Dissertation committee:
Ρούτση Χριστίνα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ψυχογυιού Μήνα, Αναπληρώτρια Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Ζακυνθινός Σπυρίδων, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αναστασία Αντωνιάδου, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Γαρυφαλλια Πουλάκου, Επίκουρη Kαθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Μιχαήλ Σαμάρκος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Αντώνιος Παπαδόπουλος, Αναπληρωτής Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
There has been accumulating interest in nebulised colistin methanesulfonate (CMS) for the treatment of ventilator-associated pneumonia (VAP). In this study, pulmonary and systemic pharmacokinetics following nebulisation of CMS at a dose of 3 MIU and 5 MIU, using a vibrating mesh nebuliser, for VAP caused by extensively drug-resistant Gram-negative pathogens was assessed. Blood samples and mini- bronchoalveolar lavage (mini-BAL) was performed post-dose at 1, 4 and 8 h. Concentrations of CMS and formed colistin in mini-BAL and plasma were determined by liquid chromatography–tandem mass spectrometry, and pharmacokinetic analysis was conducted using a population approach. The study population included three groups (n = 10 per group): (A) intravenous CMS and concomitantly nebulised CMS at a dose of 3 MIU (30 min duration); (B) nebulised CMS at a dose of 3 MIU (30 min duration) as monotherapy; and (C) nebulised CMS 5 MIU (45 min duration) as monotherapy. Mean plasma formed colistin concentrations were < 1 mg/L following CMS nebulisation as monotherapy (groups B and C). Predicted trough concentrations of formed colistin in the epithelial lining fluid (ELF) following 24-h dosing of 3 MIU and 5 MIU nebulised CMS were 120.4 mg/L and 200.7 mg/L, respectively. The model predicted that concomitant intravenous CMS (group A) had minimal impact on the formed colistin concentration in ELF. This study demonstrated high ELF formed colistin concentrations following nebulised CMS (constantly above colistin MICs), while plasma concentrations were lower than those associated with nephrotoxicity. Our results provide important information for optimisation of nebulised colistin therapy.
