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Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen
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 d...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove Medical Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061756/ https://www.ncbi.nlm.nih.gov/pubmed/30087550 http://dx.doi.org/10.2147/DDDT.S164316 |
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author | Udekwu, Klas I Weiss, Howard |
author_facet | Udekwu, Klas I Weiss, Howard |
author_sort | Udekwu, Klas I |
collection | PubMed |
description | 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 coli and Pseudomonas aeruginosa, pairs of antibiotics have been identified for which evolution of resistance to drug A increases sensitivity to drug B 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 of 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. |
format | Online Article Text |
id | pubmed-6061756 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Dove Medical Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-60617562018-08-07 Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen Udekwu, Klas I Weiss, Howard Drug Des Devel Ther Original Research 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 coli and Pseudomonas aeruginosa, pairs of antibiotics have been identified for which evolution of resistance to drug A increases sensitivity to drug B 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 of 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. Dove Medical Press 2018-07-23 /pmc/articles/PMC6061756/ /pubmed/30087550 http://dx.doi.org/10.2147/DDDT.S164316 Text en © 2018 Udekwu and Weiss. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. |
spellingShingle | Original Research Udekwu, Klas I Weiss, Howard Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
title | Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
title_full | Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
title_fullStr | Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
title_full_unstemmed | Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
title_short | Pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
title_sort | pharmacodynamic considerations of collateral sensitivity in design of antibiotic treatment regimen |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061756/ https://www.ncbi.nlm.nih.gov/pubmed/30087550 http://dx.doi.org/10.2147/DDDT.S164316 |
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