Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis

A recent study has provided the most comprehensive estimates of the global burden of antimicrobial resistance (AMR) to date. Here, we discuss those findings and how the Ineos Oxford Institute (IOI) for Antimicrobial Research is helping to address the major public health problem posed by resistance to antibiotics.

Antibiotics are a staple of modern medicine used to fight diverse infections, yet their utility as life-saving drugs is currently threatened by the rapid evolution and spread of ways by which microbes can counteract them, a process called antimicrobial resistance (AMR). For example, past projections – including “The Review on Antimicrobial Resistance” commissioned in 2014 by then UK Prime Minister David Cameron and chaired by Jim O’Neil – broadly estimated that by 2050, AMR would be responsible for approximately 10 million annual deaths, more than cancer, HIV and many other global health problems. However, the true burden of AMR has been hard to quantify, particularly for places where there is limited surveillance data. Therefore, while some estimates for the USA, Europe and some other locations are available, a global analysis has been missing.

To overcome these limitations, the “Antimicrobial Resistance Collaborators” – an international network of scientists led by researchers at the University of Oxford and at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, and which includes Professor Tim Walsh at the Ineos Oxford Institute (IOI) for Antimicrobial Research – collected and combined previously published data with information from hospitals, diagnostic laboratories, surveillance systems, and multiple other sources, including from multiple low- and middle-income countries (LMICs) for which such data is limited. This comprehensive dataset – which included 471 million individual records or isolates and 7585 study-location-years – was then used to estimate the global disease burden of AMR in 2019 and its links to 12 types of infections (such as lower respiratory infections, bloodstream infections, urinary tract infections, tuberculosis, etc), 23 bacterial pathogens (such as Escherichia coli, Staphylococcus aureus, etc), 18 drug categories or combinations of drugs for which there is resistance, and 88 pathogen–drug combinations. Importantly, the study estimated disease burden based on two alternative scenarios: if all drug-resistant infections were replaced by no infection (deaths associated with AMR) or if all drug-resistant infections were replaced by drug-susceptible infections (deaths attributable to AMR).

The results provide a sobering analysis on the burden caused by common AMR infections, estimating that if all drug-resistant infections were replaced by no infection, 4.95 million deaths could have been prevented in 2019. Furthermore, if all drug-resistant infections were replaced by drug-susceptible infections, approximately 1.27 million deaths could have been prevented. The estimated death rates attributable to AMR were the highest in sub-Saharan Africa and South Asia, and lowest in Australasia. When compared to global estimates for all other diseases in the same year, AMR would have been the third leading cause of death worldwide, only exceeded by stroke and ischaemic heart disease.

With regards to specific bacteria, E. coli was the leading pathogen associated with resistance, followed by S. aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa – the “big six”. As 4 of these 6 are Gram-negative bacteria, this highlights the acute need for effective and affordable anti-Gram-negative therapies. As for infections syndromes, lower respiratory and thorax infections (including pneumonia) were the main causes of death associated with AMR, followed by bloodstream infections (sepsis) and surgical site infections (which are a particular concern in LMICs). In terms of specific pathogen–drug combinations, methicillin-resistant S. aureus (MRSA) was the leading cause of deaths attributable to AMR, followed by multidrug-resistant Mycobacterium tuberculosis and third-generation cephalosporin-resistant E. coli, each of which was estimated to have caused more than 50.000 annual deaths.

The publication of the “Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis” study was followed by a webcast to summarize the key findings of the paper and discuss key policies and initiatives on tackling AMR. A summary by Dr. Hannah Balkhy, Assistant Director General for AMR at the World Health Organization, highlighted the sobering statistic that only around 20% of the 194 UN signatories have been fully funded to implement their “AMR national action plan”. Dr. Balkhy also noted the distinct lack of data from where the AMR burden has been reported to be highest, notably sub-Saharan Africa. In agreement, the article notes some weaknesses in the veracity of the collated data, including from LMICs and from 19 of 206 countries/territories for which no data could be obtained, which could underestimate the AMR burden, particularly for those locations. Therefore, there is an urgent need for accurate prospective studies that combine precise epidemiology information with detailed microbiology and genomics data, particularly from LMICs. Whist excellent initiatives – such as the Fleming Fund – are starting to address the problem of AMR reporting in LMICs, this will require greater engagement and support in these locations to address the critical link between the microbiology laboratory and the clinical wards, particularly for intensive care units (ICUs) and neonatal units (NICUs).

Addressing the lack of data from places where the AMR burden is high is one of the main missions of the IOI. Therefore, its researchers work in key sites in LMICs to collect precise microbiology data (including genome sequencing), detailed clinical epidemiology and accurate outcome data to provide much-needed information required to develop actionable estimates of the AMR burden that can impact global and regional policy decisions. Such granular data will inform appropriate antibiotic use including access and affordability, as well as priority areas for interventions (including Infection Prevention and Control).

This is exemplified by a recent study by Thomson et al., part of the BARNARDS observational cohort study of neonatal sepsis and antimicrobial resistance in LMICs led by the IOI. In that study, the authors examined the treatment of neonatal sepsis and whether the cost of the antibiotic mitigated prescription of the appropriate drug and completion of the antibiotic course. The findings showed that in 6 of 7 sites analysed (Bangladesh, India, Pakistan, Ethiopia, Nigeria, and Rwanda, but not South Africa), the cost of the antibiotic influenced prescription and was regularly deferred to the patient, who usually could not afford second- and third-line antibiotics combinations required for the treatment of life-threatening infections. While this study was not able to directly investigate the effect of cost on antibiotic use and sepsis survival, the data suggest that antibiotic guidelines for neonatal sepsis in LMICs, where AMR burden is high, should be revisited to consider accessibility and affordability.

During the webcast that followed the publication of the “Global burden of bacterial antimicrobial resistance in 2019” study, Dame Sally Davies, UK Special Envoy on AMR, concluded her address by stating: “It’s time to save modern medicine”. This is also the goal of the IOI, and to achieve it we will continue to undertake international, collaborative studies with global surveillance and assessment programs to understand the clinical impact of AMR in LMICs. To quote Professor Walsh: “it has always been our mission to understand the real issues of antibiotic access and impact of resistance in the poorest socio-economic sectors in the world. This will not only involve in-depth epidemiological and microbiological studies but also a detailed economic analysis in many LMICs”. Furthermore, the IOI has a targeted medicinal chemistry program for antibacterial drug discovery to enable and promote the development of breakthrough new treatments for human and animal bacterial infections. Coupled with a range of education and policy initiatives, our mission is to drive transformational global progress in tackling AMR.