Colistin-associated acute renal failure: revisited.

To the Editor: Sodium colistimethate (colistin) is a parenterally administered polymyxin antibiotic that acts by disrupting bacterial cell membranes. It has been primarily used in the treatment of life-threatening infections caused by multidrug-resistant Gram-negative bacteria, particularly Pseudomonas aeruginosa. The drug has a very narrow therapeutic ratio, with neurotoxicity and nephrotoxicity being the limiting factors. Nephrotoxicity has been reported in 20% of 317 courses of colistin therapy. (1) An additional 14 cases of colistin-associated acute renal failure have also been reported before 1974. The risk of nephrotoxicity increases in the setting of preexisting renal dysfunction (2,3) and with increasing doses. (4) Serum levels and toxicity appear to be a function of the glomerular filtration rate. (3)

We report the case of a 57-year-old man who was admitted to our hospital after sustaining a C5 vertebral fracture. The patient was previously healthy, with no significant medical history. After a posterior spinal fusion, the patient continued to remain ventilator-dependent. His hospital course was complicated by recurrent pneumonia with P aeruginosa and Enterobacter. The patient also developed Clostridium difficile colitis and peritonitis. He received multiple antibiotics including imipenem, vancomycin, gentamicin, ciprofloxacin, metronidazole, cefepime, trimethoprim-sulfamethoxazole, and colistin. None of the other medications administered to the patient are known to be nephrotoxic.

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The patient tolerated imipenem and gentamicin without any evidence of renal dysfunction. All other antibiotics were discontinued, and the patient was started on colistin at 250 mg IV every 6 hours (12 mg/kg per day; patient weight, 83 kg) because of the emergence of Pseudomonas resistant to multiple antibiotics clinically and microbiologically. Around the same time, the patient had development of hypotension, necessitating institution of dopamine therapy for approximately 48 hours (hospital days 48 and 49). The patient had acute anuric renal failure on the fourth day of colistin therapy (hospital day 50, see Figure), at which point colistin was discontinued. Physical examination was remarkable for the presence of fever and signs of fluid overload. Significant laboratory values included hemoglobin of 8.6 g/dL, white cell count of 13,000/[mm.sup.3], blood urea nitrogen of 33 mg/dL, and serum creatinine of 1.6 mg/dL. Urinalysis revealed many red cells and a few white cells, with no evidence of casts. For the management of fluid overload, the patient required 14 sessions of hemodialysis over a period of 24 days before being discharged after a 1-week period off hemodialysis.

Although colistin is a known nephrotoxic agent, the patient also had transient systemic hypotension requiring vasopressors for less than 48 hours; both these factors probably had a role in the pathogenesis of renal failure in this patient. Also, the 12 mg/kg per day dose administered to this patient is higher than the recommended daily dosage (2 to 5 mg/kg per day).

Colistin is a polypeptide antibiotic with an approximate molecular weight of 1,750. The drug and its metabolites are excreted primarily by the kidneys. The serum half-life is approximately 1.5 hours after intravenous administration. The exact magnitude of colistin protein binding is not known, but it binds tightly to cell membranes and accumulates in tissue when given as a continuous infusion. (5) Therefore, it is not surprising that hemodialysis has no role in removal of circulating colistin. Colistin is a valuable antibiotic that should be reserved for the treatment of patients with life-threatening infections caused by pan resistant organisms. Renal parameters including blood urea nitrogen, serum creatinine, urinalysis, and urine output should be serially monitored, and therapy should be discontinued at the first sign of renal dysfunction. Dosage should be based on an estimate of the actual glomerular filtration rate rather than body weight. The increasing prevalence of multiresistant Gram-negative strains in intensive care units might probably rekindle interest in colistin use, and physicians should be aware of its potential toxicities.

References

1. Koch-Weser J, Sidel VW, Federman EB, et al. Adverse effects of sodium colistimethate: manifestations and specific reaction rates during 317 courses of therapy. Ann Intern Med 1970;72:857-868.

2. Adler S, Segel DP. Nonoliguric renal failure secondary to sodium colistimethate: a report of four cases. Am J Med Sci 1971;262:109-114.

3. Elwood CM, Lucas GD, Muehrcke RC. Acute renal failure associated with sodium colistimethate treatment. Arch Intern Med 1966; 118:326-334.

4. Woolinsky E, Hines JD. Neurotoxic and nephrotoxic effects of colistin in patients with renal disease. N Engl J Med 1962;266:759-762.

5. Craig WA, Kunin CM. Significance of serum protein and tissue binding of antimicrobial agents. Annu Rev Med 1976;27:287-300.

Sumanth R. Daram, MD

Sudhanshu Gogia, MD

Bahar Bastani, MD

Division of Nephrology

Department of Internal Medicine

St. Louis University School of Medicine

St. Louis, MO

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