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Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model

Combinations of two and more drugs with different target sites are being used as a new treatment regimen for resistant clones of bacteria. Though, achieving the right combination of the drugs for optimal dosage regimen is challenging. In our study, we studied the antimicrobial effect of aditoprim, a...

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Autores principales: Maan, Muhammad Kashif, Chaudhry, Tamoor Hamid, Sattar, Adeel, Shabbir, Muhammad Abu Bakr, Ahmed, Saeed, Mi, Kun, Ahmed, Waqas, Xie, Shuyu, Xin, Li, Huang, Lingli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635024/
https://www.ncbi.nlm.nih.gov/pubmed/34867364
http://dx.doi.org/10.3389/fphar.2021.753359
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author Maan, Muhammad Kashif
Chaudhry, Tamoor Hamid
Sattar, Adeel
Shabbir, Muhammad Abu Bakr
Ahmed, Saeed
Mi, Kun
Ahmed, Waqas
Xie, Shuyu
Xin, Li
Huang, Lingli
author_facet Maan, Muhammad Kashif
Chaudhry, Tamoor Hamid
Sattar, Adeel
Shabbir, Muhammad Abu Bakr
Ahmed, Saeed
Mi, Kun
Ahmed, Waqas
Xie, Shuyu
Xin, Li
Huang, Lingli
author_sort Maan, Muhammad Kashif
collection PubMed
description Combinations of two and more drugs with different target sites are being used as a new treatment regimen for resistant clones of bacteria. Though, achieving the right combination of the drugs for optimal dosage regimen is challenging. In our study, we studied the antimicrobial effect of aditoprim, a novel dihydrofolate reductase inhibitor, and its synergistic effect with sulfamethoxazole. Synergy testing was performed by checkerboard micro dilution method and validation of different checkerboard ratios by static and dynamic time-kill analysis and in vitro pharmacokinetic/pharmacodynamics (PK/PD) model, and semi mechanistic PK/PD modeling was used to calculate and validate the synergistic effect of drug combination. Both checkerboard and static time-kill assays demonstrated the greater synergistic effect [fractional inhibitory concentration index (FICI) = 0.37] of the aditoprim [minimum inhibitory concentration (MIC) = 0.25 µg/ml]-sulfamethoxazole (MIC=>64 µg/ml) combination against all T. Pyogenes isolates. In the in vitro PK/PD model, the dosage proportion of sulfamethoxazole 4 mg/ml twice a day in combination with steady-state aditoprim 1 mg/ml efficiently repressed the growth of bacteria in 24 h with the ratio of 2-log10 decrease, related to the early inoculum against three T. Pyogenes isolates. The semi mechanistic PK/PD model projected that a combination of a high dose of aditoprim (2 mg/ml) with sulfamethoxazole (2 mg/day) was necessary to attain the killing of bacteria below the detection limit (limit of detection (LOD); i.e., 1 log10 CFU/ml) at 24 h with an MIC sulfamethoxazole (SMZ) of 64 µg/ml. However, it is anticipated that a combination of high dose of aditoprim with sulfamethoxazole is critical to attain the suppressed bacterial growth to < LOD. This study represents essential PK/PD modeling for optimization of combination of aditoprim and sulfamethoxazole to suppress growth of T. Pyogenens.
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spelling pubmed-86350242021-12-02 Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model Maan, Muhammad Kashif Chaudhry, Tamoor Hamid Sattar, Adeel Shabbir, Muhammad Abu Bakr Ahmed, Saeed Mi, Kun Ahmed, Waqas Xie, Shuyu Xin, Li Huang, Lingli Front Pharmacol Pharmacology Combinations of two and more drugs with different target sites are being used as a new treatment regimen for resistant clones of bacteria. Though, achieving the right combination of the drugs for optimal dosage regimen is challenging. In our study, we studied the antimicrobial effect of aditoprim, a novel dihydrofolate reductase inhibitor, and its synergistic effect with sulfamethoxazole. Synergy testing was performed by checkerboard micro dilution method and validation of different checkerboard ratios by static and dynamic time-kill analysis and in vitro pharmacokinetic/pharmacodynamics (PK/PD) model, and semi mechanistic PK/PD modeling was used to calculate and validate the synergistic effect of drug combination. Both checkerboard and static time-kill assays demonstrated the greater synergistic effect [fractional inhibitory concentration index (FICI) = 0.37] of the aditoprim [minimum inhibitory concentration (MIC) = 0.25 µg/ml]-sulfamethoxazole (MIC=>64 µg/ml) combination against all T. Pyogenes isolates. In the in vitro PK/PD model, the dosage proportion of sulfamethoxazole 4 mg/ml twice a day in combination with steady-state aditoprim 1 mg/ml efficiently repressed the growth of bacteria in 24 h with the ratio of 2-log10 decrease, related to the early inoculum against three T. Pyogenes isolates. The semi mechanistic PK/PD model projected that a combination of a high dose of aditoprim (2 mg/ml) with sulfamethoxazole (2 mg/day) was necessary to attain the killing of bacteria below the detection limit (limit of detection (LOD); i.e., 1 log10 CFU/ml) at 24 h with an MIC sulfamethoxazole (SMZ) of 64 µg/ml. However, it is anticipated that a combination of high dose of aditoprim with sulfamethoxazole is critical to attain the suppressed bacterial growth to < LOD. This study represents essential PK/PD modeling for optimization of combination of aditoprim and sulfamethoxazole to suppress growth of T. Pyogenens. Frontiers Media S.A. 2021-11-16 /pmc/articles/PMC8635024/ /pubmed/34867364 http://dx.doi.org/10.3389/fphar.2021.753359 Text en Copyright © 2021 Maan, Chaudhry, Sattar, Shabbir, Ahmed, Mi, Ahmed, Xie, Xin and Huang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Maan, Muhammad Kashif
Chaudhry, Tamoor Hamid
Sattar, Adeel
Shabbir, Muhammad Abu Bakr
Ahmed, Saeed
Mi, Kun
Ahmed, Waqas
Xie, Shuyu
Xin, Li
Huang, Lingli
Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
title Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
title_full Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
title_fullStr Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
title_full_unstemmed Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
title_short Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model
title_sort dose optimization of aditoprim-sulfamethoxazole combinations against trueperella pyogenes from patients with clinical endometritis by using semi-mechanistic pk/pd model
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635024/
https://www.ncbi.nlm.nih.gov/pubmed/34867364
http://dx.doi.org/10.3389/fphar.2021.753359
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