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...
Guardado en:
| Autores principales: | , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/bb40a27084e54df2bd1209475b2cda39 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:bb40a27084e54df2bd1209475b2cda39 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:bb40a27084e54df2bd1209475b2cda392021-11-16T05:13:55ZDose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model1663-981210.3389/fphar.2021.753359https://doaj.org/article/bb40a27084e54df2bd1209475b2cda392021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.753359/fullhttps://doaj.org/toc/1663-9812Combinations 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.Muhammad Kashif MaanMuhammad Kashif MaanTamoor Hamid ChaudhryAdeel SattarMuhammad Abu Bakr ShabbirSaeed AhmedKun MiWaqas AhmedShuyu XieLi XinLingli HuangLingli HuangFrontiers Media S.A.articlePK/PD modelingsulfamethoxazole resistanceaditorpimcombination therapyTrueperella pyogenessemi-mechanistic PK/PD modeling 3Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
PK/PD modeling sulfamethoxazole resistance aditorpim combination therapy Trueperella pyogenes semi-mechanistic PK/PD modeling 3 Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
PK/PD modeling sulfamethoxazole resistance aditorpim combination therapy Trueperella pyogenes semi-mechanistic PK/PD modeling 3 Therapeutics. Pharmacology RM1-950 Muhammad Kashif Maan Muhammad Kashif Maan Tamoor Hamid Chaudhry Adeel Sattar Muhammad Abu Bakr Shabbir Saeed Ahmed Kun Mi Waqas Ahmed Shuyu Xie Li Xin Lingli Huang Lingli Huang Dose Optimization of Aditoprim-Sulfamethoxazole Combinations Against Trueperella pyogenes From Patients With Clinical Endometritis by Using Semi-mechanistic PK/PD Model |
| 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. |
| format |
article |
| author |
Muhammad Kashif Maan Muhammad Kashif Maan Tamoor Hamid Chaudhry Adeel Sattar Muhammad Abu Bakr Shabbir Saeed Ahmed Kun Mi Waqas Ahmed Shuyu Xie Li Xin Lingli Huang Lingli Huang |
| author_facet |
Muhammad Kashif Maan Muhammad Kashif Maan Tamoor Hamid Chaudhry Adeel Sattar Muhammad Abu Bakr Shabbir Saeed Ahmed Kun Mi Waqas Ahmed Shuyu Xie Li Xin Lingli Huang Lingli Huang |
| author_sort |
Muhammad Kashif Maan |
| title |
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_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_sort |
dose optimization of aditoprim-sulfamethoxazole combinations against trueperella pyogenes from patients with clinical endometritis by using semi-mechanistic pk/pd model |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/bb40a27084e54df2bd1209475b2cda39 |
| work_keys_str_mv |
AT muhammadkashifmaan doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT muhammadkashifmaan doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT tamoorhamidchaudhry doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT adeelsattar doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT muhammadabubakrshabbir doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT saeedahmed doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT kunmi doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT waqasahmed doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT shuyuxie doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT lixin doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT linglihuang doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel AT linglihuang doseoptimizationofaditoprimsulfamethoxazolecombinationsagainsttrueperellapyogenesfrompatientswithclinicalendometritisbyusingsemimechanisticpkpdmodel |
| _version_ |
1718426689926594560 |