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Roberto Imberti, MD; Giorgio A. Iotti, MD; Maria Cusato, PharmD; Mario Regazzi, PharmD
Author and Funding Information

From the Direzione Scientifica (Dr Imberti), the Department of Anesthesiology and Critical Care Medicine (Dr Iotti), and the Laboratory of Clinical Pharmacokinetics (Drs Cusato and Regazzi), Fondazione IRCCS Policlinico San Matteo.

Correspondence to: Roberto Imberti, MD, Direzione Scientifica, Fondazione IRCCS Policlinico S. Matteo, 27100 Pavia, 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):234-235. doi:10.1378/chest.10-2301
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To the Editor:

We thank De Pascale et al for their interest in our article in CHEST (December 2010).1 Our study (and those by other authors) showed that after IV administration of colistin methanesulfonate (CMS), the plasma concentration of colistin is apparently suboptimal. The adverb “apparently” is necessary because the values of the pharmacodynamic indices that best predict the efficacy of (free) colistin have been determined in in vitro and animal studies,2,3 but are not yet known for humans. The results of in vitro pharmacodynamic studies of antibiotics, although very useful for correlating drug concentrations and pharmacologic effects, might not be directly translatable to the clinical setting. In the case of colistin, the picture is even more complex. In fact, colistin (like polymyxin B) binds to the lipopolysaccharides (LPS) released by killed bacteria also at concentrations below the minimum inhibitory concentration and which, therefore, have no effect on bacterial counts.4 This colistin-LPS binding could inhibit the toxic effects of the bacterial products, or contrariwise, could reduce the amount of available colistin and its bactericidal activity. The balance between the beneficial and harmful effects of LPS binding has not yet been defined.

De Pascale et al also emphasize another worrisome risk of suboptimal antibiotic concentrations: the risk of favoring the emergence of resistance to colistin. Resistance to colistin is not very common. This might be due, in part, to the fact that colistin-resistant bacteria present downregulation of several proteins (outer membrane proteins, chaperones, protein biosynthesis factors, metabolic enzymes), which reduce their biologic fitness and induce phenotype instability.5 Nevertheless, resistance to colistin is being increasingly described,6-8 likely because of the increasing use of CMS, and heteroresistance to colistin among clinical strains of multidrug-resistant Acinetobacter baumannii has also been reported recently.9 Combination therapy (eg, CMS plus another antibiotic, or CMS administered via two different routes) might reduce the risk of the emergence of resistance to colistin.

In the next 8 to 10 years we might only be able to combat pan-resistant gram-negative bacterial infections with the use of colistin, this “old” and neglected, but complex and interesting, antibiotic. The definition of the optimum dosing regimen, including total daily dose, dosing intervals, and combination therapy, will, therefore, be of paramount importance to maximize bacterial killing and minimize emergence of resistance.

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]
 
Dudhani RV, Turnidge JD, Coulthard K, et al. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;543:1117-1124. [CrossRef] [PubMed]
 
Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrob Agents Chemother. 2010;549:3783-3789. [CrossRef] [PubMed]
 
Aoki N, Tateda K, Kikuchi Y, et al. Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. J Antimicrob Chemother. 2009;633:534-542. [CrossRef] [PubMed]
 
Fernández-Reyes M, Rodríguez-Falcón M, Chiva C, Pachón J, Andreu D, Rivas L. The cost of resistance to colistin in Acinetobacter baumannii: a proteomic perspective. Proteomics. 2009;96:1632-1645. [CrossRef] [PubMed]
 
Johansen HK, Moskowitz SM, Ciofu O, Pressler T, Høiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. J Cyst Fibros. 2008;75:391-397. [CrossRef] [PubMed]
 
Ko KS, Suh JY, Kwon KT, et al. High rates of resistance to colistin and polymyxin B in subgroups of Acinetobacter baumannii isolates from Korea. J Antimicrob Chemother. 2007;605:1163-1167. [CrossRef] [PubMed]
 
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]
 
Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006;509:2946-2950. [CrossRef] [PubMed]
 

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References

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]
 
Dudhani RV, Turnidge JD, Coulthard K, et al. Elucidation of the pharmacokinetic/pharmacodynamic determinant of colistin activity against Pseudomonas aeruginosa in murine thigh and lung infection models. Antimicrob Agents Chemother. 2010;543:1117-1124. [CrossRef] [PubMed]
 
Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin against Pseudomonas aeruginosa using an in vitro model. Antimicrob Agents Chemother. 2010;549:3783-3789. [CrossRef] [PubMed]
 
Aoki N, Tateda K, Kikuchi Y, et al. Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. J Antimicrob Chemother. 2009;633:534-542. [CrossRef] [PubMed]
 
Fernández-Reyes M, Rodríguez-Falcón M, Chiva C, Pachón J, Andreu D, Rivas L. The cost of resistance to colistin in Acinetobacter baumannii: a proteomic perspective. Proteomics. 2009;96:1632-1645. [CrossRef] [PubMed]
 
Johansen HK, Moskowitz SM, Ciofu O, Pressler T, Høiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. J Cyst Fibros. 2008;75:391-397. [CrossRef] [PubMed]
 
Ko KS, Suh JY, Kwon KT, et al. High rates of resistance to colistin and polymyxin B in subgroups of Acinetobacter baumannii isolates from Korea. J Antimicrob Chemother. 2007;605:1163-1167. [CrossRef] [PubMed]
 
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]
 
Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother. 2006;509:2946-2950. [CrossRef] [PubMed]
 
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