Risk factors for nephrotoxicity onset associated with polymyxin B therapy

Dubrovskaya, Yanina; Prasad, Nishant; Lee, Yuman; Esaian, Diana; Figueroa, Deborah A.; Tam, Vincent H.

doi:10.1093/jac/dkv014

Cited by 54 publications

(49 citation statements)

References 20 publications

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“…CMS or PMB occurred 2 days after initiation of therapy, with the majority of cases occurring after 15 days of therapy [46]. Fortunately, polymyxin-associated nephrotoxicity was, however, reversible in most patients [47,50]. …”

Section: Toxicodynamics Of Polymyxinsmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Tran

Velkov

Nation

et al. 2016

International Journal of Antimicrobial Agents

156

131

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The polymyxin antibiotics [colistin and polymyxin B (PMB)] are increasingly used as a last-line option for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria. Despite having similar structures and antibacterial activity in vitro, the two clinically available polymyxins have very different pharmacological properties, as colistin (polymyxin E) is intravenously administered to patients in the form of an inactive prodrug colistin methanesulphonate (sodium). This review will discuss recent progress in the pharmacokinetics/pharmacodynamics and toxicity of colistin and PMB, the factors that affect their pharmacological profiles, and the challenges for the effective use of both polymyxins. Strategies are proposed for optimising their clinical utility based upon the recent pharmacological studies in vitro, in animals and patients. In the ‘bad bugs, no drugs’ era, polymyxins are a critically important component of the antibiotic armamentarium against difficult-to-treat Gram-negative ‘superbugs’. Rational approaches to the use of polymyxins must be pursued to increase their effectiveness and to minimise resistance and toxicity.

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Section: Toxicodynamics Of Polymyxinsmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Tran

Velkov

Nation

et al. 2016

International Journal of Antimicrobial Agents

156

131

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“…So, use of these alternate body size descriptors limits computation of doses that may be erroneously high. A good example for this potential error is with the antimicrobial Polymyxin B, which has a high incidence of nephrotoxicity [27][28][29][30][31]. For safety, dosage of this antimicrobial on IBW should lead to computation of smaller doses compared to TBW-based doses across the clinical population [31].…”

Section: Obesity and Initial Dose Selection Approachesmentioning

confidence: 99%

Treatment of bacterial infections in obese adult patients: how to appropriately manage antimicrobial dosage

Pai

2015

Current Opinion in Pharmacology

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“…However, pharmacokinetic studies have reported preferential accumulation and prolonged residence of polymyxin B in rat kidneys (7,8). Several studies have also reported a daily dose of polymyxin B as an independent risk factor associated with drug nephrotoxicity (9)(10)(11). Nevertheless, these reports did not provide a mechanistic framework correlating renal drug exposure with the onset of polymyxin B nephrotoxicity.…”

mentioning

confidence: 99%

Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

Manchandani

Zhou

Babic

et al. 2017

Antimicrob Agents Chemother

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Despite dose-limiting nephrotoxic potentials, polymyxin B has reemerged as the last line of therapy against multidrug-resistant Gram-negative bacterial infections. However, the handling of polymyxin B by the kidneys is still not thoroughly understood. The objectives of this study were to evaluate the impact of renal polymyxin B exposure on nephrotoxicity and to explore the role of megalin in renal drug accumulation. Sprague-Dawley rats (225 to 250 g) were divided into three dosing groups, and polymyxin B was administered (5 mg/kg, 10 mg/kg, and 20 mg/kg) subcutaneously once daily. The onset of nephrotoxicity over 7 days and renal drug concentrations 24 h after the first dose were assessed. The effects of sodium maleate (400 mg/kg intraperitoneally) on megalin homeostasis were evaluated by determining the urinary megalin concentration and electron microscopic study of renal tissue. The serum/renal pharmacokinetics of polymyxin B were assessed in megalin-shedding rats. The onset of nephrotoxicity was correlated with the daily dose of polymyxin B. Renal polymyxin B concentrations were found to be 3.6 Ϯ 0.4 g/g, 9.9 Ϯ 1.5 g/g, and 21.7 Ϯ 4.8 g/g in the 5-mg/kg, 10-mg/kg, and 20-mg/kg dosing groups, respectively. In megalin-shedding rats, the serum pharmacokinetics of polymyxin B remained unchanged, but the renal exposure was attenuated by 40% compared to that of control rats. The onset of polymyxin B-induced nephrotoxicity is correlated with the renal drug exposure. In addition, megalin appears to play a pivotal role in the renal accumulation of polymyxin B, which might contribute to nephrotoxicity. KEYWORDS Polymyxin B, renal drug concentration, megalin, polymyxins T here is a renewed interest in the clinical use of polymyxins due to the increased prevalence of infections caused by multidrug-resistant Gram-negative bacteria (1). Many currently available antibiotics are no longer effective against these resistant bacterial strains. Additionally, the situation is further exacerbated by the limited number of new antibacterial agents in the advanced drug development pipeline. Consequently, the polymyxins have emerged as the last treatment resort against these life-threatening infections.Polymyxins (polymyxin B and polymyxin E [colistin]) are cyclic polypeptide antibiotics which were available for clinical use in the 1950s. However, the clinical use of polymyxins was considerably reduced in the early 1970s due to concerns about nephrotoxicity (2-4). Despite being available for decades, the correlation between the pharmacokinetics and toxicodynamic profiles of polymyxin B is still not thoroughly understood. This knowledge gap often hinders the optimal clinical use of polymyxin B. There is evidence suggesting that polymyxin B is not eliminated through the renal route (5, 6). However, pharmacokinetic studies have reported preferential accumulation and prolonged residence of polymyxin B in rat kidneys (7,8). Several studies have also reported a daily dose of polymyxin B as an independent risk factor associated with...

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Risk factors for nephrotoxicity onset associated with polymyxin B therapy

Abstract: Risk factors for nephrotoxicity onset associated with polymyxin B were identified. In conjunction with susceptibility and other pharmacokinetic/pharmacodynamic data, our results can be used to optimize treatment for MDR Gram-negative infections.

Cited by 54 publications

References 20 publications

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet?

Treatment of bacterial infections in obese adult patients: how to appropriately manage antimicrobial dosage

Role of Renal Drug Exposure in Polymyxin B-Induced Nephrotoxicity

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