Quantitative Pharmacodynamic Analysis of Trimethoprim‐Sulfonamide Combination Activity Against Staphylococcus pseudintermedius

ABSTRACT Trimethoprim (TMP)‐sulfonamide combinations are widely used in veterinary medicine, yet the quantitative nature of their pharmacodynamic interaction remains incompletely characterised. This study investigated the interaction between TMP and sulfamethoxazole (SMX), sulfadiazine (SDZ) and sulfadimethoxine (SDMX) against two Staphylococcus pseudintermedius isolates using minimum inhibitory concentration (MIC) testing, time‐kill curve (TKC) experiments and semi‐mechanistic pharmacodynamic modelling incorporating a General Pharmacodynamic Interaction (GPDI) framework. TKC assays demonstrated enhanced antibacterial activity for TMP‐sulfonamide combinations compared with monotherapy, with the greatest bacterial killing observed at TMP:sulfonamide ratios of 1:4 and 1:19. The final GPDI model identified a predominantly unidirectional interaction in which sulfonamides increased TMP potency through concentration‐dependent reductions in TMP EC 50 of 86%–96% at saturating sulfonamide concentrations, corresponding to approximately 7‐ to 26‐fold maximal possible increases in TMP potency. Maximal synergy differed between sulfonamides, occurring at approximately 1:20 for TMP/SMX (~75% increase in killing), 1:40 for TMP/SDZ (~181%) and 1:5 for TMP/SDMX (~80%). Pharmacokinetic‐pharmacodynamic simulations of clinically relevant canine dosing regimens predicted transient bacterial suppression but not bacterial eradication. These findings demonstrate that TMP‐sulfonamide synergy is dynamic, concentration‐dependent and bacterial species‐specific, highlighting the importance of PK/PD‐informed optimisation of potentiated sulfonamide therapy in veterinary medicine.