Abstract
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.
Keywords
pharmacokinetics - area under the curve - extended infusion - therapeutic drug monitoring
- critical illness
