Effective antimicrobial therapy remains paramount to successful treatment of patients with critical illness, such as pneumonia and sepsis. Unfortunately, critically ill patients often exhibit altered pharmacokinetics and pharmacodynamics (PK/PD) that make this endeavor challenging. Particularly in sepsis, alterations in volume of distribution (Vd) and protein binding lead to unpredictable effects on serum levels of various antimicrobials. Additionally, metabolic pathways and excretion may be significantly impacted due to end-organ failure. These dynamic factors may increase the likelihood of deleterious effects such as treatment failure or toxicity. Meeting these challenging scenarios has led to various strategies meant to improve clinical cure without untoward consequences. Vancomycin and β-lactam antimicrobials are frequently utilized and have been the focus of dose optimization strategies including extended infusion (EI) or continuous infusion (CI). Available data suggests that administration of vancomycin by CI may reduce the risk of nephrotoxicity without increasing the risk of treatment failure, although retrospective data are largely utilized in supporting this method. Other efforts to optimize vancomycin have focused on transitioning from trough-based therapeutic drug monitoring (TDM) to area-under-the-curve: minimum inhibitory concentration (AUC:MIC) ratios. Despite the creation of more user-friendly methods of calculation and data suggesting reduced rates of nephrotoxicity, widespread implementation is limited, in part due to clinician comfort. Use of β-lactams in patients with sepsis is similarly problematic due to observational data demonstrating fluctuations in serum levels in the setting of critical illness. Implementing TDM of agents such as piperacillin-tazobactam, cefepime, and meropenem has been suggested as a method of improving time above MIC (T >MIC). This practice is limited by the lack of access to commercial assays and the failure of rigorous studies to demonstrate improved treatment success. Clinicians should be aware of these challenges and should refine their dosing strategies based on individualized patient factors to reduce treatment failure.

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