This study compared the incidence of acute kidney injury in patients treated with polymyxin B or colistin at a large academic medical center using the RIFLE criteria. The results showed that the incidence of acute renal failure was significantly higher with colistin (60.4% vs 41.8%, p=0.02). Multivariate analysis identified colistin use and older age as independent risk factors for increased nephrotoxicity. The study supports closer monitoring of patients receiving these drugs and indicates a need for further research to understand differences in nephrotoxicity between polymyxin B and colistin.

1. Darowan Akajagbor, Pharm.D., BCPS1, Kalpana Shere-Wolfe, M.D. 2,Sharon Wilson, Pharm.D., BCPS,1 Paul Dakum, B.S3, Manhattan Charurat, PhD3, Bruce Gilliam, M.D3, 4
1. Department of Pharmacy, University of Maryland Medical Center, Baltimore, MD, 2. University of Maryland School of Medicine, Baltimore, MD, 3. Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, 4. Division of Infectious Diseases,
University of Maryland School of Medicine, Baltimore, MD
Corresponding Author: Darowan Akajagbor
akajagbd@dyc.edu
No financial disclosures apply to authors
BACKGROUND
 Polymyxin antibiotics polymyxin B and colistin (colistimethate sodium)) were
originally used in the 1960’s but abandoned due to several reports of toxicities
and the availability of safer and effective alternatives
 Over the past decade, there has been a surge in the use of these agents due to
the increasing frequency of infections caused by multidrug resistant (MDR)
pathogens
 The rates of nephrotoxicity with colistin and polymyxin B reported in the literature
vary significantly due to lack of standardized definitions of Acute Renal Failure
(ARF)
 Differences in nephrotoxicity between these agents is evident but there is a
paucity of data that compares their toxicodynamics using a validated tool
 The RIFLE (Risk, Injury, Failure, Loss, ESRD) criteria is a validated tool used in
previous studies to describe the incidence of nephrotoxicity associated with
colistin
OBJECTIVE
To evaluate the incidence of Acute Kidney Injury (AKI) in patients treated with
polymyxin B and colistin in a large Academic Medical Center and to assess
the dosing strategies utilized.
METHODS
 A retrospective single center cohort study from Jan 2008 – June 2010 at the
University of Maryland Medical Center
Inclusion criteria
 ≥ 18 years of age
 ≥ 72 hours of administration of polymyxin B or colistin
Exclusion criteria
 ≥ ESRD or any form of renal replacement therapy prior to administration of
polymyxin B or colistin
 Non-intravenous routes of administration
 Statistical analysis was performed using SAS v9.2 (SAS Corporation, North
Carolina).
DISCUSSION
• The incidence of ARF was statistically significantly higher with colistin, 60.4 vs. 41.8%,
p = 0.02 (figure 1)
• Time to development of nephrotoxicity was shorter in the colistin group but was not
statistically significant
• Majority of these patients experienced reversible kidney injury (risk, injury, failure) and
only one patient progressed to ESRD (figure 1)
• Multivariate analysis for Independent risk factors for associated nephrotoxicity showed
colistin use, and older age (>30 years old) were independent risk factors associated
with a statistically significant increase in toxicity (table 3)
• Other risk factors such as concomitant nephrotoxic medications, higher dose
(>5mg/kg/day or >25,000 units/kg/day), higher APACHE II score, diabetes and history
of renal disease were not associated with an increased risk of developing toxicity
• Although there was no direct correlation between higher dose and increased risk of
nephrotoxicity, a higher percentage of patients receiving >5 mg/kg/day (IBW) of
colistin developed nephrotoxicity (figure 3a)
• Colistin dosing varied significantly, and was dosed based on either weight (IBW or
ABW) or a fixed dose of 150 mg (every 8 – 24 hours)
Study Limitations
 This study has the inherent limitation of a retrospective study where other clinical
factors not documented that could have affected nephrotoxicity was missed
 We also assessed two different time periods for the use of colistin and polymyxin B,
differences in practice from different time periods may account for the differences
observed
CONCLUSION
 Patients receiving IV colistin had an increased incidence of nephrotoxicity compared to
patients receiving polymyxin B.
 Our finding supports the need for close monitoring of patients receiving these agents
and provides additional strength to these findings by characterizing the temporal
relationship between these medications and the development of nephrotoxicity.
 Further investigation is needed to determine the etiology of the differences noted in
nephrotoxicity
REFERENCES
1. Deryke, C. A., et al. "Colistin Dosing and Nephrotoxicity in a Large Community Teaching Hospital." Antimicrob Agents
Chemother 54.10 (2010): 4503-5.
2. Doshi, N. M., K. L. Mount, and C. V. Murphy. "Nephrotoxicity Associated with Intravenous Colistin in Critically Ill Patients."
Pharmacotherapy 31.12 (2011): 1257-64.
3. Hartzell, J. D., et al. "Nephrotoxicity Associated with Intravenous Colistin (Colistimethate Sodium) Treatment at a Tertiary
Care Medical Center." Clin Infect Dis 48.12 (2009): 1724-8
4. Oliveira, M. S., et al. "Polymyxin B and Colistimethate Are Comparable as to Efficacy and Renal Toxicity." Diagn Microbiol
Infect Dis 65.4 (2009): 431-4
5. Pogue, J. M., et al. "Incidence of and Risk Factors for Colistin-Associated Nephrotoxicity in a Large Academic Health
System." Clin Infect Dis (2011)
RESULTS
BASELINE DEMOGRAPHICS
PRIMARY OUTCOME
SECONDARY OUTCOME
Table 1: RIFLE Criteria
REVERSIBLE
RISK Increase in creatinine level 1.5 x or GFR decrease by > 25%
INJURY Increase in creatinine level 2.0 x or GFR decrease by > 50%
FAILURE Increase in creatinine level 3.0 x or GFR decrease by > 75%
IRREVERSIBLE
LOSS Increase in creatinine level 4.0 x, persistent Acute Renal
Failure (ARF) or complete loss of function for > 4 weeks
ESRD End Stage Renal Disease (ESRD) > 3 months
THE INCIDENCE OF ACUTE RENAL FAILURE (ARF) WITH COLISTIMETHATE
SODIUM AND POLYMYXIN B IN AN ACADEMIC MEDICAL CENTER
Table 2. Baseline Characteristics
Colistin (n=106) Polymixin B (n=67) p value
Age (years) a 55.4± 15.30 53.3± 16.2 0.40
Male 59(55.7) 44(65.7) 0.19
White 61(58.65) 33(50.00) 0.27
APACHE II score a 22.6±6.4 22.7±5.3 0.92
ICU admission 95(89.62) 59(88.06) 0.75
SCR at beginning in mg/dL a 1.1±0.8 1.0±0.6 0.55
SCR peak, mg/dL a 2.0±1.3 1.6±1.1 0.03
Time to SCR peak , days a 6.5±6.3 7.3±9.4 0.54
Treatment duration, days a 11.7±11.4 12.5±11.9 0.66
IV contrast use 47(44.3) 33(49.3) 0.53
Concomitant Medications
Vancomycin 67(63.2) 38(56.7) 0.40
Aminoglycoside 30(28.3) 15(22.4) 0.39
ACE-I/ARB 13(12.3) 6(9.0) 0.50
Loop diuretic 59(55.7) 33(49.2) 0.41
Vasopressor 50(47.2) 23(34.3) 0.07
Tacrolimus/cyclosporine 7(6.60) 5(7.5) 0.83
Diabetes 31(29.2) 22(32.8) 0.62
Hypertension 48(45.3) 23(34.3) 0.15
AKI/CRI 12(11.3) 12(17.9) 0.22
Abbreviations: CKD = Chronic Kidney Disease; AKI = Acute Kidney Injury; IBW = Ideal Body Weight ; ABW = Actual Body Weight ; AjBW = Adjusted Body
Weight; ACE-I/ARB = Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptor Blockers
a Mean ± SD
Data represented as number (%) unless otherwise stated
Table 3. Multivariate Analysis for Independent Risk Factors for
Associated Nephrotoxicity
Hazard Ratio (HR) p value
Colistin a 2.12 0.002
Age 31-60 b 3.77 0.01
Age > 61 b 3.20 0.04
Hypertension 1.56 0.05
Vancomycin use 1.27 0.32
a In comparison to polymyxin B
b In comparison to age <30
(p = 0.02)
45.5
37.7
35
54.5
62.3
65
0 10 20 30 40 50 60 70
<3.0
3.0 – 5.0
>5.0
Toxicity NoToxicity
Figure 3a. Nephrotoxicity as a Function of Dose: COLISTIN
72.3
48.3
60
27.7
51.7
40
0 10 20 30 40 50 60 70 80
<15,000
15,000 – 25,000
>25,000
Toxicity No Toxicity
Figure 3b. Nephrotoxicity as a Function of Dose: POLYMYXIN B
Dose(mg/kgIBW)Dose(units/kgIBW)
60.4
16.0
18.9 17.9
6.6
0.9
41.8
13.4
19.4
9.0
0.0 0.0
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
ARF Risk Injury Failure Loss ESRD
Colistin Polymyxin b
%Patients
Figure 1. Incidence of Nephrotoxicity Figure 2. Kaplan-Meier Failure Estimates