Epidemiology of Acute Kidney Injury among Patients Receiving Concomitant Vancomycin and Piperacillin-Tazobactam: Opportunities for Antimicrobial Stewardship

Abstract

Despite their common use as an empirical combination therapy for the better part of a decade, there has been a recent association between combination therapy with vancomycin and piperacillin-tazobactam and high rates of acute kidney injury (AKI). The reasons for this increased association are unclear, and this analysis was designed to investigate the association. Retrospective cohort and case-control studies were performed. The primary objective was to assess if there is an association between extendedinfusion piperacillin-tazobactam in combination with vancomycin and development of AKI. The secondary objectives were to identify risk factors for AKI in patients on the combination, regardless of infusion strategy, and to evaluate the impact of AKI on clinical outcomes. T he combination of vancomycin and piperacillin-tazobactam is a commonly prescribed empirical therapy for patients with health care-associated infections, as it provides coverage against both methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa (1). There have been recent reports of relatively high rates of acute kidney injury (AKI), in the range of 15 to 35%, for patients receiving a combination of vancomycin and piperacillin-tazobactam (2-5), which are higher than those reported for patients receiving vancomycin alone (2, 5) and for patients receiving vancomycin and cefepime concomitantly (3). Although vancomycin has long been recognized as a nephrotoxic agent, and piperacillin-tazobactam has been associated with interstitial nephritis, the combination of these agents has been routinely used for many years; however, reports of increased AKI risk have only recently emerged (2-5).The reason for the high rates of AKI in patients receiving vancomycin and piperacillin-tazobactam is unclear, as is the reason for the recent increase in the frequency of reports regarding an association between patients receiving this combination and AKI. Some have hypothesized that the recently reported increased risk is related to more-aggressive vancomycin dosing based on the recently published vancomycin consensus guidelines (6).In addition to the changes in vancomycin dosing, there has also been increased interest in implementing extended-duration infusions of piperacillin-tazobactam in an attempt to optimize the time that free concentrations of the drug are above the MIC of target pathogens, as this is the pharmacokinetic/pharmacodynamic predictor of efficacy. Evidence has been mounting that extended infusion of piperacillin-tazobactam can improve outcomes in patients with invasive infections (7).In 2013, there was an anecdotal increase in cases of AKI among patients receiving vancomycin at the Detroit Medical Center (DMC), Detroit, MI. This perceived increase coincided temporally with a switch of the preferred antipseudomonal agent from cefepime to piperacillin-tazobactam, as well as the implementation of extended-infusion (3-h) administration of all antipseudomonal ␤-lactams (previously administered via standard intermit-

Nephrotoxicity during Vancomycin Therapy in Combination with Piperacillin-Tazobactam or Cefepime

“…To our knowledge, this is the largest study to date to examine the difference in AKI incidence among patients treated with VAN and FEP or PTZ. We found the AKI rate in patients treated with VAN-TZP to be 21.4%, whereas the range of the incidence found in the current literature is 9.5 to 34.8% (8)(9)(10)(11)(12)(13)(14)(15)(16). The AKI incidence in the VAN-FEP group was similar to previous reports of 12.5% (9,10).…”

Influence of β-Lactam Infusion Strategy on Acute Kidney Injury

“…The concern for AKI induced with use of TZP and VAN combination therapy raised a new clinical question-does the infusion strategy of TZP affect the incidence of AKI when used concomitantly with VAN? Documented nephrotoxicity rates in patients receiving TZP and vancomycin (VAN) combination therapy are similar, regardless of TZP infusion strategy (8,9). Results of a study including 320 patients performed by Karino and colleagues suggest comparable rates of AKI (32.5% versus 33.1%; P ϭ 1.0) in the prolonged-and intermittent-infusion groups, respectively (8).…”

“…McCormick et al completed a retrospective study of 200 patients and did not find a difference in acute kidney injuries (AKIs) between patients receiving intermittent TZP infusions versus those receiving extended infusions (11% versus 9%; P ϭ 0.637) (7). The literature to date suggests similar rates of nephrotoxicity in patients receiving TZP and vancomycin (VAN) combination therapy, regardless of TZP infusion strategy (8,9). No previous studies have reported the impact of prolonged infusions on AKI with ␤-lactams other than TZP.…”

Clinical effect of combined ulinastatin and continuous renal replacement therapy on management of severe sepsis with acute kidney injury

“…These activate Toll-like 4 receptor, and form inflammatory reaction cascade leading to pathophysiological changes in renal vascular endothelial cells and renal parenchymal cells, and eventually kidney damage [12]. Sepsis patients have changes in their neuroendocrine system such as activation of sympathetic nervous system, release of vasopressin, and activation of renin -angiotensin -aldosterone system.…”