Imaging the distribution of polymyxins in the kidney

Despite dose-limiting nephrotoxicity concerns, polymyxin B has resurged as the treatment of last resort for multidrug-resistant Gram-negative bacterial infections. However, the pharmacokinetic, pharmacodynamic, and nephrotoxic properties of polymyxin B still are not thoroughly understood. The objective of this study was to provide additional insights into the overall biodistribution and disposition of polymyxin B in an animal model. Sprague-Dawley rats were dosed with intravenous polymyxin B (3 mg/kg of body weight). Drug concentrations in the serum, urine, bile, and tissue (brain, heart, lungs, liver, spleen, kidneys, and skeletal muscle) samples over time were assayed by a validated methodology. Among all the organs evaluated, polymyxin B distribution was highest in the kidneys. The mean renal tissue/serum polymyxin B concentration ratios were 7.45 (95% confidence interval [CI], 4.63 to 10.27) at 3 h and 19.62 (95% CI, 5.02 to 34.22) at 6 h postdose. Intrarenal drug distribution was examined by immunostaining. Using a ratiometric analysis, proximal tubular cells showed the highest accumulation of polymyxin B (Mander's overlap coefficient, 0.998) among all cell types evaluated. Less than 5% of the administered dose was recovered in urine over 48 h, but all 4 major polymyxin B components were detected in the bile over 4 h. These findings corroborate previous results that polymyxin B is highly accumulated in the kidneys, but the elimination likely is via a nonrenal route. Biliary excretion could be one of the routes of polymyxin B elimination, and this should be further explored. The elucidation of mechanism(s) of drug uptake in proximal tubular cells is ongoing.T he emergence of multidrug-resistant bacterial infections has become a medical crisis worldwide (1, 2). Infections caused by Gram-negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp., are extremely challenging to treat (3-6). These infections also are associated with high rates of mortality and morbidity (7,8). Moreover, there are few new antibacterial agents available in the clinical drug development pipeline for these life-threatening infections. Consequently, this has led to the revival of old antibiotics, such as the polymyxins, as the treatment of last resort for infections caused by multidrugresistant Gram-negative pathogens (9-13).Polymyxins (primarily polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics isolated from Bacillus polymyxa (14). Commercially available polymyxin B is a mixture of several related analogs, primarily polymyxin B1, B2, and B3 and isoleucine B1 (15, 16). Polymyxin B first became available for clinical use in the 1950s, but its clinical use has been limited largely due to its nephrotoxic potential.Despite being available for clinical use for more than 50 years, there is still a paucity of published reports correlating the pharmacokinetics of polymyxin B with its toxicity profile. Furthermore, we lack a thorough understanding of the biodistribution pattern, cel...

Section: Discussionmentioning

confidence: 53%

“…Second, Yun et al provided circumstantial evidence linking polymyxin B distribution to the site of renal injury (24). We have previously shown histological evidence that the polymyxin B-induced injury was confined mainly to the proximal tubular cells of the rat kidneys (25).…”

Section: Discussionmentioning

confidence: 88%

Characterization of Polymyxin B Biodistribution and Disposition in an Animal Model

Manchandani

Zhou

Ledesma

et al. 2016

“…2A). Hence, the accumulation of polymyxin B in both A549 and HK-2 cells was determined (25) by using an anti-polymyxin B MAb. Interestingly, substantially less accumulation of polymyxin B was observed in A549 cells than in HK-2 cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Potential Toxicity of Polymyxins in Human Lung Epithelial Cells

Ahmed

Velkov

et al. 2017

Inhaled polymyxins are of considerable utility in achieving optimal exposure in the respiratory tract for the treatment of lung infections caused by multidrug-resistant Gram-negative pathogens. Current inhaled polymyxin therapy is empirical, and often large doses are used that may lead to potential pulmonary adverse effects. This study aimed to investigate the effect of polymyxins on human lung epithelial (A549) cells. The viability of A549 cells was examined after treatment with polymyxins by flow cytometry. Activation of caspases 3, 8, and 9, expression of Fas ligand (FasL), loss of mitochondrial membrane potential, and mitochondrial oxidative stress induced by polymyxin B were evaluated. The concentration of polymyxin B required to induce 50% of maximal cell death was 1.74 mM (95% confidence interval, 1.60 to 1.90 mM). Colistin was at least 2-fold less toxic than polymyxin B, while colistimethate was nontoxic. With 2.0 mM polymyxin B, 30.6% Ϯ 11.5% (mean Ϯ standard deviation) of the cells were apoptotic at 8 h and this increased to 71.3% Ϯ 3.72% at 24 h. Concentration-and time-dependent activation of caspases 3, 8, and 9 was evident, while the activation of caspase 9 was more dramatic. Furthermore, polymyxin B caused concentration-and time-dependent FasL expression, production of mitochondrial reactive oxygen species, and changes in mitochondrial membrane potential. This is the first study to demonstrate that both extrinsic death receptor and intrinsic mitochondrial pathways are involved in polymyxininduced toxicity in A549 cells. This knowledge base is critical for the development of novel strategies for the safe and effective inhalation therapy of polymyxins against Gram-negative "superbugs."

“…Because the ratios in these studies were for kidney homogenate (27,28), they would underestimate the concentration in the region of the greatest polymyxin accumulation. Immunostaining studies of sections of rodent kidneys from animals treated with PMB have shown that accumulation occurs predominantly in the renal cortex, primarily within proximal tubular cells (28,29). A synchrotron X-ray fluorescence microscopy study revealed that the concentration of a polymyxin analog in single rat (NRK-52E) and human (HK-2) kidney tubular cells in culture was several thousandfold higher than the extracellular concentration (30).…”

Section: To What Extent Do Polymyxins Accumulate In the Kidney And Whmentioning

confidence: 99%

Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B?

Zavascki

Nation

2017

183

120

Nephrotoxicity is a common adverse effect of the clinically used polymyxins, colistin and polymyxin B. This adverse effect is dose limiting for both polymyxins, as the plasma polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, colistimethate) and polymyxin B (administered as the active form). Both polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with colistimethate compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies.