Pharmacokinetics of inhaled colistin in patients with cystic fibrosis: authors' response

Abstract

Sir, We thank Li and Nation for their thoughtful comments on our study on pharmacokinetics of inhaled colistin in cystic fibrosis (CF) patients. It is well taken that colistin contains a varying mixture of ingredients including polymyxin E1, E2 and E3. We are not aware of any data that polymyxin E2 and E3 have antimicrobial activity, but their pharmacokinetic profile may differ from that of polymyxin E1. As our interest was focused on the antimicrobial activity of colistin, we have used the term colistin and colistin methanesulphonate interchangeably. We agree with Li and Nation that using the term colistin methanesulphonate may be the more appropriate terminology. However, since the other components of colistin have no established antimicrobial effect, this bears no direct practical relevance for treatment with inhaled colistin in CF patients where the antimicrobial activity is of primary relevance. The comment that polymyxin E1 and E2 contents may vary between different charges of the drug is well taken and also applies for the product used in this study. For treatment of the patients a batch with a known polymyxin composition containing 73% polymyxin E1 was used. Taking this composition into account the concentration of ‘total’ colistin was estimated. It is agreed that the precision of these calculations is limited due to the fact that during formation of colistin from colistin methanesulphonate a variety of different intermediates appear. At the time of sampling the composition thereof is not known. For the calibration curves of the HPLC assay Colistin sulphate European Pharmacopoeia standard (Colistin sulfate CRS batch2) was used. A molecular weight correction was performed to calculate the polymyxin E1 concentration. It is agreed that, for the sake of clarity, the clearance should be addressed as relative clearance. The term ‘apparent’ clearance was not used to prevent confusion with the term apparent volume of distribution.