Optimizing tuberculosis treatment efficacy : Comparing the standard regimen with Moxifloxacin-containing regimens
Copyright: © 2023 Budak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited..
Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:19 |
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| Enthalten in: |
PLoS computational biology - 19(2023), 6 vom: 27. Juni, Seite e1010823 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Budak, Maral [VerfasserIn] |
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| Links: |
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| Themen: |
Antitubercular Agents |
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| Anmerkungen: |
Date Completed 30.06.2023 Date Revised 25.10.2023 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.pcbi.1010823 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM358209080 |
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| 520 | |a Copyright: © 2023 Budak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | ||
| 520 | |a Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antitubercular Agents |2 NLM | |
| 650 | 7 | |a Moxifloxacin |2 NLM | |
| 650 | 7 | |a U188XYD42P |2 NLM | |
| 700 | 1 | |a Cicchese, Joseph M |e verfasserin |4 aut | |
| 700 | 1 | |a Maiello, Pauline |e verfasserin |4 aut | |
| 700 | 1 | |a Borish, H Jacob |e verfasserin |4 aut | |
| 700 | 1 | |a White, Alexander G |e verfasserin |4 aut | |
| 700 | 1 | |a Chishti, Harris B |e verfasserin |4 aut | |
| 700 | 1 | |a Tomko, Jaime |e verfasserin |4 aut | |
| 700 | 1 | |a Frye, L James |e verfasserin |4 aut | |
| 700 | 1 | |a Fillmore, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Kracinovsky, Kara |e verfasserin |4 aut | |
| 700 | 1 | |a Sakal, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Scanga, Charles A |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Philana Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Dartois, Véronique |e verfasserin |4 aut | |
| 700 | 1 | |a Linderman, Jennifer J |e verfasserin |4 aut | |
| 700 | 1 | |a Flynn, JoAnne L |e verfasserin |4 aut | |
| 700 | 1 | |a Kirschner, Denise E |e verfasserin |4 aut | |
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