Prolonged Infusions: The Significance of How*

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Since the European Society of Intensive Care Medicine and the Society of Critical Care Medicine set forth on the Surviving Sepsis Campaign (SSC) in 2002, estimates of absolute mortality associated with severe sepsis were determined to have had an overall decrease of 16.7% (1). Despite the 47.5% reduction in relative risk observed over the 12-year period studied, absolute mortality remained 18.4% as of 2012. These findings suggest that additional progress is yet to be made.
A key aspect of the seven-point agenda set forth by the SSC in 2002 is defining and increasing the use of appropriate treatment and care. Crucial among these treatments is antimicrobial therapy. Specifically, research has demonstrated the detrimental effects of delays in initiating antimicrobial therapy and the consequences of inappropriate antimicrobial therapy in patients with severe sepsis and septic shock (2, 3). The SSC Guidelines rightfully emphasize the importance of managing these variables in the critically ill patient. Additionally, the SSC Guidelines recommend adopting dosing strategies based upon accepted pharmacokinetic/pharmacodynamics principles and acknowledge the complexities of doing such in a patient population with significantly altered pharmacokinetics (4).
The guidelines note the clinical implications of optimizing the peak plasma concentrations of aminoglycosides and fluoroquinolones, the negative outcomes associated with inadequate early vancomycin trough concentrations, and the benefits of maximizing the duration of drug plasma concentrations exceed the minimum inhibitory concentration (MIC) of the pathogen (4). Regarding attaining these targets, some guidance is provided. The authors advocate the role of once-daily aminoglycosides in select populations and dosing regimens intended to optimize the dose of fluoroquinolones for infections such as nosocomial pneumonia and septic shock. When optimizing vancomycin pharmacokinetic/pharmacodynamics in the septic patient, emphasis on early attainment of target trough concentrations with loading doses and further guided by therapeutic drug monitoring are essential. Yet, when discussing the most frequently prescribed class of antibiotics in acute care hospitals (5), the guidelines restrict their recommendations to increasing the frequency beta-lactams are administered and acknowledge that others have alternatively recommended extending the infusions.
This blanketed approach to the beta-lactams poses several pressing questions that clinicians are left to address. While the piperacillin-tazobactam example results in the same total daily dose (4), how does a prescriber determine when to reduce the dose and increase the frequency? In the absence of pharmacokinetic data or modeling, how would these altered exposures effect the pharmacokinetic/pharmacodynamics target attainment of these drugs? To what extent can clinical outcomes and the safety profile from Phases II and III clinical trials be extrapolated to these alternative antibiotic exposures?
Fortunately, the beta-lactams adhere to a key concept of antimicrobial pharmacodynamics, the shape of the concentration time curve can matter (6). This inherent fact suggests that significant implications in the antibacterial effect of these drugs may be accomplished by merely altering the manner in which the drug is administered. It is with this knowledge that researchers have pursued delineating the role of extended and continuous infusion of this class of drugs. While grounded in traditional approaches to pharmacokinetics, researchers have leveraged complex mathematical modeling techniques such as Monte Carlo Simulations to predict antimicrobial exposures across patient populations. These exposures could then be compared to assess their ability to optimize the percent time above the MIC across the distribution of bacterial populations. Emboldened by this new knowledge, researchers have set forth to quantify the clinical benefits these models had predicted (7–9).
Considering this growing body of literature, in this issue of Critical Care Medicine, Rhodes et al (10) conducted one of the largest systematic reviews and meta-analyses to evaluate the impact of dosing strategies of piperacillin-tazobactam on outcomes in critically ill patients.
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