Adding to the armamentarium: antibiotic dosing in extended dialysis.

The dismal survival rates for critically ill patients with AKI have not improvedmuch over the past fewdecades despite many advances in renal replacement therapies (RRTs). Some of the continued poor outcomes can be attributed to the fact that the demographics of patients treated in the intensive care unit (ICU) with RRTs have changed considerably (1,2). As pharmacists, perhaps the most personally disappointing aspect of the poor survival rates is that infection remains a leading cause of death in these patients (3). Although the emergence of multidrug-resistant organisms is a challenge to all clinicians (4,5), the fact remains that the high infectious death rate in critically ill patients with AKI is usually caused by bacteria and fungi that are sensitive to drugs on the existing hospital formulary. Timely broadspectrum antibiotic dosing has been a mainstay of the Surviving Sepsis Guidelines (6); therefore, why should infection and shock continue to be the leading causes of death in critically ill patients with AKI? Adequacy of antibiotic therapy in these patients may be an important contributor to the problem. In CJASN, the work by Lorenzen et al. (7) addresses dosing of ampicillin/sulbactam in a pharmacokinetic study in this patient population. More importantly, the work by Lorenzen et al. (7) links their pharmacokinetic findings to projected pharmacodynamic effects. These investigatorsmeasuredampicillin andsulbactamplasma concentrations achieved in critically ill patients receiving an extended dialysis (ED) treatment and then determined whether the plasma concentrations would yield bactericidal values that might result in infection cure. The work of Craig (8) opened many people’s eyes to the importanceof applyingpharmacodynamicprinciples identified from in vitro and animal models to antibiotic treatment in humans. Since that time, the value of these models in the determination of antibiotic doses in patients is well accepted (9). Unfortunately, these pharmacokinetic/pharmacodynamic-derived antibiotic dosing guidelines were not designed for septic patients with AKI receiving a myriad of RRTs that result in rapid removal of antibiotics (10). Therein may lie much of the answer to question of the high infectious mortality rate in this population. When an antibiotic is brought to market, there is no mandate and certainly little incentive for the manufacturer to conduct pharmacokinetic trials in critically ill patients receiving RRTs (11). In the rare case that an RRT dosing recommendation ismade in the antibiotic’s package insert, invariably, the recommendation is for three times per week intermittent hemodialysis (IHD), which is themost common in the outpatientCKDenvironment. Even in institutions where IHD is the preferred form of RRT in the ICU, these recommendations are of limited value for two main reasons. First, drug clearance that is achievable in stable CKD patients with extant dialysis vascular access rarely can be achieved in hypotensive, critically ill patients with temporary vascular access. Consequently, the delivered IHD dose in AKI is much smaller than the prescribed hemodialysis dose (12). Second, the catabolic nature of sepsis patients and the relatively poor delivered dose of dialysis mean that IHD must be administered more often than three times per week (13). Therefore, drug dosing recommendations based on three times per week IHD do not work well in the ICU. Hemodynamic instability, fluid overload, and increased metabolic needs of critically ill patients with AKI led to the development of new types of RRT. ContinuousRRTs (CRRTs) are nowused as frequently as IHD in ICUs worldwide (14). Antibiotic dosing in CRRT has been reviewed recently (15–18). The advantage of antibiotic dosing in CRRT is that drug removal is relatively constant, resulting in relatively predictable drug dosing. The work by Lorenzen et al. (7) studies a newer, hybrid form of RRT that uses a standard hemodialysismachine but a longer treatment time, thus allowing for less-aggressive solute and volume removal per unit time than standard IHD (19). However, these technical advantages may be outweighed by the challenges in antibiotic dosing using hybrid hemodialysis therapies like ED (20,21). With ED (and IHD), patients with AKI have impaired drug clearance for part of the day and potentially supraphysiologic clearance during the ED procedure.With two different clearance rates occurring each day, it is evident that when the dose is given in relation to ED may be a more important factor than what dose. In the study by Lorenzen et al. (7), ED is instituted 3 hours after the ampicillin/sulbactam 2/1-g infusion ended. The ED session removed .80% of the ampicillin/sulbactam dose. With these drug administration parameters and ED operating characteristics, Lorenzen et al. (7) correctly conclude that the pharmacodynamic target (time greater than minimum inhibitory concentration (MIC) of at least 50% of the dosing College of Pharmacy, University of Michigan, Ann Arbor, Michigan