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Ecological and evolutionary mechanisms driving within-patient emergence of antimicrobial resistance

Nature Reviews Microbiology (2024)Cite this article

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Abstract

The ecological and evolutionary mechanisms of antimicrobial resistance (AMR) emergence within patients and how these vary across bacterial infections are poorly understood. Increasingly widespread use of pathogen genome sequencing in the clinic enables a deeper understanding of these processes. In this Review, we explore the clinical evidence to support four major mechanisms of within-patient AMR emergence in bacteria: spontaneous resistance mutations; in situ horizontal gene transfer of resistance genes; selection of pre-existing resistance; and immigration of resistant lineages. Within-patient AMR emergence occurs across a wide range of host niches and bacterial species, but the importance of each mechanism varies between bacterial species and infection sites within the body. We identify potential drivers of such differences and discuss how ecological and evolutionary analysis could be embedded within clinical trials of antimicrobials, which are powerful but underused tools for understanding why these mechanisms vary between pathogens, infections and individuals. Ultimately, improving understanding of how host niche, bacterial species and antibiotic mode of action combine to govern the ecological and evolutionary mechanism of AMR emergence in patients will enable more predictive and personalized diagnosis and antimicrobial therapies.

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Fig. 1: Four ecological and evolutionary mechanisms of within-patient emergence of antimicrobial resistance.
Fig. 2: Within-patient emergence of antimicrobial resistance across different modes of emergence, body sites, organisms and antibiotics.
Fig. 3: Addressing limitations of within-patient antimicrobial resistance emergence studies.

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Acknowledgements

The authors thank members of Microbial Evolution Research Manchester for discussion of the ideas in this manuscript. They gratefully acknowledge funding from the Wellcome Trust (Collaborative Award in Science 220243/Z/20/Z).

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Authors and Affiliations

  1. Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK

    Matthew J. Shepherd, Taoran Fu, Anastasia Kottara & Michael A. Brockhurst

  2. Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK

    Niamh E. Harrington, Kendall Cagney, Steve Paterson & Joanne L. Fothergill

  3. Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

    James D. Chalmers

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M.J.S. researched data for the article, substantially contributed to discussion of content, wrote the article, and reviewed and edited the article. M.A.B., N.E.H. and J.L.F. substantially contributed to discussion of content, wrote the article, and reviewed and edited the article. A.K., K.C. and S.P. substantially contributed to discussion of content, and reviewed and edited the article. T.F. researched data for the article and substantially contributed to discussion of content. J.D.C. reviewed and edited the article.

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Glossary

Antibiotic

An antibiotic is an agent that is used against bacteria and can be classified as bactericidal (kills bacteria) or bacteriostatic (inhibits bacterial growth).

Antimicrobial resistance

(AMR). The ability of microorganisms — bacteria, viruses, fungi or parasites — to withstand the effects of drugs that would normally inhibit or kill them. This phenomenon occurs when these organisms adapt and develop resistance mechanisms against antimicrobial agents, rendering previously effective treatments ineffective. Clinically, AMR is defined as when the minimum inhibitory concentration of the antimicrobial required to halt growth of a bacterium exceeds the clinical breakpoint, which is the highest concentration of that antimicrobial that can be given to a patient.

Antimicrobial tolerance

The ability of a population of microorganisms to survive transient exposure to a microbicidal agent. It differs from resistance in that the agent remains effective against the microorganism as measured by the minimum inhibitory concentration but requires more prolonged treatment to successfully eliminate the infection.

Bacterial persistence

When a subpopulation of bacteria has a much higher tolerance to an antibiotic than the majority, that population is described as persistent. When the pressure of the antibiotic is removed, this persistent community can re-emerge, leading to recurrent infection despite antibiotic treatment.

Cross-resistance

Antimicrobial resistance that evolves through adaptation to another antimicrobial agent. This can occur when evolution of resistance to one agent confers resistance to another, typically due to a resistance mechanism that equally affects the action of all drugs within a class or to a nonspecific mechanism such as multidrug efflux pumps.

Eco-evolutionary

The reciprocal interactions and feedback between ecological processes and evolutionary changes in populations over short time scales. Ecological shifts promote adaptation of populations to their changing environments, and the resulting evolutionary changes can in turn shape ecological interactions. In the context of infections — the within-patient niche ecology will shape the evolution of antibiotic resistance, which can then affect the ecology of the infection itself through failure to clear the infection, disease progression and loss of sensitive strains and microflora.

Fitness costs

The physiological or energetic cost of an advantage in reproductive success (fitness). For example, the fitness benefit of resistance to an antibiotic may come at the cost of a reduced growth rate. Importantly, this trade-off becomes a disadvantage when the antibiotic is absent.

Fixation

The state in which a genetic variant becomes the only variant present for that specific locus. All individuals within the population share that same allele.

Genetic drift

The change in frequency of an allele owing to random chance. The impact of such random effects is stronger at smaller population sizes. Newly generated random mutations present at very low frequency must escape random loss due to genetic drift even if they provide a benefit before becoming established at a higher frequency in the population.

Horizontal gene transfer

(HGT). The process by which microorganisms may exchange genetic material that bypasses vertical transmission from parent to offspring.

Hypermutator

A microbial strain with an unusually high mutation rate, often caused by deficiencies in DNA repair mechanisms. Under selection pressure from an antimicrobial agent, this rapid accumulation of spontaneous genetic mutations may accelerate the process of selection and thus evolution of antimicrobial resistance by increasing the likelihood of a mutation-conferring resistance to occur.

Selection

The process by which genetic variations within a population become more prevalent because they confer traits that influence the fitness of the organisms in their environment. In the context of antimicrobial therapy, selection refers to the survival and growth of resistant strains and the loss of sensitive ones during treatment.

Selective sweep

An evolutionary event whereby a highly advantageous mutation rapidly increases in frequency owing to strong positive selective pressure. As it does, the genetic diversity in the region of the mutation decreases, creating a detectable signature of reduced allele frequency.

Spontaneous mutations

Also known as de novo mutations. Heritable alterations in the genome of a microorganism that arise spontaneously during replication or repair and were not previously present in the population or acquired from external sources of genetic material.

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Shepherd, M.J., Fu, T., Harrington, N.E. et al. Ecological and evolutionary mechanisms driving within-patient emergence of antimicrobial resistance. Nat Rev Microbiol (2024). https://doi.org/10.1038/s41579-024-01041-1

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