Are there any ways around the exposure-limiting nephrotoxicity of the polymyxins?

https://doi.org/10.1016/j.ijantimicag.2016.11.001Get rights and content

Highlights

  • Risk factors for nephrotoxicity include nephrotoxins, dose and serum concentration.

  • Both polymyxins are nephrotoxic; polymyxin B may be less nephrotoxic than colistin.

  • Ascorbic acid might help prevent polymyxin-induced nephrotoxicity.

  • Nephrotoxicity is usually mild and reversible.

  • Clinical efficacy and safety of polymyxin combination regimens should be evaluated.

Abstract

The polymyxins (colistin and polymyxin B) have emerged over the past 20 years as essential antibacterial agents that often are the only remaining active class against troublesome multidrug-resistant Gram-negative bacilli such as carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae. The utility of this class is limited by its dose-dependent nephrotoxicity, which can occur in more than one-half of patients receiving therapy with either agent. Strategies are urgently needed to optimise the use of this class of agents to ensure optimal activity while minimising the treatment-limiting nephrotoxicity. This review will focus on risk factors for polymyxin-associated nephrotoxicity, potential strategies for limiting this exposure-dependent toxicity and, finally, unknowns and future research directions pertinent to this topic.

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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