Dispersal and selection of antimicrobial resistance in bacterial communities

Amalia Bogri

Research output: Book/ReportPh.D. thesis

11 Downloads (Pure)

Abstract

Antimicrobial resistance is rapidly becoming a serious threat to global health and is already responsible for millions of deaths every year. Currently, antibiotics are the only widely accessible and effective treatment against bacterial infections. However, their extensive use in both medical and agricultural settings has led to an alarming increase in antimicrobial resistance worldwide, foreshadowing a grim ‘post-antibiotic’ era of untreatable infections.

The primary driver behind the surge in antimicrobial resistance is the steadily increasing use of antimicrobial agents globally. However, observational epidemiological studies have reported inconsistencies between the levels of antimicrobial consumption and the observed occurrence of resistance in various communities. Moreover, interventions to reduce antimicrobial use do not always result in a proportional reduction of resistance within the same populations. This suggests that other factors also play a role in the dynamics of antimicrobial use and resistance. Bacterial transmission has been proposed as a key factor in the spread of antimicrobial resistance, and it is imperative to investigate its impact for developing effective mitigation strategies.

Investigating the effect of bacterial transmission on the dissemination of resistance in real populations presents notable challenges. Observational epidemiological studies typically utilise data on resistant pathogenic bacteria alone due to a lack of information on the non-pathogenic and/or susceptible strains; yet, these components are essential in understanding bacterial transmission. In addition, while informative, observational studies may contain several confounding factors. In contrast, experimental epidemiology allows for the controlled investigation of specific parameters for a clearer understanding of bacterial transmission’s role. This PhD study employs in silico, in vitro and in vivo experiments to examine the interplay between bacterial transmission and antimicrobial resistance in three respective manuscripts.

In Manuscript I, we theoretically investigated how antimicrobial use, the fitness cost of resistance, and bacterial transmission affect the frequency of antimicrobial resistance in a host population. We developed a mathematical model incorporating within-host, between-host, and between-population dynamics. The in silico experiments revealed that bacterial transmission not only facilitated the coexistence of the resistant and the susceptible strains, but often led to increased resistance levels, as anticipated. Interestingly, when the fitness cost of resistance was low, high transmission frequency resulted in a reduction of resistance. Furthermore, transmission between two host populations resulted in decreased resistance in the population which received more intensive antimicrobial treatment. While initially counterintuitive from an epidemiological standpoint, these theoretical findings align well with the ecological theories of temporal niche partitioning and metapopulation rescue.

Mathematical models have been invaluable in providing insights into the ecological dynamics of antimicrobial resistance, but experimental validation of the models is crucial. The experimental investigation of antimicrobial resistance transmission is limited, largely due to its complexity and the challenges in replicating the host dynamics. In Manuscript II, we sought to validate our previous mathematical model through in vitro experiments using bacterial isolates, with an experimental setup that mimicked within-host and between-host dynamics. We conducted eight experiments with populations of hosts containing susceptible and resistant strains of Escherichia coli, which were periodically treated with the antibiotic ciprofloxacin in both the presence and absence of bacterial transmission. Upon expanding our model to include novel mutations, we observed high agreement between the in silico predictions and the in vitro results. The presence of mutations was then investigated through whole genome sequencing. Our experiments confirmed that bacterial transmission can have contrasting effects on antimicrobial resistance frequency, either promoting or depressing the spread of the resistant strain depending on the conditions of antimicrobial treatment.

Finally, in vivo experimental epidemiology of antimicrobial resistance is crucial for understanding the intricate dynamics of bacterial transmission. In Manuscript III, we propose gregarious cockroaches (Pycnoscelus surinamensis) as an in vivo animal model for studying the spread of antimicrobial resistance. Our findings, obtained through metagenomic sequencing and analyses, show that tetracycline treatment impacts the gut microbiome of the cockroaches. The tetracycline treatment decreased the diversity of the bacterial community and increased the relative abundance of tetracycline resistance genes. Notably, interactions between untreated and treated individuals led to increased resistance to tetracycline in the untreated group. Furthermore, treated individuals interacting with untreated ones exhibited a slight recovery of their gut bacterial community. The study underscores the potential for antimicrobial resistance to spread in populations not directly exposed to antimicrobials.

Understanding the multifaceted effects of bacterial transmission on resistance frequency is critical for developing effective strategies to combat antimicrobial resistance. It is essential to consider the delicate balance between limiting the spread of resistant strains and allowing for the circulation and maintenance of susceptible strains. The results presented in this thesis demonstrate how the combination of theoretical modelling and experimental validation, in vitro and in vivo, is both informative and feasible. This PhD work lays the groundwork for more extensive studies on the experimental epidemiology of antimicrobial resistance.
Original languageEnglish
Place of PublicationKgs. Lyngby
PublisherTechnical University of Denmark
Number of pages191
Publication statusPublished - 2024

Fingerprint

Dive into the research topics of 'Dispersal and selection of antimicrobial resistance in bacterial communities'. Together they form a unique fingerprint.

Cite this