Abstract
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.
Highlights
Trueperella Pyogenes is a pathogen found in farm animals, recognized globally due to its commensal behavior that can cause subcutaneous abscesses, pneumonia, suppurative arthritis, and other associated infections in agriculture animals
According to minimum inhibitory concentration (MIC) values, T. pyogenes was sensitive to ADP (MIC 0.25 μg/ml) but it was resistant to SMZ (MIC 128 μg/ml)
The fractional inhibitory concentration index (FICI) of two drug combinations showed the additive interaction between two drugs
Summary
Trueperella Pyogenes is a pathogen found in farm animals, recognized globally due to its commensal behavior that can cause subcutaneous abscesses, pneumonia, suppurative arthritis, and other associated infections in agriculture animals. T. Pyogenes is a pathogenic environmental bacterium that typically causes an acute, purulent form of endometritis referred to as clinical endometritis. Pyogenes is a pathogenic environmental bacterium that typically causes an acute, purulent form of endometritis referred to as clinical endometritis In animals, these pathogen usually locate on the skin surface, mucosa of the upper respiratory, and urogenital tracts (Rzewuska et al, 2019). These pathogen usually locate on the skin surface, mucosa of the upper respiratory, and urogenital tracts (Rzewuska et al, 2019) This bacterium was found in the microflora of bovine rumen, the gastrointestinal tract of swine (Jarosz et al, 2014), and the microbiota of udder of healthy cattle (Galán-Relaño et al, 2020)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
