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Mechanisms and drivers of antimicrobial resistance in a large Bangladeshi public hospital

Dhaka Medical College Hospital, Dhaka, Bangladesh

Carbapenem-resistant Enterobacterales (CRE) are a group of multidrug resistant bacteria responsible for severe and often deadly infections in healthcare settings, yet few studies have examined the transmission dynamics of CRE in hospitals in South Asia. A recent paper led by Professor Tim Walsh from the Ineos Oxford Institute for Antimicrobial Research (IOI) combines epidemiological, clinical, and genomic data to characterize the mechanisms of drug resistance and modes of dissemination of CRE in a large public hospital in Bangladesh.

Carbapenems are a class of highly effective antibiotics that are usually reserved for the treatment of multidrug resistant (MDR) bacterial infections. However, carbapenem resistance is becoming increasingly common, particularly within the Enterobacterales – a group of diverse bacteria that includes Escherichia coli and Klebsiella pneumoniae. Despite CREs being deemed endemic in South Asia and representing a critical threat to healthcare settings owing to limited treatment options, there are significant gaps in our understanding of the prevalence and molecular mechanism of carbapenem resistance in this region.

To address this problem, Dr. Refath Farzana (as part of her Doctoral Commonwealth Fellowship, Medicine, Bangladesh), under the supervision of Professor Tim Walsh, conducted a study at Dhaka Medical College Hospital (DMCH), the largest public hospital in Bangladesh. The study, published in Clinical Infectious Diseases, analysed clinical specimens from 1831 enrolled patients. Using a combination of culture methods, antibiotic susceptibility testing and species identification based on mass spectrometry, the authors found that 534 of the patients were infected with Enterobacterales, including 194 with CRE. Therefore, around 1 in 10 patients (194 of 1831, or 10.6%) had a CRE infection, which the research team identified as being predominantly caused by drug-resistant E. coli or K. pneumoniae.

Our study at DMCH shows a high mortality associated with CRE, necessitating the urgent need for targeted diagnostics, appropriate antibiotic use and infection control interventions.

The authors also generated whole genome sequences for 643 Enterobacterales isolates, including 210 CRE, which helped to better understand the mechanisms of antibiotic resistance in the hospital. For example, these data showed that the most common determinant of resistance was blaNDM, a gene that encodes for a protein (the NDM enzyme) that can destroy carbapenems so that they no longer kill bacteria. These analyses also identified different clusters of CRE bacteria, with some being specific to individual hospital wards and present in patients with overlapping hospital stays. These findings suggest that it is possible that those MDR bacteria were transmitted between patients, or acquired by these individuals from a common source during their hospital visit.

By analyzing the clinical records of the patients, the researchers also found that while the majority (94%) were treated with antibiotics upon admission to the hospital, most of them (73%) did not receive an appropriate antibiotic that would be effective against their infection. Previous exposure to antimicrobials, and admission to the burns unit or the intensive care unit were found to be associated with a higher risk of infection by CRE. Importantly, CRE infections were associated with higher in-hospital mortality, with nearly 1 in 4 CRE patients (28%) succumbing to infection within 30 days of admission, which was roughly twice the mortality rate of patients infected with Enterobacterales bacteria without resistance to carbapenems (13.5%).

Collectively, this work has generated the largest dataset combining clinical, microbiological and genomic data from a hospital in South Asia. Despite its limitations, including routine practice at DMCH resulting in only a limited number of clinical specimens being sent for microbiological investigation, the study provides critical scientific evidence on how CRE resist antibiotics, spread within hospitals and impact on clinical outcomes in locations where MDR infections represent a substantial public health problem. Many public hospitals in South Asia are vastly overburdened, antibiotics are routinely delivered empirically, and capacity to diagnose the type of infection and drug resistance is often limited. As such, capturing comprehensive information on infections in a low socio-economic cohort from a large public hospital in Bangladesh is likely to be representative of other resource limited healthcare settings in a region inhabited by nearly 2 billion people.

The problem of antimicrobial resistance at DMCH can be minimised by establishing 24/7 microbiology laboratory services with simultaneous implementation of an effective infection prevention and control program

Professor Tim Walsh, Director of Biology at the IOI and Professor of Medical Microbiology in the Department of Biology at the University of Oxford, who supervised the study, highlighted how the findings are likely extendable to other hospitals in the region: “This is a remarkable and immense piece of research - the largest study from a South Asian public hospital combining outcome, microbiology, and genomics. It is well known that carbapenem resistance is very high in South Asia, but our study at DMCH shows a high mortality associated with CRE, necessitating the urgent need for targeted diagnostics, appropriate antibiotic use and infection control interventions. Although our study was limited to DMCH, our data can be extrapolated to most, if not all, Bangladeshi public hospitals arguing the case for national and international investment in the public health sector to tackle life-threatening infections, such as sepsis.”

The findings of this study have potential implications for how best to control MDR infections in these settings. As explained by Dr. Refath Farzana, who led the study: “The problem of antimicrobial resistance at DMCH can be minimised by establishing 24/7 microbiology laboratory services for the patients, free at the point of use, with simultaneous implementation of an effective infection prevention and control program”.

Read the full paper: Farzana, R., Jones, L.S. et al., Genomic insights into the mechanism of carbapenem resistance dissemination in Enterobacterales from a tertiary public heath setting in South Asia. Clinical Infectious Diseases (2022) https://doi.org/10.1093/cid/ciac287