Carbapenem-resistant Enterobacterales at a quaternary public hospital in Durban, KwaZulu-Natal: Ascertaining the clinical and molecular paradigm shift following COVID-19

The widespread use of carbapenems has resulted in the rapidly increasing occurrence and distribution of difficult-to-treat resistant gram-negative bacteria (DTR-GNB), such as carbapenem-resistant Enterobacterales (CREs), worldwide.^{1, 2, 3} Infections caused by CREs pose a serious public health threat and are associated with significant patient morbidity and mortality.⁴ Additionally, they have been categorised as “critical” according to the first published global priority pathogen list in 2017 by the World Health Organization (WHO).⁵

Enterobacterales are currently recognised as the leading cause of serious community-acquired and nosocomial infections and are among the commonest bacteria isolated from clinical specimens.⁶,⁷ The production of beta(β)-lactamase (bla) enzymes, called carbapenemases, is the most frequently-mediated mechanism by which Enterobacterales develop carbapenem resistance.²,⁷,⁸,⁹ Carbapenemases belong to the Ambler structural classification, being serine β-lactamases (Class A and D) and metallo-β-lactamases (Class B), which differ in their response to antimicrobial agents, impacting selection choices in patient management.⁴,⁸,¹⁰

The landscape of antimicrobial resistance (AMR) was greatly challenged during the outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).¹¹,¹²,¹³ The COVID-19 pandemic had impacted negatively on the implementation of antimicrobial stewardship (AMS) programmes, escalating the prevalence of multidrug-resistant organisms (MDROs) secondary to the mass consumption (and misuse) of broad-spectrum antibiotics.¹⁴,¹⁵ Global data revealed blaKPC, blaOXA-48 and blaNDM to be the dominant carbapenemase-encoding genes in these CRE infections, comprising predominantly of respiratory and bloodstream specimen types, with some isolates harbouring multiple carbapenemases.¹⁶,¹⁷,¹⁸,¹⁹

However, although COVID-19 had been associated with an increased incidence in hospital-acquired resistant bacterial co-infections,²⁰,²¹,²² some studies revealed that prolonged personal protective equipment (PPE) use and strict, well-enforced infection prevention and control (IPC) strategies during this time period, were beneficial in minimising the spread of MDROs in certain healthcare environments.¹¹,²³,²⁴

Maphumulo et al. demonstrated a prevalence of blaNDM-1 and blaOXA-181 carbapenemase genes in a retrospective study comprising 194 clinical CRE isolates from Inkosi Albert Luthuli Central Hospital (IALCH), a quaternary public sector hospital in Durban, South Africa (SA), during 2013 to 2017, which was prior to COVID-19.²⁵ Whether the paradigm had now shifted to encompass other or multiple carbapenemase-encoding genes in this adult and paediatric population, especially following amplified antibiotic prescribing practises during the COVID-19 pandemic, remains unknown.

The paucity of such significant data within this specialised referral health facility impedes the implementation of swift IPC measures, the strengthening of AMS interventions, and the provision of baseline information on currently circulating carbapenemases to advocate for newer therapeutic agents active against certain carbapenemase-producing Enterobacterales (CPEs). This study therefore aimed to determine the influence of COVID-19 on the comparative prevalence, demography, molecular characterisation, and patient clinical outcomes of CRE infections at IALCH.

The global spread of CRE-associated infections poses a substantial healthcare burden, with carbapenemase-encoding genes being the predominant driver of resistance. This study investigated the comparative pre- and post-COVID-19 prevalence of CREs in a quaternary public hospital in Durban, South Africa, providing insight into demographics, microbiological characteristics, antibiotic susceptibility profiles, molecular characterisation, and patient clinical outcomes. The phenotypic and genotypic paradigm shift ascertained relative to the multitude of aspects particularly analysed amid the COVID-19 time periods, represents, per literature search to date, a novel study for Africa.

The overall CRE prevalence of 10.5% in this healthcare institution constituted 6.72% and 13.58% during the pre- and post-pandemic periods, respectively. This is strikingly alarming in relation to data from the Antimicrobial Testing Leadership and Surveillance (ATLAS) global surveillance programme that reported CRE detection rates in Latin America and Middle-East Africa to be between 4.7-5.7% in 2018 (before COVID-19), increasing only to 10.4-12.9% in 2022 (following COVID-19).²⁹ Additionally, a study by Sader et al comprising 64 medical centres worldwide, including Europe and Asia-Pacific regions, elicited a 4.1% CRE prevalence during 2020-2022,³⁰ which is less than one-third the prevalence in our findings (12.72%) for the same period.

Further to the SA government National State of Disaster declaration in respect of the COVID-19 pandemic onset, the CRE prevalence had declined slightly from 12.29% to 12.24% in the subsequent year, likely due to implementation of the various lockdown restrictions imposed. As supported by other studies, heightened IPC practices and more stringent isolation protocols entail added potential contributory factors for the reduced MDROs seen in some clinical

settings after COVID-19.¹¹,²⁴,³¹ However, as evidenced by the continuous annual rise in prevalence by more than 2% thereafter, this initial trend in our study was unsustained – an outcome contrary to the verdicts by Linn et al in South-East Asian hospitals,³² but in agreement with a Cape Town study where an almost 3-fold escalation in nosocomial infections occurred during the third COVID-19 wave.³³

The median age of 16 years (IQR 0-39) for the total period differs greatly from other reports that included both paediatric and adult patients, where older populations were mainly affected by CRE infections.³⁴,³⁵,³⁶,³⁷ The preponderance of males, in addition to intensive and high-care unit patient locations, are findings consistent with previous studies within the South African context.⁷,³⁷ The noteworthy reduction in CRE prevalence in neonates and infants following the pandemic may be parallel to a general observation in Hong Kong where diligent hand hygiene measures, in conjunction to other efforts, possibly mitigated drug-resistant bacterial burden.¹¹ Wielders et al indicated a median number of two isolates for patients having multiple CREs³⁸ – this similarity aligned with our study where the average number of isolates for the same cohort of individuals ranged between 2.76-2.93, overall.

Blood culture and urine encompassed the majority of sterile and non-sterile specimen types, respectively, regardless of the COVID-19 period, representing a finding synonymous with a vast expanse of national and global studies.⁶,³⁷,³⁹,⁴⁰,⁴¹,⁴² The increase in endotracheal aspirate and sputum samples – the former of which signifies the second commonest non-sterile specimen in this setting – is inferential of the post-pandemic surge in respiratory tract infections, conforming to the top two sample types amongst other research outputs.⁴³,⁴⁴,⁴⁵,⁴⁶,⁴⁷ Klebsiella pneumoniae accounted for the largest overall proportion (85.7%) of CRE species at IALCH, corresponding to the well-established dominance highlighted by various publications.³⁴,³⁵,³⁷,⁴³,⁴⁵,⁴⁶,⁴⁸,⁴⁹ Moreover, its significant post-pandemic escalation synchronises with the results obtained by Jeon et al in four South Korean university hospitals during 2018-2021, denoting an important aspect that necessitates further monitoring.⁵⁰

Amid the armamentarium of antibiotic classes tested for CREs, extensive in vitro resistance was exhibited. Barring carbapenems, this was most apparent for β-lactams (≥94%), followed by trimethoprim-sulfamethoxazole (≥89%) and ciprofloxacin (≥81%). The higher rate of resistance that prevailed after COVID-19 in the abovementioned instances may be a consequence secondary to increased empiric antibiotic consumption²⁰ or enhance surveillance and reporting systems during this period.³⁴ Similar to gentamicin, a converse association existed for amikacin and tigecycline, both of which, in accordance with findings from other studies,²¹,³⁴,³⁷,⁴⁵,⁴⁷,⁵¹,⁵² recorded significantly lower degrees of resistance, thus reiterating the vital role attained by these agents for use in settings plagued by CRE treatment option limitations.

The revelation that 90.2% of CREs in this quaternary hospital were positive for carbapenemase production is not surprising, given the fact that CPE rates differ greatly (20.7-97.4%) depending on epidemiological characteristics, frequency of molecular detection, and other influential variables.⁷,²¹,³⁴,⁴⁰,⁴⁹,⁵²,⁵³,⁵⁴ The unexpected drop in total CPEs following COVID-19, together with the ensuing genotypic shift from blaNDM to blaOXA-48 in this patient population, provides insight into the evolving dynamics of CPE dissemination. Our post-pandemic findings, which benchmarks the current situation, is in keeping with recent data showcasing blaOXA-48 as the commonest carbapenemase-encoding gene circulating in SA, followed by blaNDM,³⁴,³⁷ but diverges from prior research undertaken at IALCH where blaNDM remained the predominant carbapenemase (86%) during 2013-2017.²⁵ This is probably due to antibiotic selection pressure of widespread carbapenem use, efficient plasmid spread, and diagnostic limitations that may result in earlier regional endemicity from sustained silent transmission.⁸,³⁷

Enterobacter cloacae complex followed the reign of Klebsiella pneumoniae amongst all CPEs, with an almost tripled proportion of blaOXA-48 observed in the latter during COVID-19 onwards. The rise elicited in individual isolates harbouring ≥2 carbapenemases is a cause for grave concern due to the potential complications that may arise in managing such CRE infections.³⁴ Klebsiella pneumoniae strains containing dual blaNDM and OXA-48 was chiefly implicated in our study, which, depending on specimen type and regional distribution, demonstrates variable agreement to other findings pertaining to CPE samples with combination carbapenemases.²¹,³⁴,³⁷,⁴³,⁵²,⁵⁵,⁵⁶ As reported by Bedenic et al, this typifies the pathogenic fitness of Klebsiella pneumoniae and its ability for progressive acquisition and horizontal spread of numerous resistance determinants owing to selection pressure from broad-spectrum antibiotic usage in the COVID-19 era.¹⁶

Irrespective of the COVID-19 period, majority (42.2%) of all-cause mortality specific to CPE-infected patients occurred ≤7 days from sample collection. However, an even more worrisome finding was the overall 30-day mortality rate (77%) which was conspicuously higher than some

international norms (24-49%), courtesy a publication by Oka et al.⁵³ Pre-pandemic CPE-associated mortality (37.5%), which primarily occurred in the under 1-year age category, escalated to 43.4% subsequent to COVID-19, with an evolution towards adults aged 20-59 years old, underscoring the possible role played by the myriad of pandemic-related factors in this transition of clinical outcomes.¹¹,²¹,⁵⁶ In relation to the contrasting time periods, this was further emphasised by the switch in gender propensity, with a greater proportion of deaths attributed to females. Demographic temporal shifts, analogous to ours or otherwise, have also been elucidated amid the limited comparative studies of this nature that reported on patient survival,²¹,⁵⁷ some notwithstanding COVID-19.⁷,⁵¹

Klebsiella pneumoniae was responsible for the overwhelming volume of deaths, particularly in the changeover of carbapenemase-encoding genes from blaNDM to blaOXA-48. Importantly, this also included the emergence of isolates bearing other uncommon or multiple carbapenemases not previously described locally, as indicated in a post-pandemic report by Thomas et al.⁵⁶ Our analysis that sterile site specimens, including intensive and high-care unit patient locations, were key contributory factors that increased the odds of inpatient mortality, concurred with a multicentre study incorporating public and private hospitals in the Western Cape province.³⁷ This, in itself, though supported by additional data, pays tribute to the fact that no matter the healthcare sector type, the burden of CPEs amongst CREs in SA, is prominent.^{7, 33, 34, 40, 46, 51}

In patients that died, the marked proportion of reduced susceptibility (<30%) of the predominating carbapenemase-specific CRE species against the wide array of antibiotics tested, is undoubtedly concerning. Compounding this situation within this specialised referral hospital is the unavailability of the newer β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations, such as ceftazidime-avibactam, including agents like cefiderocol as an alternative treatment option, and aztreonam for metallo-β-lactamases. This unfortunate circumstance was also contextualised in a study by So-ngern et al in a tertiary healthcare centre in North-East Thailand where it was similarly deduced that aminoglycosides, tigecycline and colistin may serve as viable therapeutic options.⁴⁷

It must be noted, however, that according to scientific reviews¹⁴,⁵⁸ and both local and global best practice management guidelines for CRE infections,³,⁵⁹,⁶⁰ the newer generation BL/BLI antibiotics are preferred. Selection depends on organism identification, site of infection,

phenotypic antimicrobial susceptibility testing, and resistance mechanism determination, with genotypic characterisation for carbapenemase producers. Studies illustrating the excellent susceptibility of ceftazidime-avibactam (87-100%) against CRE strains positive for blaOXA-48 and blaKPC show promise for use in our setting, given that blaOXA-48 denotes the most rampant carbapenemase circulating in IALCH and SA.³⁷,⁵⁴

As outlined by Finlayson et al, the unprecedented alteration in the landscape of antibiotic resistance underpins the imperative need for multisectoral, concerted approaches to streamline the accessibility and responsible use of the newer agents.⁶¹ Consequently, our research findings strongly recommend that the KZN DoH consider and address this need with great urgency. The CRE trends within this clinical setting correlated to poor patient outcomes provides comprehensive baseline data to impart policy reforms that advocate for these newer, effective antibiotics.

This study provides crucial insight into the comparative trend analysis of various aspects surrounding CRE infections relative to COVID-19 in a South African quaternary healthcare setting. The rising CRE burden, coupled by the clinical and molecular paradigm shift elicited within this referral public hospital, is unmistakable. The ascertainment of CRE-associated demographic, microbiological, and patient outcome data – in addition to delineating the pre-and post-pandemic distribution of carbapenemase-encoding genes – represents a first for this facility, thereby providing crucial baseline data in this regard. Our findings highlight the imperative need for ongoing epidemiological surveillance and advise conducting routine carbapenemase testing in selected CRE-infected patients – this impacts IPC strategies and influences treatment selection choices amid strengthening AMS protocols. However, of fundamental importance, this study advocates for the urgent necessity of multidisciplinary, collaborative efforts directed at promulgating accessibility to the newer BL/BLI drug combinations, such as ceftazidime-avibactam, including agents like aztreonam and cefiderocol, in providing directed therapy against CREs – such interventions epitomise the invaluable potential in significantly improving patient clinical outcomes.

Taking cognisance of practical feasibility, particularly in resource-constrained settings, stepwise implementation to the recommendations offers a pragmatic approach. Clinically, this may entail deriving centre-specific criteria for adopting CRE screening among patients with certain risk factors or those being admitted to intensive care units, as opposed to universal testing. Regional or referral diagnostic laboratories with strengthened capacity should be prioritised to offer cost-effective phenotypic or molecular laboratory assays that timeously inform IPC practices. KZN DoH policy changes that promote ongoing drug access for targeted therapy due to CRE infections is encouraged. The abovementioned measures, where adopted, should constitute multidisciplinary health expert input and agreement, thereby balancing clinical benefit and affordability, while simultaneously supporting antimicrobial stewardship.

NB conceptualised the study, developed the methodology, wrote the protocol, submitted the applications for ethical approval and required consents, applied for funding, conducted the laboratory work, analysed the results, designed the visual representations, and wrote the original manuscript. KSSH was the project supervisor who evaluated and approved the proposed study idea, as well as reviewed and edited the protocol and manuscript. SM was the

co-supervisor who provided project design guidance, including appraisal and editing of the protocol and manuscript. RS assisted with molecular diagnostic laboratory workup, genotypic analysis, and manuscript review.

This project was supported by the National Health Laboratory Service K-Project Funding (K-Project Number PR2448733).

Supplementary File

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