Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B?

Abstract

Nephrotoxicity is a common adverse effect of the clinically used polymyxins, colistin and polymyxin B. This adverse effect is dose limiting for both polymyxins, as the plasma polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, colistimethate) and polymyxin B (administered as the active form). Both polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with colistimethate compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies.

Keywords: acute kidney injury; colistimethate; colistin; polymyxin B; toxicodynamics.

FIG 1

Overview of the pharmacokinetic pathways for CMS (colistimethate) and colistin (left) and polymyxin B (right). The thickness of the arrows indicates the relative magnitude of the respective clearance pathways when kidney function is normal. After administration of CMS, extensive renal excretion of the prodrug occurs with some of the excreted CMS converting to colistin within the kidneys and bladder. As a result, only a relatively small fraction of each CMS dose is converted to colistin within the body. This colistin formed systemically when delivered to the kidneys undergoes extensive tubular reabsorption; the same renal disposition applies to polymyxin B administered as such.

FIG 2

Summary of the overall incidence of acute kidney injury (AKI) in patients treated with colistimethate (CMS) or polymyxin B (PMB). AKI was defined as a twofold increase in serum creatinine or an increase of at least 1 mg/dl if initial creatinine was higher than 1.4 mg/dl in the study of Oliveira et al. (36), according to RIFLE criteria in the studies of Akajagbor et al. (37), Phe et al. (34), and Rigatto et al. (39), and according to AKIN criteria in the study of Tuon et al. (38). The incidences of AKI in CMS- and PMB-treated patients, respectively, were 26.0% (10 of 39 patients) and 27.0% (8 of 30) in the study of Oliveira et al. (36), 60.4% (64 of 106) and 41.8% (28 of 67) in the study of Akajagbor et al. (37), 48.2% (40 of 83) and 23.1% (24 of 104) in the cohort without cystic fibrosis patients in the study of Phe et al. (34), 38.9% (14 of 36) and 20.8% (20 of 96) in the study of Tuon et al. (38), and 74.1% (60 of 81) and 46.1% (189 of 410) in the study of Rigatto et al. (39)