Colistimethate toxicity. Report of a fatal case in a previously healthy child

The increasing prevalence of multidrug-resistant Gram-negative infections has led to renewed interest in the use of systemic polymyxin B. However, the nephrotoxic properties of polymyxin B are still poorly understood. The objective of this study was to characterize nephrotoxicity associated with polymyxin B, with an emphasis on examining the impact of dosing frequencies on the onset of nephrotoxicity. Sprague-Dawley rats were divided into two groups and administered the same total daily dose of polymyxin B subcutaneously but with different dosing frequencies (either 20 mg/kg of body weight every 24 h [q24h] or 5 mg/kg q6h). Drug concentrations in renal tissue were compared between the two groups at 24 h. Kidney tissues were harvested at 48 h and compared histologically. Serum creatinine was measured daily for up to 10 days, and nephrotoxicity was defined as a significant elevation in serum creatinine (>2؋ baseline). Kaplan-Meier analysis was used to compare the onset of nephrotoxicity. Polymyxin B-induced nephrotoxicity manifested as elevation in serum creatinine and acute tubular necrosis. Extensive injury of the proximal tubules was observed. The lesions were more severe and higher drug concentrations were achieved in the kidneys of the q6h dosing group. The q24h dosing group experienced a more gradual onset of nephrotoxicity, which could be attributed to the lower kidney tissue drug concentrations (48.5 ؎ 17.4 g/g versus 92.1 ؎ 18.1 g/g of polymyxin B1, P ‫؍‬ 0.04). Preferential accumulation of polymyxin B in the kidneys suggests that uptake to renal cells is a nonpassive process and q24h dosing was less nephrotoxic than q6h dosing.

Section: Discussionsupporting

confidence: 91%

Characterization of Polymyxin B-Induced Nephrotoxicity: Implications for Dosing Regimen Design

Abdelraouf

Braggs

Yin

et al. 2012

“…Toxicity, specifically nephrotoxicity, is a major concern when colistin is administered, mainly because of some previous reports ( medication which reported significant nephrotoxicity (1,16,20,34). However, recent data, including results from our study, in which nephrotoxicity was 8%, suggest that colistin toxicity is less prominent than previously reported (1,5).…”

Section: Discussioncontrasting

confidence: 57%

“…During the ensuing decades, colistin was used in the treatment of several types of infections, including infectious diarrhea and urinary tract infections, as well as in bowel decontamination. Early clinical experience with colistin showed a high incidence of toxicity, namely, nephrotoxicity, sometimes with fatal consequences (2,20,34). During the last 2 decades, the use of the antibiotic was mainly restricted to topical ophthalmic and otic use as well as to the treatment of acute exacerbations of lung infections due to multiresistant Pseudomonas aeruginosa strains in patients with cystic fibrosis (9,28,36,38).…”

mentioning

confidence: 99%

Combination Therapy with Intravenous Colistin for Management of Infections Due to Multidrug-Resistant Gram-Negative Bacteria in Patients without Cystic Fibrosis

Kasiakou

Michalopoulos

Soteriades

et al. 2005

169

115

Colistin, an antibiotic almost abandoned for intravenous administration for many years due to its reported toxicity, has been recently reintroduced in clinical practice due to the emergence of multidrug-resistant gram-negative bacteria and the lack of development of new antibiotics to combat them. To assess the safety and effectiveness of intravenous colistin, in combination with other antimicrobial agents, in the treatment of serious infections in patients without cystic fibrosis, a retrospective cohort study in a 450-bed tertiary-care hospital in Athens, Greece, was performed. Patients who were hospitalized from 1 October 2000 to 31 January 2004 and received intravenous colistin for more than 72 h were further analyzed. The primary outcome measure was the in-hospital mortality; secondary end points were the clinical outcome of the infections and the occurrence of colistin toxicity. Fifty patients received intravenous colistin with a median (mean) daily dose of 3 (4.5) million IU for 16.5 (21.3) days for the management of 54 episodes of infections due to multidrug-resistant gramnegative bacteria. The predominant infections were pneumonia (33.3%), bacteremia (27.8%), urinary tract infection (11.1%), and intra-abdominal infection (11.1%). The responsible pathogens were Acinetobacter baumannii (51.9%), Pseudomonas aeruginosa (42.6%), and Klebsiella pneumoniae (3.7%) strains (no pathogen was isolated from one case). In-hospital mortality was 24% (12/50 patients). Clinical response (cure or improvement) of the infection was observed in 66.7% of episodes (36/54). In the studied group, serum creatinine levels were decreased, at the end of colistin treatment, by an average of 0.2 ؎ 1.3 mg/dl compared to baseline levels. Deterioration of renal function during colistin therapy was observed in 4/50 patients (8%). Coadministration of other antimicrobial agents with spectrum against gram-negative microorganisms and the absence of a control group constitute the major limitations of this study. The use of intravenous colistin for the treatment of infections due to multidrug-resistant gram-negative bacteria appears to be safe and effective.

“…With their rapid bactericidal activities and current low levels of resistance (6,12,16,34), the polymyxins, and colistin (also known as polymyxin E) in particular, have undergone a revival as agents for treatment of infections caused by MDR P. aeruginosa, A. baumannii, and Klebsiella pneumoniae (6,20,30). Previously relegated to the status of a reserve agent after early reports of a "high" incidence of toxicity (21,44), colistin is now a last line of defense for the treatment of infections with MDR gram-negative organisms (3,30,33).…”

mentioning

confidence: 99%

Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against Pseudomonas aeruginosa

Bergen

Rayner

et al. 2006

334

242

There is a dearth of information on the pharmacodynamics of "colistin," despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., ϳ0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving "colistin," in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.