The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

https://accpjournals.onlinelibrary.wiley.com/doi/epdf/10.1002/phar.2209

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).

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.

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

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

Polymyxin B and colistin are currently used as a “last-line” treatment for multidrug-resistant Gram-negative bacteria. However, very little is known about the pharmacological differences between polymyxin B1, polymyxin B2, colistin A, and colistin B, the major cyclic lipopeptide components present in polymyxin B and colistin products. Here, we report on the in vitro and in vivo antimicrobial activity and toxicity of these major lipopeptide components. All four lipopeptides had comparable minimum inhibitory concentrations (MICs) ( −3) and nephrotoxicity (mild to moderate histological damage) in mouse models. However, polymyxin B1 and colistin A showed significantly higher (>3-fold) in vitro apoptotic effect on human kidney proximal tubular HK-2 cells than polymyxin B2 and colistin B, respectively. Compared to the commercial polymyxin and colistin ...

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Antimicrobial Activity and Toxicity of the Major Lipopeptide Components of Polymyxin B and Colistin: Last-line Antibiotics against Multidrug-Resistant Gram-negative Bacteria.

Bacteremia due to carbapenem-resistant Enterobacteriaceae in neutropenic patients with hematologic malignancies

Objectives: The objectives of this study were to assess risk factors for acute kidney injury (AKI) in patients treated with polymyxin B, a last resort antibiotic against Gram-negative bacteria, with a focus on dose, and to determine the impact of AKI on mortality of these patients. Methods: A multicentre prospective cohort study was performed including patients ≥18 yearstreatedwith intravenouspolymyxin Bfor ≥48 h. TheprimaryoutcomewasAKIdefinedbyRIFLEcriteria. Secondaryoutcomes were 30 day mortality and failure stage of AKI. Multivariate analysis with a Cox regression model was performed. The probability of developing AKI was determined in a logistic regression model. Results: Four-hundred-and-ten patients were included. AKI occurred in 189 (46.1%) patients. Polymyxin B dose ≥150 mg/day was a risk factor for AKI: adjusted HR ¼1.95, 95% CI¼1.31‐2.89, P ¼0.01. Higher weight and age were also independentlyassociated with AKI. The probabilityof developing AKI significantly increased with doses between 150 and 199 mg/day, regardless of patient weight, with no significant increase with higher doses. Higher weight also increased the risk in patients receiving the same daily doses. AKI was barely associated with increased risk for 30 day mortality (adjusted HR¼1.35, 95% CI¼0.99‐1.85, P¼0.06), while ≥150 mg/day did not increase this risk despite its association with AKI.

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Risk factors for acute kidney injury (AKI) in patients treated with polymyxin B and influence of AKI on mortality: a multicentre prospective cohort study

Thiela Freitas

Papers

Risk factors for acute kidney injury (AKI) in patients treated with polymyxin B and influence of AKI on mortality: a multicentre prospective cohort study