 6 studies were analyzed to compare the mortality rates of patients between the CAZ-AVI and standard antibiotic treatment groups. The CAZ-AVI group comprised 394 cases, while the standard antibiotic treatment group had 334 cases. A heterogeneity test was conducted on the selected studies, revealing a range of 0.32% to 14%, indicating no significant statistical heterogeneity among the different studies. Therefore, the FEM was employed to consolidate the data from these studies. The meta-analysis demonstrated a statistically significant disparity in mortality rates between the CAZ-AVI and standard antibiotic treatment groups, with the former exhibiting lower mortality rates (95% CI: 0.33–0.64, P<0.00001) (Figure 2C).

Meta-analysis of laboratory outcomes

Five studies were included in the analysis to compare the bacterial clearance rate between the CAZ-AVI and standard antibiotic treatment groups. The CAZ-AVI group comprised 358 cases while the standard antibiotic treatment group had 294 cases. Heterogeneity testing revealed a significant heterogeneity among the included studies (I² =53%, P=0.07), thus the random-effects model was applied for the data synthesis. The meta-analysis results indicated a statistically significant difference in bacterial clearance rate between the CAZ-AVI and standard antibiotic treatment groups, with the former showing a higher rate (95% CI: 1.37–4.00, P=0.002) (Figure 3A). The results indicated that ceftazidime and avibactam in the treatment of drug-resistant KP infection had a higher bacterial clearance rate than other drug treatments.

Figure 3 Forest map of meta-analysis for laboratory outcomes. (A) Comparison of bacterial clearance between the experimental group and the standard antibiotic treatment group. (B) PCT comparison between the ceftazidime-avibactam group and the standard antibiotic treatment group. (C) Original CRP comparison between the ceftazidime-avibactam group and the standard antibiotic treatment group. CRP, C-reactive protein; CI, confidence interval; PCT, procalcitonin; SD, standard deviation.

Two studies were conducted to compare the PCT levels of patients between the CAZ-AVI and standard antibiotic treatment groups, involving 81 cases in the CAZ-AVI group and 80 cases in the standard antibiotic treatment group. Statistical heterogeneity was observed among the literature studies, prompting the utilization of REM for data synthesis. The meta-analysis results indicated no significant variance in PCT levels between the CAZ-AVI and standard antibiotic treatment groups (OR: −0.03, 95% CI: −0.93 to 0.86, P=0.94) (Figure 3B). These results indicated that PCT levels were not statistically significant between ceftazidime/avibactam and other drugs in the treatment of drug-resistant KP infection. A total of 2 studies compared the CRP levels of patients in the CAZ-AVI group with those in the standard antibiotic treatment group, with 81 cases in the CAZ-AVI group and 80 cases in the standard antibiotic treatment group. Statistical heterogeneity was found among the included literature studies, leading to the use of the REM for data combination. The Meta-analysis results indicated no significant disparity in CRP levels between the standard antibiotic treatment and CAZ-AVI groups (OR: −23.47, 95% CI: −50.20 to 3.25, P=0.09) (Figure 3C). These results indicated that CRP levels were not statistically significant between ceftazidime, avibactam and other drugs in the treatment of drug-resistant KP infection.

Sensitivity analysis

The clinical efficacy study incorporated a substantial amount of literature, prompting the utilization of this outcome index for sensitivity analysis. By removing the literature with the highest proportion weight and then recalculating the literature effect, the resulting (OR: 2.72, 95% CI: 1.79–4.12, P<0.00001) (Figure 4). This statistical significance indicates the reliability of the findings in this study.

Figure 4 Forest map of sensitivity analysis between the ceftazidime-avibactam group and the standard antibiotic treatment group. CI, confidence interval.

Literature bias test

The outcome indicators analyzed in this study exhibited bias, and the findings revealed asymmetry in the funnel plot, suggesting the presence of bias (Figure 5).

Figure 5 Funnel chart of bias analysis between the ceftazidime-avibactam group and the standard antibiotic treatment group. MD, mean deviation; OR, odds ratio; SE, standard error.

Discussion

This Meta-analysis of eight studies provides important evidence supporting the superiority of ceftazidime/avibactam in the treatment of CRKP lung infections. It was found that patients in the ceftazidime/avibactam treatment group had a significantly higher clinical cure rate compared to the control regimen (OR: 2.56, 95% CI: 1.84–3.58, P<0.00001). Also, the ceftazidime/avibactam group demonstrated significantly higher bacterial clearance (OR: 2.34, 95% CI: 1.37–4.00, P=0.002). In addition, a key and important finding was that patients in the ceftazidime/avibactam-treated group had a significantly lower mortality rate than those in the control group (P<0.00001).

With the increasing application of carbapenem antibiotics in recent years, the prevalence rate of CRKP pulmonary infection has increased year by year, and only a few antibiotics are effective for CRKP pulmonary infection, among which the treatment regimen based on polycolistin has a good effect (23,24). However, the nephrotoxicity and neurotoxicity of polycolistin limit its use as a first-line agent for the treatment of CRKP pulmonary infection (25). Ceftazidime/avibactam is synthesized by the third-generation cephalosporin ceftazidime and a new β-lactamase inhibitor, avibactam, providing a new option for the treatment of CRKP pulmonary infection (9,10). However, there is a relative lack of high-quality evidence on its clinical efficacy and safety in the treatment of drug-resistant KP. The findings of this study strongly fill this evidence gap. This study confirms that ceftazidime/avibactam in the treatment of CRKP lung infections is more effective in controlling the disease, reducing the inflammatory response, improving the immune function, shortening the duration of illness and mechanical ventilation, and ultimately reducing the risk of poor prognosis compared with other treatment options. The significant advantages of its clinical efficacy and bacterial clearance are in line with the direction of the recommendations of the current relevant treatment guidelines (26,27). The remarkable efficacy of ceftazidime/avibactam is closely related to the broad-spectrum enzyme inhibitory properties of avibactam, which represents a particular breakthrough against KPC enzyme-mediated resistance (9,10). However, recent reports have shown that NDM-1-positive strains may reduce ceftazidime/avibactam susceptibility (28), while the percentage of such strains in this study was not clearly defined, and further stratified analyses in combination with molecular typing are needed in the future.

This study included a total of 6 partial literatures that presented safety indicators such as mortality and adverse reactions, with 5 of them reporting on these indexes. The findings indicated that in comparison to the standard antibiotic treatment group, the ceftazidime-avibactam group exhibited lower occurrence of adverse reactions and mortality (P<0.00001), aligning with the outcomes of the meta-analysis performed by Cao et al. (29-31). Sensitivity analysis confirmed the stability and reliability of the combined effect (P<0.00001). Some studies (29) have also shown that the pharmacokinetics of ceftazidime and avibactam are more stable and no serious adverse reactions occur in the treatment of CRKP. The reason may be related to the inhibitory effect of avibactam on β-lactamase molecules and its protective effect on ceftazidime.

This study is the first to comprehensively assess the efficacy and safety of ceftazidime/avibactam in CRKP lung infections by Meta-analysis, using strict inclusion criteria and sensitivity analysis to ensure reliability of results. The study innovatively reveals the significant clinical benefit of ceftazidime/avibactam in CRKP, which provides a high-level evidence-based basis for the first-line drug selection in critical infections. There are certain limitations of this study that need to be explained. Firstly, there is a relative paucity of prospective studies directly comparing the efficacy of ceftazidime/avibactam with other alternative medications (e.g., polymyxin, tigecycline, aminoglycosides, or combinations thereof), resulting in a limited number of publications and sample sizes included in this Meta-analysis, and the conclusions need to be further validated by large-scale, multicenter, randomized, controlled trials with larger sample sizes of data. Second, sources of heterogeneity among the included studies, such as differences in patient age, severity of underlying disease, duration of infection, and control group treatment regimens (drug type, dosage, combinations, etc.), may have biased the results of this study. The patients included in this study were concentrated in the Asian region, while the Iranian study reported a high prevalence of the Tet (B) gene of 37% (32), suggesting that the regional distribution of resistance genes may influence the efficacy of the control regimen, which is a potential source of heterogeneity in this meta-analysis. Future cross-regional studies are needed to validate the generalizability of ceftazidime/avibactam. Unfortunately, this study was unable to conduct adequate subgroup analyses to explore the impact of these factors on the results. Future studies should focus on addressing these limitations and exploring the impact of different resistance mechanisms (e.g., KPC, NDM, OXA-48, etc.) or molecular typing (33) on the efficacy of ceftazidime/avibactam, as well as the value of optimizing dosing regimens (e.g., extended infusion). In addition, in-depth studies of CRKP resistance mechanisms (e.g., involving mutations in the gyrA gene or the prevalence of tetracycline-resistant genes are also essential to understand the development of resistance and to guide therapeutic strategies (34).

Conclusions

This Meta-analysis confirms that ceftazidime/avibactam significantly improves clinical cure rates and bacterial clearance in patients with CRKP lung infections, as well as reduces all-cause mortality, with efficacy against KPC/OXA-48 strains. Its safety profile (lower risk of nephrotoxicity than polymyxin regimens) supports its use as a first-line treatment option for CRKP pneumonia. Future studies need to focus on the development of novel inhibitors for NDM-positive infections and the dynamic monitoring of regional resistance profiles to address the evolving threat of drug resistance.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-386/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-386/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-386/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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