Colistin-associated acute renal failure: revisited.

To the Editor: Daram et al (1) recently presented a case report outlining the occurrence of acute renal failure, purported to be caused by "colistin," in a 57-year-old male. In their letter to the editor, (1) the authors cited four papers from the literature spanning the period 1962 to 1971, related to the potential for colistin to cause nephrotoxicity. While we agree with Daram et al in their conclusion that physicians should be aware of the potential toxicities of colistin if it is to be used intravenously, (1) we would like to clarify a few important issues raised in their letter to the editor and also refer to more recent literature on its potential to cause nephrotoxicity and on its clinical pharmacology.

Daram et al (1) acknowledged that the total daily dose of sodium colistin methanesulfonate (CMS) administered to their patient (12 mg/kg/d in 4 divided doses) was more than double the currently recommended daily dose for a renally healthy person. In addition, the patient had transient systemic hypotension, and it was considered that this too may have had a role in the pathogenesis of the acute renal failure. (1) Moreover, gentamicin and imipenem (dosage information not provided), both of which are potential nephrotoxins, were administered before commencement of CMS for approximately 10 and 17 days respectively. The nephrotoxicity observed in the patient described in their report, (1) therefore, needs to be interpreted within the context of the higher-than-normal dose of CMS administered and the recent exposure of the patient to other potentially nephrotoxic drugs (gentamicin, imipenem) and other events (systemic hypotension).

Because of the increase in the number of infections caused by multidrug-resistant Gram negative bacteria and the resultant need to use parenteral CMS as salvage therapy, there has been a resurgence of interest in this "old" antibiotic. Conway et al (2) closely examined the early reports of CMS toxicity, which were cited by Daram et al as papers one to four in their letter to the editor. (1) Conway et al concluded that those early reports revealed an exaggerated risk of toxicity which can be attributed to the fact that in those early studies there was an inappropriate selection of patients to receive CMS, use of higher than currently recommended doses and inadequate monitoring. (2) Recent experience is that IV CMS, administered as a 10 to 30 minute infusion at a dose of 5 to 6 mg/kg/d in 2 or 3 divided doses, does not appear to be nephrotoxic in patients with normal renal function. (2-5) Indeed, recently IV CMS has been reported to be less nephrotoxic than IV aminoglycosides, using creatinine clearance as an index of renal function. (4)

We would urge clinicians and researchers not to use the term colistin and CMS interchangeably. As discussed in our recent review, (6) it is important to draw the distinction between colistin (available commercially as its sulfate salt) and CMS (which is the form administered parenterally, as its sodium salt). Following administration, CMS is converted to colistin in vivo, and we have shown that both of them circulate in the body. (3,7) Their unique chemistries manifest into considerably different antibacterial activity (colistin is more active than CMS), (8) pharmacokinetic (3,7,9) and toxicity (colistin is more toxic than CMS) profiles. (6,10) The enabling technologies to measure CMS and colistin separately in biologic fluids have only recently become available, (11,12) and we have demonstrated that CMS is mainly renally eliminated, whereas colistin is extensively eliminated by nonrenal mechanisms. (7,9) We have recently demonstrated (unpublished finding) that both CMS and colistin are cleared by hemodialysis, and we are not aware of any literature supporting the claim by Daram et al (1) that "hemodialysis has no role in removal of circulating colistin" or CMS.

In summary, Daram et al (1) provide useful information on the potential nephrotoxicity associated with CMS, especially when it is administered in higher than normal IV doses and in patients who have been exposed to other nephrotoxic insults (eg, other drugs, systemic hypotension). Further information on the toxicodynamics of CMS (and colistin) is urgently required for its use in the treatment of infections caused by multidrug-resistant Gram negative bacteria.

Acknowledgments

We gratefully acknowledge financial support from the Australian National Health and Medical Research Council.

Jian Li, PhD

Craig R. Rayner, PharmD

Roger L. Nation, PhD

Facility for Anti-infective Drug

Development and Innovation

Victorian College of Pharmacy 

Monash University

Melbourne, Australia

References

1. Daram SR, Gogia S, Bastani B. Colistin-associated acute renal failure: revisited. South Med J 2005;98:257-258.

2. Conway SP, Etherington C, Munday J, et al. Safety and tolerability of bolus intravenous colistin in acute respiratory exacerbations in adults with cystic fibrosis. Ann Pharmacother 2000;34:1238-1242.

3. Li J, Coulthard K, Milne R, et al. Steady-state pharmacokinetics of intravenous colistin methanesulphonate in patients with cystic fibrosis. J. Antimicrob, Chemother 2003;52:987-992.

4. Al-Aloul M, Miller H, Alapati S, et al. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 2005;39:15-20.

5. Falagas ME, Rizos M, Bliziotis IA, et al. Toxicity after prolonged (more than four weeks) administration of intravenous colistin. BMC Infect Dis 2005;5:1.

6. Li J, Nation RL, Milne RW, et al. Evaluation of colistin as an agent against multi-resistant Gram-negative bacteria. Int J Antimicrob Agents 2005;25:11-25.

7. Li J, Milne RW, Nation RL, et al. Pharmacokinetics of colistin methanesulphonate and colistin in rats following an intravenous dose of colistin methanesulphonate. J Antimicrob Chemother 2004;53:837-840.

8. Li J, Turnidge J, Milne R, et al. In vitro pharmacodynamic properties of colistin and colistin methanesulfonate against Pseudomonas aeruginosa isolates from patients with cystic fibrosis. Antimicrob Agents Chemother 2001;45:781-785.

9. Li J, Milne RW, Nation RL, et al. Use of high-performance liquid chromatography to study the pharmacokinetics of colistin sulfate in rats following intravenous administration. Antimicrob Agents Chemother 2003;47:1766-1770.

10. Barnett M, Bushby SR, Wilkinson S. Sodium sulphomethyl derivatives of polymyxins. Br J Pharmacol 1964;23:552-574.

11. Li J, Milne RW, Nation RL, et al. A simple method for the assay of colistin in human plasma, using pre-column derivatization with 9-fluorenylmethyl chloroformate in solid-phase extraction cartridges and reversed-phase high-performance liquid chromatography. J Chromatogr B Biomed Sci Appl 2001;761:167-175.

12. Li J, Milne RW, Nation RL, et al. Simple method for assaying colistin methanesulfonate in plasma and urine using high-performance liquid chromatography. Antimicrob Agents Chemother 2002;46:3304-3307.