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Colistin Penetration in the Alveolar Lining Fluid of Critically Ill Patients Treated With IV Colistimethate Sodium FREE TO VIEW

Nikolaos Markou, MD; Marizoza Fousteri, MSc; Sophia L. Markantonis, PhD; Eleni Boutzouka, MD; Evdokia Tsigou, MD; George Baltopoulo, MD, PhD
Author and Funding Information

From Thriasion Hospital (Dr Markou); the School of Pharmacy, Laboratory of Biopharmaceutics and Pharmacokinetics (Ms Fousteri and Dr Markantonis), University of Athens; and ICU, “KAT” Hospital, Athens University School of Nursing (Drs Boutzouka, Tsigou, and Baltopoulo).

Correspondence to: Nikolaos Markou, MD, Thriasion Hospital, 24 Sholiou St, Ag Paraskevi 15342, Greece; e-mail: nikolaos_markou@hotmail.com


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):232-233. doi:10.1378/chest.10-1860
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To the Editor:

We read with great interest the study by Imberti et al1 in CHEST (December 2010). This is the first study on colistin penetration in the alveolar lining fluid (ALF) after IV administration of colistimethate sodium (CMS) in humans; the writers report that after 2 days of treatment, colistin was undetectable in the ALF. Interestingly, their conclusion seems to be supported by the findings of a recent study in piglets with experimental pneumonia: colistin was undetectable in lung tissue after three IV doses of CMS.2 However, we believe that colistin penetration in the ALF after systemic administration of CMS may not be negligible.

Some previous experimental data from animals and humans suggest that at least some colistin penetrates the lung after IV infusion of CMS. Aoki et al,3 using a bioassay, found that after IV administration of a single very high dose of CMS in mice, colistin penetration evaluated as a ratio of area under the curve from end of infusion to two hours in homogenized lungs and serum was 61%. Reed et al,4 using a high performance liquid chromatography (HPLC) assay of colistin in patients with cystic fibrosis, found that colistin concentrations in sputum after at least 3 days of CMS IV exceeded observed plasma concentrations.

We recently measured colistin concentrations in the serum and the ALF of two mechanically ventilated multitrauma patients treated with CMS IV (225 mg tid) for sepsis. Collection of data was approved by the hospital’s ethics committee. Patient 1 was a 40-year-old man with a blood stream infection. Patient 2 was a 50-year-old woman with ventilator-associated pneumonia. Both patients underwent fiberoptic bronchoscopy and BAL for bacterial sampling. Two aliquots of 50 mL normal saline (N/S) were infused. The alveolar sample (retrieved from the second aliquot) was strained through a single-layer gauze and then cold-centrifuged. Paired samples of BAL supernatant and serum were assayed for colistin using an HPLC assay, as described previously.5 Colistin concentrations in the ALF were calculated by determining the amount of urea in BAL and serum, to account for the dilutional effect of instilled N/S. Results are shown in Table 1. In both patients, concentrations of colistin in the ALF greatly exceeded concentrations in the serum. Because colistin has a high molecular weight and relatively poor lipid solubility, high colistin levels in the ALF can probably be attributed to avid tissue binding6 or to some as-yet-unknown mechanism of active drug transport through the alveolar-capillary membrane. The much higher drug penetration in patient 2 may be due to the presence of active bacterial infection (pneumonia) or possibly to a time lag between the serum concentration curve and the ALF concentration curve for colistin, as is the case for many other antibiotics.7

Table Graphic Jump Location
Table 1 —Colistin Penetration in Alveolar Lining Fluid After Colistimethate Sodium IV Infusion

Dose was 225 mg tid. ALF = alveolar lining fluid; CMS = colistimethate sodium.

How can we explain the discrepancy between our data and the findings of Imberti et al?1 As Imberti et al1 observe, antibiotic levels in BAL can be very low because of the dilutional effects of N/S infusion. Thus, despite the high sensitivity of the assay for colistin they used in their study, the colistin levels in BAL might have been lower than the limit of detection of their assay (50 ng/mL). An additional factor that may have contributed to low colistin levels in their study was the administration of a relatively low dose of colistin. Given the important clinical implications of the findings of Imberti et al1 and the questions that linger on the subject of colistin penetration in the ALF, we believe that further study is needed to clarify colistin pharmacokinetics in the ALF, preferably with newer and more reliable approaches (such as bronchoscopic microsampling7).

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]
 
Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intensive Care Med. 2010;367:1147-1155. [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]
 
Reed MD, Stern RC, O’Riordan MA, Blumer JL. The pharmacokinetics of colistin in patients with cystic fibrosis. J Clin Pharmacol. 2001;416:645-654. [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]
 
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]
 
Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother. 2008;521:24-36. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Colistin Penetration in Alveolar Lining Fluid After Colistimethate Sodium IV Infusion

Dose was 225 mg tid. ALF = alveolar lining fluid; CMS = colistimethate sodium.

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]
 
Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intensive Care Med. 2010;367:1147-1155. [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]
 
Reed MD, Stern RC, O’Riordan MA, Blumer JL. The pharmacokinetics of colistin in patients with cystic fibrosis. J Clin Pharmacol. 2001;416:645-654. [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]
 
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]
 
Kiem S, Schentag JJ. Interpretation of antibiotic concentration ratios measured in epithelial lining fluid. Antimicrob Agents Chemother. 2008;521:24-36. [CrossRef] [PubMed]
 
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