1 INTRODUCTION
Vancomycin is one of the most widely prescribed antibiotics in the hospital setting (Baggs, Fridkin, Pollack, Srinivasan, & Jernigan, 2016). It remains a first line therapeutic option for infections caused by methicillin-resistant Staphylococcus aureus (C. Liu et al., 2011; Rybak et al., 2020), enterococci and other resistant Gram positive bacteria. Kidney injury is a common adverse effect (Im et al., 2017) with rates varying from 5% to 43% depending on the population treated and concomitant medications (van Hal, Paterson, & Lodise, 2013). Less is known about how other medications increase and decrease kidney injury. Recently, a clinical trial (Combination Antibiotics for Methicillin Resistant Staphylococcus aureus, CAMERA2), aimed to evaluate the combination therapy of a beta-lactam (primarily flucloxacillin) with vancomycin for efficacy (Tong et al., 2020). However, the trial was stopped early as more patients in the combination therapy group developed kidney injury as defined by increased serum creatinine when compared to standard therapy (Tong et al., 2020). Further, CAMERA2 failed to identify an efficacy benefit with combination therapy, only that toxicity was increased among the those that received vancomycin and flucloxacillin in combination. Even less is known about agents that can prevent kidney injury due to vancomycin. Imipenem-cilastatin/relebactam has been shown to decrease serum creatinine of mice that received vancomycin (He, Souza, Matvekas, Crass, & Pai, 2021) with similar findings reported in retrospective clinical studies (Hakeam, AlAnazi, Mansour, AlFudail, & AlMarzouq, 2019).
Clinical studies for evaluating acute kidney injury (AKI) with vancomycin have primarily focused on assessment of serum creatinine and various clinical classification schemes based on serum creatinine and urinary output (He et al., 2021; Nakamura, Kokuryo, Hashimoto, & Inui, 1999). While serum creatinine is a commonly used surrogate of both kidney injury and function, it is slow to change after an injury event and is neither highly sensitive nor specific for meaningful injury and functional changes. Animal studies offer the ability to study newer biomarkers that are more sensitive and specific for detecting injury and to assess drug accumulation in the kidney. For vancomycin induced kidney injury, kidney injury molecule-1 (KIM-1) has been demonstrated as the most sensitive and specific urinary biomarker for prediction of histopathologic damage (Pais et al., 2019). KIM-1 has also been shown as highly correlated with functional changes (i.e. glomerular filtration changes) due to vancomycin (Chang et al., 2022; Pais, Chang, Liu, & Scheetz, 2022).
Since the findings of nephrotoxicity as classified by serum creatinine in CAMERA2 were unexpected, the purpose of this study was to assess the biologic plausibility of increased kidney injury caused by the addition of flucloxacillin to vancomycin by employing sensitive urinary biomarkers such as KIM-1, urinary output, and vancomycin accumulation in the kidney in our translational rat model (Avedissian, Pais, O’Donnell, et al., 2019; Pais, Liu, Avedissian, et al., 2020). Simultaneously, we sought to determine if kidney injury was lessened with the addition of imipenem/cilastatin in the same rat model. To address these questions, we studied kidney injury in Sprague Dawley rats : administered saline, vancomycin alone, vancomycin plus flucloxacillin, or vancomycin plus imipenem-cilastatin.