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Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-8434-0744
Number of Authors: 22018 (English)In: Drug Design, Development and Therapy, ISSN 1177-8881, E-ISSN 1177-8881, Vol. 12, p. 2249-2257Article in journal (Refereed) Published
Abstract [en]

Introduction: Antibiotics have greatly reduced the morbidity and mortality due to infectious diseases. Although antibiotic resistance is not a new problem, its breadth now constitutes a significant threat to human health. One strategy to help combat resistance is to find novel ways to use existing drugs, even those that display high rates of resistance. For the pathogens Escherichia coif and Pseudomonas aeruginosa, pairs of antibiotics have been identified for which evolution of resistance to drug A increases sensitivity to drug 1.3 and vice versa. These research groups have proposed cycling such pairs to treat infections, and similar treatment strategies are being investigated for various cancer forms as well. While an exciting treatment prospect, no cycling experiments have yet been performed with consideration of pharmacokinetics and pharmacodynamics. To test the plausibility of such schemes and optimize them, we create a mathematical model with explicit pharmacokinetic/pharmacodynamic considerations.

Materials and methods: We evaluate antibiotic cycling protocols using pairs of such antibiotics and investigate the speed of ascent of multiply resistant mutants.

Results: Our analyses show that when using low concentrations of antibiotics, treatment failure will always occur due to the rapid ascent and fixation o f resistant mutants. However, moderate to high concentrations of some combinations of bacteriostatic and bactericidal antibiotics with multiday cycling prevent resistance from developing and increase the likelihood of treatment success.

Conclusion: Our results call for guarded optimism in application and development of such treatment protocols.

Place, publisher, year, edition, pages
2018. Vol. 12, p. 2249-2257
Keywords [en]
collateral sensitivity, antibiotics, treatment efficacy, in vitro pharmacodynamics, mathematical modeling
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:su:diva-159188DOI: 10.2147/DDDT.S164316ISI: 000439517500001PubMedID: 30087550OAI: oai:DiVA.org:su-159188DiVA, id: diva2:1240766
Available from: 2018-08-22 Created: 2018-08-22 Last updated: 2019-12-16Bibliographically approved

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