An international research team has developed a new genomic technique that can track the spread of multiple superbugs in a hospital simultaneously. In a proof-of-concept study, scientists at the Wellcome Sanger Institute, the University of Oslo, Fondazione IRCCS Policlinico San Matteo, and collaborators, applied a new “pan-pathogen” deep sequencing approach to capture all the common infectious bacteria in a hospital, at once. Current methods culture and sequence all pathogens separately, which takes longer and requires more work. The team’s prospective study results suggested that each intensive care unit (ICU) patient tested was colonized by at least one treatment-resistant bacteria, while the majority were colonized by several resistant bacteria simultaneously.
The scientists hope their technology could help prevent and manage common hospital (nosocomial) infections more quickly and effectively than has previously been possible. As drug resistance is a widespread issue in hospitals and other clinical settings, this system could identify, track, and limit the spread of common multiple treatment-resistant bacteria at the same time. The approach might also be integrated with existing hospital clinical surveillance systems.
Nicholas Thomson, PhD, head of the parasites and microbes program and group leader at the Wellcome Sanger Institute, said, “Antibiotic-resistant infections are an ongoing issue in hospitals, and while healthcare professionals work hard to minimize these as much as possible, it’s hard to fight against something you can’t fully see. Integrating a deep genomic sequencing approach into healthcare systems in this way gives those working in hospitals a new opportunity to see and track these bacteria, assisting in diagnosing infections and allowing outbreaks to be identified and controlled. Integration of this approach could help develop and improve guidelines for assessing and managing the risk of treatment-resistant infections for all the patients in a hospital, particularly those on intensive care units.”
Thomson is co-senior author of the team’s published study in The Lancet Microbe, titled “Pan-pathogen deep sequencing of nosocomial bacterial pathogens in Italy in spring 2020: a prospective cohort study.” In their paper, the team concluded: “The approach we describe could facilitate the development of improved future guidelines for assessing and managing the risk of nosocomial infections for different patient populations, particularly on intensive care units.”
Nosocomial infections caused by multidrug-resistant bacterial pathogens are a major cause of mortality and morbidity among patients in hospital, the authors wrote. “Nosocomial infections pose a considerable risk to patients who are susceptible, and this is particularly acute in intensive care units when hospital-associated bacteria are endemic.” The threat is potentially elevated under circumstances when the numbers of critically ill patients being admitted is high, such as occurred during the COVID-19 pandemic. “During the first wave of the COVID-19 pandemic, the surge of patients presented a significant obstacle to the effectiveness of infection control measures,” the team continued.
Bacteria are commonly found in or on the body without causing harm, but if certain strains get into the bloodstream due to a weakened immune system they can cause severe and life-threatening infections, unless they can be effectively treated with antibiotics. As an added challenge for healthcare providers, some of these bacteria are antimicrobial resistant (AMR). Infections caused by AMR bacteria are a major issue in hospitals. The authors cite figures indicating that these treatment-resistant bacteria are predicted to cause more deaths than cancer by 2050. And while some hospitals test for AMR bacteria on arrival, no system effectively tracks all multi-drug resistant bacteria throughout a hospital.
Over the last 15 years, genomic surveillance has become a powerful tool for tracking pathogen evolution and transmission, giving critical insights to help manage the spread of disease. However, current methods involve culturing a single strain of bacteria in a sample at a time and then conducting whole genome sequencing for all of them separately. This is a labor-intensive process, which can easily take several days and only provides a partial snapshot of all the clinically relevant bacteria found in a sample. “This limitation can, in principle, be remedied by picking and sequencing multiple colonies per sample, but this is, in practice, both expensive and time consuming,” the investigators pointed out.
For their newly reported study, the team developed an approach that captured whole genome sequencing data across multiple pathogens at once. This “pan-pathogen” deep sequencing approach could provide genomic data as rapidly as hospitals can process the samples.
The investigators’ study captured the whole population of pathogenic bacteria found in multiple hospital intensive care units (ICUs) and ordinary wards during the first wave of the 2020 COVID-19 pandemic. The team took samples from 256 patients in an Italian hospital, capturing bacteria found in the gut, upper airways, and lungs. The 2,418 DNA samples could be associated with 52 species of bacteria. Sixty-six percent (2,148) of these were made up of different strains of the seven most common bacterial infections seen in hospitals. Researchers could see the type of bacteria patients had, including any well-known antibiotic-resistant pathogens found in hospitals. “Our study presents the first attempt to recover bacterial strains at single nucleotide polymorphism-level resolution, while simultaneously capturing most clinically relevant major bacterial pathogens present in the gut, upper airways, or lungs of the patients,” they stated.
The investigators found that patients in ICUs were colonized by at least one bacterium with the potential to cause severe disease at any time, and that clinically important AMR genes were present in at least 40% of these. The team effectively mapped the spread of hospital bacteria across a five-week sampling timeframe, allowing them to also predict which bacteria were most likely to appear in infections acquired while in the hospital. They noted, “The deep-sequencing approach used in the study enabled quantification of antimicrobial resistance prevalence and estimation of hospital transmission. By sampling patients within a region severely affected by both the COVID-19 pandemic and endemic circulation of nosocomial bacterial pathogens, we were able to assess transmission in a high-risk setting.”
Co-senior author Jukka Corander, PhD, at the Wellcome Sanger Institute and the University of Oslo, said, “Our method that captures genetic information on multiple bacterial strains at the same time has the potential to transform the genomic surveillance of pathogens, enabling us to capture essential information both quicker and more comprehensively than ever before without losing resolution.”
The authors said the study serves as a proof-of-concept of “… how to use the power of deep sequencing to investigate multiple relevant pathogenic organisms simultaneously instead of a siloed approach based on whole-genome sequencing of single isolates of individual species.” In their discussion, they added, “The wealth of data generated by deep sequencing is an increasingly accessible way to explore bacterial variation in several ecological niches. Our study shows that this approach is also feasible for scrutiny of clinically relevant nosocomial bacteria, serving as a first step toward its further development and use as a research tool in clinical microbiology.” Corander added, “With our proof-of-concept study, this approach can now confidently be used in future research to capture the full breadth of high-risk bacteria in an area, and hopefully by hospitals to help track and limit the spread of treatment-resistant bacteria.”
First author Harry Thorpe, PhD, at the University of Oslo, is a visiting worker at the Wellcome Sanger Institute. Thorpe stated, “Our study is an example of how we can use the power of genomics to create a full picture of antibiotic-resistant bacteria across intensive care units and also elsewhere in hospitals. Antibiotic-resistant bacteria evolve and spread quickly, and therefore our tracking methods have to keep pace with them. Knowing the sequencing of all the bacteria in a sample gives a more complete picture of the diversity found in an area, which is crucial in predicting risk and understanding the external factors involved in the spread of a specific strain.”
Fausto Baldanti, PhD, director of the microbiology and virology unit, Fondazione IRCCS Policlinico San Matteo, added: “Our Unit detected the first COVID-19 case in the Western world, and we witnessed the dawn of the pandemic along with the huge scientific effort worldwide on SARS-COV-2. However, the study by our researchers showed that superbugs did not disappear. Indeed, the simultaneous presence of multiple species of drug-resistant bacteria in ICU wards admitting COVID-19 patients could have been a relevant component of the clinical manifestation of the new disease in those dramatic days.”
