Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia

Abstract

Objectives To assess the pharmacokinetics of formed colistin in plasma and the safety of two different high doses of colistimethate sodium administered via nebulization in critically ill surgical patients with hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP). Patients and methods Formed colistin plasma concentrations were measured in critically ill surgical patients with pneumonia treated with two different doses of nebulized colistimethate sodium (3 MIU/8 h versus 5 MIU/8 h). Adverse events possibly related to nebulized colistimethate sodium were recorded. Results Twenty-seven patients (15 in the 3 MIU/8 h group and 12 in the 5 MIU/8 h group) were included. Colistin plasma concentrations were unquantifiable (<0.1 mg/L) in eight (53.3%) patients in the 3 MIU/8 h group and in seven patients (58.3%) in the 5 MIU/8 h group. Median (IQR) quantifiable colistin plasma concentrations before nebulization and at 1, 4 and 8 h were 0.17 (0.12–0.33), 0.20 (0.11–0.24), 0.17 (0.12–0.23) and 0.17 (0.11–0.32) mg/L, respectively, in the 3 MIU/8 h group and 0.20 (0.11–0.35), 0.24 (0.12–0.44), 0.24 (0.10–0.49) and 0.23 (0.11–0.44) mg/L, respectively, in the 5 MIU/8 h group, with no differences between the two groups at any time. Renal impairment during nebulized treatment was observed in three patients in each group, but was unlikely to be related to colistimethate sodium treatment. Nebulized colistimethate sodium therapy was well tolerated and no bronchospasms or neurotoxicity events were observed. Conclusions In this limited observational case series of critically ill patients with HAP or VAP treated with high doses of nebulized colistimethate sodium, systemic exposure was minimal and the treatment was well tolerated.

Intrapulmonary concentrations of meropenem administered by continuous infusion in critically ill patients with nosocomial pneumonia: a randomized pharmacokinetic trial

“…All patients received empirical combination therapy with 3 MIU/8 h of nebulized colistimethate sodium (CMS) (Accord®, Accord Healthcare, Barcelona, Spain). Nebulization was performed using a vibrating-mesh nebulizer (Aeroneb Pro®, Aerogen, Galway, Ireland) as it was described in a previous study [28].…”

Nebulized Colistin in Ventilator-Associated Pneumonia and Tracheobronchitis: Historical Background, Pharmacokinetics and Perspectives

“…Nineteen were retrospective studies [15,[18][19][20][21][23][24][25][26][27][29][30][31][32][33]35,36,38,39], four prospective observational studies [28,34,40,41] and two randomized control trials (RCTs) [22,37]. Twelve studies concerned the administration of nebulized CMS alone for treating VAP and VAT [15,18,19,22,[26][27][28][32][33][34]36,41]. Thirteen studies compared the administration of nebulized CMS alone to the combination of intravenous and nebulized CMS for treating VAP [20,21,[23][24][25][29][30][31]35,[37][38][39]…”

“…Between 2005 and 2016, either low-1.2 to 4 million IU/day- [15,18,20,21,23,24,28,31,32,34] or high-4 million IU/day- [19,22,25,27,29,33,35,36] CMS doses were nebulized. From 2015, very high doses-9 to 15 million IU/day-were nebulized [37][38][39][40][41]. These very high doses were based on studies performed in 2008-2010 in anesthetized and mechanically ventilated piglets whose lungs were infected by the bronchial inoculation with high concentrations of P. aeruginosa [42].…”

Cryptococcal infection in HIV-infected patients with CD4+ T-cell counts under 100/μL diagnosed in a high-income country: a multicentre cohort study

“…As a result of the impact of assessment criteria and administration route on observed nephrotoxicity rates, subsequent subgroup analyses of the nephrotoxicity rate were performed in a secondary analysis population that included only studies using internationally recognized assessment criteria (RIFLE, AKIN or KDIGO) and excluded ten studies in which less than 50% patients received systemic polymyxins [19,26,53,66,71,119,143,147,155,243]. The results of these subanalyses are presented here, whereas metaanalyses of the nephrotoxicity rate including all 237 studies regardless of AKI criteria and administration route are presented in Supplementary Figs S1 to S17.…”

“…S16). In order to determine the rate of neurotoxicity associated with systemic polymyxin treatment, studies in which less than half of patients received systemic polymyxins [19,26,53,66,71,119,155] were excluded; in this analysis, the rate of neurotoxicity was 0.032 (95% CI 0.022e0.048); Fig. 5(b) and Supplementary Fig.…”