Efficacy and safety of novel beta-lactam/beta-lactamase inhibitor combinations in multidrug-resistant gram-negative bacterial infections: A systematic review and meta-analysis
Keywords:
multidrug-resistant gram-negative bacteria, beta-lactamase inhibitors, microbiological eradication, infectious diseaseAbstract
Background and aim: Multidrug-resistant Gram-negative bacterial infections (MDR-GNB) pose a significant global health challenge, limiting the effectivity of standard antibiotics treatment and contributing to increased morbidity and mortality. Beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations have emerged as promising alternatives to standard antibiotic therapy. This systematic review and meta-analysis aim to evaluate the efficacy and safety of BL/BLI combinations in MDR-GNB infections.
Methods: A comprehensive literature search was conducted, including clinical trials comparing BL/BLI combinations with standard antibiotic therapy or placebo. Primary outcomes included clinical cure rates (CCR), microbiological eradication, mortality, adverse events, and survival rates. The risk of bias was assessed using the Revised Tool for Risk of Bias in Randomized Trials (RoB 2.0). Meta-analysis was performed using Review Manager 5.4, and heterogeneity was quantified using the I² statistic.
Results: Seventeen studies assessed CCR, demonstrating a significant advantage for BL/BLI combinations (Odds ratio (OR) 2.43 (95% CI 1.95–3.03) ). Thirteen studies reported microbiological eradication, favoring the intervention group (OR 2.45(1.42–4.24)). Twenty studies analyzed mortality, revealing a lower risk in the intervention group (OR 0.44(0.31–0.64)). Eight studies examined adverse events, indicating a lower incidence in the BL/BLI group (OR 0.600.40–0.91)). Three studies evaluated survival rates, showing a significant benefit with BL/BLI combinations (OR 2.02(1.10–3.71)).
Conclusions: BL/BLI combinations in MDR-GNB infections significantly improved clinical cure rates, microbiological eradication, and survival. It also reduced mortality and adverse events, highlighting th superiority compared to standard therapy in MDR-GNB
References
1. Tang KWK, Millar BC, Moore JE. Antimicrobial resistance (AMR). Br J Biomed Sci. 2023;80. doi: 10.3389/bjbs.2023.11387.
2. Exner M, Bhattacharya S, Christiansen B, et al. Antibiotic resistance: what is so special about multidrug-resistant Gram-negative bacteria? GMS Hyg Infect Control. 2017;12:Doc05. doi: 10.3205/dgkh000290.
3. Ruppé É, Woerther P-L, Barbier F. Mechanisms of antimicrobial resistance in Gram-negative bacilli. Ann Intensive Care. 2015;5:21. doi: 10.1186/s13613-015-0061-0.
4. Macesic N, Uhlemann A-C, Peleg AY. Multidrug-resistant Gram-negative bacterial infections. The Lancet. 2025;405:257-72. doi: 10.1016/S0140-6736(24)02081-6.
5. Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P. The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev. 2008;32:234-58. doi: 10.1111/j.1574-6976.2008.00105.x.
6. Levy N, Bruneau J-M, Le Rouzic E, et al. Structural basis for E. coli penicillin binding protein (PBP) 2 inhibition, a platform for drug design. J Med Chem. 2019;62:4742-54. doi: 10.1021/acs.jmedchem.9b00338.
7. Rice KC, Bayles KW. Molecular control of bacterial death and lysis. Microbiology and Molecular Biology Reviews. 2008;72:85-109. doi: 10.1128/MMBR.00030-07.
8. Cho H, Uehara T, Bernhardt TG. Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery. Cell. 2014;159:1300-11. doi: 10.1016/j.cell.2014.11.017.
9. Papp-Wallace KM. The latest advances in β-lactam/β-lactamase inhibitor combinations for the treatment of Gram-negative bacterial infections. Expert Opin Pharmacother. 2019;20:2169-84. doi: 10.1080/14656566.2019.1660772.
10. Soriano A, Montravers P, Bassetti M, et al. The use and effectiveness of ceftazidime-avibactam in real-world clinical practice: EZTEAM study. Infect Dis Ther. 2023;12:891-917. doi: 10.1007/s40121-023-00762-9.
11. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021:n71. doi: 10.1136/bmj.n71.
12. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019:l4898. doi: 10.1136/bmj.l4898.
13. McGuinness LA, Higgins JPT. Risk-of-bias visualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2021;12:55-61. doi: 10.1002/jrsm.1411.
14. Falagas ME, Kasiakou SK, Saravolatz LD. Colistin: the revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clinical Infectious Diseases. 2005;40:1333-41. doi: 10.1086/429323.
15. Zhang S, Liao X, Ding T, Ahn J. Role of β-lactamase inhibitors as potentiators in antimicrobial chemotherapy targeting Gram-negative bacteria. Antibiotics. 2024;13:260. doi: 10.3390/antibiotics13030260.
16. Laçinel Gürlevik S, Oygar PD, Köseoğlu B, Hazırolan G, Cengiz AB, Ozsurekci Y. Is the high dose extended infusion of meropenem useful in the treatment of highly resistant gram-negative bacteria in children? Journal of Infection and Chemotherapy. 2025;31:102498. doi: 10.1016/j.jiac.2024.08.013.
17. Chen Y, Huang H-B, Peng J-M, et al. Efficacy and safety of ceftazidime-avibactam for the treatment of carbapenem-resistant Enterobacterales bloodstream infection: a systematic review and meta-analysis. Microbiol Spectr. 2022;10. doi: 10.1128/spectrum.02603-21.
18. Chen J, Hu Q, Zhou P, Deng S. Ceftazidime-avibactam versus polymyxins in treating patients with carbapenem-resistant Enterobacteriaceae infections: a systematic review and meta-analysis. Infection. 2024;52:19-28. doi: 10.1007/s15010-023-02108-6.
19. Lagacé-Wiens P, Walkty A, Karlowsky J. Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. Core Evid. 2014:13. doi: 10.2147/CE.S40698.
20. Zhong H, Zhao X-Y, Zhang Z-L, et al. Evaluation of the efficacy and safety of ceftazidime/avibactam in the treatment of Gram-negative bacterial infections: a systematic review and meta-analysis. Int J Antimicrob Agents. 2018;52:443-50. doi: 10.1016/j.ijantimicag.2018.07.004.
21. Tsolaki V, Mantzarlis K, Mpakalis A, et al. Ceftazidime-avibactam to treat life-threatening infections by carbapenem-resistant pathogens in critically ill mechanically ventilated patients. Antimicrob Agents Chemother. 2020;64. doi: 10.1128/AAC.02320-19.
22. Tumbarello M, Trecarichi EM, Corona A, et al. Efficacy of ceftazidime-avibactam salvage therapy in patients with infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae. Clinical Infectious Diseases. 2019;68:355-64. doi: 10.1093/cid/ciy492.
23. Sternbach N, Leibovici Weissman Y, Avni T, Yahav D. Efficacy and safety of ceftazidime/avibactam: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy. 2018;73:2021-9. doi: 10.1093/jac/dky124.
24. Che H, Wang R, Wang J, Cai Y. Ceftazidime/avibactam versus carbapenems for the treatment of infections caused by Enterobacteriaceae: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents. 2019;54:809-13. doi: 10.1016/j.ijantimicag.2019.09.007.
25. Shi Y, Hu J, Liu P, et al. Ceftazidime-avibactam-based versus tigecycline-based regimen for the treatment of carbapenem-resistant Klebsiella pneumoniae-induced pneumonia in critically ill patients. Infect Dis Ther. 2021;10:2721-34. doi: 10.1007/s40121-021-00542-3.
26. Torres A, Zhong N, Pachl J, et al. Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial. Lancet Infect Dis. 2018;18:285-95. doi: 10.1016/S1473-3099(17)30747-8.
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Roy Novri Ramadhan, Sophia Zahra, Derren DCH Rampengan, Aloysius Denzel Joshua Reviano, Muhammad Nabhan Yasin, Ruthvika Jayanthi, Adrian Faza Raditya, Ketut Wahyu Adi Saputra, Arya Ega, Melissa Valentina Ariyanto, Maulana Antiyan Empitu, Hendriketa da Silva , Ika N. Kadariswantiningsih
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Transfer of Copyright and Permission to Reproduce Parts of Published Papers.
Authors retain the copyright for their published work. No formal permission will be required to reproduce parts (tables or illustrations) of published papers, provided the source is quoted appropriately and reproduction has no commercial intent. Reproductions with commercial intent will require written permission and payment of royalties.
How to Cite
