Chest
Volume 138, Issue 6, December 2010, Pages 1333-1339
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Original Research
Critical Care Medicine
Steady-State Pharmacokinetics and BAL Concentration of Colistin in Critically Ill Patients After IV Colistin Methanesulfonate Administration

https://doi.org/10.1378/chest.10-0463Get rights and content

Background

Infections caused by multidrug-resistant gram-negative bacteria have caused a resurgence of interest in colistin. To date, information about pharmacokinetics of colistin is very limited in critically ill patients, and no attempts have been made to evaluate its concentration in BAL.

Methods

In this prospective, open-label study, 13 adult patients with ventilator-associated pneumonia caused by gram-negative bacteria were treated with colistin methanesulfonate (CMS) IV, 2 million International Units (174 mg) q8h, a usually recommended dose, for at least 2 days. Blood samples were collected from each patient at time intervals after the end of infusion. BAL was performed at 2 h. Colistin was measured by a selective, sensitive high-performance liquid chromatography-based method. Pharmacokinetic parameters were determined by noncompartmental analysis.

Results

Patients received 2.19 ± 0.38 mg/kg (range, 1.58-3.16) of CMS per dose. At steady state, mean ± SD plasma colistin maximum (Cmax) and trough (Ctrough) concentrations were 2.21 ± 1.08 and 1.03 ± 0.69 μg/mL, respectively. Mean ± SD area under the plasma concentration-time curve from 0 to 8 h (AUC0-8), apparent elimination half-life, and apparent volume of distribution were 11.5 ± 6.2 μg × h/mL, 5.9 ± 2.6 h, and 1.5 ± 1.1 L/kg, respectively. Cmax/minimum inhibitory concentration (MIC) ratio and AUC0-24/MIC ratio (MIC = 2 μg/mL) were 1.1 ± 0.5 and 17.3 ± 9.3, respectively. Colistin was undetectable in BAL. Nephrotoxicity was not observed.

Conclusions

Although the pharmacodynamic parameters that better predict the efficacy of colistin are not known in humans, in critically ill adult patients the IV administration of CMS 2 million International Units (174 mg) q8h results in apparently suboptimal plasma concentrations of colistin, which is undetectable in BAL. A better understanding of the pharmacokinetic-pharmacodynamic relationship of colistin is urgently needed to determine the optimal dosing regimen.

Section snippets

Study Population

The pharmacokinetics and concentration of colistin in BAL were evaluated in 13 adult patients (aged 20-70 years; 10 men, three women) who during their ICU stay developed ventilator-associated pneumonia caused by A baumannii (11 patients) and P aeruginosa (two patients). In nine patients, Acinetobacter was multidrug resistant. Patients with creatinine clearance < 80 mL/min were excluded. The creatinine clearance was calculated according to the formula ClCr = UCr × V/PCr, where UCr is the

Pharmacokinetics of Colistin

The mean ± SD dose of CMS administered, calculated from the most accurate approximation of each patient's weight, was 2.19 ± 0.38 mg/kg per dose (range 1.58-3.16). The time course of the plasma concentration of colistin is shown in Figure 1.

A wide interindividual variability was seen in all pharmacokinetic parameters. The maximum concentration of colistin occurred 1 h after beginning CMS infusion, confirming the previously reported relatively rapid conversion of CMS to colistin.1 At steady

Pharmacokinetics of Colistin

Information about the pharmacokinetics of colistin in critically ill patients is very limited.17, 18, 19 Moreover, the dose regimens commonly used until now are based on pharmacokinetic studies in which colistin was measured by microbiological assays that were not able to discriminate between CMS (inactive) and colistin (the active form). In this study conducted in critically ill patients with ventilator-associated pneumonia, we have investigated the steady-state plasma pharmacokinetics and the

Conclusions

In critically ill adult patients, the IV administration of CMS, 2 million International Units (174 mg) q8h, results in apparently suboptimal plasma concentration of colistin, which, moreover, was undetectable in BAL. However, because despite all these limits IV CMS has been successful in the treatment of multidrug-resistant gram-negative infections, and because colistin binds to tissues, the pharmacokinetic-pharmacodynamic relationship of this antibiotic should be investigated further.

Acknowledgments

Author contributions: Dr Imberti: contributed to study design, data analysis and interpretation, writing the manuscript, and providing final approval of the version submitted for publication.

Dr Cusato: contributed to study design, performing HPLC measurements, data analysis and interpretation, writing the manuscript, and providing final approval of the version submitted for publication.

Dr Villani: contributed to performing HPLC measurements, interpreting data, and providing final approval of

References (37)

  • ME Falagas et al.

    Inhaled colistin as monotherapy for multidrug-resistant gram (-) nosocomial pneumonia: a case series

    Respir Med

    (2009)
  • IB Duncan

    Susceptibility of 1,500 isolates of Pseudomonas aeruginosa to gentamicin, carbenicillin, colistin, and polymyxin B

    Antimicrob Agents Chemother

    (1974)
  • J Koch-Weser et al.

    Adverse effects of sodium colistimethate. Manifestations and specific reaction rates during 317 courses of therapy

    Ann Intern Med

    (1970)
  • CM Elwood et al.

    Acute renal failure associated with sodium colistimethate treatment

    Arch Intern Med

    (1966)
  • DJ Price et al.

    Effects of large doses of colistin sulphomethate sodium on renal function

    BMJ

    (1970)
  • M Barnett et al.

    Sodium sulphomethyl derivatives of polymyxins

    Br Pharmacol Chemother

    (1964)
  • PJ Bergen et al.

    Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa

    Antimicrob Agents Chemother

    (2006)
  • J Li et al.

    In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis

    Antimicrob Agents Chemother

    (2001)
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