Nitesh Brijlal, Sandra Lihle Maphumulo, Ravesh Singh, Khine Swe Swe-Han, Carbapenem-resistant Enterobacterales at a quaternary public hospital in Durban, KwaZulu-Natal: Ascertaining the clinical and molecular paradigm shift following COVID-19, International Journal of Clinical Microbiology, Volume 1, Issue 4, 2026, Pages 13-38, ISSN 2690-4721, https://doi.org/10.14302/issn.2690-4721.ijcm-26-6425. (https://openaccesspub.org/international-journal-of-clinical-microbiology/article/carbapenem-resistant-enterobacterales-at-a-quaternary-public-hospital-in-durban-kwazulu-natal-ascertaining-the-clinical-and-molecular-paradi-2405) Abstract: Background Extensive carbapenem use has resulted in an increasing occurrence of difficult-to-treat resistant gram-negative bacteria (DTR-GNB), such as carbapenem-resistant Enterobacterales (CREs). The international antimicrobial resistance (AMR) landscape was profoundly impacted due to varying antibiotic prescribing practices following coronavirus disease 2019 (COVID-19). The resultant evolution in multidrug-resistant organism (MDRO) trends underscored this study’s aim in establishing the COVID-19 pandemic’s influence on the prevalence, molecular characterisation, and clinical outcome of CRE infections at a South African quaternary public hospital. Methods Demographics, microorganism identification, antibiograms, and patient outcomes with associated factors were extracted retrospectively from electronic records at Inkosi Albert Luthuli Central Hospital (IALCH). Carbapenemase-encoding genes from CRE isolates were prospectively identified by conventional multiplex polymerase chain reaction. Comparisons between the pre-COVID-19 (01 January 2018 to 05 March 2020) and post-COVID-19 (06 March 2020 to 31 May 2023) periods were conducted. Results A total of 1481 (n) CRE samples were analysed from 985 patients, with an age range of 2 days to 91-years-old. The post-COVID-19 CRE prevalence (13.58%) was more than double the pre-pandemic prevalence (6.72%). Klebsiella pneumoniae (85.7%; 1269/1481) was the predominant microbial species, followed by Enterobacter cloacae (6.4%; 95/1481), both of which exhibited in vitro resistance to majority of antibiotic classes. Of the 357 molecularly-tested isolates, 322 (90.2%) were carbapenemase-producers, with an upsurge in blaOXA-48 (20.8%; 15/72 versus 61.2%; 137/224, p < 0.001) and decrease in blaNDM (69.4%; 50/72 versus 17.9%; 40/245, p < 0.001) in Klebsiella pneumoniae relative to the COVID-19 periods. Overall, majority of deaths (42.2%; 57/135) occurred within 7 days of CRE isolation, while logistic regression analysis showed that intensive/high-care unit admission and sterile site infection were significantly associated with increased all-cause mortality. Conclusion There is a rising CRE burden and shift in carbapenemase-encoding gene prevalence within this referral healthcare institution following COVID-19. This study highlights the need for ongoing epidemiological surveillance and suggests conducting routine carbapenemase testing for CRE infections amongst selected patients. Multisectoral collaborative approaches streamlining accessibility to the newer β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations, such as ceftazidime-avibactam, including agents like aztreonam and cefiderocol, are urgently required to provide directed therapy, thereby potentially improving patient clinical outcomes. Keywords: Carbapenem-resistant Enterobacterales; carbapenemase; COVID-19; β-lactam/β-lactamase inhibitor