Principles of Antimicrobial Prescription in Intensive Care Unit Patients With Acute Kidney Injury

Description of Antimicrobial Prescribing Practices in the Intensive Care Unit

Antimicrobials are listed consistently in the top 10 drugs prescribed annually in the intensive care unit (ICU), with 70% of patients receiving at least one antimicrobial agent during their stay. Approximately one third of patients receive antimicrobials as combination therapy empirically before de-escalation occurs. Hospital expenditures for systemic antimicrobials in the United States was approximately $3.1 billion dollars in 2010. Vancomycin, piperacillin-tazobactam, levofloxacin, ceftriaxone, and gentamicin accounted for the five most frequently prescribed antimicrobials in the ICU in a study of 183 hospitals in 2011.

There is a difficult balance between over- and underdosing antimicrobials in critically ill patients. The concern for toxicity associated with prescribing too much of an antimicrobial is real, especially for drugs with narrow therapeutic indexes such as aminoglycosides and vancomycin. For both of these antibiotic drug classes, a supratherapeutic trough can result in nephrotoxicity. Prescribing too much of an antimicrobial often occurs because of a decreased clearance, as in the case of acute kidney injury (AKI). Approximately 19% to 67% of drugs are prescribed excessively in kidney disease. Specifically, antimicrobials are dosed higher than recommended in elderly patients with chronic kidney disease and are common causes for AKI as well. A decline in drug clearance forces the clinician to determine the need for a change in dose, frequency, or both to avoid potential toxicity.

The adverse consequences of underdosing antimicrobials is amplified in critically ill patients because of the severity of their illness. An inadequate dose can be the result of improvement in clearance when a patient's renal function recovers and dose adjustment is overlooked. Often we focus on the concern for toxicity and decreasing antimicrobial doses, but when the acute scenario resolves, we may increase the possibility of therapeutic failure resulting from inadequate dose readjustment. Another reason for inadequate dosing is that population-based data providing recommendations for standard dosing do not typically include a critically ill population. Therefore doses may be insufficient for this specialized patient population.

Current studies are gaining better insight into inadequate dosing of antimicrobials in critically ill patients. For example, in the case of β-lactams, an assessment of current dosing indicated that only 16% of patients had antibiotic concentrations above the minimum inhibitory concentration (MIC) of the pathogen for 50% of the dosing interval and were less likely to have a positive outcome. These inadequate concentrations may be due to increases in volume of distribution resulting from capillary leak and fluid resuscitation during the systemic inflammatory response syndrome (SIRS). Patients with SIRS undergo a hyperdynamic effect from the activation of inflammatory mediators that could result in increased drug clearance. Last, the concept of augmented renal clearance (ARC) may explain the inadequate concentrations of antimicrobials. ARC is defined as a creatinine clearance (CrCl) greater than 120 mL/min and has been associated with subtherapeutic concentrations and worsened patient outcomes. ARC is hypothesized to be a natural response to critical illness in patients with a greater physiologic reserve. Risk factors for ARC include age 50 years or younger, admission for trauma, and a modified Sequential Organ Function Assessment score of 4 or less. Therefore patients with a low estimated CrCl and a high CrCl complicate antibiotic dosing because of the limited available data. This chapter discusses the relevant pharmacokinetic (PK) and pharmacodynamic (PD) concepts that must be considered for appropriate antibiotic prescribing in critically ill patients with an emphasis on those with AKI.

Considerations Regarding Antmicrobial Therapy and Acute Kidney Injury