| 1. |
- Aad, G., et al.
(författare)
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- 2013
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Ingår i: Journal of Instrumentation. - 1748-0221. ; 8
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Balaban, Nathalie Q., et al.
(författare)
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Definitions and guidelines for research on antibiotic persistence
- 2019
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Ingår i: Nature Reviews Microbiology. - : Nature Publishing Group. - 1740-1526 .- 1740-1534. ; 17:7, s. 441-448
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Forskningsöversikt (refereegranskat)abstract
- Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.
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| 3. |
- Berryhill, Brandon A., et al.
(författare)
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Evaluating the potential efficacy and limitations of a phage for joint antibiotic and phage therapy of Staphylococcus aureus infections
- 2021
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 118:10
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Tidskriftsartikel (refereegranskat)abstract
- In response to increasing frequencies of antibiotic-resistant pathogens, there has been a resurrection of interest in the use of bacteriophage to treat bacterial infections: phage therapy. Here we explore the potential of a seemingly ideal phage, PYOSa, for combination phage and antibiotic treatment of Staphylococcus aureus infections. This K-like phage has a broad host range; all 83 tested clinical isolates of S.aureus tested were susceptible to PYOSa. Because of the mode of action of PYOSa, S. aureus is unlikely to generate classical receptor-site mutants resistant to PYOSa; none were observed in the 13 clinical isolates tested. PYOSa kills S. aureus at high rates. On the downside, the results of our experiments and tests of the joint action of PYOSa and antibiotics raise issues that must be addressed before PYOSa is employed clinically. Despite the maintenance of the phage, PYOSa does not clear populations of S. aureus. Due to the ascent of a phenotyically diverse array of small-colony variants following an initial demise, the bacterial populations return to densities similar to that of phage-free controls. Using a combination of mathematical modeling and in vitro experiments, we postulate and present evidence for a mechanism to account for the demise-resurrection dynamics of PYOSa and S. aureus. Critically for phage therapy, our experimental results suggest that treatment with PYOSa followed by bactericidal antibiotics can clear populations of S. aureus more effectively than the antibiotics alone.
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| 4. |
- Geli Rolfhamre, Patricia, 1979-
(författare)
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From Penicillin Binding Proteins to Community Interventions : Mathematical and Statistical Models Related to Antibiotic Resistance
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotic resistance has become a major public health concern and mathematical models are important analytical tools for the understanding, evaluation and prediction of the resistance problem and related control strategies.The risk of emerging antibiotic resistance and selection has rarely been a concern in the design of antibiotic drug dosing regimens. In the first paper, a selection of antibiotic resistant subpopulations for different antibiotic dosing regimens was studied in vitro. The demonstrated complex relationship was influenced by both the rise of new mutants and a postantibiotic effect (PAE) (continued inhibition of bacterial growth after removal of the antibiotic drug). By constructing a mathematical model that incorporated biologically relevant parameters, we were able to assess the risks of resistance development under different dosing strategies.In the second paper, the model for PAEs is further developed to determine the implications for different dosing regimens. The result challenges the conventional notion that long PAEs promote extended drug dosing intervals and it allows new hypotheses to be tested experimentally based on the findings from the theoretical framework.Since PAE experiments often are time-consuming and laborious, very few studies have been reporting variation for this phenomenon. In the third paper, an extension to capture the stochastic behavior of bacterial population growth under drug exposure is made. The stochastic nature of the model is also an important complement to the existing deterministic models on drug dose drug effect relationships.The last paper describes a controlled clinical intervention study aiming at determining whether the frequency of trimethoprim resistance in E. coli can be decreased by a sudden and drastic reduction in trimethoprim use. In addition to evaluating the intervention effect, the model, given estimated parameters, is also used for predicting other interesting outcomes.
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| 5. |
- Levin, Bruce R., et al.
(författare)
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Theoretical considerations and empirical predictions of the pharmaco- and population dynamics of heteroresistance
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 121:16
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotics are considered one of the most important contributions to clinical medicine in the last century. Due to the use and overuse of these drugs, there have been increasing frequencies of infections with resistant pathogens. One form of resistance, heteroresistance, is particularly problematic; pathogens appear sensitive to a drug by common susceptibility tests. However, upon exposure to the antibiotic, resistance rapidly ascends, and treatment fails. To quantitatively explore the processes contributing to the emergence and ascent of resistance during treatment and the waning of resistance following cessation of treatment, we develop two distinct mathematical and computer- simulation models of heteroresistance. In our analysis of the properties of these models, we consider the factors that determine the response to antibiotic- mediated selection. In one model, heteroresistance is progressive, with each resistant state sequentially generating a higher resistance level. In the other model, heteroresistance is non- progressive, with a susceptible population directly generating populations with different resistance levels. The conditions where resistance will ascend in the progressive model are narrower than those of the non- progressive model. The rates of reversion from the resistant to the sensitive states are critically dependent on the transition rates and the fitness cost of resistance. Our results demonstrate that the standard test used to identify heteroresistance is insufficient. The predictions of our models are consistent with empirical results. Our results demand a reevaluation of the definition and criteria employed to identify heteroresistance. We recommend that the definition of heteroresistance should include a consideration of the rate of return to susceptibility.
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| 6. |
- Nicoloff, Hervé, et al.
(författare)
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The high prevalence of antibiotic heteroresistance in pathogenic bacteria is mainly caused by gene amplification
- 2019
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 4:3, s. 504-514
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Tidskriftsartikel (refereegranskat)abstract
- When choosing antibiotics to treat bacterial infections, it is assumed that the susceptibility of the target bacteria to an antibiotic is reflected by laboratory estimates of the minimum inhibitory concentration (MIC) needed to prevent bacterial growth. A caveat of using MIC data for this purpose is heteroresistance, the presence of a resistant subpopulation in a main population of susceptible cells. We investigated the prevalence and mechanisms of heteroresistance in 41 clinical isolates of the pathogens Escherichia coli, Salmonella enterica, Klebsiella pneumoniae and Acinetobacter baumannii against 28 different antibiotics. For the 766 bacteria-antibiotic combinations tested, as much as 27.4% of the total was heteroresistant. Genetic analysis demonstrated that a majority of heteroresistance cases were unstable, with an increased resistance of the subpopulations resulting from spontaneous tandem amplifications, typically including known resistance genes. Using mathematical modelling, we show how heteroresistance in the parameter range estimated in this study can result in the failure of antibiotic treatment of infections with bacteria that are classified as antibiotic susceptible. The high prevalence of heteroresistance with the potential for treatment failure highlights the limitations of MIC as the sole criterion for susceptibility determinations. These results call for the development of facile and rapid protocols to identify heteroresistance in pathogens.
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| 7. |
- Norström, Tobias, 1976-
(författare)
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On Fusidic Acid Resistance in Staphylococcus Aureus
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Controlling bacterial infections with antibiotics is central to modern health care. However, increasing bacterial resistance to antibiotics threatens effective therapy. This thesis concerns the use of the antibiotic fusidic acid, and novel analogues of fusidic acid, to treat topical infections caused by the bacterial pathogen Staphylococcu aureus. It also addresses genetic mechanisms by which S. aureus develops resistance to fusidic acid.Pre-clinical microbiological tests were made on two structurally different groups of fusidic acid analogues developed by Leo Pharma. These drugs were tested against S. aureus and Streptococcus pyogenes strains, measuring MIC, in vitro concentration-dependent bacteriocidal or bacteriostatic effects, and in vivo efficacy in clearing topical infections. We developed a new superficial skin infection animal model (the ‘tape-stripping model’) designed for testing topical antibiotics, including the novel fusidic acid analogues, against S. aureus and S. pyogenes. Some new compounds giving promising results will be further tested and developed by Leo Pharma. Fusidic acid inhibits protein synthesis by binding to elongation factor EF-G on the ribosome. Previously described resistance mechanisms are mutations in the gene coding for EF-G (fusA), or, in some strains, the presence of a gene (fusB, fusC or fusD) coding for a protein that protects EF-G from fusidic acid.We discovered two novel classes of spontaneous FusR mutants in S. aureus with the small colony variant (SCV) phenotype which is associated with persistent infections. The FusR SCV’s are very frequent, slow growing, cross-resistant to aminoglycosides, and auxotrophic for hemin or menadione. Some of the FusR SCV mutations are in structural domain V of EF-G (classic fusA mutations map overwhelmingly in domain III). The remaining FusR SCV’s are unmapped but their additive effect on MIC together with the fusB plasmid suggests the possibility that their mechanism of resistance is also associated with the translation machinery.
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| 8. |
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