Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins?
Section snippets
Introduction and history of polymyxin-associated nephrotoxicity
The polymyxin class of antibiotics was discovered midway through the 20th century; however, preliminary studies of the antibiotics in this class revealed that the majority of agents were too toxic to the mammalian kidney to be used safely in humans [1], [2]. Exceptions to this finding were polymyxin B (PMB) and polymyxin E (colistin), and over the next two decades these ‘safe’ polymyxins were brought to market to combat Pseudomonas spp. and other Gram-negative infections. At the time that these
Risk factors for polymyxin-associated nephrotoxicity
It is now known that the risk of developing polymyxin-associated nephrotoxicity is not negligible but is highly variable and strongly dependent on patient- and dose-specific risk factors. Several studies both of colistin and PMB have reported increased age as an independent risk factor for developing acute kidney injury (AKI). Rigatto et al. noted a significant age difference in patients receiving PMB who developed AKI and those who did not (66.7 ± 15.3 years vs. 61.7 ± 17.9 years,
Strategies to minimise polymyxin-associated nephrotoxicity
In addition to limiting the above risk factors, most notably concomitant nephrotoxin exposures and the daily dose of either colistin or PMB, there are two other major potential strategies to minimise nephrotoxicity rates that warrant consideration: preferential use of one of the polymyxin agents; and the use of antioxidants such as ascorbic acid.
As discussed earlier, initial beliefs surrounding preferential use of either polymyxin favoured the use of colistin owing to beliefs that colistin was
Unknowns and future directions
Despite significant advancements in our understanding of modifiable risk factors associated with the development of AKI among patients receiving polymyxins, significant unknowns remain. Importantly, well-controlled data that support strategies such as decreasing polymyxin dose, limiting concomitant nephrotoxin exposure, preferential use of PMB over colistin, or co-administration of antioxidants are lacking. In addition, with respect to preferential use of PMB, potential decreases in
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Polymyxin-induced nephrotoxicity and its predictors: a systematic review and meta-analysis of studies conducted using RIFLE criteria of acute kidney injury
2021, Pharmacological ResearchCitation Excerpt :Several studies have reported nephrotoxicity as a major dose-limiting adverse effect of polymyxins, nevertheless, there is no consensus in defining nephrotoxicity [21,22]. The incidence rate could also be influenced by patient- and/or dose-specific risk factors including age, receipt of concomitant nephrotoxic medications, diabetes mellitus, hypoalbuminaemia, and dose, among others [23,24]. Moreover, the criteria used to classify renal damage resulted a wide-range of incidences.
The value of antimicrobial peptides in the age of resistance
2020, The Lancet Infectious DiseasesCitation Excerpt :First used clinically in 1959, towards the end of the 20th century, the polymyxin antibiotic class with its annotated dose-dependent nephrotoxicity had once again started being used to combat superbugs. The well known colistin now remains the last viable therapeutic option for Gram-negative bacteria.165 However, in late 2015, the first plasmid-mediated polymyxin-resistance gene (MCR-1) was reported, indicating that this last-line antibiotic is losing its effectiveness, and the world was confronted with a revelation of the antibiotic resistance crisis.166
The footprints of mitochondrial impairment and cellular energy crisis in the pathogenesis of xenobiotics-induced nephrotoxicity, serum electrolytes imbalance, and Fanconi's syndrome: A comprehensive review
2019, ToxicologyCitation Excerpt :Polymyxins are a class of antibiotics administered as the last line therapy against gram-negative multidrug-resistant bacterial infections (Velkov et al., 2013). Unfortunately, nephrotoxicity is a severe and dose-limiting adverse event associated with the clinical application of polymyxin antibiotics (Falagas et al., 2005; Pogue et al., 2016; Velkov et al., 2013). Drug-induced nephrotoxicity could significantly decrease the efficiency of polymyxin antibiotic therapy.
Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies
2019, Diagnostic Microbiology and Infectious DiseaseCitation Excerpt :Polymyxins were discovered in 1947 (Storm et al., 1977), but their use was almost abandoned after many reports of acute renal injury in critically ill patients (Awdishu, 2017). However, polymyxins are being reintroduced in clinical practice due to the scarcity of effective antibiotics to treat emerging infections caused by gram-negative bacteria (Falagas and Kasiakou, 2005; Pogue et al., 2016; Rabanal et al., 2017). Among polymyxins, only colistin and polymyxin B are currently used due to their lower toxicity when compared to other drugs of the class (Falagas and Kasiakou, 2006; Kadar et al., 2013; Rabanal et al., 2017).
The nephroprotective properties of taurine in colistin-treated mice is mediated through the regulation of mitochondrial function and mitigation of oxidative stress
2019, Biomedicine and PharmacotherapyCitation Excerpt :However, the COL-induced renal injury is a deleterious clinical complication [4,5]. Drug-induced nephrotoxicity serves as a dose-limiting factor for COL therapy and decreases the drug efficacy in patients [4–7]. COL-associated renal injury occurs at a high rate [6].
Development of dilipid polymyxins: Investigation on the effect of hydrophobicity through its fatty acyl component
2018, Bioorganic ChemistryCitation Excerpt :Concerns with polymyxin’s nephrotoxicity and neurotoxicity as well as the availability of less toxic alternatives hampered their widespread clinical usage in the past. However, a rejuvenated interest in polymyxins have been observed recently due to the alarming increase of MDR pathogens that are impervious to most antibiotics, but also due to improved understanding of polymyxin’s pharmacokinetic/pharmacodynamic properties and how they relate to alleviating toxicity [1,2]. Polymyxin B and E, also known as colistin (Fig. 1A) are currently used in the clinic as monotherapy or as part of combination therapy with other antibiotics when standard treatment options fail [3].