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Correspondence |

Colistin Use in Critically Ill Patients: In Search of the Optimal Dosing FREE TO VIEW

Gennaro De Pascale, MD; Claudio Sandroni, MD; Massimo Antonelli, MD
Author and Funding Information

From the Department of Anesthesiology and Intensive Care, Catholic University of the Sacred Heart, Agostino Gemelli Hospital.

Correspondence to: Gennaro De Pascale, MD, Department of Anesthesiology and Intensive Care, Catholic University of the Sacred Heart, Agostino Gemelli Hospital, Largo A. Gemelli, 8, 00168, Rome, Italy; e-mail: gennaro.depascale@email.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. doi:10.1378/chest.10-2031
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To the Editor:

We read with interest the recent article in CHEST (December 2010) by Imberti et al,1 which described steady-state serum pharmacokinetics and BAL concentration of colistin after IV administration of colistin methanesulfonate (CMS) in adult patients with ventilator-associated pneumonia caused by gram-negative bacteria. After having administered the recommended daily CMS dose of 6 million International Units, divided into three doses, colistin levels in BAL were undetectable, whereas the ratio of the area under the plasma concentration-time curve to the minimum inhibitory concentration (AUC0-24/MIC) (MIC = 2 mcg/mL) was suboptimal (17.3 ± 9.3 without considering unbounded colistin fraction). As a comparison, a recent in vitro model2 showed that optimal bactericidal effects of colistin against Pseudomonas aeruginosa were observed when the ratio of the area under the unbound concentration-time curve to MIC was around 30.

The results of Imberti et al1 are consistent with those of Markou et al3 and Plachouras et al,4 who showed that even administering 9 million units per day of CMS—a dose 50% higher than that recommended by the manufacturer—the average maximum colistin concentration in plasma at the steady state was 2.93 and 2.3 mg/L, respectively, a level that is slightly above the Clinical and Laboratory Standards Institute MIC breakpoint (2 mg/L) for Acinetobacter baumannii and P aeruginosa, and that would most probably result in suboptimal maximal concentration/MIC ratios for many strains in the upper range of the MIC values.

All these papers raise questions about whether the currently used dosages of colistin methanesulfonate are appropriate in the critically ill patient, in whom larger distribution volume and increased plasma concentrations of α1-acid glycoprotein, an acute-phase protein with polymyxin-binding capabilities,5 may result in free colistin concentrations that are lower than those expected. Unfortunately, suboptimal antibiotic concentrations favor the development of drug-resistant bacterial strains. Because bacterial species against which colistin is used are already multidrug resistant and since no new antibiotics against gram-negative bacteria are expected to be available in the next few years, we think that further studies aimed to define the optimal CMS/colistin dosing regimen are urgently needed.

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]
 
Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin againstPseudomonas aeruginosausing anin vitromodel. Antimicrob Agents Chemother. 2010;54:3783-3789. [CrossRef] [PubMed]
 
Markou N, Markantonis SL, Dimitrakis E, et al. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study. Clin Ther. 2008;301:143-151. [CrossRef] [PubMed]
 
Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009;538:3430-3436. [CrossRef] [PubMed]
 
Dudhani RV, Li J, Nation RL. Plasma binding of colistin involves multiple proteins and is concentration dependent: potential clinical implications. In: Program and Abstracts of the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2009; San Francisco, CA. A1-576.
 

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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]
 
Bergen PJ, Bulitta JB, Forrest A, Tsuji BT, Li J, Nation RL. Pharmacokinetic/pharmacodynamic investigation of colistin againstPseudomonas aeruginosausing anin vitromodel. Antimicrob Agents Chemother. 2010;54:3783-3789. [CrossRef] [PubMed]
 
Markou N, Markantonis SL, Dimitrakis E, et al. Colistin serum concentrations after intravenous administration in critically ill patients with serious multidrug-resistant, gram-negative bacilli infections: a prospective, open-label, uncontrolled study. Clin Ther. 2008;301:143-151. [CrossRef] [PubMed]
 
Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria. Antimicrob Agents Chemother. 2009;538:3430-3436. [CrossRef] [PubMed]
 
Dudhani RV, Li J, Nation RL. Plasma binding of colistin involves multiple proteins and is concentration dependent: potential clinical implications. In: Program and Abstracts of the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12-15, 2009; San Francisco, CA. A1-576.
 
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