Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis
Background:Mycobacteriumtuberculosis [Mtb] could be present in different metabolic population in the lung lesions, and nonreplicating persisters [NRP], associated with latent tuberculosis [TB], are the most difficult to kill.Objective: Test the combination of tedizolid, moxifloxacin, and faropenem f...
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| Format: | Article |
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Frontiers Media S.A.
2021-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.616294/full |
| _version_ | 1818426368099090432 |
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| author | Shashikant Srivastava Shashikant Srivastava Shashikant Srivastava Kayle N. Cirrincione Devyani Deshpande Tawanda Gumbo Tawanda Gumbo Tawanda Gumbo |
| author_facet | Shashikant Srivastava Shashikant Srivastava Shashikant Srivastava Kayle N. Cirrincione Devyani Deshpande Tawanda Gumbo Tawanda Gumbo Tawanda Gumbo |
| author_sort | Shashikant Srivastava |
| collection | DOAJ |
| description | Background:Mycobacteriumtuberculosis [Mtb] could be present in different metabolic population in the lung lesions, and nonreplicating persisters [NRP], associated with latent tuberculosis [TB], are the most difficult to kill.Objective: Test the combination of tedizolid, moxifloxacin, and faropenem for activity against NRP using Mtb SS18b in the hollow fiber model [HFS-TB].Methods: Tedizolid and moxifloxacin were tested as, first, two-drug combination against log-phase growth [LPG] and, second, slowly replicating bacilli [SRB] under acidic condition and with faropenem to create a three-drug combination regimen. Finally, standard regimen [isoniazid-rifampin-pyrazinamide] was used as comparator in the HFS-TB experiment with NRP Mtb. HFS-TB units were sampled for drug-concentration measurement as well as for estimation of bacterial burden using solid agar and mycobacterial growth indicator tube [MGIT] method. Linear regression was used to calculate the kill slopes with each treatment regimen and analysis of variance (ANOVA) to compare the regimen.Results: Tedizolid at standard dose in combination with high-dose moxifloxacin killed 3.05 log10 CFU/ml LPG Mtb and 7.37 log10 CFU/ml SRB in the bactericidal and sterilizing activity HFS-TB experiments, respectively. There was no statistical difference between tedizolid-moxifloxacin-faropenem combination and the standard regimen as both killed 7.35 log10 CFU/ml NRP Mtb in 21 days. There was no emergence of resistance to any of the drugs studied in the three HFS-TB experiments.Conclusion: The experimental regimen of tedizolid, moxifloxacin, and faropenem could effectively kill NRP population of Mtb, and given the efficacy against different metabolic population of Mtb could serve as a pan-TB regimen. Clinical studies are warranted to validate the in vitro findings. |
| first_indexed | 2024-12-14T14:28:43Z |
| format | Article |
| id | doaj.art-73503d5c9abd41d69a6d80d1c1a4a283 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-14T14:28:43Z |
| publishDate | 2021-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-73503d5c9abd41d69a6d80d1c1a4a2832022-12-21T22:57:52ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-01-011110.3389/fphar.2020.616294616294Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosisShashikant Srivastava0Shashikant Srivastava1Shashikant Srivastava2Kayle N. Cirrincione3Devyani Deshpande4Tawanda Gumbo5Tawanda Gumbo6Tawanda Gumbo7Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United StatesDepartment of Immunology, UT Southwestern Medical Center, Dallas, TX, United StatesDepartment of Pulmonary Immunology, University of Texas Health Science Center at Tyler, Tyler, TX, United StatesCenter for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United StatesCenter for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United StatesCenter for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, United StatesPraedicare Laboratories and Quantitative Preclinical & Clinical Sciences Department Praedicare Inc., Dallas, TX, United StatesDepartment of Medicine, University of Cape Town, Observatory, Cape Town, South AfricaBackground:Mycobacteriumtuberculosis [Mtb] could be present in different metabolic population in the lung lesions, and nonreplicating persisters [NRP], associated with latent tuberculosis [TB], are the most difficult to kill.Objective: Test the combination of tedizolid, moxifloxacin, and faropenem for activity against NRP using Mtb SS18b in the hollow fiber model [HFS-TB].Methods: Tedizolid and moxifloxacin were tested as, first, two-drug combination against log-phase growth [LPG] and, second, slowly replicating bacilli [SRB] under acidic condition and with faropenem to create a three-drug combination regimen. Finally, standard regimen [isoniazid-rifampin-pyrazinamide] was used as comparator in the HFS-TB experiment with NRP Mtb. HFS-TB units were sampled for drug-concentration measurement as well as for estimation of bacterial burden using solid agar and mycobacterial growth indicator tube [MGIT] method. Linear regression was used to calculate the kill slopes with each treatment regimen and analysis of variance (ANOVA) to compare the regimen.Results: Tedizolid at standard dose in combination with high-dose moxifloxacin killed 3.05 log10 CFU/ml LPG Mtb and 7.37 log10 CFU/ml SRB in the bactericidal and sterilizing activity HFS-TB experiments, respectively. There was no statistical difference between tedizolid-moxifloxacin-faropenem combination and the standard regimen as both killed 7.35 log10 CFU/ml NRP Mtb in 21 days. There was no emergence of resistance to any of the drugs studied in the three HFS-TB experiments.Conclusion: The experimental regimen of tedizolid, moxifloxacin, and faropenem could effectively kill NRP population of Mtb, and given the efficacy against different metabolic population of Mtb could serve as a pan-TB regimen. Clinical studies are warranted to validate the in vitro findings.https://www.frontiersin.org/articles/10.3389/fphar.2020.616294/fullspecial populationtuberculosisnonreplicating persistersregimenhollow fiber model |
| spellingShingle | Shashikant Srivastava Shashikant Srivastava Shashikant Srivastava Kayle N. Cirrincione Devyani Deshpande Tawanda Gumbo Tawanda Gumbo Tawanda Gumbo Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis Frontiers in Pharmacology special population tuberculosis nonreplicating persisters regimen hollow fiber model |
| title | Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis |
| title_full | Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis |
| title_fullStr | Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis |
| title_full_unstemmed | Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis |
| title_short | Tedizolid, Faropenem, and Moxifloxacin Combination With Potential Activity Against Nonreplicating Mycobacterium tuberculosis |
| title_sort | tedizolid faropenem and moxifloxacin combination with potential activity against nonreplicating mycobacterium tuberculosis |
| topic | special population tuberculosis nonreplicating persisters regimen hollow fiber model |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.616294/full |
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