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How We Think Drug Resistant Infections Evolve May Be Wrong

New study findings have challenged the traditional view that antimicrobial resistance (AMR) emerges from pathogens that acquire new genetic mutations, offering new hope in the battle against the global problem.

The World Health Organisation (WHO) has declared AMR to be one of the "biggest threats to global health". Professor Dame Sally Davies, UK special envoy on antimicrobial resistance, had previously warned it is "one of the main threats to the country, alongside terrorism and pandemic".

The authors of the new study, published in Nature Communications, emphasised in a press release that the "rapid spread of multi-resistant pathogenic bacteria, that cannot be treated with any existing antimicrobial medicines", is of great concern. In 2019, AMR was associated with nearly five million deaths worldwide, and "within-host drivers of resistance" remain poorly understood. 

A research team led by the University of Oxford set out to test the hypothesis that antimicrobial resistance evolved rapidly in diverse populations of Pseudomonas aeruginosa, an opportunistic pathogen that is an important cause of hospital-acquired infection, particularly in immunocompromised and critically ill patients, and thought to cause more than 550,000 deaths globally each year.

The researchers used a novel approach that involved studying changes in the genetic diversity and antibiotic resistance of P aeruginosa collected from patients before and after antibiotic treatment. 

Subjects were recruited for the study between June 2015 and October 2018 and within 3 days after ICU admission, as part of the observational, prospective, multicentre European epidemiological cohort study, ASPIRE-ICU [The Advanced understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in Europe–Intensive Care Units]. To be eligible, the patients needed to be on mechanical ventilation at ICU admission and have an expected length of hospital stay 48 hours or longer.

Each patient was screened for P aeruginosa soon after being admitted to ICU, with samples then collected at regular intervals thereafter. Endotracheal aspirate was collected from 35 patients with up to 12 Pseudomonas isolates per patient sample. A total of 441 isolates were collected and characterised via resistance phenotyping and genome sequencing.

Pathogen Communities Harbour Pre-Existing Resistant Genotypes

The researchers found that approximately two thirds of patients were infected by a single Pseudomonas strain. "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," the authors explained. 

However, the researchers were surprised when they found that the remaining third of patients were actually infected by "multiple strains" of Pseudomonas.

Crucially, resistance increased by about 20% when patients with mixed strain infections were treated with antibiotics compared to patients with single strain infections, explained the authors. 

"The rapid increase in resistance in patients with mixed strain infections was driven by natural selection for pre-existing resistant strains that were already present at the onset of antibiotic treatment," they noted. These strains usually made up a minority of the pathogen population that was present at the start of antibiotic treatment, but the antibiotic resistance genes that they carried gave them a "strong selective advantage" under antibiotic treatment.

However, although AMR emerged more quickly in multi-strain infections, the authors said that their findings suggested it may also be "lost more rapidly" in these conditions. 

"When samples from single strain and mixed strain patients were cultured in the absence of antibiotics, the AMR strains grew more slowly compared with non-AMR strains," said the authors, which supported the hypothesis that AMR genes carry "fitness trade-offs", such that they are selected against when no antibiotics are present. 

"These trade-offs were stronger in mixed strain populations than in single strain populations, suggesting that within-host diversity can also drive the loss of resistance in the absence of antibiotic treatment," they suggested.

The findings challenge the traditional view that people are generally infected by a single genetic clone of pathogenic bacteria, and that resistance to antibiotic treatment evolves because of natural selection for new genetic mutations that occur during the infection. The results suggest that instead, patients were "commonly co-infected by multiple pathogen clones", with resistance emerging as a result of "selection for pre-existing resistant clones, rather than new mutations", the authors said.

The key finding of the study is that "resistance evolves rapidly in patients colonised by diverse Pseudomonas aeruginosa populations due to selection for pre-existing resistant strains", according to lead investigator Professor Craig Maclean, from the Department of Biology at the University of Oxford. He added that the rate at which resistance evolved in patients varied widely across pathogens and speculated that high levels of within-host diversity might explain why some pathogens such as Pseudomonas "rapidly adapt" to antibiotic treatment.

Different Approach Might Be More Beneficial

The findings of the study could help develop more effective interventions to prevent AMR infections from developing in vulnerable patients, according to the authors.

They suggested 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 to combat AMR than interventions that aim to prevent new resistance mutations arising 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," they point out. 

Conventional methods used in clinical microbiology labs are "systematically biased" against the detection of pathogen diversity, making it difficult to assess the importance of pre-existing diversity in resistance across bacterial pathogens, the authors cautioned. 

"The diagnostic methods that we use to study antibiotic resistance in patient samples have changed very slowly over time, and our findings underscore the importance of developing new diagnostic methods that will make it easier to assess the diversity of pathogen populations in patient samples," emphasised Professor Maclean.

Professor Willem van Schaik, director of the Institute of Microbiology and Infection at the University of Birmingham, who was not directly involved with the research, commented: "This study strongly suggests that clinical diagnostic procedures may need to be expanded to include more than one strain from a patient, to accurately capture the genetic diversity and antibiotic resistance potential of strains that colonise critically ill patients."

The study was funded by Wellcome Trust, Innovative Medicines Initiative Joint Undertaking under COMBACTE-MAGNET (Combatting Bacterial Resistance in Europe-Molecules against Gram-negative Infections), and COMBACTE-NET (Combatting Bacterial Resistance in Europe-Networks).

Nat Commun. 2023;14:4083. Full text

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