Characterization of polymyxin B-induced nephrotoxicity: implications for dosing regimen design

Abstract

The increasing prevalence of multidrug-resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the nephrotoxic properties of polymyxin B are still poorly understood. The objective of this study was to characterize nephrotoxicity associated with polymyxin B, with an emphasis on examining the impact of dosing frequencies on the onset of nephrotoxicity. Sprague-Dawley rats were divided into two groups and administered the same total daily dose of polymyxin B subcutaneously but with different dosing frequencies (either 20 mg/kg of body weight every 24 h [q24h] or 5 mg/kg q6h). Drug concentrations in renal tissue were compared between the two groups at 24 h. Kidney tissues were harvested at 48 h and compared histologically. Serum creatinine was measured daily for up to 10 days, and nephrotoxicity was defined as a significant elevation in serum creatinine (≥2× baseline). Kaplan-Meier analysis was used to compare the onset of nephrotoxicity. Polymyxin B-induced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. Extensive injury of the proximal tubules was observed. The lesions were more severe and higher drug concentrations were achieved in the kidneys of the q6h dosing group. The q24h dosing group experienced a more gradual onset of nephrotoxicity, which could be attributed to the lower kidney tissue drug concentrations (48.5 ± 17.4 μg/g versus 92.1 ± 18.1 μg/g of polymyxin B1, P = 0.04). Preferential accumulation of polymyxin B in the kidneys suggests that uptake to renal cells is a nonpassive process and q24h dosing was less nephrotoxic than q6h dosing.

Fig 1

Concentrations of the major components of polymyxin B (PB) in rat kidneys. Data are shown as means ± standard deviations. PB1, polymyxin B1; ile-PB1, isoleucine polymyxin B1; PB2, polymyxin B2; PB3, polymyxin B3.

Fig 2

Histological comparison of renal lesions. Shown are the renal cortical tissue and the outer stripe of the medulla of normal kidney (A and B), with q24h dosing (C and D), and with q6h dosing (E and F). Hematoxylin and eosin stain and ×200 magnification were used for all panels. For panels C and D, the q24h dosing was associated with focal tubular cell necrosis (arrows) in both locations, together with focal tubular cell cytoplasmic attenuation (open arrow). For panels E and F, the q6h dosing was associated with more severe changes in both locations, including tubular cell necrosis (arrows), extensive cytoplasmic attenuation (open arrow), and vacuolization (box).

Fig 3

Comparison of the onset of nephrotoxicity between the dosing groups.