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.