Ceftazidime–avibactam monotherapy versus combination therapy for carbapenem-resistant Gram-negative bacterial infections: a secondary meta-analysis of predominantly critically ill cohorts
Abstract
BackgroundCarbapenem-resistant Gram-negative bacterial (CR-GNB) infections pose a critical threat to global public health, particularly in critically ill patients where treatment options are severely limited. Ceftazidime–avibactam (CAZ/AVI) is a novel β-lactam/β-lactamase inhibitor combination that has become a cornerstone therapy, yet its optimal use—as monotherapy or in combination with other agents—remains debated.ObjectiveTo systematically evaluate the comparative efficacy, renal safety, and risk of on-treatment resistance emergence between CAZ/AVI monotherapy and combination therapy in adult patients with confirmed CR-GNB infections. Because individual-patient data were unavailable, pooled estimates are derived from mixed cohorts in which approximately 82% of participants were ICU-admitted critically ill patients (critically ill is defined as intensive care unit admission or APACHE II score ≥15).MethodsThis study is a secondary reanalysis of the aggregate dataset compiled by Hsu et al. (2024); no de novo systematic search was performed. Studies comparing CAZ/AVI monotherapy versus any combination regimen for the treatment of CR-GNB infections were eligible. The primary outcome was 30-day all-cause mortality. The secondary outcomes included in-hospital, 14-day, and 90-day mortality; clinical cure; microbiological eradication; acute kidney injury (AKI); and on-treatment resistance emergence. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. The heterogeneity was assessed via I2 statistics, and publication bias was evaluated using funnel plots and Egger’s test. Subgroup analyses were prespecified by pathogen type, infection site, combination regimen, geographic region, and study design.ResultsTwenty-five studies (23 retrospective cohorts and two prospective cohorts) enrolling 2,676 patients were included. The pooled 30-day mortality was 31.2% in the combination group and 32.8% in the monotherapy group, with no significant difference (RR = 0.91, 95% CI 0.79–1.04, P = 0.17; I2 = 34%). In-hospital mortality (RR = 1.00, 95% CI 0.78–1.27), 14-day mortality (RR = 1.54, 95% CI 0.26–9.28), and 90-day mortality (RR = 1.18, 95% CI 0.64–2.18) showed no significant between-group differences. Clinical cure rates were comparable (RR = 0.95, 95% CI 0.84–1.08; I2 = 39%). Microbiological eradication did not differ significantly between groups (RR = 1.15, 95% CI 1.00–1.33; P = 0.05; I2 = 31%). AKI incidence did not differ overall (RR = 0.92, 95% CI 0.69–1.22; I2 = 42%), although a post hoc analysis showed a non-statistically significant trend toward higher nephrotoxicity for polymyxin-containing combination regimens (RR = 1.28, 95% CI 0.94–1.74). On-treatment resistance emergence did not differ significantly between groups (RR = 0.71, 95% CI 0.42–1.21; P = 0.21; I2 = 19%). Subgroup analyses consistently showed no mortality benefit across pathogen types, infection sites, or specific combination agents. Sensitivity analyses confirmed the robustness of the findings, and no significant publication bias was detected.ConclusionThis secondary meta-analysis, based on the aggregate dataset compiled by Hsu et al. (2024), suggests that CAZ/AVI combination therapy does not confer a statistically significant survival or clinical cure advantage over monotherapy in patients with CR-GNB infections, although it was associated with a non-significant trend toward higher microbiological eradication and lower on-treatment resistance emergence. Given the predominantly observational nature of the included studies, high-quality randomized controlled trials are urgently warranted to guide clinical decision-making. Until higher-certainty evidence becomes available, these very-low-certainty findings support cautious, individualized decision-making: CAZ/AVI monotherapy may be a reasonable default therapeutic option for many patients, whereas combination therapy could be considered in selected high-risk scenarios, carefully balancing the unproven microbiological signals against increased toxicity and cost.
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BibTeX
@article{yue2026ceftazidimeavibactam,
title = {{Ceftazidime–avibactam monotherapy versus combination therapy for carbapenem-resistant Gram-negative bacterial infections: a secondary meta-analysis of predominantly critically ill cohorts}},
author = {Deyong Yue and Ling Zhu and Lihua Gu and Jing Guo and Dan Zhou and Congbiao Liu and Lyuping Hu},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2004710},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2004710},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Ceftazidime–avibactam monotherapy versus combination therapy for carbapenem-resistant Gram-negative bacterial infections: a secondary meta-analysis of predominantly critically ill cohorts
AU - Deyong Yue
AU - Ling Zhu
AU - Lihua Gu
AU - Jing Guo
AU - Dan Zhou
AU - Congbiao Liu
AU - Lyuping Hu
PY - 2026
DA - 2026/11/06
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2004710
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2004710
AB - BackgroundCarbapenem-resistant Gram-negative bacterial (CR-GNB) infections pose a critical threat to global public health, particularly in critically ill patients where treatment options are severely limited. Ceftazidime–avibactam (CAZ/AVI) is a novel β-lactam/β-lactamase inhibitor combination that has become a cornerstone therapy, yet its optimal use—as monotherapy or in combination with other agents—remains debated.ObjectiveTo systematically evaluate the comparative efficacy, renal safety, and risk of on-treatment resistance emergence between CAZ/AVI monotherapy and combination therapy in adult patients with confirmed CR-GNB infections. Because individual-patient data were unavailable, pooled estimates are derived from mixed cohorts in which approximately 82% of participants were ICU-admitted critically ill patients (critically ill is defined as intensive care unit admission or APACHE II score ≥15).MethodsThis study is a secondary reanalysis of the aggregate dataset compiled by Hsu et al. (2024); no de novo systematic search was performed. Studies comparing CAZ/AVI monotherapy versus any combination regimen for the treatment of CR-GNB infections were eligible. The primary outcome was 30-day all-cause mortality. The secondary outcomes included in-hospital, 14-day, and 90-day mortality; clinical cure; microbiological eradication; acute kidney injury (AKI); and on-treatment resistance emergence. Risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using random-effects models. The heterogeneity was assessed via I2 statistics, and publication bias was evaluated using funnel plots and Egger’s test. Subgroup analyses were prespecified by pathogen type, infection site, combination regimen, geographic region, and study design.ResultsTwenty-five studies (23 retrospective cohorts and two prospective cohorts) enrolling 2,676 patients were included. The pooled 30-day mortality was 31.2% in the combination group and 32.8% in the monotherapy group, with no significant difference (RR = 0.91, 95% CI 0.79–1.04, P = 0.17; I2 = 34%). In-hospital mortality (RR = 1.00, 95% CI 0.78–1.27), 14-day mortality (RR = 1.54, 95% CI 0.26–9.28), and 90-day mortality (RR = 1.18, 95% CI 0.64–2.18) showed no significant between-group differences. Clinical cure rates were comparable (RR = 0.95, 95% CI 0.84–1.08; I2 = 39%). Microbiological eradication did not differ significantly between groups (RR = 1.15, 95% CI 1.00–1.33; P = 0.05; I2 = 31%). AKI incidence did not differ overall (RR = 0.92, 95% CI 0.69–1.22; I2 = 42%), although a post hoc analysis showed a non-statistically significant trend toward higher nephrotoxicity for polymyxin-containing combination regimens (RR = 1.28, 95% CI 0.94–1.74). On-treatment resistance emergence did not differ significantly between groups (RR = 0.71, 95% CI 0.42–1.21; P = 0.21; I2 = 19%). Subgroup analyses consistently showed no mortality benefit across pathogen types, infection sites, or specific combination agents. Sensitivity analyses confirmed the robustness of the findings, and no significant publication bias was detected.ConclusionThis secondary meta-analysis, based on the aggregate dataset compiled by Hsu et al. (2024), suggests that CAZ/AVI combination therapy does not confer a statistically significant survival or clinical cure advantage over monotherapy in patients with CR-GNB infections, although it was associated with a non-significant trend toward higher microbiological eradication and lower on-treatment resistance emergence. Given the predominantly observational nature of the included studies, high-quality randomized controlled trials are urgently warranted to guide clinical decision-making. Until higher-certainty evidence becomes available, these very-low-certainty findings support cautious, individualized decision-making: CAZ/AVI monotherapy may be a reasonable default therapeutic option for many patients, whereas combination therapy could be considered in selected high-risk scenarios, carefully balancing the unproven microbiological signals against increased toxicity and cost.
SN - 1663-9812
ER -