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Roberto Imberti, MD; Giorgio A. Iotti, MD; Maria Cusato, PharmD; Mario Regazzi, PharmD
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From the Direzione Scientifica (Dr Imberti), the Department of Anesthesia and Resuscitation (Dr Iotti), and the Laboratory of Clinical Pharmacokinetics (Drs Cusato and Regazzi), Fondazione IRCCS Policlinico S. Matteo.

Correspondence to: Roberto Imberti, MD, Fondazione IRCCS Policlinico S. Matteo, Viale Golgi 19, Pavia 27100, Italy; e-mail: r.imberti@smatteo.pv.it


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;139(1):233-234. doi:10.1378/chest.10-2107
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To the Editor:

The issue raised by Markou et al is extremely important: Does colistin penetrate significantly into lung tissue? The clinical implications are evident, but at the moment, there is not a definitive answer to this question. Li et al1 cite several studies in humans showing that IV colistin methanesulfonate (CMS) (also called colistimethate) is effective in the treatment of pneumonia caused by multidrug-resistant, gram-negative bacteria1 that indicate that colistin does indeed penetrate into lung tissue. In contrast, studies in animals and humans evaluating the concentrations of colistin or CMS in lung tissue have produced conflicting results. Albeit with methodologic weaknesses in the quantification of CMS and colistin, the pioneer studies performed by Ziv et al2 and Kunin and Bugg3 showed that after IV administration colistin penetrates and accumulates in lung tissue, with the concentration of the bound form being considerably higher than that of the free form. By contrast, Lu et al4 were unable to detect colistin in lung tissue after IV administration of CMS in their experimental model of pneumonia. The reasons for these conflicting results2-4 may lie in the different methods used for protein precipitation and CMS and colistin extraction from body tissues. Indeed, it has recently been demonstrated that the type and volume of precipitating agents used are critical for CMS and colistin recovery.5 In our study,6 we showed that colistin was undetectable in BAL 2 h after the start of an IV CMS infusion (Fig 1A), but it was present at a relevant concentration in the BAL of a patient who received CMS by aerosol (Fig 1B), suggesting significant distal lung deposition. Our findings can be interpreted as indicating either low tissue penetration or colistin tissue binding. In fact, as the result of its chemical properties, colistin (which is a polycation, while CMS is a polyanion) can bind to lung tissue, thus hindering its recovery during BAL.

Figure Jump LinkFigure 1. Typical chromatograms obtained using fluorescence detection from BAL fluid. A, 2 h after IV administration of 187 mg (2 million International Units) CMS. B, 1 h after administration of CMS per aerosol. CMS = colistin methanesulfonate; Col. A = colistin A; Col. B = colistin B.Grahic Jump Location

Animal studies have shown that direct administration of colistin (intranasal or nebulized) to the lung is superior to IV administration in the treatment of experimental pneumonia.4,7 Nebulized CMS has the advantage of not causing any serious systemic adverse events, but colistin lung deposition decreases with the severity of pneumonia and aeration loss,4 a problem shared by all types of nebulized antibiotics. The association of IV and nebulized CMS could raise the lung tissue concentrations of colistin and, it is hoped, favor the cure of pneumonia. Randomized clinical trials comparing nebulized colistin with combination therapy (IV plus nebulization) should be able to determine which is the better therapeutic strategy to use.

Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006;69:589-601. [CrossRef] [PubMed]
 
Ziv G, Nouws JFM, van Ginneken CAM. The pharmacokinetics and tissue levels of polymyxin B, colistin and gentamicin in calves. J Vet Pharmacol Ther. 1982;51:45-58. [CrossRef] [PubMed]
 
Kunin CM, Bugg A. Binding of polymyxin antibiotics to tissues: the major determinant of distribution and persistence in the body. J Infect Dis. 1971;1244:394-400. [CrossRef] [PubMed]
 
Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in experimental pneumonia caused byPseudomonas aeruginosaIntensive Care Med. 2010;367:1147-1155. [CrossRef] [PubMed]
 
Jin L, Li J, Nation RL, Nicolazzo JA. Brain penetration of colistin in mice assessed by a novel high-performance liquid chromatographic technique. Antimicrob Agents Chemother. 2009;5310:4247-4251. [CrossRef] [PubMed]
 
Imberti R, Cusato M, Villani P, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically ill patients after IV colistin methanesulfonate administration. Chest. 2010;1386:1333-1339. [CrossRef] [PubMed]
 
Aoki N, Tateda K, Kikuchi Y, et al. Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistantPseudomonas aeruginosaJ Antimicrob Chemother. 2009;633:534-542. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Typical chromatograms obtained using fluorescence detection from BAL fluid. A, 2 h after IV administration of 187 mg (2 million International Units) CMS. B, 1 h after administration of CMS per aerosol. CMS = colistin methanesulfonate; Col. A = colistin A; Col. B = colistin B.Grahic Jump Location

Tables

References

Li J, Nation RL, Turnidge JD, et al. Colistin: the re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections. Lancet Infect Dis. 2006;69:589-601. [CrossRef] [PubMed]
 
Ziv G, Nouws JFM, van Ginneken CAM. The pharmacokinetics and tissue levels of polymyxin B, colistin and gentamicin in calves. J Vet Pharmacol Ther. 1982;51:45-58. [CrossRef] [PubMed]
 
Kunin CM, Bugg A. Binding of polymyxin antibiotics to tissues: the major determinant of distribution and persistence in the body. J Infect Dis. 1971;1244:394-400. [CrossRef] [PubMed]
 
Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in experimental pneumonia caused byPseudomonas aeruginosaIntensive Care Med. 2010;367:1147-1155. [CrossRef] [PubMed]
 
Jin L, Li J, Nation RL, Nicolazzo JA. Brain penetration of colistin in mice assessed by a novel high-performance liquid chromatographic technique. Antimicrob Agents Chemother. 2009;5310:4247-4251. [CrossRef] [PubMed]
 
Imberti R, Cusato M, Villani P, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically ill patients after IV colistin methanesulfonate administration. Chest. 2010;1386:1333-1339. [CrossRef] [PubMed]
 
Aoki N, Tateda K, Kikuchi Y, et al. Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistantPseudomonas aeruginosaJ Antimicrob Chemother. 2009;633:534-542. [CrossRef] [PubMed]
 
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