JAC Advance Access originally published online on April 26, 2006
Journal of Antimicrobial Chemotherapy 2006 58(1):222-223; doi:10.1093/jac/dkl169
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Correspondence |
Comment on: Pharmacokinetics of inhaled colistin in patients with cystic fibrosis
Facility for Anti-infective Drug Development and Innovation, Victorian College of Pharmacy, Monash University Melbourne, Australia
*Corresponding author. Tel: +61-3-9903-9702; Fax: +61-3-9903-9629; E-mail: Jian.Li{at}vcp.monash.edu.au
Keywords: colistin methanesulphonate , pharmacokinetics , inhalation , cystic fibrosis
Sir,
Ratjen et al.1 recently published an important paper in JAC reporting the pharmacokinetics of colistin after inhalation of colistin methanesulphonate in patients with cystic fibrosis (CF). HPLC was used to measure the concentrations of the formed colistin. The paper raises a number of important issues that deserve comment.
It is important not to use the terms colistin and colistin methanesulphonate (sodium salt, or colistimethate-Na in the paper1) interchangeably. The chemistry, pharmacokinetics, pharmacodynamics and toxicity of these two entities are substantially different;2–5 most importantly, colistin is formed from colistin methanesulphonate both in vitro6 and in vivo.7,8 Even though some manufacturers (such as Grünenthal, Germany) label the content of injection vials of colistin methanesulphonate with ‘158 mg colistin methanesulphonate is equal to 66 mg colistin’, this labelling is misleading because it is based on antibacterial activity measured with microbiological assays and does not mean that there is 66 mg of colistin in each vial. Therefore, we strongly recommend that any pharmacokinetic calculations on colistin or colistin methanesulphonate should not be based on ‘66 mg colistin’.
The HPLC assay used by Ratjen et al.1 was very similar to the one reported previously from another laboratory9 using derivatization with 9-fluorenylmethyl chloroformate on solid-phase extraction C18 cartridges; in the previously reported HPLC assay,9 colistin sulphate was employed to prepare calibration curves for measurement of colistin (base) in biological fluids. In the paper of Ratjen et al.,1 it is not clear whether colistin sulphate, colistin A or colistin methanesulphonate (sodium) was used for the calibration curves of the HPLC assay. Ratjen et al.1 reported the amount (0.18–16.13 mg) of ‘colistin methate’ recovered in urine was equal to a mean 4.3 ± 1.3% (range 0.3–24.2%) of the inhaled dose. Unfortunately, it is not clear how the concentrations of ‘colistin methate’ in urine were measured. It appears that the urinary recovery was calculated based on the recovered amount of colistin (base) and the dose of ‘66 mg colistin’. Considering the hydrolysis of colistin methanesulphonate to colistin in vivo4,7,8 and in vitro6, such calculation of urinary recovery using the dose of ‘66 mg colistin’1 is inappropriate. In addition, it is unclear whether the authors1 have allowed for the molecular weight difference between colistin methanesulphonate (sodium, average molecular weight 1743), colistin sulphate (average molecular weight 1403, if they used it for calibration curves for colistin) and colistin (average molecular weight 1163)2 when the concentrations of ‘colistin’ were calculated.
Ratjen et al.1 used the HPLC peak for polymyxin E1 to generate calibration curves for colistin concentrations. Usually, the two major components of colistin, colistin A (polymyxin E1) and colistin B (polymyxin E2), account for more than 85% of colistin,10 but the ratio of these two components may vary substantially between 3:1 and 1:1.9,10 It is not clear how the authors1 calculated the concentrations of polymyxin E1 in the HPLC assay as the commercially available colistin sulphate is a mixture of many components.9,10 In addition, we are not aware of any literature indicating that polymyxin E2 has no antibacterial activity; hence, the claim by Ratjen et al.1 that ‘colistin is a pro-drug that is converted into its active component polymyxin E1’ is questionable. Indeed, polymyxin E1 is one of the constituents of colistin.
It should be noted that the clearance of colistin reported by Ratjen et al.1 should be regarded as an apparent clearance because the amount of the inhaled dose of colistin methanesulphonate reaching the systemic circulation in the form of colistin is unknown.
In summary, Ratjen et al.1 provided some potentially useful information on the pharmacokinetics of colistin after inhalation of colistin methanesulphonate. However, because of lack of clarity regarding the quantification of colistin in biological fluids and the pharmacokinetic analysis, caution is required when these data are used as reference for inhalation therapy of colistin methanesulphonate in CF patients.
Transparency declarations
We do not have any financial, commercial or proprietary interest in any drug, device or equipment mentioned in this piece of correspondence.
Acknowledgements
We acknowledge the financial support of the Australian National Health and Medical Research Council.
References
1
Ratjen F, Rietschel E, Kasel D, et al. (2006) Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother 57:306–11.
2 Li J, Nation RL, Milne RW, et al. (2005) Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents 25:11–25.[CrossRef][Web of Science][Medline]
3
Li J, Milne RW, Nation RL, et al. (2003) Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration. Antimicrob Agents Chemother 47:1766–70.
4
Li J, Milne RW, Nation RL, et al. (2004) Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate. J Antimicrob Chemother 53:837–40.
5
Li J, Turnidge J, Milne R, et al. (2001) In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 45:781–5.
6
Li J, Milne RW, Nation RL, et al. (2003) Stability of colistin and colistin methanesulfonate in aqueous media and plasma studied by high-performance liquid chromatography. Antimicrob Agents Chemother 47:1364–70.
7
Li J, Coulthard K, Milne R, et al. (2003) Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J Antimicrob Chemother 52:987–92.
8
Li J, Rayner CR, Nation RL, et al. (2005) Pharmacokinetics of colistin methanesulfonate and colistin in a critically ill patient receiving continuous venovenous hemodiafiltration. Antimicrob Agents Chemother 49:4814–5.
9 Li J, Milne RW, Nation RL, et al. (2001) A simple method for the assay of colistin in human plasma, using pre-column derivatization with 9-fluorenylmethyl chloroformate in solid-phase extraction cartridges and reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 761:167–75.[CrossRef][Medline]
10 Decolin D, Leroy P, Nicolas A, et al. (1997) Hyphenated liquid chromatographic method for the determination of colistin residues in bovine tissues. J Chromatogr Sci 35:557–64.[Web of Science][Medline]
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  F. Ratjen, H. Beier, and H. Grasemann Pharmacokinetics of inhaled colistin in patients with cystic fibrosis: authors' response J. Antimicrob. Chemother., July 1, 2006; 58(1): 223 - 223. [Full Text] [PDF]
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