Surveying Antibiotic Resistance: When Looking Up Also Means Looking For!

In the midst of the COVID-19 pandemic, a global economic crisis and on the verge of war (*sigh*) between Russia and Ukraine, the last thing we want to hear is that we are facing yet another health crisis, one related to bacteria and their ability to resist and survive antibiotic treatment… but we are.

We have discussed this on several occasions before. The abuse and misuse of antibiotics in human medicine, veterinary medicine and agriculture have helped some of the deadliest bacterial pathogens to develop and acquire antimicrobial resistance, leaving us with limited or zero treatment options to handle the infections they cause in humans. There are already bacterial strains in our hospitals that have become resistant to every single antibiotic—the so-called superbugs.

The not-so-funny thing about this is that the global emergence of multidrug-resistant superbugs is not a recent event, but a phenomenon scientists have been warning about for many years now. Antibiotic resistance has become a silent pandemic that bears a striking resemblance to the climate emergency: it is a threat that slowly escalates over time, goes unnoticed by most, can only be tackled via coordinated action by multiple actors at a global scale and is likely to end pretty badly if we do nothing about it—and yet, it seems that only a few care.

The global emergence of multidrug-resistant superbugs is not a recent event, but a phenomenon scientists have been warning about for many years now

Quantifying the magnitude of the antimicrobial resistance threat is no easy task, but is certainly necessary in order to build awareness and properly assess the situation. In 2017, the British economist Jim O’Neill published a report that constituted the first rough evaluation of the global burden of antimicrobial resistance, a report that has been used by many (including myself) to illustrate the severity of the problem. The O’Neill report estimated that by the year 2050 antimicrobial resistance would cause up to 10 million deaths annually (more than cancer!) and would also be associated with a considerable economic loss.

More recently, a new study published in the prestigious scientific journal The Lancet used data from 204 countries and territories on 23 bacterial pathogens and 88 combinations of pathogens and antimicrobial agents to provide a more comprehensive and updated model. The study estimates that antimicrobial resistance was directly responsible for the death of 1.27 million people in 2019, and indirectly associated with the death of up to 4.95 million in the same year! Therefore, in 2019, antimicrobial resistance killed more people than malaria (864,000 deaths) and HIV (643,000 deaths)!

A new study published in 'The Lancet' estimates that antimicrobial resistance was directly responsible for the death of 1.27 million people in 2019, and indirectly associated with the death of up to 4.95 million in the same year! Therefore, antimicrobial resistance killed more people than malaria (864,000 deaths) and HIV (643,000 deaths)!

The study identified the six deadliest pathogens (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pneumoniae), four of which are also listed in the WHO’s critical-priority category of resistant bacterial pathogens. Of note, one out of five deaths caused by antimicrobial-resistant bacteria in 2019 occurred in children under five. Death rates attributable to antimicrobial resistance were particularly high in western sub-Saharan Africa and South Asia, although they were significant and rising in all regions of the world, Europe and the United States being no exception.

Photo: CDC / Unsplash

Actions Needed to Fight Antimicrobial Resistance

The actions needed to fight antimicrobial resistance are rather obvious: (1) we need a more rational use of antibiotics, so better stewardship programmes need to be developed, (2) educational courses for the general population and the medical community have to be implemented to raise public awareness, (3) large investments in research and development of novel antibiotics (preferably new classes!) or alternative therapeutic options need to be a top priority, and (4) efforts to develop and reinforce national and international surveillance programmes are needed to keep an eye on the spread of resistant bacteria and resistance genes and to prevent resistant infections in the first place. Unfortunately, although antimicrobial resistance has been shown to kill twice as many people as HIV—for which up to US$50 billion in research funding is raised every year—the amount of resources and funding allocated to fighting antimicrobial resistance is far less buoyant. This urgently needs to be addressed.

While all fronts are equally important in the fight against antimicrobial resistance, it seems that surveillance efforts are often being neglected as we fail to understand the nature of local resistant pathogens and the routes they use for dissemination. Studies on the clonal typing of bacterial isolates, which are needed to determine whether the emergence of antibiotic resistance is caused by the spread of resistant strains or through the exchange of resistance genes, are rarely performed. At ISGlobal, we are deeply concerned about this obvious knowledge gap. Therefore, over the past three years, in close collaboration with the department of microbiology at Barcelona’s Hospital Clínic, we have been working to consolidate a small surveillance network involving up to 24 hospitals in Catalonia. During this time, the MERCyCAT network, as it is known, has been carefully collecting and monitoring top bacterial pathogens from the WHO’s critical-priority category, and microbiologists have characterised their clonal relatedness as well as the carriage of resistance genes, also known as the resistome.

While all fronts are equally important in the fight against antimicrobial resistance, it seems that surveillance efforts are often being neglected as we fail to understand the nature of local resistant pathogens and the routes they use for dissemination

Such studies have proven to be very effective, as we have been able to identify and prevent the dissemination of successful superbugs in our hospitals. However, we have also learned that the methodologies used for outbreak investigations in our laboratories need an urgent overhaul, as we realised they are not fast enough. Studies on the clonal relatedness of isolates from suspected outbreaks largely depend on the availability of said isolates once suspicion triggers a retrospective batch study, typically a few months after the start of the outbreak. Publication of outbreak situations to the wider scientific community takes even longer. In the end, the quick detection of clonal dissemination within healthcare institutions or in patients with putative relapsing infections is still challenging due to the available technologies providing retrospective results, whereas we should aim to provide real-time epidemiological results.

Photo: CDC / Unsplash

With this objective in mind, we have been searching for state-of-the-art molecular and phenotypic technologies that fulfil these requirements and have finally turned to spectroscopic methods. Over the past decade, mass spectrometry has proven extremely helpful to microbiologists in the rapid identification of bacterial isolates at the species level, which has become a turning point in clinical diagnostic methods. This time, though, we have focused on Fourier-transform infrared spectroscopy, or FTIR. FTIR quantifies the absorption of infrared light, which is related to the chemical composition of the sample, thus providing a unique spectrum for each sample—a “fingerprint”, as it were. Fingerprints from different samples can then be compared and their similarity quantified to determine the degree of relatedness in isolates recovered from different patients, hospitals or geographic regions, in just a matter of hours and with minimal sample handling and processing, thereby providing results almost in real time.

Over the past three years, in close collaboration with the department of microbiology at Barcelona’s Hospital Clínic, we have been working to consolidate a small surveillance network involving up to 24 hospitals in Catalonia

Pilot studies in our group have shown that this technique is able to detect and classify clinical isolates from K. pneumoniae, A. baumannii and S. aureus responsible for hospital outbreaks or relapsing infections in less than three hours with resolution at least comparable to that of conventional methods. Preliminary results from these studies were presented in 2021 at the prestigious European Congress of Clinical Microbiology and Infectious Diseases. There are still some pitfalls that need to be overcome, but as this technology evolves and gets optimised, we are confident it might well be the solution to rapid bacterial surveillance and outbreak investigation. Rapid and accurate identification of multidrug-resistant superbugs will provide fundamental information to guide recommendations on treatments of choice, dose regimens, empirical treatment, and the implementation of infection and control measures and policies, as well as to promote targeted drug development.

In short, it is essential—even vital—to look up and to recognise that antimicrobial resistance is an emerging public health threat that needs to be dealt with, the sooner the better. Once we have recognised the threat, though, it is critical to look for and monitor the dissemination of resistance if we want to have a chance to stop it!