Unraveling Trimethoprim-Sulfonamide synergy against Escherichia coli through semi-mechanistic PK/PD modeling

Abstract Trimethoprim/sulfonamide (TMP/S) is an antibiotic combination used in human and veterinary medicine for its synergistic effect. However, the recommended TMP/S dose ratio (1:5) in animals does not yield the targeted in vivo concentration ratio of 1:19, considered optimal for many human pathogens. Moreover, the diversity of TMP/S combinations used in veterinary medicine questions the relevance of a single universal ratio. Pharmacodynamic (PD) studies are therefore needed to characterize TMP/S time- and concentration-effect relationships. This study assessed three TMP/S combinations against three Escherichia coli strains using in vitro time-kill studies, with TMP and sulfonamides tested alone and in combination at multiple ratios. A semi-mechanistic pharmacokinetic (PK)/PD model was developed to quantify drug interactions and evaluated in a hollow-fiber infection model (HFIM) simulating poultry and equine PK for TMP/sulfadiazine (SDZ). Sulfonamides alone exhibited comparable maximal effects, lower than TMP alone. Bacterial regrowth was attributed to adaptive TMP resistance. Synergy was driven by TMP, reducing sulfonamide EC 50 values up to 92%. The most synergistic ratio was strain- and sulfonamide-dependent and differed from 1:19. HFIM results indicated that current TMP/SDZ dosing regimens are suboptimal in poultry but adequate in equine. Overall, these findings highlighted the importance of PK/PD-guided optimization for antibiotic combinations.