A groundbreaking research study led by the University of Oxford has revealed a new understanding of how antimicrobial resistance (AMR) emerges in patients with bacterial infections. Published in the journal Nature Communications, the findings have the potential to shape the development of more effective interventions to prevent the development of AMR infections in vulnerable patients.
Contrary to the traditional belief that individuals are typically infected by a single genetic clone of pathogenic bacteria, the study challenges this view. It suggests that patients are commonly co-infected by multiple strains of pathogens, and resistance to antibiotic treatment arises through the selection of pre-existing resistant clones rather than new mutations.
The researchers employed a novel approach, examining changes in the genetic diversity and antibiotic resistance of Pseudomonas aeruginosa, a pathogenic bacteria species, collected from 35 intensive care unit (ICU) patients in 12 European hospitals. Pseudomonas aeruginosa is a significant cause of hospital-acquired infections, particularly among immunocompromised and critically ill patients, and is responsible for over 550,000 global deaths annually.
Each patient underwent screening for Pseudomonas aeruginosa upon admission to the ICU, with subsequent samples collected at regular intervals. Genomic analyses and antibiotic challenge tests were used to quantify bacterial diversity and antibiotic resistance within patients.
While approximately two-thirds of the patients in the study were infected by a single strain of Pseudomonas, the remaining third were infected by multiple strains. Interestingly, patients with mixed strain infections exhibited a 20% higher increase in resistance when treated with antibiotics compared to those with single strain infections. The rapid emergence of resistance in patients with mixed strain infections was driven by the natural selection of pre-existing resistant strains present at the onset of antibiotic treatment. These strains, although initially constituting a minority of the pathogen population, possessed antibiotic resistance genes that conferred a strong selective advantage in the presence of antibiotics.
However, the study suggests that while AMR arises more quickly in multi-strain infections, it may also be lost more rapidly under these conditions. When samples from patients with single and mixed strain infections were cultured without antibiotics, the growth of AMR strains was slower compared to non-AMR strains. This supports the hypothesis that AMR genes carry fitness trade-offs and are selected against when antibiotics are absent. These trade-offs were more pronounced in mixed strain populations, indicating that within-host diversity can drive the loss of resistance without antibiotic treatment.
According to the researchers, the findings imply that interventions focused on limiting bacterial spread between patients, such as improved sanitation and infection control measures, may be more effective in combating AMR than interventions targeting the prevention of new resistance mutations during infection, such as drugs that reduce bacterial mutation rates. This is particularly crucial in high infection rate settings, such as among immunocompromised patients.
The findings also highlight the need for clinical tests to capture the diversity of pathogen strains present in infections rather than relying on a limited number of pathogen isolates, assuming clonality of the pathogen population. This could enable more accurate predictions of the success or failure of antibiotic treatments in individual patients, similar to how diversity measurements in cancer cell populations aid in predicting the efficacy of chemotherapy.
Lead researcher Professor Craig Maclean from the University of Oxford’s Department of Biology emphasized the key finding that resistance evolves rapidly in patients colonized by diverse Pseudomonas aeruginosa populations due to the selection of pre-existing resistant strains. He underscored the importance of developing new diagnostic methods to assess the diversity of pathogen populations in patient samples, as existing diagnostic procedures have evolved slowly over time.
The World Health Organization has identified AMR as one of the top 10 global public health threats facing humanity. It occurs when bacteria, viruses, fungi, and parasites no longer respond to antimicrobial medicines like antibiotics, rendering infections increasingly challenging or impossible to treat. The rapid spread of multi-resistant pathogenic bacteria that cannot be treated with existing antimicrobial drugs is of particular concern. In 2019, AMR was associated with nearly 5 million deaths worldwide.
Commenting on the study, Professor Willem van Schaik, Director of the Institute of Microbiology and Infection at the University of Birmingham, highlighted the need to expand clinical diagnostic procedures to include more than one strain from a patient to accurately capture genetic diversity and antibiotic resistance potential in critically ill patients. He also stressed the importance of ongoing infection prevention efforts in reducing the risk of hospital-acquired colonization and subsequent infection by opportunistic pathogens.
Professor Sharon Peacock, a microbiology and public health expert from the University of Cambridge, echoed these sentiments, emphasizing the study’s implications for infection prevention and control measures in ICUs and hospitals more broadly, given the significant challenge posed by multidrug-resistant infections caused by organisms like Pseudomonas aeruginosa.
Source: University of Oxford