PhD Candidate, University of South Australia
Lung infections caused by multidrug-resistant (MDR) Gram-negative pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae are recognised as a significant global health challenge . Management of these ‘superbugs’ with effective new antibiotics is not possible, as no new antimicrobial agents will be clinically available in the near future. Due to the emergence of MDR Gram-negative bacteria and a scarcity of new effective antibiotics, polymyxins, a class of old antibiotics, have undergone clinical resurgence as a last-resort for the treatment of life-threatening lung infections1. Currently, polymyxins are clinically available as colistin and polymyxin B. Colistin is administered in the form of an inactive prodrug, colistin methanesulphonate (CMS), which is subsequently converted to colistin in vivo; in contrast, polymyxin B is administered in its pharmacologically active sulphate salt form. References to ‘polymyxins’ apply to both CMS/colistin and polymyxin B.
Traditionally, treatment of lung infections involved parenteral administration of polymyxins. However, recent pharmacokinetic/pharmacodynamic (PK/PD) and clinical studies have demonstrated that parenteral use of polymyxins is suboptimal for the treatment of lung infections due to limited drug exposure in the epithelial lining fluid (ELF) and dose-limiting nephrotoxicity . Over the last decade, pulmonary administration of polymyxins has become an alternative in treating lung infections. Inhalation therapy of colistin reduces systemic exposure, and this minimises potential systemic side effects. Despite the clinical use of nebulised polymyxins, limited PK/PD/toxicodynamic (PK/PD/TD) studies are available to guide the selection of optimum inhalational dosage regimen. The sub-optimised inhalation therapies of polymyxins have compromised its therapeutic efficacy, and resulted in undesirable side effects (i.e., cough) and accelerate the development of resistance2. Well-designed preclinical PK/PD/TD studies are urgently needed to inform rational inhalational dosage regimens that maximise antimicrobial efficacy and minimise toxicity, with the important goal of preserving this last-line therapy. The overarching aim of my PhD project was to utilise preclinical PK/PD/TD studies and in silico mechanism–based PK/PD modeling to optimise the inhalational dosage regimens of polymyxins (i.e. colistin and polymyxin B) in patients.
Abstract: Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD) and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were conducted in neutropenic infected mice and the data were analyzed by a population PK model. Dose-fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC = 1 mg/L for all three strains). Histopathological examination of lung was undertaken at 24 h post treatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. AUC/MIC was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R(2)=0.70-0.88 for ELF and R(2)=0.70-0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1326-1506 in ELF and 3.14-4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.
Pub.: 01 Jun '17, Pinned: 20 Oct '17