Colistin: An Update on the Antibiotic of the 21st Century

Silpak Biswas; Jean-Michel Brunel; Jean-Christophe Dubus; Martine Reynaud-Gaubert; Jean-Marc Rolain

Disclosures

Expert Rev Anti Infect Ther. 2012;10(8):917-934. 

In This Article

PK Properties of Colistin

As details about PK properties of colistin base and CMS are beyond the scope of this review article, the authors will give a short note on PK properties. Interested readers should refer to the recent reviews on this topic.[21,35,39]

CMS is an inactive prodrug of colistin that exhibits a low level of protein binding. CMS is a prodrug that is hydrolyzed after intravenous administration to produce active colistin (formed colistin).[20] After administration of CMS, colistin appears in plasma rapidly.[20]

Initial PK studies on colistin base and CMS relied on bioassays,[40] which are still used in some places. Chromatographic procedures using HPLC[41] or liquid chromatography–tandem mass spectrometry[42,43] have only been developed relatively recently and used by several groups in order to complete a series of major modern PK studies.

An initial PK study in rats, using a novel specific HPLC assay, was conducted in 2003 after direct intravenous administration of CMS. The derived clearance value 0.010 ± 0.008 ml/min/kg was much lower than the expected renal clearance by glomerular filtration.[44] This low renal clearance suggested extensive tubular reabsorption, which was later confirmed by the same group.[45] More recently, a dose-ranging PK study was conducted by Marchand et al. using a new liquid chromatography–tandem mass spectrometry assay.[46] They reported that the PKs of CMS and formed colistin appear linear following the intravenous administration of CMS to rats over a range of doses, generating clinically relevant plasma concentrations. Previously, Li et al. developed a sensitive HPLC method to determine colistin levels in plasma.[47] This HPLC method is very useful to measure colistin sulfate.

Recent studies demonstrate that the PK properties of colistin base and CMS are different in critically ill and CF patients. In 2008, Markou et al. published PK data of the colistin in critically ill patients using a chromatographic assay.[36] In this study, CMS dosage regimens administered to these critically ill adult patients were associated with suboptimal Cmax/MIC ratios for many strains of Gram-negative bacilli. Markou et al.[36] and Imberti et al.[48] reported plasma colistin Cmax at a steady state of 1.15–5.14 mg/l and 0.68–4.65 mg/l, respectively, in critically ill patients with moderate-to-good renal function. Li et al. reported that CF patients administered intravenous CMS had a range of peak plasma concentrations (Cmax) of formed colistin of 1.2–3.1 mg/l at steady state.[49] Another PK study in critical care patients was published in 2009 by Plachouras et al..[37] The colistin base elimination half-life was much longer than that of CMS.[50] Very recently, Garonzik et al. described the effects of CMS and formed colistin in 105 critically ill patients.[51] Among these patients, some were on hemodialysis and some were undergoing continuous renal replacement therapy. This study discusses the problem and lack of study of CMS dosing, in addidtion, this population PK analysis suggests the traditional CMS doses are often suboptimal.[51] Plachouras et al. also found that with standard dosing it will take 2–3 days before the steady-state concentration of colistin is obtained for a typical individual.[37] Aforementioned studies by Plachouras et al.[37] and Garonzik et al.[51] provide suggestions on higher dosing of CMS and formed colistin in critically ill patients based on their population PK study. The very recent study by Dalfino et al. provided some insight into the high colistin dosage prescribed for critically ill patients.[52] In total, 28 infectious cases due to A. baumannii (46.4%), K. pneumoniae (46.4%) and P. aeruginosa (7.2%) were analyzed in this study. The CMS dosing schedule was based on a loading dose of 9 MU, and a 9 MU twice-daily fractioned maintenance dose, titrated on renal function. Clinical cure was observed in 82.1% of cases. The result shows that in severe infections by colistin-only susceptible Gram-negative bacteria, the high-dose extended interval CMS regimen has a high efficacy without significant renal toxicity.

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