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.

Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand

“…The rate of good response to polymyxin B observed in this study should not related to the prior use of carbapenems or a combination of polymyxin B and carbapenems because all isolated bacteria from the patients were resistant to carbapenems and the results from the recent randomized controlled trial (RCT) revealed that the outcomes of the patients infected with XDR Gram-negative bacteria who received a combination of colistin and meropenem was not significantly better than those who received colistin alone 14. Regarding the nephrotoxicity of polymyxin B, the findings from our study were in accordance with the recent reviews reporting that polymyxin B was associated with less risk of nephrotoxicity than colistin 15,16…”

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti‐infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP)

“…Similarly, plasma polymyxin B concentrations achieved among patients receiving the current upper limit daily dose are not likely to be reliably efficacious in many clinical scenarios including respiratory tract infections . Second, it is not possible to simply increase the daily doses of CMS or polymyxin B beyond doses recommended in this document due to the potential for nephrotoxicity that is the major dose‐limiting adverse effect . Third, the emerging body of evidence in preclinical lung infection models suggests poor in vivo response to the polymyxins when administered parenterally .…”

“…Thus a lack of clarity remains about how optimally to utilize and dose colistin and polymyxin B . Unfortunately, polymyxins are highly nephrotoxic agents, and acute kidney injury (AKI) occurs frequently with conventional doses . Given the narrow therapeutic windows (low therapeutic indices) of polymyxins, this guideline provides clinicians with a practical framework for use in treating infections caused by MDR and XDR gram‐negative pathogens.…”

The challenge of converting Gram‐positive‐only compounds into broad‐spectrum antibiotics

“…With the increase in carbapenem‐resistant infections, colistin, a drug that was previously removed from the clinic due to high toxicity, has been reintroduced to the clinic. Colistin is far from an ideal drug, as 50–60% of people taking colistin experience acute kidney injury . Additionally, colistin resistance has emerged, and alarmingly the resistance can be easily spread via horizontal gene transfer of plasmids .…”

“…Colistin is far from an ideal drug, as 50-60% of people taking colistin experience acute kidney injury. [37][38][39] Additionally, colistin resistance has emerged, and alarmingly the resistance can be easily spread via horizontal gene transfer of plasmids. [9][10][11]40 The first plasmid associated with colistin resistance was discovered in 2016 in China, 11 but has already spread throughout the world.…”