Evaluation of Short Versus Long Course of Tobramycin Combined with Piperacillin/Tazobactam Against Antibiotic-Resistant Pseudomonas aeruginosa in a Hollow Fibre Infection Model

Aminoglycosides are commonly partnered with β-lactam antibiotics for empirical treatment of severe Gram-negative bacterial infections, including those caused by Pseudomonas aeruginosa. However, the optimal duration of aminoglycoside therapy when co-administered with β-lactam antibiotics remains poorly defined. This study compared the antibacterial efficacy of short (one-day, three-day) versus long course (seven-day) of tobramycin therapy, co-administered with piperacillin/tazobactam, against piperacillin/tazobactam-resistant clinical isolates of P. aeruginosa in a hollow fibre infection model (HFIM). A broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of the antibiotics. The HFIM experiments were performed using two piperacillin/tazobactam-resistant clinical isolates, CTAP-32 and CTAP-72 (both with piperacillin/tazobactam MICs > 128 mg/L). The clinical dose of tobramycin (10 mg/kg/day IV) was simulated for one, three, and seven days, each in combination with piperacillin/tazobactam (4.5 g every six hours infused over 30 min). In the HFIM, the one-day, three-day, and seven-day courses of tobramycin administered with piperacillin/tazobactam resulted in comparable bacterial kill with ~3log10 CFU/mL bacterial density reduction within the first 8 h of treatment against the CTAP-32 bacterial isolate. Similarly, these three combination regimens resulted in equivalent bacterial killing effects against the CTAP-72 isolate with a ~5log10 CFU/mL bacterial reduction during the initial treatment period. However, despite this early decline, comparable bacterial regrowth was observed thereafter with the short versus the long course of tobramycin co-administered with piperacillin/tazobactam. In conclusion, short-course and long-course tobramycin therapy, when combined with piperacillin/tazobactam, achieved comparable antibacterial efficacy against P. aeruginosa isolates in the HFIM. However, these findings warrant further validation in clinical studies.