Septic shock due to bacterial infections is one of the main causes of death in intensive care units of the developed world. To a great extent, the efforts to improve the outcomes of life-threatening infections including septic shock have focused on the deployment of antimicrobials of ever increasing potency. However, many pathogenic bacterial strains have acquired resistance to available and even recently introduced antibiotics. Alternate pharmacokinetic strategies constitute another pathway to increased antimicrobial efficacy. In this study, we have demonstrated that a single very high dose of gentamicin can eliminate sensitive and moderately resistant bacterial strains at an accelerated rate with a lower risk of regrowth in an in vitro pharmacodynamic model compared to standard (once daily-equivalent) dosing. This approach may be clinically viable if potential toxicity concerns can be addressed.