Risk factors for acute kidney injury in patients treated with polymyxin B or colistin methanesulfonate sodium

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Abstract

Polymyxin B (PMB) and colistin, administered as the prodrug colistin methanesulfonate sodium (CMS), are increasingly used to treat carbapenem-resistant Gram-negative bacteria. Nephrotoxicity is the major dose-limiting adverse effect of both polymyxins. A retrospective cohort study of 132 patients was conducted to evaluate risk factors for acute kidney injury (AKI), classified according to Acute Kidney Injury Network criteria, in patients treated with ≥48 h of intravenous PMB or CMS, with particular focus on potential differences between each polymyxin. The overall incidence of AKI was 25.8% (34/132) [20.8% (20/96) and 38.9% (14/36) in patients treated with PMB and CMS, respectively; P = 0.06]. In the Cox regression model, doses ≥2 million International Units (MIU) of PMB or >9 MIU of CMS were the only variable independently associated with AKI [adjusted hazard ratio (aHR) = 2.11, 95% confidence interval (CI) 1.01–4.41; P = 0.04]. Vancomycin co-administration was strongly associated with AKI, although this was not statistically significant (aHR = 2.22, 95% CI 0.98–5.04; P = 0.058). There was no statistically significant difference in the incidence of AKI between patients treated with PMB or CMS in the multivariate model (aHR = 1.74, 95% CI 0.82–3.69; P = 0.15). High dose was the main risk factor for AKI regardless of the polymyxin administered. Vancomycin co-administration likely increases the risk of AKI. Although there was a higher overall incidence of AKI in patients treated with CMS compared with PMB, CMS was not significantly associated with this outcome after adjusting for the above variables.

Introduction

The increased incidence of carbapenem-resistant Enterobacteriaceae, Acinetobacter baumannii and Pseudomonas aeruginosa, mainly determined by the dissemination of carbapenemase-producing strains, has led to the re-emergence of polymyxins in clinical practice since they are the last-resort treatment against most infections by these organisms [1], [2].

The bactericidal effect of polymyxins has been shown to be most associated with the unbound (free) area under the concentration–time curve to minimum inhibitory concentration ratio (fAUC/MIC), which emphasises the importance of achieving adequate exposures to these drugs [3]. However, nephrotoxicity is the main dose-limiting adverse effect both of polymyxin B (PMB) and colistin [administered as the prodrug colistin methanesulfonate sodium (CMS)], with rates of acute kidney injury (AKI) ranging from 30% to 60% in recent studies using standardised definitions [4], [5], [6], [7], [8], [9], [10], [11], [12], [13].

There is no clear evidence of increased renal toxicity of one polymyxin compared with the other. In fact, there are only two studies comparing both drugs regarding toxicity: one has found no difference between them [14] and the other has demonstrated a higher incidence of toxicity with CMS [9]. The aim of this study was to assess risk factors for AKI in a cohort of patients at the same institution treated with PMB and CMS, with particular focus on the potential differences between each polymyxin.

Section snippets

Patients and study design

This was a retrospective cohort study carried out at Hospital Universitário Evangélico de Curitiba, a 700-bed tertiary care teaching hospital in Curitiba, Brazil. Patients were enrolled using the hospital's pharmacy database from January 2009 to January 2011. Inclusion criteria were patients receiving intravenous PMB or CMS for ≥48 h. Exclusion criteria were patients <18 years old and patients receiving renal replacement therapy at the beginning of treatment. PMB or CMS were prescribed according

Patient characteristics

A total of 132 patients were included in the study. Most patients were male (80; 60.6%) and the mean ± standard deviation (S.D.) age was 46.5 ± 21.5 years. Most patients (82; 62.1%) had no co-morbidities, with a median [interquartile range (IQR)] Charlson score of 0 (0.5–2.5). In total, 56 patients (42.4%) were admitted for trauma (n = 41) or burns (n = 15), and 72 (54.5%) were surgical patients including 67 (50.8%) admitted for emergency surgery; other less frequent conditions were cardiovascular

Discussion

This study evaluated the incidence of and risk factors for AKI in a cohort of patients treated with polymyxins mostly composed by young adults with baseline normal creatinine levels and few co-morbidities. The overall incidence of AKI during therapy (25.8%) may be considered low in comparison with other studies evaluating AKI through a standardised criteria, especially considering that most patients in the current cohort treated with PMB and all patients treated with CMS received relatively

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