Polymyxin B Nephrotoxicity: From Organ to Cell Damage

Vattimo, Maria de Fátima Fernandes; Watanabe, Mirian; Fonseca, Cassiane Dezoti da; Neiva, Luciana Barros de Moura; Pessoa, Edson Andrade; Borges, Fernanda Teixeira

doi:10.1371/journal.pone.0161057

Cited by 48 publications

(37 citation statements)

References 49 publications

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“…In a recent in vitro study, Vattimo et al investigated the PMB nephrotoxic effect at the cellular level and demonstrated that PMB renal toxicity is characterized by mitochondrial dysfunction and free radical generation in a pig proximal tubular epithelial cell line (immortalized LLC-PK1 cells) and in rat kidneys (19). The authors of this study also reported a reduced percentage of viable cells in response to higher PMB concentrations, which confirmed the concentration-dependent toxicity of PMB.…”

Section: Discussionsupporting

confidence: 72%

Nephrotoxicity Associated with Intravenous Polymyxin B Once- versus Twice-Daily Dosing Regimen

Okoduwa

Ahmed

Guo

et al. 2018

Antimicrob Agents Chemother

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Nephrotoxicity is a known adverse effect of polymyxin B (PMB). Animal data suggest that once-daily dosing may reduce the rate and delay the onset of acute kidney injury (AKI). In a multicenter retrospective study, we evaluated adult patients with a creatinine clearance (CrCl) of ≥30 ml/min who received ≥48 h of PMB therapy. The primary endpoint was the difference in rate of AKI comparing once- and twice-daily PMB dosing. The secondary endpoints included the time to AKI and the recovery of renal function. Of 273 eligible patients, 100 from each group were matched on the basis of propensity scores. In the matched groups, nephrotoxicity, defined according to risk, injury, failure, loss, and end-stage renal disease (RIFLE) criteria, was more frequent with once- than with twice-daily dosing (47% versus 17%, respectively; = 0.0005). After adjusting for residual differences by multivariate conditional logistic regression, once-daily dosing was more likely to result in nephrotoxicity (adjusted odds ratio, 2.5; 95% confidence interval [CI], 1.413 to 4.541; = 0.002). Among 64 patients who developed AKI, the median onsets were similar between the groups (7 days with once versus 6 days with twice-daily dosing, = 0.095). Of 37 patients who had their serum creatinine evaluated subsequently, 29/37 (78%) had recovery of renal function. No patient required renal replacement therapy. Our findings suggest that AKI is significantly more common with PMB once daily than with twice-daily dosing with no difference in time to AKI. A prospective randomized study is warranted to validate these results.

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Section: Discussionsupporting

confidence: 72%

Nephrotoxicity Associated with Intravenous Polymyxin B Once- versus Twice-Daily Dosing Regimen

Okoduwa

Ahmed

Guo

et al. 2018

Antimicrob Agents Chemother

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“…Pulmonary delivery of polymyxins has offered a great promise for the treatment of lung infections (13,14) caused by MDR Gram-negative pathogens, as intravenous administration leads to poor drug disposition at the infection site (7) and nephrotoxicity can occur in up to 60% of patients (9)(10)(11). However, the mechanism of polymyxin-associated pulmonary toxicity has not been examined.…”

Section: Discussionmentioning

confidence: 99%

Potential Toxicity of Polymyxins in Human Lung Epithelial Cells

Ahmed

Velkov

et al. 2017

Antimicrob Agents Chemother

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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."

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“…Polymyxin antibiotics have previously been hypothesized to mediate adverse effects via overproduction of ROS (31). We measured ROS production in 2-D-cultured PTECs in response to increasing concentrations of PMB exposure using both CellROX (a free radical sensor that fluoresces when oxidized by ROS) and MitoSOX (a fluorogenic dye that detects intracellular mitochondrial superoxide).…”

Section: Resultsmentioning

confidence: 99%