MAJOR ARTICLE
Incidence of and Risk Factors for ColistinAssociated Nephrotoxicity in a Large Academic Health System Jason M. Pogue,1,2 Jiha Lee,2 Dror Marchaim,2,3 Victoria Yee,2 Jing J. Zhao,4 Teena Chopra,2,3 Paul Lephart,5 and Keith S. Kaye2,3 1Department of Pharmacy Services, Sinai-Grace Hospital, Detroit Medical Center; 2Wayne State University School of Medicine, Detroit; 3Division of Internal Medicine, Department of Infectious Diseases, 4Department of Pharmacy Services, Harper University Hospital, and 5Detroit Medical Center University Laboratories, Detroit Medical Center, Michigan
Background. Colistin, originally abandoned due to high rates of nephrotoxicity, has been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature, largely obtained from outside the United States, suggests a lower rate of nephrotoxicity than historically reported. Methods. A retrospective cohort of all patients who received colistin for $48 hours at the Detroit Medical Center over a 5-year period was performed to determine the rate of colistin-associated nephrotoxicity as defined by the RIFLE criteria. Results. Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P , .001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of $5.0 mg/kg per day of ideal body weight (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.3–103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42–10.2), and coadministration of $3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42–32.49). Conclusions. In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients in a dose-dependent manner. Higher colistin doses, similar to those commonly used in the United States, led to a relatively high rate of nephrotoxicity. These data raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens.
Colistin, a polymyxin antimicrobial agent, was originally used in the 1960s, but due to nephrotoxicity rates approaching 50%, it was abandoned as other ‘‘less toxic’’ antimicrobials became available [1]. Colistin has recently reemerged as a last line therapeutic agent for the treatment of multidrug-resistant pathogens including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenem-resistant Enterobacteriaceae.
Received 18 April 2011; accepted 25 July 2011. Correspondence: Jason M. Pogue, PharmD, Department of Pharmacy, SinaiGrace Hospital, Detroit Medical Center, Wayne State University, 6071 W Outer Drive, Detroit, MI 48235 (
[email protected]). Clinical Infectious Diseases 2011;53(9):879–884 Ó The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected]. 1058-4838/2011/539-0004$14.00 DOI: 10.1093/cid/cir611
Since its recent reemergence, data suggest that colistin is associated with a much lower rate of renal toxicity compared with historical reports. The majority of recent studies report toxicity rates of 10%–30% [2–6]. An important consideration regarding these recent data that describe lower rates of renal toxicity is that they were obtained mostly from studies outside the United States where relatively low doses of colistin are used (compared with dosing in the United States). In these reports, common colistin doses ranged from 1 to 9 million international units (IU) daily, with the majority in the 3–6 million IU range. When converted to milligrams of colistin base activity (CBA), the dosing unit used in the United States, the range used in these trials was 30–270 mg of CBA per day. Standard dosing in the United States for colistin is 5 mg/kg CBA per day, which in a 70-kg patient would come to 350 mg of
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CBA per day—and in an obese patient, daily doses might be much higher, depending on which dosing weight is used. Although the package insert recommends ideal body weight (IBW), some practicing clinicians will use actual body weight or an adjusted body weight in an attempt to achieve higher serum concentrations. Therefore, with the toxicity due to colistin presumed to be a dose-dependent phenomenon [7], these newer reports regarding colistin nephrotoxicity from non-US locations might not accurately reflect the toxicity in the United States. In fact, a recent report of otherwise healthy (APACHE II score 8.3 6 6.5), young (median age 27 6 12 years) American veterans being treated for A. baumannii infections reported a nephrotoxicity rate of 45% with colistin [8]. Within the Detroit Medical Center (DMC), the use of colistin has increased over the past 5 years. The objectives of this study were to determine the incidence of and risk factors for colistinassociated nephrotoxicity in a large US healthcare system. METHODS Study Design, Setting, and Patient Population
A retrospective cohort study was conducted among adult (.18 years old) patients who received intravenous colistin at the DMC from 1 January 2005 to 31 December 2009. DMC is a university-affiliated tertiary 8-hopital healthcare system, with more than 2200 inpatient beds in the Detroit metropolitan area. Patients were identified through a review of pharmacy databases. Patients were excluded if they were #18 years of age, received #48 hours of colistin, received concomitant inhaled colistin, or had a need for hemodialysis or other form of renal replacement therapy before receipt of colistin. If a patient received multiple courses of colistin, only the first one was included in the analysis. Colistimethate for injection was used and dosed in milligrams of CBA throughout the study period. For this analysis, colistin daily doses were calculated by analyzing the amount of CBA given in a 24-hour period. For assessment of the relationship between dose and toxicity, the daily dose that the patient was on when they met the criteria for nephrotoxicity was used for analysis. No patients in the study had dose adjustments made prior to the occurrence of toxicity. Before 2009, no formal dosing recommendations were available at the DMC, and dosing practices varied greatly, with some clinicians utilizing package insert–recommended dosing, and some using alternative dosing regimens. In 2009, colistin-dosing guidelines were developed by the DMC Antimicrobial Stewardship Committee, approved by the DMC Pharmacy and Therapeutics Committee, and adopted by all DMC site pharmacists. The institutional review boards of DMC and Wayne State University approved this study prior to its initiation. 880
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Study Variables and Definitions
Nephrotoxicity was defined according to the RIFLE criteria (Table 1). Variables captured from the patient chart included demographics, comorbid conditions (including Charlson score and renal insufficiency before receipt of colistin, which was defined as having a history of chronic kidney disease or being in acute renal failure (meeting RIFLE criteria from baseline creatinine at the time of commencement of colistin therapy), concomitant use of other known nephrotoxins (including aminoglycosides, loop diuretics, intravenous dye, vasopressors, amphotericin B), and concomitant antimicrobial exposure. Colistin dose was recorded as milligram per kilogram of both actual and IBW. Statistical Analysis
Statistical analyses were performed by using SAS software, version 9.2. Bivariate analyses were performed by using the Fisher exact test for categorical variables and the independent sample t test or the Wilcoxon rank-sum test for continuous variables. Multivariate analysis of risk factors for colistin nephrotoxicity was constructed by using logistic regression. All variables with a P value of ,.1 in the bivariate analyses were considered for inclusion in the multivariate analysis. Additional variables that demonstrated a trend toward association with toxicity were forced into the model at the discretion of the investigators. A stepwise selection procedure was used to select variables for inclusion in the final model. The final selected model was tested for confounding. If a covariate affected the ß-coefficient of a variable in the model by .10%, then the confounding variable was maintained in the multivariable model. All P values were 2-sided. RESULTS The study cohort consisted of 126 unique patients. Characteristics of patients in the cohort are listed in Table 2. Nephrotoxicity, as defined per RIFLE criteria [9], occurred in 54 (43%) patients. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. No patients had long-term kidney failure or required hemodialysis after their course of colistin therapy. Thirty-day all-cause mortality rates were similar Table 1. RIFLEa Criteria for Nephrotoxicity Risk
Increased creatinine level 3 1.5 or GFR decrease .25%
Injury
Increased creatinine level 3 2 or GFR decrease .50%
Failure
Increased creatinine level 3 3 or GFR decrease .75%
Loss
Persistent acute renal failure or loss of function .4 weeks
ESRD
ESRD .3 months
Abbreviations: ESRD, end-stage renal disease; GFR, glomular filtration rate. a
Modified from reference 9.
among patients who developed nephrotoxicity and those who did not (37% vs 30%, respectively; P 5 .38). In bivariate analysis, patients with diabetes mellitus (P 5 .03) and those receiving multiple concomitant nephrotoxins (P 5 .04) were at increased risk for the development of nephrotoxicity while on colistin therapy (Table 2). Patients who developed nephrotoxicity received significantly higher doses of colistin (measured as milligram per kilogram of IBW) compared with patients who did not develop nephrotoxicity (mean of 5.3 mg/kg per day vs 3.95 mg/kg per day; P , .001, and median of 5.48 vs 3.85 mg/kg per day; P 5 .02). When colistin dose was divided into 7 levels and into 3 tertiles (Table 3), there was a significant trend between increasing levels of colistin dosage and increased frequency of development of nephrotoxicity in both analyses (P , .001 for both analyses). To ensure that the dose-dependent toxicity was not simply a function of patients with worse baseline renal function
receiving smaller doses, we analyzed the dosing averages for patients with or without toxicity in different categories of creatinine clearance (CLcr). Patients were categorized as having CLcr .50, between 30 and 49, or ,30. In each of these groups, patients with toxicity had received a higher colistin dose than those without toxicity. Toxicity was seen in 37 of 84 (44%) patients with a clearance .50, with an average dose of 5.4 mg/kg in those who developed toxicity, compared with 4.3 mg/kg in those who did not. Among patients with a clearance of 30–49, the toxicity rate was 14 of 25 (56%) with a similar difference in average dose among those who did not experience toxicity (5.9 vs 4.4 mg/kg, respectively). In the clearance ,30 group the toxicity rate was lower at 3 of 17 (18%), but again the dose difference between those with and without toxicity was striking with an average of 3.9 and 2.0 mg/kg in each group, respectively. Furthermore, within each strata of CLcr, there was a significant association between increasing colistin dose and increased risk
Table 2. Bivariate Analysis of Risk Factors for Colistin-Associated Nephrotoxicity Entire cohort (n 5 126)
Toxicity group (n 5 54)
Nontoxicity group (n 5 72)
P value
OR (95% CI)
Demographics Agea
59.7 6 16.3
59.3 6 17.0
60.1 6 15.4
.77
Male
73 (58)
30 (56)
43 (60)
.72
0.91 (.60–1.37)
African American
77 (61)
30 (56)
47 (65)
.28
0.78 (.51–1.21)
3 (2–5) 15 (8–26)
3 (1–4) 15 (6.5–27.0)
48 (38)
27 (50)
21 (29)
.03
2.43 (1.16–5.02)
9 (7)
5 (9)
4 (6)
.50
1.73 (.44–6.79)
Comorbid conditions and healthcare exposures Charlsonb score Length of stay prior to receipt of colistin (days)b Diabetes mellitus Peripheral vascular disease
4 (2–5) 14.5 (10.0–25.0)
.07 .67
ICU status
94 (75)
44 (81)
50 (69)
.12
1.94 (.83–4.53)
Mechanical ventilation
78 (62)
31 (57)
47 (65)
.46
0.72 (.35–1.48)
25 (20)
7 (13)
18 (25)
Degree of sepsis No sepsis
.47
Sepsis
34 (27)
18 (33)
16 (22)
Severe sepsis Septic shock
49 (39) 18 (14)
21 (39) 8 (15)
28 (39) 10 (14)
32 (25)
11 (20)
21 (29)
.26
Vasopressors
19 (15)
11 (20)
8 (11)
.21
2.0 (.76–5.5)
Aminoglycosides
42 (33)
20 (37)
22 (31)
.45
1.33 (.62–2.82)
Loop diuretic
70 (56)
38 (70)
32 (44)
.004
3.0 (1.4–6.3)
Rifampin
75 (60)
37 (69)
38 (53)
.10
1.95 (.93–4.02)
28 (22)
6 (11)
22 (31)
1
39 (31)
16 (30)
23 (31)
2
42 (33)
21 (39)
21 (29)
$3
17 (13)
11 (20)
6 (9)
Renal insufficiency prior to colistin
0.62 (.27–1.43)
Medications
Total concomitant nephrotoxins 0
.04
Data are presented as number (%) unless otherwise noted. Abbreviations: CI, confidence interval; ICU, intensive care unit; OR, odds ratio. a
Mean 6 SD.
b
Median (interquartile range).
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Table 3. Colistin Nephrotoxicity as a Function of Dose Dose (mg/kg IBW)
Table 4. Multivariate Analysis for Independent Risk Factors for Colistin-Associated Nephrotoxicity
Nontoxicity, no. (row %)
Toxicity, no. (row %)
8 (89)
1 (11)
2.1–2.9
17 (85)
3 (15)
3.0–3.9 4.0–4.9
14 (58) 17 (77)
10 (42) 5 (23)
5.0–5.9
6 (30)
14 (70)
Receipt of $3 concomitant nephrotoxinsa
6.80 (1.42–32.49)
6.0–6.9
4 (25)
12 (75)
ICU status
1.67 (0.58–4.80)
7.0–7.9
4 (40)
6 (60)
2 (40)
3 (60)
Dose 3.0–4.9 mg/kg per day of IBWb
3.31 (0.84–12.97)
$8.0
#2.0a
Diabetes mellitus
2.00 (0.89–4.46)
Rifampin coadministration
3.81 (1.42–10.20)
Receipt of 1 concomitant nephrotoxina
1.71 (0.45–6.54)
Receipt of 2 concomitant nephrotoxinsa
1.69 (0.45–6.34)
,3.0a
25 (86)
4 (14)
3.0–4.9
31 (67)
15 (33)
Dose $5.0 mg/kg per day of IBWb
$5.0
16 (31)
35 (69)
Abbreviations: IBW, ideal body weight; ICU, intensive care unit. a
In comparison to patients not receiving concomitant nephrotoxins.
b
In comparison to reference dose of ,3.0 mg/kg per day.
Abbreviation: IBW, ideal body weight. a
P , .001 for trend.
for renal insufficiency (P , .001 for CLcr .50 and CLcr 30–49; P 5 .01 for CLcr ,30, complete data not shown). In multivariate analysis, independent predictors of nephrotoxicity included a colistin dose of $5.0 mg/kg per day of IBW (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.30– 103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42–10.20), and coadministration of $3 concomitant nephrotoxins (OR, 6.80 [95% CI, 1.42–32.49]) (Table 4). Out of the 54 patients who developed nephrotoxicity, 42 (78%) developed renal insufficiency within the first week of therapy, whereas the other 12 (22%) developed renal insufficiency in the second week of therapy. For 16 (30%) patients, toxicity was reversible, with 10 reverting to normal renal function within the first week and 6 recovering in the second week after discontinuation of colistin. Nineteen (35%) of these patients died before recovery of renal function, and 19 (35%) were lost to long-term follow-up making analysis of reversibility of nephrotoxicity impossible, although they had not recovered their renal function upon discharge. CONCLUSIONS This study presents results from a cohort of US patients experiencing colistin-associated nephrotoxicity during a 5-year period. The most important finding, in light of recent data suggesting relatively low rates of nephrotoxicity, was that 43% of our patients developed some degree of renal insufficiency. Development of renal insufficiency occurred in a dose-dependent manner. These rates of nephrotoxicity were similar to those reported in a recent study by Hartzell et al [8], in which a dosing strategy similar to the one in this study was used. The dose-dependent nephrotoxicity reported in this study helps explain why recent studies have reported relatively low rates of nephrotoxicity compared with older literature. These 882
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23.41 (5.30–103.55)
lower rates probably resulted from use of a relatively low colistin dose. One alarming finding of this study was that nephrotoxicity began to develop at doses of colistin that are lower than doses currently recommended in the United States. Toxicity exceeded 30% among patients receiving colistin doses between 3.0 and 4.9 mg/kg per day (based on IBW) and reached 69% when doses $5.0 mg/kg per day were administered. These are particularly alarming data for institutions that base dosing regimens on adjusted or actual body weight, because patients who are dosed in this manner will commonly receive doses .5.0 mg/kg per day of IBW. Because it was a common practice at our institution during the study period to dose colistin based on actual body weight, we analyzed the interrelation between dose and toxicity as a function of actual body weight and found that patients receiving $4.0 mg/kg per day of their actual body weight had a rate of nephrotoxicity of 55% (complete data not shown). These data reporting high rates of colistin toxicity are particularly alarming when coupled with recent reports suggesting that potentially subtherapeutic levels were achieved when relatively low doses of colistin (ie, based on standard European dosing recommendations) are administered [10, 11]. Thus, attainable levels of colistin might be insufficient to effectively treat some pathogens categorized as ‘‘susceptible’’ to colistin by current breakpoints (susceptible at a minimum inhibitory concentration [MIC] #2 mcg/mL), without causing significant nephrotoxicity. The current study raises the questions of whether optimal dosing of colistin can be safely achieved and whether susceptibility breakpoints need to be reexamined. This concern is strengthened by the recently published preliminary results of a National Institutes of Health–funded pharmacokinetic/pharmacodynamic (PK/PD) study attempting to determine the optimal dosing of colistin for efficacy [12]. In this study, Garonzik et al [12] proposed the following maintenance dose equation for optimizing colistin for efficacy
purposes: Daily dose of colistin (in CBA) 5 Colistin steady-state average 3 (1.50 3 CLcr 1 30). Using this equation, if the MIC of a pathogen was 1 mcg/mL, then an average steady-state colistin concentration of 2.5 mcg/mL would be necessary to achieve an area under the curve/MIC of 60 (as recommended by the authors). Based on this equation, if a patient has a CLcr of 70 mL/min, then a total daily dose of 338 mg of CBA would be needed to achieve the desired PK/PD target. Therefore, if the patient’s IBW is .68 kg, a daily dose of .5 mg/kg per day would be necessary, which according to our analysis would significantly increase risk for nephrotoxicity. It is important to note that the susceptibility breakpoint for Gram-negative bacilli to colistin is currently 2 mcg/mL, and a daily dose exceeding 670 mg of CBA would be required to effectively treat the above patient with a ‘‘susceptible’’ pathogen with an MIC to colistin of 2 mcg/mL. These data suggest that an MIC breakpoint for colistin of 0.5 mcg/mL, or at the most 1 mcg/mL, might be more appropriate than 2 mcg/mL in terms of safety. Previous reports have associated total cumulative colistin exposure with toxicity [8, 13]. However, in the current study, the vast majority of toxicity occurred within the first week of therapy, and thus no clear association between cumulative colistin dose and nephrotoxicity was seen. This rapid onset is similar to another recent report from Deryke et al [14] showing that all patients who developed nephrotoxicity did so within the first 5 days of colistin therapy. Another interesting and important finding of this study was that rifampin coadministration increased the risk for nephrotoxicity .3-fold. Rifampin as a risk factor for colistin-associated toxicity had not been described previously. Although rifampin is not often considered to be a nephrotoxic agent, there are reports of tubular damage, glomerulonephritis, and interstitial nephritis seen with the agent [15–17]. These data are particularly important for institutions that routinely recommend rifampin in combination with colistin therapy for treatment of multidrug resistant Gram-negative pathogens. Interestingly, aminoglycosides were not associated with increased risk for nephrotoxicity in this analysis. This study has several limitations. First, the issue of confounding by indication cannot be fully adjusted for in multivariate analysis. Patients who received higher doses of colistin might have been determined by the treating physician to be at increased risk for poor outcome (and thus also at increased risk for nephrotoxicity) and treated more aggressively. Second, we were unable to identify a suitable reference or control group for comparison to our colistin cohort. At the DMC, patients receiving therapy other than colistin (ie, tigecycline) for carbapenem-resistant organisms were not comparable. Patients receiving colistin had a higher severity of illness, longer duration of hospitalization prior to infection, notable delays in time to receipt of effective therapy, and more invasive infections
compared with patients treated with tigecycline [18]. In addition, our analysis of concomitant nephrotoxins might be considered by some clinicians to be incomplete. For example, we did not analyze nonsteroidal anti-inflammatory drugs, angiotensinconverting enzyme inhibitors, or vancomycin as concomitant nephrotoxins. Although some recent literature suggests an association between vancomycin and renal failure [19–21], these data are controversial and at the time of the analysis experts disagree to the extent that vancomycin is nephrotoxic. A final potential limitation is that we did not calculate scores that measure the acute severity of illness, such as APACHE. Whereas the patients with and without toxicity were similar in terms of intensive care unit status, degree of sepsis, Charlson comorbidity index, preexisting renal function, and use of vasopressors, it is possible that patients who developed acute renal insufficiency might have had a higher acute severity of illness. This study provides important data regarding the incidence and dose-dependent nature of nephrotoxicity among patients receiving colistin. It also identifies important modifiers of nephrotoxicity risk among patients receiving colistin, such as coadministration of rifampin or other potential nephrotoxins. Unfortunately, this study also raises new and challenging questions, such as the optimal dosing regimen for colistin and whether risk for nephrotoxicity might be decreased by avoidance of certain concomitant drugs such as rifampin. These findings should be taken into account with other toxicity, PK/PD, and synergy data in an attempt to optimize the safety and efficacy of colistin therapy. Note Potential conflicts of interest. J. M. P. has served on the speaker’s bureau and as a consultant, J. J. Z. has served as a consultant, and K. S. K. has served on the speaker’s bureau, as a consultant, on advisory boards, and has received research grants from Pfizer, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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