Study reveals new mechanism for the rapid evolution of multidrug-resistant infections in patients
OXFORD UNIVERSITY
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Summary
Antibiotic resistance represents a global health threat, but the drivers of resistance within the host remain poorly understood. Pathogen populations are often assumed to be clonal within hosts and resistance is thought to arise due to de novo selection of variants . Here we show that mixed strain populations are common in the opportunistic pathogen P. aeruginosa . Crucially, resistance evolves rapidly in patients colonized by multiple strains through selection of preexisting resistant strains.
In contrast, resistance evolves sporadically in patients colonized by single strains due to selection for new resistance mutations. However, strong trade-offs between resistance and growth rate occur in mixed strain populations, suggesting that within-host diversity may also drive loss of resistance in the absence of antibiotic treatment. In summary , we show that within-host diversity of pathogen populations plays a key role in shaping the emergence of resistance in response to treatment.
Comments
A research study led by the University of Oxford provides transformative new insight into how antimicrobial resistance (AMR) emerges in patients with bacterial infections. The findings, published in the journal Nature Communications , could help develop more effective interventions to prevent the development of AMR infections in vulnerable patients.
The study’s findings challenge the traditional view that people are usually infected by a single genetic clone (or ’strain’) of pathogenic bacteria, and that resistance to antibiotic treatment evolves due to natural selection as new genetic mutations occur. during infection. The results suggest that instead, patients are often co-infected by multiple pathogen clones, and resistance arises as a result of selection for pre-existing resistant clones , rather than new mutations.
The researchers used a novel approach that studied changes in the genetic diversity and antibiotic resistance of a species of pathogenic bacteria (Pseudomonas aeruginosa) collected from patients before and after antibiotic treatment. Samples were isolated from 35 intensive care unit (ICU) patients in 12 European hospitals. Pseudomona aeruginosa is an opportunistic pathogen that is a major cause of hospital-acquired infections, particularly in immunocompromised and critically ill patients, and is believed to cause more than 550,000 deaths worldwide each year.
Each patient was screened for Pseudomona aeruginosa shortly after being admitted to the ICU, and then samples were collected at regular intervals thereafter. The researchers used a combination of genomic analyzes and antibiotic challenge tests to quantify bacterial diversity and antibiotic resistance within the patient.
The majority of patients in the study (approximately two-thirds) were infected with a single strain of Pseudomonas. AMR evolved in some of these patients due to the spread of new resistance mutations that occurred during infection, supporting the conventional model of resistance acquisition. Surprisingly, the authors found that the remaining third of the patients were actually infected by multiple strains of Pseudomona.
Crucially, resistance increased by approximately 20% more when patients with mixed-strain infections were treated with antibiotics, compared to patients with single-strain infections . The rapid rise of resistance in patients with mixed strain infections was driven by natural selection of pre-existing resistant strains that were already present at the start of antibiotic treatment. These strains generally constituted a minority of the pathogen population that was present at the beginning of antibiotic treatment, but the antibiotic resistance genes they carried gave them a strong selective advantage under antibiotic treatment.
However, although AMR emerged more quickly in multi-strain infections, the findings suggest that it may also be lost more quickly under these conditions. When patient samples were cultured with single strains and mixed strains in the absence of antibiotics, RAM strains grew more slowly compared to non-RAM strains. This supports the hypothesis that RAM genes entail fitness trade-offs, such that they are selected against when antibiotics are not present. These trade-offs were stronger in mixed-strain populations than in single-strain populations, suggesting that within-host diversity may also drive loss of resistance in the absence of antibiotic treatment.
According to the researchers, the findings suggest that interventions aimed at limiting the spread of bacteria between patients (such as improved sanitation and infection control measures) may be a more effective intervention in combating antimicrobial resistance than interventions that They aim to prevent new resistance mutations that arise during infection. , such as drugs that decrease the bacterial mutation rate. This is likely to be especially important in settings where the infection rate is high, such as patients with compromised immunity.
The findings also suggest that clinical testing should move toward capturing the diversity of pathogen strains present in infections, rather than testing only a small number of pathogen isolates (based on the assumption that the pathogen population is indeed clonal). This could allow for more accurate predictions about whether or not antibiotic treatments will be successful in individual patients, similar to how measurements of diversity in cancer cell populations can help predict the success of chemotherapy.
Lead researcher Professor Craig Maclean, from the Department of Biology at the University of Oxford, said: "The key finding of this study is that resistance evolves rapidly in patients colonized by diverse populations of Pseudomona aeruginosa due to selection of resistant strains. pre-existing ." "The rate at which resistance evolves in patients varies widely among pathogens, and we speculate that high levels of diversity within the host may explain why some pathogens, such as Pseudomona, adapt quickly to antibiotic treatment."
He added: "The diagnostic methods we use to study antibiotic resistance in patient samples have changed very slowly over time, and our findings underline the importance of developing new diagnostic methods that will facilitate the assessment of the diversity of populations of pathogens in patient samples.
The World Health Organization has declared AMR to be one of the top 10 global public health threats facing humanity.
AMR occurs when bacteria, viruses, fungi and parasites no longer respond to medications such as antibiotics, making infections increasingly difficult or impossible to treat. Of particular concern is the rapid spread of multidrug-resistant pathogenic bacteria, which cannot be treated with any of the existing antimicrobial drugs. In 2019, AMR was associated with nearly 5 million deaths worldwide.
Professor Willem van Schaik, director of the Institute of Microbiology and Infections at the University of Birmingham (who was not directly involved in the study) said: "This study strongly suggests that clinical diagnostic procedures may need to be expanded to include more than a strain" from a patient, to accurately capture the genetic diversity and antibiotic resistance potential of strains colonizing critically ill patients. He also highlights the importance of continued infection prevention efforts that aim to reduce the risk of hospitalized patients being colonized and subsequently infected by opportunistic pathogens during their hospital stay.”
Sharon Peacock, Professor of Microbiology and Public Health at the University of Cambridge (who was not directly involved in the study), said: "Multi-drug resistant infections caused by a variety of organisms, including Pseudomona aeruginosa, are a major challenge for the management of ICU patients worldwide. The findings of this study add further evidence of the vital importance of infection prevention and control measures in ICUs and hospital settings more broadly that reduce the risk of contracting P .aeruginosa and other pathogenic organisms.”
