The main topic of our research is multidrug- and extensively drug-resistant gram-negative bacilli, mainly resistance conferred by extended-spectrum beta-lactamases and carbapenemases. Contributions of the group to this field in the past include the identification of epidemic clones of Klebsiella pneumoniae and Pseudomonas aeruginosa that are responsible for a large part of the dissemination of antimicrobial resistance in these species. The group has also worked extensively with Escherichia coli, most notably with the epidemic clone ST131 and its subclone H30-Rx. Gradually the focus has shifted towards pursuing explanations for the successfulness of these epidemic clones and to understand how they interact with the human microbiota. The focus has also shifted towards more experimental research, and more interventional and translational research.
The research group focuses is organized in three main themes:
- Mechanisms of resistance and molecular epidemiology in extensively drug-resistant gram-negative bacilli
- The impact of antimicrobials on the intestinal microbiome, and
- How bacteriophages can be used therapeutically.
Mechanisms and epidemiology of Antimicrobial Resistance (AMR)
We have a strong focus on extensively drug-resistant Gram-negative bacilli such as K. pneumoniae, E. coli, P, aeruginosa, and the Acinetobacter baumannii-complex. We explore the activity of novel antimicrobials including beta-lactam beta-lactamase inhibitors against contemporary clinical isolates featuring complex mechanisms of resistance. In addition to acquired beta-lactamase we study various chromosomal resistance mechanisms and the transcription levels of various resistance genes.
The overarching goal is to understand how to preserve the lifespan of novel antimicrobial agents, by identifying strategies that will reduce selection of resistance.
Moreover, we are interested in the clonality of strains harboring extensive drug-resistance and why some bacterial clones are epidemic, while others occur sporadically. We also have projects ongoing where we track plasmids directly from clinical samples, and employ novel techniques such as optical mapping of genomes, which is compared with long-read sequencing. Some of the novel techniques are explored for their utility in low-income settings. Finally, we continue the work from previous projects where we have employed isothermal microcalorimetrics for antimicrobial susceptibility testing, and where we also study the properties of metabolic signatures for species determination directly from clinical samples.
Microbiome studies
The intestinal microbiome serves as a reservoir for carriage of antimicrobial resistant bacteria, such as extended-spectrum β-lactamase (ESBL) producing Escherichia coli (EP-EC). Specific phylogenetic clonal linages in E. coli, such as phylogroup B2, sequence type (ST) 131 and the ST131 subclone H30-Rx have been linked to pandemic spread and increased potential to cause severe infections because of higher virulence.
In previous projects, we have shown that some successful clonal lineages in the fecal microbiota are prone to develop a long-term carriage and increase the risk disease, and if this has implications on the diversity of the fecal microbiota. Such studies were continued in a still ongoing EU-project (JPIAMR; PILGRIM) where we assess the impact of prescription quality, infection control, and antimicrobial stewardship on gut microbiota domination by healthcare-associated pathogens. This is a comprehensive, multinational, multicenter clinical trial aiming to assess the impact of inadequate antibiotic prescription on intestinal domination by extended-spectrum beta-lactamase producing Enterobacteriaceae, vancomycin-resistant enterococci, or infection with C. difficile. The study follows the progression from first acquisition of drug-resistant organisms to infection with these bacteria at individual patient level. Changes in the microbiota are assessed both with 16S rDNA metagenomics sequencing, and with phenotypic microbiota characterization.
The same techniques as are used in the above-mentioned previous and still ongoing trials are also employed in studies of the collateral damage of various antimicrobials on the microbiota and the resulting selection of antimicrobial resistance. This is studied both for novel antimicrobials in the development pipeline and for established antimicrobials. Studies are done both in healthy volunteers and in patients.
Bacteriophage studies
Bacteriophages are viruses that can selectively infect and cause lysis (lytic phages) of bacteria, and can thus be used as antimicrobials. They are highly species-specific and the susceptibility of bacteria can also differ greatly within a species. Phages can be isolated from sewage or various environmental sources and are enriched and characterized in the laboratory to study efficacy in bacterial killing as well as safety. We have mainly worked with phages versus K. pneumoniae and P. aeruginosa, but are also focusing on S. aureus. We have studied the effects of phages in animal models with promising results and are planning for human trials of various sub-acute infections and potentially also harmful carriage in the microbiome.
We aim to use phages clinically as precision-therapy, where a unique combination of phages will be selected to target a specific pathogen. This strategy also means that acute infections are more difficult to target, and thus we are focusing on more subacute infections. Examples of targeted infections are P. aeruginosa infections in cystic fibrosis and bone and joint infections in S. aureus. We are also interested in strategies for decolonization of carriage with extensively drug-resistant Gram-negative bacilli – most notably gut carriage.