Emergence of Multi-Drug Resistant Infections in Patients

The findings of the study call into question the conventional wisdom that people normally experience infections by a single genetic clone (or’strain’) of harmful bacteria, and that resistance to antibiotic treatment arises as a result of natural selection for new genetic changes that occur during infection. Instead, the findings show that patients are frequently co-infected by numerous pathogen clones, with resistance evolving as a result of selection for pre-existing resistant clones rather than new mutations.

Lead researcher Professor Craig Maclean, from the University of Oxford’s Department of Biology, said: ‘The key finding of this study is that resistance evolves rapidly in patients colonized by diverse Pseudomonas aeruginosa populations due to selection for pre-existing resistant strains. The rate at which resistance evolves in patients varies widely across pathogens, and we speculate that high levels of within-host diversity may explain why some pathogens, such as Pseudomonas, rapidly adapt to antibiotic treatment.’

The researchers took a novel strategy, examining changes in the genetic diversity and antibiotic resistance of a pathogenic bacteria species (Pseudomonas aeruginosa) collected from patients before and after antibiotic therapy. The samples were collected from 35 ICU patients across 12 European hospitals. Pseudomonas aeruginosa is an opportunistic bacteria that is a leading source of hospital-acquired infection, especially in immunocompromised and severely ill patients, and is responsible for more than 550,000 fatalities worldwide each year.

Each patient was tested for Pseudomonas aeruginosa shortly after admission to the ICU, and samples were obtained at regular intervals thereafter. To measure within-patient bacterial diversity and antibiotic resistance, the researchers employed a mix of genomic analysis and antibiotic challenge tests.

The majority of patients in the research (about two-thirds) were infected with a single Pseudomonas strain. Some of these individuals developed AMR as a result of the transmission of novel resistance mutations during infection, supporting the conventional paradigm of resistance acquisition. Surprisingly, the scientists discovered that the remaining third of patients had various strains of Pseudomonas.

When patients with mixed strain infections were treated with antibiotics, resistance rose by roughly 20% more than when patients with single strain infections were treated. Natural selection for pre-existing resistant strains that were already present at the start of antibiotic therapy drove the rapid growth in resistance in individuals with mixed strain infections. These strains were often a minority of the pathogen population at the start of antibiotic therapy, but the antibiotic resistance genes they contained provided them with a significant selection advantage under antibiotic treatment.

Although AMR evolved faster in multi-strain infections, the findings suggest that it may potentially be lost faster in these situations. When single strain and mixed strain patients’ samples were cultivated in the absence of antibiotics, AMR strains developed more slowly than non-AMR strains. This lends support to the theory that AMR genes have fitness trade-offs and are hence selected against when no antibiotics are present. These trade-offs were more pronounced in mixed strain populations than in single strain populations, implying that within-host variation can also cause resistance loss in the absence of antibiotic treatment.

The findings suggest that interventions aimed at limiting the spread of bacteria between patients (such as improved sanitation and infection control measures) may be more effective in combating AMR than interventions aimed at preventing new resistance mutations arising during infection, such as drugs that reduce the bacterial mutation rate. This is especially relevant in conditions with a high infection rate, such as people with weakened immunity.

The findings also suggest that clinical diagnostics should shift away from testing for a restricted number of pathogen isolates (based on the assumption that the pathogen population is effectively clonal) and toward capturing the diversity of pathogen strains present in infections. This should allow for more accurate predictions of whether antibiotic treatments would be successful or unsuccessful in specific patients, similar to how assessments of variety in cancer cell populations can help predict chemotherapy success.

AMR has been named one of the top ten worldwide public health dangers confronting humanity by the World Health Organization. When bacteria, viruses, fungi, and parasites no longer respond to antibiotics, infections become increasingly difficult or impossible to treat. The rapid rise of multi-resistant pathogenic bacteria, which cannot be treated with any available antimicrobial medications, is of great concern. AMR was linked to roughly 5 million deaths worldwide in 2019.

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