Nephrotoxicity Associated With Intravenous Colistin in Critically Ill Patients

Neha M. Doshi, Pharm.D.; Kari L. Mount, Pharm.D.; Claire V. Murphy, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(12):1257-1264. 

In This Article

Abstract and Introduction

Abstract

Study Objectives. To determine the frequency of nephrotoxicity associated with colistin therapy by using a standardized definition and to identify risk factors for colistin-induced nephrotoxicity in critically ill patients.
Design. Single-center, retrospective cohort analysis. Setting. University-affiliated tertiary care center.
Patients. Forty-nine adults admitted to an intensive care unit who received intravenous colistin for at least 48 hours between July 2007 and July 2009.
Measurements and Main Results. Nephrotoxicity was determined by using the standardized RIFLE criteria: risk, injury, failure, loss, and end-stage renal disease. Patients who had end-stage renal disease or required renal replacement therapy before initiation of colistin were excluded. Of the 49 patients included in the analysis, 15 (31%) developed nephrotoxicity, and only two patients (4%) had irreversible cases. Patients with chronic kidney disease (40% in the group with nephrotoxicity vs 3% in the group without nephrotoxicity, p=0.002) and hypertension (87% vs 56%, p=0.037) at baseline had a higher risk of developing nephrotoxicity. In addition, patients with nephrotoxicity were more likely to have received intravenous contrast material (33% vs 0%, p=0.002). The risk of developing nephrotoxicity was 6.5 times higher in patients who had been given at least two concomitant nephrotoxic agents compared with no other nephrotoxic agents (p=0.034).
Conclusion. The frequency and severity of colistin-induced nephrotoxicity in critically ill patients was consistent with previous reports in non–critically ill patients. Most cases of nephrotoxicity demonstrated in this study were mild and reversible. Patients receiving colistin therapy who have hypertension or chronic kidney disease should be monitored closely, and administration of additional nephrotoxic agents should be avoided in all patients when possible. Large, prospective trials are warranted to confirm these results.

Introduction

Throughout the last decade, the incidence of nosocomial infections due to multidrug-resistant gram-negative organisms has steadily increased.[1] The National Nosocomial Infections Surveillance System reported that from 1975 to 2003, the rate of cases of nosocomial pneumonia related to Acinetobacter species increased from 1.5% to 6.9%, and a similar increase was noted for Pseudomonasaeruginosa (from 9.6% to 18.1%). Multidrug-resistant gram-negative organisms including P.aeruginosa and Acinetobacter baumannii have developed resistance to almost all available antibiotics, thereby severely limiting treatment options. In addition, there is a shortage of new antibiotics being developed that specifically target multidrug-resistant gram-negative pathogens. Consequently, colistin is being revisited as a last resort for the treatment of infections caused by gram-negative organisms resistant to currently available antibiotics. To date, colistin resistance rates for P. aeruginosa and A. baumannii isolates are very low worldwide. A 2011 report from the SENTRY Antimicrobial Surveillance Program evaluation of 40,625 gram-negative bacilli found a 0.4% resistance rate to colistin for P. aeruginosa (9130 isolates) and 0.9% for Acinetobacter species (4686 isolates).[2]

Colistin is a peptide antibiotic that first became available in 1950 and continued to be widely used throughout the 1960s and 1970s.[3] Colistin is a bactericidal drug that binds to lipopolysaccharides and phospholipids in the outer cell membrane of gram-negative bacteria. It competitively displaces divalent cations from the phosphate groups of membrane lipids, disrupting the outer cell membrane and ultimately resulting in leakage of the intracellular contents and death of the bacteria.[4] Although this detergent effect on the cell wall makes colistin an extremely effective antibiotic, this effect also makes it difficult for the bacteria to create resistance mechanisms against colistin. Unfortunately, during its early stages of use, colistin was associated with high rates of adverse renal and neurologic toxicities. Therefore, the use of colistin was gradually replaced with newer antibiotics with fewer adverse effects.

The most commonly reported adverse reaction to intravenous colistin is nephrotoxicity. Although the exact mechanism for nephrotoxicity remains unclear, it is theorized to be related to an increase in membrane permeability within the convoluted tubule epithelial cells in the kidney. The resulting influx of cations, anions, and water causes edema and lysis of the renal tubule epithelial cells.[5,6]

Rates of nephrotoxicity have ranged from as high as 100% in older studies to as low as 0% in some of the more recent studies.[7–9] Theories that may explain the inconsistency in reports include differing patient populations, varying dosages, and variation in the product used. Another difficulty in determining the true incidence of nephrotoxicity associated with intravenous colistin therapy is the lack of a standardized definition. The earliest studies evaluating nephrotoxicity with colistin failed to describe the method used to determine nephrotoxicity.[9,10] Although studies in the last several decades have used specific criteria to define nephrotoxicity, a wide variety of definitions have been used, making it difficult to compare the results. Some of the definitions for nephrotoxicity used in previous studies include an increase of more than 50% from the baseline serum creatinine concentration, serum creatinine value greater than 2.0 mg/dl, glomerular filtration rate decrease by 50% or more, or the requirement for renal replacement therapy in patients with normal baseline renal function.[10,11]

More recently, three studies used the RIFLE criteria—risk, injury, failure, loss, end-stage renal disease (Figure 1)—as a measure of the degree of colistin-induced nephrotoxicity.[3,12,13] The RIFLE criteria represent the first definition for nephrotoxicity to include categorization of varying degrees of acute nephrotoxicity that are reversible in nature (risk, injury, and failure) based on both change in glomerular filtration rate and serum creatinine concentration. In addition, the RIFLE criteria include outcome measures (loss of kidney function and end-stage renal disease [ESRD]) that indicate more permanent renal damage. The RIFLE criteria have been validated and continue to be used in literature describing colistin-associated nephrotoxicity.[1]

Figure 1.

The RIFLE (risk, injury, failure, loss, and end-stage renal disease) criteria used for determining nephrotoxicity. GFR = glomerular filtration rate.

Although there are conflicting reports on the overall incidence of nephrotoxicity with intravenous colistin, limited data are available regarding nephrotoxicity in the critically ill population. Critically ill patients may be at an even higher risk for developing nephrotoxicity with intravenous colistin therapy because of the frequent use of concomitant nephrotoxic agents such as aminoglycosides, vasopressors, diuretics, and intravenous contrast media. In addition, critically ill patients commonly present with disease states associated with hypoperfusion, which may also increase the risk of acute renal failure.

Because of the limited evidence regarding colistin-associated nephrotoxicity in critically ill patients, in this retrospective analysis we sought to evaluate the rate of nephrotoxicity by using a standardized definition and to identify risk factors for colistin-induced nephrotoxicity in critically ill patients.

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