Efficacy and safety of novel beta-lactam/beta-lactamase inhibitor combinations in multidrug-resistant gram-negative bacterial infections: a systematic review and meta-analysis

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

doi:10.23750/abm.2026.18826

Authors

Roy Novri Ramadhan Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0000-0001-6100-9015
Sophia Zahra Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
Derren DCH Rampengan Faculty of Medicine, Universitas Sam Ratulangi, Manado, Indonesia https://orcid.org/0009-0002-5482-0613
Aloysius Denzel Joshua Reviano Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0001-7345-5036
Muhammad Nabhan Yasin Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0001-4478-0470
Ruthvika Jayanthi Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
Adrian Faza Raditya Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0009-5160-4529
Ketut Wahyu Adi Saputra Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0003-2069-1208
Arya Ega Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0009-0005-0596-8007
Melissa Valentina Ariyanto Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0000-0001-8145-3965
Maulana Antiyan Empitu Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia https://orcid.org/0000-0002-6448-7642
Hendriketa da Silva Faculty of Medicine and Health Sciences, Universidade Nacional Timor-Lorosae, Dili, Timor-Leste https://orcid.org/0009-0004-6095-3070
Ika N. Kadariswantiningsih Universitas Airlangga

Keywords:

multidrug-resistant gram-negative bacteria, beta-lactamase inhibitors, microbiological eradication, infectious disease

Abstract

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

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