Polymyxin B causes DNA damage in HK-2 cells and mice

Yun, Bo Hyon; Zhang, T.; Azad, Mohammad Abul Kalam; Wang, J.; Nowell, Cameron J.; Kalitsis, Paul; Velkov, Tony; Hudson, DF; Li, J.

doi:10.1007/s00204-018-2192-1

Cited by 22 publications

(17 citation statements)

References 56 publications

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“…The present literature highlights the key role of DNA damage, metabolic and inflammatory perturbations, oxidative stress, cell cycle arrest, apoptosis, and autophagy in polymyxin-induced death of renal tubular cells in vitro and in vivo. A recent study showed the formation of micronuclei and multilobed nuclei, chromosome mis-segregation, and genome instability in HK-2 cells and mouse kidneys after polymyxin B treatment ( Yun et al, 2018 ). Increased expression of kidney γ H2AX (phosphorylated H2A histone family member X) suggested persistent DNA damage in kidneys by polymyxins.…”

Section: Polymyxin Toxicitymentioning

confidence: 99%

“…Increased expression of kidney γ H2AX (phosphorylated H2A histone family member X) suggested persistent DNA damage in kidneys by polymyxins. A transient cell cycle arrest followed by continuation with unrepaired DNA damage was speculated as a result of checkpoint perturbations by polymyxin B treatment ( Yun et al, 2018 ). Intraperitoneal administration of colistin (16 mg/kg per day in two divided doses) caused the upregulation of CCNB1 and CDC2 genes in mouse kidneys, suggesting cell cycle arrest at the G2/M phase ( Eadon et al, 2013 ).…”

Section: Polymyxin Toxicitymentioning

confidence: 99%

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Rescuing the Last-Line Polymyxins: Achievements and Challenges

et al. 2021

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Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of “safer” antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative “superbugs,” every effort must be made to improve the clinical utility of the last-line polymyxins. Significance Statement Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.

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Section: Polymyxin Toxicitymentioning

confidence: 99%

Section: Polymyxin Toxicitymentioning

confidence: 99%

Rescuing the Last-Line Polymyxins: Achievements and Challenges

et al. 2021

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“…In this process, there is a substantial intracellular accumulation of the drug which is mediated by the endocytic receptor, megalin, as well as other transporters [7]. The high intracellular concentration of polymyxins has been demonstrated in both human (HK-2) and rat (NRK-52E) kidney cells, which allowed experiments in animal and cell culture models to further explore this phenomenon [8,9]. The accumulation of polymyxins leads to drug-induced cell apoptosis which in turn results in decreased renal function and histopathological damage.…”

Section: Mechanisms Of Nephrotoxicitymentioning

confidence: 99%

Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

et al. 2019

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Polymyxins are valuable antimicrobials for the management of multidrug-resistant Gram-negative bacteria; however, nephrotoxicity associated with these drugs is a very common side effect that occurs during treatment. This article briefly reviews nephrotoxic mechanisms and risk factors for polymyxin-associated acute kidney injury (AKI) and discusses dosing strategies that may mitigate kidney damage without compromising antimicrobial activity. Polymyxins have a very narrow therapeutic window and patients requiring treatment with these drugs are frequently severely ill and have multiple comorbidities, which increases the risk of AKI. Notably, there is a significant overlap between therapeutic and toxic plasma polymyxin concentrations that substantially complicates dose selection. Recent dosing protocols for both colistin and polymyxin B have been developed and may help fine tune dose adjustment of these antibiotics. Minimizing exposure to modifiable risk factors, such as other nephrotoxic agents, is strongly recommended. The dose should be carefully selected, particularly in high-risk patients. The administration of oxidative stress-reducing drugs is a promising strategy to ameliorate polymyxin-associated AKI, but still requires support from clinical studies.

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“… 7 Abdelraouf et al 4 concluded that polymyxin B was saturable into the proximal renal tubular epithelial cells of pigs, and was mainly absorbed through the cell apical membrane, suggesting that the megalin transporter plays an important role in the uptake and accumulation of polymyxin B in the kidney of rats. According to the relevant literature, 6 , 15 polymyxin B-induced nephrotoxicity is related to DNA damage of related cells caused by the drug, resulting in chromosome segregation and genomic instability in cellular mitosis, as well as oxidative stress, mitochondrial damage, and changes in the lactate dehydrogenase activity of target cells, resulting in apoptosis and necrosis of renal proximal tubular epithelial cells. 16 , 17 …”

Section: Discussionmentioning

confidence: 99%

Effect of Different Dosage Frequency of Polymyxin B on Rat Nephrotoxicity

Sun

Hu²,

Zhang

et al. 2021

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Background Polymyxin B, as the final treatment against multidrug-resistant Gram-negative bacilli, is widely used in clinical practice. However, little is known about the nephrotoxicity of polymyxin B. The purpose of this study was to elucidate the relationship between polymyxin B nephrotoxicity and daily administration frequency. Methods Sprague–Dawley rats were randomly divided into three groups: 18 mg/kg/q24 h group (Group A, once daily), 9 mg/kg/q12 h group (Group B, twice daily), and normal saline control group (Group C). The rats were injected subcutaneously for 5 consecutive days with the same daily total dose and different frequency of administration. The serum creatinine (SCr) and blood urea nitrogen (BUN) of each group before administration (0 h), and 8 and 24 h after administration, were measured by tail vein blood sampling. On the sixth day, the rats in each group were killed, the left kidney was taken for pathological section observation, and the results of each group were compared. Results After 96 h of administrated polymyxin B, the total average level of SCr in Group A was 56.98±12.42 μmol/L, that of Group B was 52.02±8.68 μmol/L, and that of Group C was 34.36±5.39 μmol/L. BUN was 9.86±4.58, 10.54±4.08, and 3.55±0.73 mmol/L in Groups A, B, and C, respectively. The daily urinary protein excretion was 5004.45±1333.84 μg in Group A, 4608.04±1444.42 μg in Group B, and 2096.33±215.28 μg in Group C. In addition, according to the observation of pathological slices, compared with Group A, the number of exfoliated and necrotic cells of renal tubules in Group B was higher, and the morphological changes were more serious. Conclusion The experimental results showed that the renal toxicity in rats treated with a twice-daily subcutaneous dose of polymyxin B was higher than that in rats treated with once-daily dose of polymyxin B.

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Polymyxin B causes DNA damage in HK-2 cells and mice

Cited by 22 publications

References 56 publications

Rescuing the Last-Line Polymyxins: Achievements and Challenges

Rescuing the Last-Line Polymyxins: Achievements and Challenges

Polymyxin Acute Kidney Injury: Dosing and Other Strategies to Reduce Toxicity

Effect of Different Dosage Frequency of Polymyxin B on Rat Nephrotoxicity

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