Study reveals new mechanism for rapid evolution of multi-drug resistant infections in patients

July 17, 2023
Findings challenge the traditional view that antimicrobial resistance (AMR) emerges from pathogens that acquire new mutations.

A research study led by the University of Oxford provides a transformational 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 AMR infections developing in vulnerable patients.

The study's results defy the conventional notion that individuals typically acquire a solitary genetic clone (or 'strain') of harmful bacteria when infected, and that resistance to antibiotic treatment evolves through the natural selection of new genetic mutations that arise during the infection. Instead, the findings propose that patients frequently experience co-infection by numerous clones of pathogens, wherein resistance emerges due to the selection of pre-existing resistant clones, as opposed to new mutations.

The scientists employed an innovative methodology to examine alterations in the genetic variability and antibiotic resistance of a specific bacterial species (Pseudomonas aeruginosa) obtained from patients prior to and following antibiotic therapy. The specimens were isolated from 35 patients in intensive care units (ICUs) across 12 European hospitals. Pseudomonas aeruginosa is an opportunistic pathogen responsible for significant hospital-acquired infections, particularly among immunocompromised and severely ill individuals, and is estimated to contribute to over 550,000 annual fatalities worldwide.

Upon admission to the ICU, each patient underwent screening for Pseudomonas aeruginosa, and subsequent samples were collected at regular intervals. The research team employed a blend of genomic analyses and antibiotic challenge tests to measure the extent of bacterial diversity and antibiotic resistance within each patient.

Around two-thirds of the patients participating in the study were found to be infected by a solitary strain of Pseudomonas. In some of these cases, antimicrobial resistance (AMR) developed as a result of the transmission of fresh resistant mutations that emerged during the infection, aligning with the established understanding of how resistance is acquired. However, intriguingly, the researchers made the surprising discovery that the remaining one-third of patients were actually infected by multiple strains of Pseudomonas.

When patients with mixed strain infections received antibiotic treatment, there was an approximately 20% higher escalation in resistance compared to patients with single strain infections. The rapid surge in resistance observed in patients with mixed strain infections was primarily attributed to the natural selection of pre-existing resistant strains that were already present at the initiation of antibiotic therapy. Although these strains typically constituted a minority of the initial pathogen population, their possession of antibiotic resistance genes conferred them a significant selective advantage in the presence of antibiotics.

Nevertheless, despite the accelerated emergence of antimicrobial resistance (AMR) in multi-strain infections, the study's findings indicate that such resistance may also be more prone to rapid decline under certain conditions. When samples from patients with single strain infections and those with mixed strain infections were cultured without the presence of antibiotics, the growth rate of AMR strains was comparatively slower in comparison to non-AMR strains. This observation supports the hypothesis that AMR genes entail fitness trade-offs, meaning they are negatively selected when antibiotics are absent. Notably, these trade-offs were more pronounced in mixed strain populations as opposed to single strain populations, suggesting that the presence of within-host diversity can contribute to the loss of resistance in the absence of antibiotic treatment.

University of Oxford release on Newswise