New Study Challenges Traditional Perspective on Antimicrobial Resistance

A groundbreaking research conducted by Oxford University sheds light on the rapid evolution of multi-drug resistant infections, presenting a new mechanism that challenges conventional views on antimicrobial resistance (AMR). The study reveals that the presence of multiple pathogen clones in patients leads to accelerated AMR, rather than the emergence of new resistance mutations in a single strain. These findings suggest that interventions focusing on preventing the spread of bacteria between patients could prove to be more effective in combating AMR.

Traditionally, it was believed that AMR arises from pathogens acquiring new mutations, but the study’s analysis of samples from ICU patients presents a different perspective. The research indicates that highly diverse pathogen communities already harbor pre-existing resistant genotypes. Therefore, resistance emerges as a result of selection for these pre-existing resistant clones rather than the occurrence of new mutations.

The study employed a novel approach, examining changes in genetic diversity and antibiotic resistance of the bacterium Pseudomonas aeruginosa in patients before and after antibiotic treatment. The researchers collected samples from 35 ICU patients in 12 European hospitals, focusing on Pseudomonas aeruginosa—a significant cause of hospital-acquired infections, particularly in immunocompromised and critically ill individuals, resulting in over 550,000 global deaths annually.

The findings demonstrated that approximately two-thirds of the patients were infected by a single strain of Pseudomonas. In these cases, AMR developed due to the spread of new resistance mutations during infection, aligning with the conventional model of resistance acquisition. Surprisingly, the remaining one-third of patients were found to be infected by multiple strains of Pseudomonas.

Significantly, when patients with mixed-strain infections were treated with antibiotics, resistance increased by approximately 20% more compared to patients with single-strain infections. This rapid increase in resistance in mixed-strain infections was attributed to natural selection favoring pre-existing resistant strains already present at the beginning of antibiotic treatment. Although these resistant strains constituted a minority of the pathogen population, the antibiotic resistance genes they carried provided a strong selective advantage under antibiotic pressure.

Interestingly, while AMR emerged more swiftly in multi-strain infections, the study suggests that it may also be lost more rapidly under these conditions. When samples from both single-strain and mixed-strain patients were cultured without antibiotics, the growth rate of AMR strains was slower than that of non-AMR strains. This supports the hypothesis that AMR genes carry fitness trade-offs, meaning they are selected against when antibiotics are absent. The trade-offs were found to be more pronounced in mixed-strain populations than in single-strain populations, implying that within-host diversity can drive the loss of resistance in the absence of antibiotic treatment.

Based on these findings, the researchers propose that interventions aimed at limiting bacterial spread between patients, such as improved sanitation and infection control measures, may be a more effective strategy to combat AMR than interventions targeting the prevention of new resistance mutations during infection, such as drugs that reduce bacterial mutation rates. This is particularly relevant in settings with high infection rates, such as patients with compromised immune systems.

Additionally, the study suggests a shift in clinical testing methods to capture the diversity of pathogen strains present in infections, rather than relying on testing a limited number of pathogen isolates assuming clonality. This approach 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 chemotherapy outcomes.

Lead researcher Professor Craig Maclean from the University of Oxford emphasizes that the study’s key finding is the rapid evolution of resistance due to the selection for pre-existing resistant strains in patients colonized by diverse Pseudomonas aeruginosa populations. He highlights the need for improved diagnostic methods to assess the genetic diversity and antibiotic resistance potential of strains that colonize critically ill patients.

The World Health Organization considers AMR one of the top 10 global public health threats. It occurs when bacteria, viruses, fungi, and parasites no longer respond to available medicines like antibiotics, making infections increasingly difficult to treat or untreatable altogether. The proliferation of multi-resistant pathogenic bacteria, which cannot be treated with existing antimicrobial medicines, is a particularly concerning aspect of AMR. In 2019, AMR was associated with nearly 5 million deaths worldwide.

Professor Willem van Schaik from the University of Birmingham’s Institute of Microbiology and Infection, who was not directly involved in the study, emphasizes the need to expand clinical diagnostic procedures to include multiple strains from a patient. This would accurately capture the genetic diversity and antibiotic resistance potential of strains that colonize critically ill patients, further highlighting the importance of infection prevention and control measures in ICU and hospital settings.

Professor Sharon Peacock, a microbiology and public health expert from the University of Cambridge, who was not directly involved in the study, emphasizes the significance of the study’s findings for patient management in ICU settings worldwide. She underscores the importance of ongoing infection prevention efforts to reduce the risk of patients being colonized and subsequently infected by opportunistic pathogens during their hospital stay.

The study’s participants were patients involved in the Advanced Understanding of Staphylococcus aureus and Pseudomonas aeruginosa Infections in Europe—Intensive Care Units (ASPIRE-ICU) trial. This trial, nested within routine surveillance of ICU patients in Europe, aims to enhance our understanding of Staphylococcus aureus and Pseudomonas aeruginosa infections in the region.

Reference: “Mixed strain pathogen populations accelerate the evolution of antibiotic resistance in patients” published in Nature Communications on July 12, 2023. DOI: 10.1038/s41467-023-39416-2.

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• Oxford University study: [Link to the study](provide the URL here)
• Nature Communications publication: [Link to the publication](provide the URL here)
• ASPIRE-ICU trial: [Link to the trial information](provide the URL here)
• World Health Organization (WHO) on AMR: [Link to WHO’s AMR information](provide the URL here)