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Colistin- and Polymyxin-Induced Nephrotoxicity: Focus on Literature Utilizing the RIFLE Classification Scheme of Acute Kidney Injury Matthew Pike and Emmanuel Saltiel Journal of Pharmacy Practice published online 18 September 2014 DOI: 10.1177/0897190014546116 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/09/17/0897190014546116
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New York State Council of Health-system Pharmacists
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Continuing Education Article
Colistin- and Polymyxin-Induced Nephrotoxicity: Focus on Literature Utilizing the RIFLE Classification Scheme of Acute Kidney Injury
Journal of Pharmacy Practice 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014546116 jpp.sagepub.com
Matthew Pike, PharmD1, and Emmanuel Saltiel, PharmD, FCCP, FASHP2
Abstract With the reintroduction of colistimethate and polymyxin B into clinical practice, a review of their individual and comparative nephrotoxicity attributes as reported in contemporary literature was undertaken. Given variability in definitions used for acute kidney injury, a particular focus was placed on studies utilizing the Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria of assessment to provide for standardized comparison. Primary risk factors examined included the influence of dosing and the receipt of concomitant nephrotoxins. The typical severity and time course of renal injury that develops were also analyzed. Nephrotoxicity rates with colistimethate appear to approach 50%, and could be of lower frequency and severity with polymyxin B based on limited literature. Acute kidney injury generally appears to be mild to moderate in magnitude and reversible in nature, though as many as 20% of patients experiencing it may require renal replacement therapy of some duration. The majority of studies showed some relationship with dosing- variably reported as being associated with daily dose or cumulative exposure. Traditional nephrotoxic agents did not appear to confer additional risk individually in the majority of investigations, though receipt of multiple concurrent nephrotoxins did yield a relationship in several. Further studies will be required to better characterize the renal adverse effect profile of these agents, particularly in the case of polymyxin B. Keywords Colistin, Colistimethate, Polymyxin, Nephrotoxicity, RIFLE
Goals 1. 2. 3.
Discuss the mechanism of, risk factors for, and frequency of colistimethate/polymyxin B-associated nephrotoxicity. Discuss the nephrotoxic potential of colistimethate and polymyxin B. Address treatment options for patients with colistimethate-associated nephrotoxicity.
Continuing Education Learning Objectives 1. 2. 3. 4. 5. 6. 7.
Define the RIFLE criteria for drug-induced nephrotoxicity. Design a plan by which to assess the risk of nephrotoxicity for a patient being started on colistimethate therapy. Design a plan by which to monitor for kidney damage in a patient receiving colistimethate. List potential treatment options for patients with colistimethate-associated nephrotoxicity and identify limitations of each option. Address the contributions of daily dose, cumulative total dose, and dose based on ideal versus actual body weight toward the development of colistimethate-associated kidney damage. List concurrent nephrotoxins which may increase the risk of colistimethate-associated kidney damage. Identify the expected time course of colistimethate-associated nephrotoxicity. 1
Carle Foundation Hospital, Urbana, IL, USA Comprehensive Pharmacy Services, Los Angeles, CA, USA
Introduction
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Polymyxins are a group of polypeptide antibiotics that were discovered in 1947. Designated as polymyxins A-E, 2 of this group—polymyxin B and polymyxin E (colistin)—have been
Corresponding Author: Matthew Pike, Carle Foundation Hospital, Urbana, IL 61801, USA. Email: [email protected]
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used in clinical practice. The 2 have similar antibacterial spectra and rapid bactericidal activity. Colistin was discovered in 1949 and was first used therapeutically in Japan and Europe during the 1950s and in the United States, in the form of colistimethate sodium, in 1959. However, the intravenous (IV) formulations of colistin and polymyxin B were gradually abandoned in most parts of the world by the early 1980s because of the reported high incidence of nephrotoxicity and the availability of alternative antibiotics deemed to have better safety profiles.1 In recent years, polymyxins have attracted considerable interest as antibiotics for use against multidrug-resistant (MDR) pathogens. Over the last 2 decades, there has been a tremendous increase in the prevalence of infections caused by MDR gram-negative bacteria, especially Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.2 Polymyxins can be one of a limited number of, or in some cases the only, available active antibiotics left to be utilized in treatment of infections with these MDR bacteria. Given the need for reintroduction into practice the utilization of these polymyxin agents, a review and reassessment of its nephrotoxic potential and the traits surrounding it is necessary. This review will be targeted toward colistimethate, as it has been more commonly utilized than polymyxin B following the resurgence in use. Therefore, a more expansive amount of contemporary data have been published describing experience with its nephrotoxic potential. Additionally, a special focus will be paid to studies utilizing Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria.
Figure 1. RIFLE classification scheme for acute renal failure. Copied and incorporated with permission from Dr. Rinaldo Bellomo.4 SCreat, Serum Creatinine; GFR, Glomerular Filtration Rate; UO, Urine Output; ARF, Acute Renal Failure; ESKD, End Stage Kidney Disease.
Table 1. Colistimethate Sodium / Colistin Base Conversions.a 1-mg Colistin base 1-mg Colistimethate sodium 1-mg Colistin base
Equals Equals Equals
2.4-mg Colistimethate sodium 12 500-IU Colistimethate sodium 30 000-IU Colistin base
a
Data acquired from Falagas and Kasiakou.15
Influence of Dosing Mechanism of Nephrotoxicity Although not fully understood, a similar underlying mechanism may exist between the antibacterial and the nephrotoxic effects of polymyxin antibiotics. Damage to renal tubular cells occurs, and this has been reported to potentially occur due to the effects on membrane structure leading to increased permeability and cell death.3 This is much like the detergent mechanism on the cell membrane of gram-negative bacteria which results in killing and antimicrobial efficacy.
Risk Factors for Nephrotoxicity A variety of correlations with and risk factors for colistimethateinduced nephrotoxicity have been isolated across studies. Given the multitude of literature regarding colistimethate now coming to light with the resurgence of its use, along with the variability in how nephrotoxicity rates have been described, an attempt was made to focus only on studies that described nephrotoxicity in terms of RIFLE criteria (Figure 1), the detailed description of which is provided elsewhere.4 Nine such studies specifically examining colistimethate were isolated and utilized for this review.5-13
Some have suggested that enhanced rates of nephrotoxicity seen in older studies may have been the result of inappropriate dosing strategies used at the time. Insufficient monitoring of hydration and renal status in the past, with subsequent inadequate titration of dosing based on renal function, has also been proposed as one possible culprit.14 Another factor may be related to confusion regarding doses prescribed according to colistimethate sodium versus colistin base, along with the various conversions between these compounds in milligrams and international units. From the data given in Table 1, it can easily be seen how such confusion could arise, particularly with some variation in labeling and descriptions of recommended dosing across nations and over time. Interpretation of literature regarding nephrotoxicity rates has also been made more difficult at times due to insufficient description of doses actually received in this regard. For purposes of this review, all further discussion of dosing across various studies is in terms of milligrams of colistin base, unless otherwise noted. Regardless of the above-mentioned factors clouding appropriate use, a dose-related nephrotoxicity phenomenon still appears to exist according to the majority of studies. Both the magnitude of the daily dose and the cumulative dose received have variably been reported as primary determinants of nephrotoxicity. The impact of determining dose based upon ideal body
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weight (IBW) versus actual body weight (ABW) may play a significant role in this relationship as well. It is recommended via the prescribing information of branded and generic colistimethate injection products in the United States to dose the drug based on IBW in obese individuals.16-20 Pogue et al, in retrospective review of a cohort of 126 predominantly intensive care unit (ICU)-based patients receiving colistimethate therapy, reported a median dose of 5.48 mg/kg/d IBW at the time of meeting nephrotoxicity criteria versus 3.85 mg/kg/d IBW in those patients not developing nephrotoxicity (P ¼ .02).5 In fact, 69% of patients receiving a daily dose of 5.0 mg/kg/d IBW developed nephrotoxicity versus only 33% of those receiving 3.0 to 4.9 mg/kg/d IBW. A dose of 5.0 mg/kg/d IBW was found to be an independent risk factor for nephrotoxicity upon multivariate analysis. When consideration is given to dosing based on ABW, thresholds for increasing nephrotoxicity were lowered further. Nephrotoxicity rates of 55% were seen at doses 4.0 mg/kg/d ABW. Cumulative dose data were not specifically described but was noted not to be a risk factor in this study, as most renal dysfunction occurred early in therapy. In this study, the overall nephrotoxicity rates were found to be 43%. Similarly, in a retrospective study of 30 patients receiving colistimethate therapy, DeRyke et al reported a median dose of 5.5 mg/kg/d IBW in those developing nephrotoxicity versus 4.4 mg/kg/d IBW in those not developing nephrotoxicity (P ¼ .011).6 When based on ABW, median doses of 4.2 mg/kg/d were associated with nephrotoxicity versus 4.0 mg/kg/d in those not developing nephrotoxicity, a differential that did not result in statistical significance. However, patients who were considered to have received excessive doses (defined as > 0.4 mg/kg/d above the recommended dose for a given level of renal function) due to use of ABW as opposed to IBW were 13.2 times more likely to develop acute kidney injury (P ¼ .005). In this study, cumulative dose was again not found to be a risk factor for renal dysfunction. Total median IV doses of 1838 and 1823 mg were reported in those patients developing and not developing nephrotoxicity, respectively. An overall nephrotoxicity rate of 33% was reported in this investigation. In a cohort of 66 patients, Hartzell et al also retrospectively examined associations with colistimethate-induced nephrotoxicity.7 In this study, the dose in mg/kg/d was not found to be associated with acute kidney injury. Patients developing and not developing renal insult received mean daily doses of 4.4 and 4.2 mg/kg/d, respectively. Information as to whether or not doses were based on IBW or ABW was not provided. Mean cumulative dose (6454 vs 4727 mg, P ¼ .005) was found to be significantly associated with developing versus not developing nephrotoxicity in this study. Fifty-nine patients received only IV therapy, while 6 patients received additional inhaled colistimethate therapy. It was not clear in the study description as to whether or not inhaled therapy was tallied in the cumulative dose statistics. The overall nephrotoxicity rate found in this analysis was 45%. Kwon et al retrospectively evaluated 71 patients in an effort to describe nephrotoxicity of colistimethate.8 The median dose received for the entire cohort was 4.6 mg/kg/d, although description was not provided regarding what body
weight (ie, ABW vs IBW) that doses were based upon or on the weight characteristics of their population. Examination of differential in nephrotoxicity rates according to dose in mg/kg/d was not reported. They did however note that the cumulative dose of colistimethate was significantly associated with the development of nephrotoxicity. A median total dose of 41.6 mg/kg was noted in those patients who developed nephrotoxicity. Overall, nephrotoxicity was encountered in 53.5% of patients in this study. In a prospective, observational investigation of 102 patients undertaken by Sorli et al, various dosing schemes of colistimethate were allowed and subsequently examined.9 The study compared 1 million units (80 mg) IV every 8 hours (Q8H), 2 million units (160 mg) IV Q8H, 3 million units (240 mg) IV Q8H, and ‘‘other’’ doses, with all being expressed as colistimethate sodium. Doses in terms of colistin base according to IBW were approximately 1.5, 2.9, 4.4, and 1.5 mg/kg/d, respectively. The daily dose was not found to be associated with colistimethate-induced nephrotoxicity. On univariate analysis, median cumulative dosing was significantly linked with renal injury at the end of therapy assessment—97.3 million units colistimethate (3243.3 mg colistin base) versus 103.9 million units colistimethate (3463.3 mg colistin base) in those without and with nephrotoxicity, respectively (P ¼ .047). However, these same findings were not isolated upon multivariate analysis of the data. The overall nephrotoxicity rate in this study approached 52%. Of interest is that the study in question also examined plasma concentrations of colistin. On the univariate analysis, both peak and trough levels were correlated with nephrotoxicity at day 7 and at the end of therapy, and trough levels had a significant correlation upon multivariate analysis. The authors also pointed out that once steady state is achieved, peak and trough serum levels are essentially the same numerically. Gauthier et al published a retrospective analysis devoted specifically to a 42 patient cohort of mostly ICU-based patients that were overweight or obese (defined as body mass index (BMI) of 25-29.9 and > 30 kg/m2, respectively).10 While renal toxicity was not found to be correlated with mean dose in mg/kg/d based on IBW at 3.31 mg/kg/d in the toxicity group versus 3.14 mg/kg/d in the nontoxicity group, a compelling relationship was found when considered based on actual body weight (P ¼ .02). Actual body weight doses in the toxicity and nontoxicity groups were 1.81 mg/kg/d and 2.19 mg/kg/d, respectively. Median cumulative doses received were not found to have an impact on toxicity (2450 mg in the toxicity group and 2320 mg in the nontoxicity group). Patients developing nephrotoxicity were significantly larger based on mean ABW (110.5 vs 86.8 kg, P ¼ .02) and median BMI (33.5 vs 30.4 kg/m2, P ¼ .015). Although no linear relationship between dosing weight and nephrotoxicity was elucidated, upon multivariate analysis, a BMI of 31.5 kg/m2 was associated with enhanced risk of nephrotoxicity (P ¼ .025). The overall nephrotoxicity rate in this study was 48%, which is quite similar to the toxicity rates seen across the other RIFLE-based studies considered. However, the IBW-based doses used appeared to be less than those employed in the previously described studies. Although the prior studies discussed elucidated some form of relationship between dosing, either daily or cumulative, and
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acute kidney injury, several RIFLE-based studies analyzed did not discover such a correlation. One such study was the retrospective review by Ko et al of 119 predominantly ICU-based patients.11 Mean doses received were reported to be 230.8 and 250.4 mg/d in patients with and without acute kidney injury, respectively. Within this study, attributes of the subpopulations developing early (within 7 days) and late (after 7 days) nephrotoxicity were also compared. For this subset, mean dose was also not significantly correlated with renal insult (232.6 vs 259.5 mg/d, respectively). Although weight characteristics of the study population were not reported, it was detailed that standard dosing utilized in this study was 5 mg/kg/d (divided 3 times daily) in normal renal function, and mean baseline serum creatinine was normal for the cohort. Data regarding the potential impact of cumulative doses were not assessed. The overall acute kidney injury rate in this study was approximately 55%. In a retrospective review of a larger (n ¼ 174) and predominantly ICU-based patient population, Collins et al did not find a relationship between weight-based daily dosing and rates of nephrotoxicity.12 Patients developing renal dysfunction received a dose of 4.06 mg/kg/d versus 3.96 mg/kg/d in those not developing renal dysfunction. Analysis was also performed of doses ranging from 3 to 4.9 mg/kg/d compared to doses 5 mg/kg/d, which also did not yield any statistically significant associations. Doses were reported to have been based on ABW, although weight descriptions of the patient population were not provided. The impact of colistimethate cumulative dose on nephrotoxicity potential was not reported. The overall nephrotoxicity rate in this investigation was 48%. In another smaller retrospective study involving 49 ICU patients who had received colistimethate, Doshi et al similarly did not find a relationship between dosing and development of renal toxicity.13 Doses received were examined in terms of both ABW and IBW. In each case, no correlation was found for risk of colistimethate-induced nephrotoxicity and mean doses administered (for those developing and not developing nephrotoxicity, respectively: 2.9 mg/kg/d vs 2.6 mg/kg/d based on ABW; 4 mg/ kg/d vs 3.8 mg/kg/d based on IBW). Median cumulative dose was also not linked to nephrotoxicity risk (2850 mg in those developing nephrotoxicity and 1200 mg in those not developing this adverse effect). The overall nephrotoxicity rate was 31% in this study.
Concomitant Nephrotoxins The additive/synergistic or potentiating effects of other medications on cumulative nephrotoxicity risk is always a matter of concern in patients on colistimethate therapy. By nature of that, many studies have examined the relationships of these drugs when administered concomitantly with colistimethate. Frequently analyzed agents have included aminoglycosides, vancomycin, IV contrast, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), nonsteroidal anti-inflammatory agents (NSAIDs), calcineurin inhibitors, amphotericin B, and pressor agents. The interplay of multiple parings of these agents has also been investigated in several studies.
Aminoglycosides are well known for their nephrotoxicity potential, and practitioners may frequently be wary of utilizing these agents along with colistimethate therapy. Interestingly, the RIFLE-based studies reviewed have essentially reported a lack of significant effect on nephrotoxicity rates when colistimethate and aminoglycosides are utilized together.5-7,9-11 The analysis performed by Doshi et al did however note a statistical trend for a concomitant aminoglycoside association (P ¼ .069).13 So, while such concerns about enhancing renal adverse effects intuitively make sense, substantial risk may not be born out in practice. Cautious use of dual aminoglycoside þ colistimethate therapy may therefore be possible if necessitated clinically. Vancomycin is another antibiotic frequently linked with possible renal adverse effects. Similar to aminoglycosides, none of the studies reviewed that examined vancomycin associations isolated additional nephrotoxicity risk with concomitant colistimethate.6-8,9-11,13 Therefore, avoidance of vancomycin and utilization of alternative agents for gram-positive coverage in those patients receiving colistimethate would seemingly not be substantiated according to the examined literature. Five of the considered studies adequately examined the relationship between IV contrast and nephrotoxicity rates during colistimethate therapy. Exact types and quantities of IV contrast received were predominantly not defined. Four of these investigations did not reveal a correlation between receipt of contrast agents and higher risk of nephrotoxicity.6-8,10 However, Doshi et al did note a statistically significant association with IV contrast material.13 Diuretics may show an association with colistimethate nephrotoxicity according to some reviewed studies. Deryke et al reported a statistically significant association with diuretics (class of diuretic not defined) and renal toxicity while on colistimethate in univariate analysis.6 However, when patients receiving pressors were excluded from the analysis, such a relationship did not exist. Low numbers of patients in this study prevented a multivariate analysis from being performed. Pogue et al similarly found a statistically significant relationship with loop diuretics upon univariate analysis, although the same relationship was not reported upon multivariate analysis.5 In the study performed by Sorli et al, loop diuretic use was not found to be associated with colistimethate nephrotoxicity at day 7 of therapy on univariate analysis, but an association was significant at the end of therapy.9 In similar vein to the study by Pogue et al, multivariate analysis did not uncover any statistically significant relationships. Other reviewed studies adequately examining this potential association did not yield any statistically significant results.7,8,10,13 Pressor agents were sufficiently examined for potentiation of nephrotoxicity in 5 studies, although only the analysis of DeRyke et al found a significant association with colistimethate nephrotoxicity.5-7,10,13 Use of ACE inhibitor or ARB was suitably analyzed in 3 studies, none of which found a correlation with renal adverse effects on colistimethate therapy.6,10,13 Four studies inspected possible links between NSAID use and nephrotoxicity of colistimethate. Of these, 3 studies found no relationship, while the study by Sorli et al found a significant association at the end of therapy on univariate
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analysis although not at the earlier point of day 7 of therapy or upon multivariate analysis.8-10,13 Calcineurin inhibitors were only examined in 2 reports.8,10 The study by Kwon et al discovered a statistically compelling relationship with colistimethate nephrotoxicity in both univariate and multivariate analyses.8 However, Gauthier et al uncovered no such relationship.10 A discussion of which calcineurin inhibitor agents were predominantly utilized in the study was not provided. Only the study by Doshi et al reported specifically on the possibility of an amphotericin B association, although no statistical correlation was isolated.13 Additionally, and while not traditionally considered a nephrotoxic agent, Pogue et al unearthed upon multivariate analysis that concomitant rifampin administration was associated with colistimethate nephrotoxicity (although the same relationship was not seen during univariate analysis of variables).5 Although many of the above-mentioned pharmacologic agents did not appear to have a relationship with colistimethate nephrotoxicity individually, exposure to multiple potential nephrotoxins with inclusion of colistimethate did appear to yield significant associations in 4 studies where this was examined. Pogue et al discovered upon multivariate analysis that receipt of 3 potentially renal toxic agents concomitantly was associated with colistimethate nephrotoxicity.5 Of note, vancomycin exposure was not considered in this study, as the authors felt that its nephrotoxic nature was still debatable based on the current literature. Collins et al isolated upon multivariate analysis that receipt of one or more concurrent nephrotoxins was significantly associated with colistimethate renal toxicity.12 Vancomycin and loop diuretics represented the largest exposures to potentially nephrotoxic drugs in this study, with >50% of study patients having received concomitant therapy with at least one of these agents, while >10% of study patients had also received an aminoglycoside or IV contrast dye. Relationships with individual agents were not reported. Doshi et al found that receipt of 2 additional potential nephrotoxins was significantly linked with colistimethate nephrotoxicity on multivariate analysis.13 Sorli et al displayed in their report that coadministration of 2 additional potentially nephrotoxic agents was significantly correlated with colistimethate nephrotoxicity.9
Additional Risk Factors Beyond the impact of dosing and concurrent nephrotoxic agents, other associations have at times been reported with various patient-specific factors and disease states. However, the variables analyzed have been assorted and frequently dissimilar among investigations. Two of the most commonly considered or isolated items across the studies examined were age and hyperbilirubinemia. Several studies have suggested some association with increasing age and propensity for colistimethate-induced kidney injury6,10,12 although at the same time others have not yielded such results.5,7,8,11,13 The majority of all patients across these investigated studies were in the sixth to seventh decade of life, with the exception of the study by Hartzell et al, which featured predominantly patients in their third decade of life by way of studying a younger population through a military institution.7
Two studies that analyzed total bilirubin as a variable elucidated a statistically significant relationship with colistimethate nephrotoxicity.8,11 It is worth noting that both of these studies examined populations of Korean patients. In one study,11 patients manifesting acute kidney injury had a higher total bilirubin than those who did not (2.6 mg/dL vs 1.0 mg/dL, P < .05). Additionally, within the nephrotoxicity group, those with early injury occurring within 7 days had a significantly higher bilirubin than those developing toxicity later in the course (3.3 mg/ dL vs 0.6 mg/dL, P < .05). In the other study,8 statistically more patients in the group developing nephrotoxicity had hyperbilirubinemia, defined as a total bilirubin >5 mg/dL, than those who did not (P ¼ .026). However, in the study by Gauthier et al, no association was revealed with utilizing the same total bilirubin threshold.10 This study featured patients in the United States, although it is worth noting that the overall size of the cohort was smaller (n ¼ 42 vs 70). None of the other analyzed studies examined any associations with bilirubin. It would appear that further study of hyperbilirubinemia as a possible risk factor is warranted, particularly in non-Korean populations, as a component of genetic interplay cannot be ruled out. The exact mechanism responsible for this relationship between higher total bilirubin levels and renal toxicity of colistimethate has also not been determined, but a similar relationship has been reported in the context of aminoglycoside nephrotoxicity.21-24
Severity and Time Course of Nephrotoxicity All the examined studies, through utilization of RIFLE criteria, provided descriptive information regarding severities of renal toxicity encountered.5-13 The percentage of patients developing nephrotoxicity falling into the Risk category ranged from 15% to 44% across studies and varied from 5% to 47% for those falling into the Injury category. The largest differential occurred in the Failure category, with reported rates spanning between 13% and 80%. Taking into account the reported quantities of patients developing nephrotoxicity while on colistimethate therapy across all of the examined studies, approximately 30%, 30%, and 40% progressed to the Risk, Injury, and Failure categories of RIFLE criteria, respectively. Of note, the majority of all patients in the considered studies had normal baseline renal function, frequently owing to exclusion criteria for significant renal dysfunction utilized within many of the analyses. Some patients developing nephrotoxicity while on colistimethate therapy have required renal replacement therapy. This was reported across many of the reviewed investigations.8,10-12 The rate of patients with acute kidney injury requiring such modalities approached 20% and varied between 0% and 28% across the studies examined. Few patients in the reviewed studies were documented as having persistence in nephrotoxicity as defined by Loss and End Stage Renal Disease (ESRD) categorizations of RIFLE criteria. This may be somewhat indicative of the reversibility of colistimethate-induced renal toxicity. However, limitations may exist in the data accrued due to the nature of how Loss and ESRD criteria are defined (ie, Loss criteria being defined at >4
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weeks and ESRD criteria being defined at >3 months). Lack of adequate follow-up information within these time frames could either owe to patient mortality or postdischarge status. When acute kidney injury occurred, the time of onset was most frequently within the first 5 to 7 days of therapy. Pogue et al reported that approximately 78% of their patient cohort with nephrotoxicity had occurrence within the first 7 days of therapy.5 Ko et al had similar results with 71% of the observed nephrotoxicity occurring within the first week of colistimethate exposure, while Sorli et al found approximately 49% of acute kidney insult occurring within that time frame.9,11 In the review by Kwon et al, a median onset of 7.5 days to acute kidney injury was elucidated.8 The patient cohort analyzed by Gauthier et al had median onset of 5 days to the appearance of renal injury, while DeRyke et al had all 10 patients developing nephrotoxicity on colistimethate do so within 5 days of therapy initiation.6,10 Considering the totality of the information examined and presented, acute kidney injury that may develop while on colistimethate therapy most often appears to be mild to moderate in magnitude. It is also more often than not reversible in nature and frequently not requiring more invasive measures such as dialysis. Given these traits, higher tolerance for occurrence of renal adverse effects may be reasonable in order to maintain the potential for positive infection-related outcomes with continuation of therapy in the face of toxicity.
Relative Nephrotoxicity Traits of Colistimethate and Polymyxin B As can be seen from the preceding discussion, overall nephrotoxicity rates with colistimethate according to RIFLE criteria have been variable and in the range 31% to 55%,5-13 with a weighted average of approximately 47% based on the sample sizes in the respective studies. Less studies specifically utilizing RIFLE criteria are present to assess polymyxin B-induced acute kidney injury although some have been reported in the literature. Kubin et al retrospectively examined 73 patients having received polymyxin B in an attempt to characterize risk factors for nephrotoxicity as described by RIFLE criteria.25 Median dose received was 1.8 mg/kg/d (18 000 units/kg/d) and was reported to have been calculated on total (actual) body weight. Intermittent dosing was utilized with the bulk of patients receiving every 12 hours (Q12H; 52%) or Q24H (40%) dosing. Upon multivariate analysis of data, patients with BMI 25 kg/m2 displayed significantly higher rates of acute kidney injury than those with lower BMI (P ¼ .045), although comparative weight-based dosing between the 2 groups was found to be statistically similar at 1.7 mg/kg/d (17 000 units/kg/d) and 1.9 mg/kg/d (19 000 units/kg/ d), respectively (P ¼ .551). While not examined via multivariate regression, the median cumulative dose of polymyxin B was found to be significantly higher in the group experiencing acute kidney injury (1578 vs 800 mg, P ¼ .02). Concomitant vancomycin exposure was also found to confer additional risk of nephrotoxicity on polymyxin B therapy (P ¼ .03), although use of other individual potential nephrotoxins (aminoglycosides, IV contrast, diuretics, calcineurin inhibitors, amphotericin B) did not yield such an
association. Use of ACE inhibitor/ARB was not assessed, and no patients received NSAIDs. Age was not found to confer additional risk, and hyperbilirubinemia was not assessed statistically. Median time to onset of renal toxicity was 4 days. Of those developing nephrotoxicity, approximately 55% were categorized as Injury or Failure per RIFLE criteria. Of those developing acute renal adverse effects, 16% required renal replacement therapy, and the overall rate of nephrotoxicity in this study was 60%. In 2013, Akajagbor et al reported nephrotoxicity characteristics on a retrospective cohort of patients having received either polymyxin B or colistimethate at their institution during the time period 2008 to 2010.26 In patients with normal renal function, polymyxin B was dosed at 15 000 to 25 000 units/kg/d as a continuous infusion, while colistimethate was dosed intermittently but by way of a variety of strategies (5 mg/kg/d IBW, 5 mg/kg/ d ABW or a fixed dose of 150 mg Q12H). It was not specified as to what weight polymyxin B was dosed upon. Presumably, dosing occurred based on ABW, as data available in a supplement to the article indicate mean calculated doses based on IBW were closer to 22 000 units/kg/d in the study. A total of 173 patients were included in the analysis, with 89% being an ICU-based population. Overall, nephrotoxicity developed in 41.8% and 60.4% of patients receiving polymyxin B and colistimethate, respectively (P ¼ .02), with a median onset of approximately 4 days and a mean time to peak serum creatinine of approximately 7 days. Patients in both the polymyxin B and the colistimethate groups fell into the RIFLE criteria categories in a relatively similar distribution to that mentioned previously regarding colistimethateonly studies, although numerically higher percentages of polymyxin B patients were in the Risk and Injury subsets, while larger percentages of colistimethate patients fell into more advanced divisions of renal injury. Of 64 patients, 7 (11%) experiencing acute kidney injury on colistimethate were categorized in the Loss designation, while only 1 patient in the colistimethate group progressed to end-stage kidney disease (ESKD). Of note, no patients in the polymyxin B group progressed to Loss or ESKD categories as defined by RIFLE criteria. Proportions of patients requiring renal replacement therapy were not specifically described. On multivariate analysis of the entire cohort, age 31 to 60 years old (P ¼ .022) and colistimethate use (P ¼ .002) were independently associated with nephrotoxicity. Concomitant nephrotoxins were not noted to significantly potentiate renal toxicity, with at least 25% of patients having received one or more of the following: aminoglycosides, vancomycin, IV contrast, diuretics, and pressors. Hyperbilirubinemia was not assessed as a possible risk factor. It was reported that average daily and cumulative doses were comparable for those developing and not developing nephrotoxicity in both the polymyxin B and the colistimethate groups. However, it was noted that nephrotoxicity rates tended to increase for colistimethate based on dose according to IBW (54.5%, 62.3%, and 65% for doses of 5 mg/kg/d, respectively). Mean calculated doses of colistimethate received in the study were approximately 2.9 mg/kg/d IBW (3.9 mg/kg/d ABW) per the supplemental data provided. Similar results were found in another recent retrospective cohort review of 225 patients by Phe et al.27 In that study, the
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prevalence of nephrotoxicity based on RIFLE criteria was higher with colistimethate than with polymyxin B in a matched cohort review (55.3% vs 21.1%, P ¼ .003). The onset of nephrotoxicity was also significantly earlier in patients administered colistimethate (P ¼ .003). In the intention-to-treat analysis, rates of acute kidney injury for colistimethate and polymyxin B were 33.9% and 23.1% (P ¼ .08), respectively. In patients without cystic fibrosis, respective rates were 48.2% and 23.1% (P < .001). Examining stratification according to RIFLE categories, and in contrast to the analysis by Akajagbor and colleagues, numerically larger percentages of colistimethate patients were in Risk and Injury groupings and a greater percentage of polymyxin B patients reached the Failure designation (although the only statistically significant differential occurred in the Risk category, with a substantially larger portion of colistimethate patients: 14% vs 4.8%, P ¼ .02). Upon multivariate analysis, duration of therapy was found to be a significant risk factor for nephrotoxicity for both colistimethate and polymyxin B (P ¼ .02 for each). Daily dose based on ideal body weight was also found to be a significant risk factor for colistimethate (P ¼ .02), although daily doses were not found to be for polymyxin B. Interestingly, cystic fibrosis was found to be a protective factor against acute renal toxicity for colistimethate upon the multivariate analysis (P ¼ .04). Such analysis was not permitted for polymyxin B as no patients with cystic fibrosis were present in that cohort. Age was also found to be an independent risk factor for acute kidney injury in the colistimethate group (P ¼ .03), although not for polymyxin B. Of note, patients in the colistimethate cohort were substantially younger than patients in the polymyxin B cohort (mean 46.4 years vs 71.4 years, P < .001). Hyperbilirubinemia was not assessed as a risk factor in this analysis. Mean doses utilized in this study were 1.8 mg/kg/d IBW (18 000 units/kg/d IBW) for polymyxin B and 4.6 mg/kg/d IBW for colistimethate. Based on ABW, respective mean doses were 1.5 mg/kg/d (15 000 units/kg/d) and 4.1 mg/kg/d. Cumulative doses were not reported.
discontinuation of colistimethate treatment—that is, balancing the generally reversible nature of its nephrotoxicity, along with potentially deleterious effects of withholding antimicrobial therapy, versus attempts to mitigate further insult to the kidney. In the setting of continued treatment with colistimethate, sufficient dose reduction based on estimated glomerular filtration rate according to published recommendations is imperative. This is particularly true in light of the possible correlations between dose and renal toxicity presented earlier.
Conclusion Given the growing amount of current literature on the subject, in addition to the variability in definitions applied, an attempt was made to describe the renal injury characteristics of colistimethate (and secondarily for polymyxin B as well) in terms of studies utilizing a standardized definition in the RIFLE criteria. At dosing strategies currently used, and in prevailing clinical contexts, unacceptably high rates of nephrotoxicity are still seen with colistimethate therapy. However, the magnitude of kidney toxicity often encountered and the frequently reversible nature do not rule out therapy and are reassuring on some level. The finding of inconsistent associations between use of concomitant nephrotoxins and renal adverse effects may also add an element of confidence in some therapeutic scenarios. Although data are limited, the findings of comparatively lower nephrotoxicity rates with polymyxin B are intriguing and warrant further study—ideally in the form of prospective studies versus colistimethate. Given the complexities of colistimethate pharmacokinetics, in addition to clinical experience with safety and efficacy thus far in contemporary settings, such investigations would be of value. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
Treatment of Nephrotoxicity No definitive treatment modalities for colistimethate-induced nephrotoxicity have been isolated. Care is predominantly supportive in nature. Renal replacement therapy is occasionally required as noted previously. Maintaining adequate hydration is advisable. Avoiding continued administration of concomitant nephrotoxins when possible would appear to be intuitive while noting the previously described data that the relationship between colistimethate-induced kidney injury and accompanying nephrotoxic agents has frequently not been established. Discontinuation of colistimethate therapy, with use of alternative antibiotic options available, may be advisable when therapeutically feasible. However, given the typical clinical circumstances under which colistimethate therapy is employed, the presence of other treatment modalities may be minimal or nonexistent. Therefore, clinical decisions must be made regarding overall risks and benefits of continuation versus
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Supplemental Material The online [appendices/data supplements/etc] are available at http:// jpp.sagepub.com/supplemental.
References 1. Falagas M, Kasiakou S. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 2005;40:1333-1341. 2. Biswas S, Brunel J, Dubus J, et al. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther. 2012; 10(8):917-934. 3. Falagas M, Kasiakou S. Toxicity of polymyxins: a systematic review of the evidence from old and recent studies. Crit Care. 2006;10(1):R27.
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4. Bellomo R, Ronco C, Kellum J, et al. Acute renal failure- definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care. 2004;8(4):R204-R212. 5. Pogue J, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. 2011;53(9):879-884. 6. DeRyke C, Crawford A, Uddin N, et al. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother. 2010;54(10):4503-4505. 7. Hartzell J, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis. 2009;48(12):1724-1728. 8. Kwon J, Lee J, Huh W, et al. Predictors of acute kidney injury associated with intravenous colistin treatment. Int J Antimicrob Agents. 2010;35(5):473-477. 9. Sorli L, Luque S, Grau S, et al. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infect Dis. 2013;13:380. 10. Gauthier T, Wolowich W, Reddy A, et al. Incidence and predictors of nephrotoxicity associated with intravenous colistin in overweight and obese patients. Antimicrob Agents Chemother. 2012; 56(5):2392-2396. 11. Ko H, Jeon M, Choo E, et al. early acute kidney injury is a risk factor that predicts mortality in patients treated with colistin. Nephron Clin Pract. 2011;117(3):c284-8. 12. Collins J, Haynes K, Gallagher J. Emergent renal dysfunction with colistin pharmacotherapy. Pharmacotherapy. 2013;33(8):812-816. 13. Doshi N, Mount K, Murphy C. Nephrotoxicity associated with intravenous colistin in critically ill patients. Pharmacotherapy. 2011;31(12):1257-1264. 14. Spapen H, Jacobs R, Van Gorp V, et al. Renal and neurological side effects of colistin in critically ill patients. Ann Intensive Care. 2011;1(1):14.
15. Falagas M, Kasiakou S. Use of international units when dosing colistin will help decrease confusion related to various formulations of the drug around the world. 2006;50(6):2274-2275. 16. Coly-mycin M injection [package insert]. JHP Pharmaceuticals, LLC, Rochester, Michigan; 2013. 17. Colistimethate injection [package insert]. X-GEN Pharmaceuticals, Inc., Big Flats, New York; 2012. 18. Colistimethate injection [package insert]. Paddock Laboratories, Inc., Minneapolis, Minnesota; 2012 19. Colistimethate injection [package insert]. Fresenius Kabi USA, LLC., Lake Zurich, Illinois; 2013. 20. Colistimethate injection [package insert]. Heritage Pharmaceuticals, Inc. Eatontown, New Jersey; 2014. 21. Cortes J, Gamba G, Contreras A, et al. Amikacin nephrotoxicity in patients with chronic liver disease. Rev Invest Clin. 1990; 42(2):93-98. 22. Oliveira J, Silva C, Barbieri C, et al. Prevalence and risk factors for aminoglycoside nephrotoxicity in intensive care units. Antimicrob Agents Chemother. 2009;53(7):2887-2891. 23. Desai T, Tsang T. Aminoglycoside nephrotoxicity in obstructive jaundice. Am J Med. 1988;85(1):47-50. 24. Lucena M, Andrade R, Cabello M, et al. Aminoglycosideassociated nephrotoxicity in extrahepatic obstructive jaundice. J Hepatol. 1995;22(2):189-196. 25. Kubin C, Ellman T, Phadke V, et al. Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy. J Infect. 2012;65(1):80-87. 26. Akajagbor D, Wilson S, Shere-Wolfe K, et al. Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin b in critically ill patients at a tertiary care medical center. Clin Infect Dis. 2013;57:1300-1303. 27. Phe K, Lee Y, McDaneld P, et al. Comparison of nephrotoxicity rates associated with colistimethate versus polymyxin B therapy: in vitro assessment and a multicenter cohort study. Antimicrob Agents Chemother. 2014;58(5):2740-2746.
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Colistin- and Polymyxin-Induced Nephrotoxicity: Focus on Literature Utilizing the RIFLE Classification Scheme of Acute Kidney Injury Matthew Pike and Emmanuel Saltiel Journal of Pharmacy Practice published online 18 September 2014 DOI: 10.1177/0897190014546116 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2014/09/17/0897190014546116
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Continuing Education Article
Colistin- and Polymyxin-Induced Nephrotoxicity: Focus on Literature Utilizing the RIFLE Classification Scheme of Acute Kidney Injury
Journal of Pharmacy Practice 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190014546116 jpp.sagepub.com
Matthew Pike, PharmD1, and Emmanuel Saltiel, PharmD, FCCP, FASHP2
Abstract With the reintroduction of colistimethate and polymyxin B into clinical practice, a review of their individual and comparative nephrotoxicity attributes as reported in contemporary literature was undertaken. Given variability in definitions used for acute kidney injury, a particular focus was placed on studies utilizing the Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria of assessment to provide for standardized comparison. Primary risk factors examined included the influence of dosing and the receipt of concomitant nephrotoxins. The typical severity and time course of renal injury that develops were also analyzed. Nephrotoxicity rates with colistimethate appear to approach 50%, and could be of lower frequency and severity with polymyxin B based on limited literature. Acute kidney injury generally appears to be mild to moderate in magnitude and reversible in nature, though as many as 20% of patients experiencing it may require renal replacement therapy of some duration. The majority of studies showed some relationship with dosing- variably reported as being associated with daily dose or cumulative exposure. Traditional nephrotoxic agents did not appear to confer additional risk individually in the majority of investigations, though receipt of multiple concurrent nephrotoxins did yield a relationship in several. Further studies will be required to better characterize the renal adverse effect profile of these agents, particularly in the case of polymyxin B. Keywords Colistin, Colistimethate, Polymyxin, Nephrotoxicity, RIFLE
Goals 1. 2. 3.
Discuss the mechanism of, risk factors for, and frequency of colistimethate/polymyxin B-associated nephrotoxicity. Discuss the nephrotoxic potential of colistimethate and polymyxin B. Address treatment options for patients with colistimethate-associated nephrotoxicity.
Continuing Education Learning Objectives 1. 2. 3. 4. 5. 6. 7.
Define the RIFLE criteria for drug-induced nephrotoxicity. Design a plan by which to assess the risk of nephrotoxicity for a patient being started on colistimethate therapy. Design a plan by which to monitor for kidney damage in a patient receiving colistimethate. List potential treatment options for patients with colistimethate-associated nephrotoxicity and identify limitations of each option. Address the contributions of daily dose, cumulative total dose, and dose based on ideal versus actual body weight toward the development of colistimethate-associated kidney damage. List concurrent nephrotoxins which may increase the risk of colistimethate-associated kidney damage. Identify the expected time course of colistimethate-associated nephrotoxicity. 1
Carle Foundation Hospital, Urbana, IL, USA Comprehensive Pharmacy Services, Los Angeles, CA, USA
Introduction
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Polymyxins are a group of polypeptide antibiotics that were discovered in 1947. Designated as polymyxins A-E, 2 of this group—polymyxin B and polymyxin E (colistin)—have been
Corresponding Author: Matthew Pike, Carle Foundation Hospital, Urbana, IL 61801, USA. Email: [email protected]
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used in clinical practice. The 2 have similar antibacterial spectra and rapid bactericidal activity. Colistin was discovered in 1949 and was first used therapeutically in Japan and Europe during the 1950s and in the United States, in the form of colistimethate sodium, in 1959. However, the intravenous (IV) formulations of colistin and polymyxin B were gradually abandoned in most parts of the world by the early 1980s because of the reported high incidence of nephrotoxicity and the availability of alternative antibiotics deemed to have better safety profiles.1 In recent years, polymyxins have attracted considerable interest as antibiotics for use against multidrug-resistant (MDR) pathogens. Over the last 2 decades, there has been a tremendous increase in the prevalence of infections caused by MDR gram-negative bacteria, especially Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae.2 Polymyxins can be one of a limited number of, or in some cases the only, available active antibiotics left to be utilized in treatment of infections with these MDR bacteria. Given the need for reintroduction into practice the utilization of these polymyxin agents, a review and reassessment of its nephrotoxic potential and the traits surrounding it is necessary. This review will be targeted toward colistimethate, as it has been more commonly utilized than polymyxin B following the resurgence in use. Therefore, a more expansive amount of contemporary data have been published describing experience with its nephrotoxic potential. Additionally, a special focus will be paid to studies utilizing Risk-Injury-Failure-Loss-End Stage Kidney Disease (RIFLE) criteria.
Figure 1. RIFLE classification scheme for acute renal failure. Copied and incorporated with permission from Dr. Rinaldo Bellomo.4 SCreat, Serum Creatinine; GFR, Glomerular Filtration Rate; UO, Urine Output; ARF, Acute Renal Failure; ESKD, End Stage Kidney Disease.
Table 1. Colistimethate Sodium / Colistin Base Conversions.a 1-mg Colistin base 1-mg Colistimethate sodium 1-mg Colistin base
Equals Equals Equals
2.4-mg Colistimethate sodium 12 500-IU Colistimethate sodium 30 000-IU Colistin base
a
Data acquired from Falagas and Kasiakou.15
Influence of Dosing Mechanism of Nephrotoxicity Although not fully understood, a similar underlying mechanism may exist between the antibacterial and the nephrotoxic effects of polymyxin antibiotics. Damage to renal tubular cells occurs, and this has been reported to potentially occur due to the effects on membrane structure leading to increased permeability and cell death.3 This is much like the detergent mechanism on the cell membrane of gram-negative bacteria which results in killing and antimicrobial efficacy.
Risk Factors for Nephrotoxicity A variety of correlations with and risk factors for colistimethateinduced nephrotoxicity have been isolated across studies. Given the multitude of literature regarding colistimethate now coming to light with the resurgence of its use, along with the variability in how nephrotoxicity rates have been described, an attempt was made to focus only on studies that described nephrotoxicity in terms of RIFLE criteria (Figure 1), the detailed description of which is provided elsewhere.4 Nine such studies specifically examining colistimethate were isolated and utilized for this review.5-13
Some have suggested that enhanced rates of nephrotoxicity seen in older studies may have been the result of inappropriate dosing strategies used at the time. Insufficient monitoring of hydration and renal status in the past, with subsequent inadequate titration of dosing based on renal function, has also been proposed as one possible culprit.14 Another factor may be related to confusion regarding doses prescribed according to colistimethate sodium versus colistin base, along with the various conversions between these compounds in milligrams and international units. From the data given in Table 1, it can easily be seen how such confusion could arise, particularly with some variation in labeling and descriptions of recommended dosing across nations and over time. Interpretation of literature regarding nephrotoxicity rates has also been made more difficult at times due to insufficient description of doses actually received in this regard. For purposes of this review, all further discussion of dosing across various studies is in terms of milligrams of colistin base, unless otherwise noted. Regardless of the above-mentioned factors clouding appropriate use, a dose-related nephrotoxicity phenomenon still appears to exist according to the majority of studies. Both the magnitude of the daily dose and the cumulative dose received have variably been reported as primary determinants of nephrotoxicity. The impact of determining dose based upon ideal body
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weight (IBW) versus actual body weight (ABW) may play a significant role in this relationship as well. It is recommended via the prescribing information of branded and generic colistimethate injection products in the United States to dose the drug based on IBW in obese individuals.16-20 Pogue et al, in retrospective review of a cohort of 126 predominantly intensive care unit (ICU)-based patients receiving colistimethate therapy, reported a median dose of 5.48 mg/kg/d IBW at the time of meeting nephrotoxicity criteria versus 3.85 mg/kg/d IBW in those patients not developing nephrotoxicity (P ¼ .02).5 In fact, 69% of patients receiving a daily dose of 5.0 mg/kg/d IBW developed nephrotoxicity versus only 33% of those receiving 3.0 to 4.9 mg/kg/d IBW. A dose of 5.0 mg/kg/d IBW was found to be an independent risk factor for nephrotoxicity upon multivariate analysis. When consideration is given to dosing based on ABW, thresholds for increasing nephrotoxicity were lowered further. Nephrotoxicity rates of 55% were seen at doses 4.0 mg/kg/d ABW. Cumulative dose data were not specifically described but was noted not to be a risk factor in this study, as most renal dysfunction occurred early in therapy. In this study, the overall nephrotoxicity rates were found to be 43%. Similarly, in a retrospective study of 30 patients receiving colistimethate therapy, DeRyke et al reported a median dose of 5.5 mg/kg/d IBW in those developing nephrotoxicity versus 4.4 mg/kg/d IBW in those not developing nephrotoxicity (P ¼ .011).6 When based on ABW, median doses of 4.2 mg/kg/d were associated with nephrotoxicity versus 4.0 mg/kg/d in those not developing nephrotoxicity, a differential that did not result in statistical significance. However, patients who were considered to have received excessive doses (defined as > 0.4 mg/kg/d above the recommended dose for a given level of renal function) due to use of ABW as opposed to IBW were 13.2 times more likely to develop acute kidney injury (P ¼ .005). In this study, cumulative dose was again not found to be a risk factor for renal dysfunction. Total median IV doses of 1838 and 1823 mg were reported in those patients developing and not developing nephrotoxicity, respectively. An overall nephrotoxicity rate of 33% was reported in this investigation. In a cohort of 66 patients, Hartzell et al also retrospectively examined associations with colistimethate-induced nephrotoxicity.7 In this study, the dose in mg/kg/d was not found to be associated with acute kidney injury. Patients developing and not developing renal insult received mean daily doses of 4.4 and 4.2 mg/kg/d, respectively. Information as to whether or not doses were based on IBW or ABW was not provided. Mean cumulative dose (6454 vs 4727 mg, P ¼ .005) was found to be significantly associated with developing versus not developing nephrotoxicity in this study. Fifty-nine patients received only IV therapy, while 6 patients received additional inhaled colistimethate therapy. It was not clear in the study description as to whether or not inhaled therapy was tallied in the cumulative dose statistics. The overall nephrotoxicity rate found in this analysis was 45%. Kwon et al retrospectively evaluated 71 patients in an effort to describe nephrotoxicity of colistimethate.8 The median dose received for the entire cohort was 4.6 mg/kg/d, although description was not provided regarding what body
weight (ie, ABW vs IBW) that doses were based upon or on the weight characteristics of their population. Examination of differential in nephrotoxicity rates according to dose in mg/kg/d was not reported. They did however note that the cumulative dose of colistimethate was significantly associated with the development of nephrotoxicity. A median total dose of 41.6 mg/kg was noted in those patients who developed nephrotoxicity. Overall, nephrotoxicity was encountered in 53.5% of patients in this study. In a prospective, observational investigation of 102 patients undertaken by Sorli et al, various dosing schemes of colistimethate were allowed and subsequently examined.9 The study compared 1 million units (80 mg) IV every 8 hours (Q8H), 2 million units (160 mg) IV Q8H, 3 million units (240 mg) IV Q8H, and ‘‘other’’ doses, with all being expressed as colistimethate sodium. Doses in terms of colistin base according to IBW were approximately 1.5, 2.9, 4.4, and 1.5 mg/kg/d, respectively. The daily dose was not found to be associated with colistimethate-induced nephrotoxicity. On univariate analysis, median cumulative dosing was significantly linked with renal injury at the end of therapy assessment—97.3 million units colistimethate (3243.3 mg colistin base) versus 103.9 million units colistimethate (3463.3 mg colistin base) in those without and with nephrotoxicity, respectively (P ¼ .047). However, these same findings were not isolated upon multivariate analysis of the data. The overall nephrotoxicity rate in this study approached 52%. Of interest is that the study in question also examined plasma concentrations of colistin. On the univariate analysis, both peak and trough levels were correlated with nephrotoxicity at day 7 and at the end of therapy, and trough levels had a significant correlation upon multivariate analysis. The authors also pointed out that once steady state is achieved, peak and trough serum levels are essentially the same numerically. Gauthier et al published a retrospective analysis devoted specifically to a 42 patient cohort of mostly ICU-based patients that were overweight or obese (defined as body mass index (BMI) of 25-29.9 and > 30 kg/m2, respectively).10 While renal toxicity was not found to be correlated with mean dose in mg/kg/d based on IBW at 3.31 mg/kg/d in the toxicity group versus 3.14 mg/kg/d in the nontoxicity group, a compelling relationship was found when considered based on actual body weight (P ¼ .02). Actual body weight doses in the toxicity and nontoxicity groups were 1.81 mg/kg/d and 2.19 mg/kg/d, respectively. Median cumulative doses received were not found to have an impact on toxicity (2450 mg in the toxicity group and 2320 mg in the nontoxicity group). Patients developing nephrotoxicity were significantly larger based on mean ABW (110.5 vs 86.8 kg, P ¼ .02) and median BMI (33.5 vs 30.4 kg/m2, P ¼ .015). Although no linear relationship between dosing weight and nephrotoxicity was elucidated, upon multivariate analysis, a BMI of 31.5 kg/m2 was associated with enhanced risk of nephrotoxicity (P ¼ .025). The overall nephrotoxicity rate in this study was 48%, which is quite similar to the toxicity rates seen across the other RIFLE-based studies considered. However, the IBW-based doses used appeared to be less than those employed in the previously described studies. Although the prior studies discussed elucidated some form of relationship between dosing, either daily or cumulative, and
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acute kidney injury, several RIFLE-based studies analyzed did not discover such a correlation. One such study was the retrospective review by Ko et al of 119 predominantly ICU-based patients.11 Mean doses received were reported to be 230.8 and 250.4 mg/d in patients with and without acute kidney injury, respectively. Within this study, attributes of the subpopulations developing early (within 7 days) and late (after 7 days) nephrotoxicity were also compared. For this subset, mean dose was also not significantly correlated with renal insult (232.6 vs 259.5 mg/d, respectively). Although weight characteristics of the study population were not reported, it was detailed that standard dosing utilized in this study was 5 mg/kg/d (divided 3 times daily) in normal renal function, and mean baseline serum creatinine was normal for the cohort. Data regarding the potential impact of cumulative doses were not assessed. The overall acute kidney injury rate in this study was approximately 55%. In a retrospective review of a larger (n ¼ 174) and predominantly ICU-based patient population, Collins et al did not find a relationship between weight-based daily dosing and rates of nephrotoxicity.12 Patients developing renal dysfunction received a dose of 4.06 mg/kg/d versus 3.96 mg/kg/d in those not developing renal dysfunction. Analysis was also performed of doses ranging from 3 to 4.9 mg/kg/d compared to doses 5 mg/kg/d, which also did not yield any statistically significant associations. Doses were reported to have been based on ABW, although weight descriptions of the patient population were not provided. The impact of colistimethate cumulative dose on nephrotoxicity potential was not reported. The overall nephrotoxicity rate in this investigation was 48%. In another smaller retrospective study involving 49 ICU patients who had received colistimethate, Doshi et al similarly did not find a relationship between dosing and development of renal toxicity.13 Doses received were examined in terms of both ABW and IBW. In each case, no correlation was found for risk of colistimethate-induced nephrotoxicity and mean doses administered (for those developing and not developing nephrotoxicity, respectively: 2.9 mg/kg/d vs 2.6 mg/kg/d based on ABW; 4 mg/ kg/d vs 3.8 mg/kg/d based on IBW). Median cumulative dose was also not linked to nephrotoxicity risk (2850 mg in those developing nephrotoxicity and 1200 mg in those not developing this adverse effect). The overall nephrotoxicity rate was 31% in this study.
Concomitant Nephrotoxins The additive/synergistic or potentiating effects of other medications on cumulative nephrotoxicity risk is always a matter of concern in patients on colistimethate therapy. By nature of that, many studies have examined the relationships of these drugs when administered concomitantly with colistimethate. Frequently analyzed agents have included aminoglycosides, vancomycin, IV contrast, diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), nonsteroidal anti-inflammatory agents (NSAIDs), calcineurin inhibitors, amphotericin B, and pressor agents. The interplay of multiple parings of these agents has also been investigated in several studies.
Aminoglycosides are well known for their nephrotoxicity potential, and practitioners may frequently be wary of utilizing these agents along with colistimethate therapy. Interestingly, the RIFLE-based studies reviewed have essentially reported a lack of significant effect on nephrotoxicity rates when colistimethate and aminoglycosides are utilized together.5-7,9-11 The analysis performed by Doshi et al did however note a statistical trend for a concomitant aminoglycoside association (P ¼ .069).13 So, while such concerns about enhancing renal adverse effects intuitively make sense, substantial risk may not be born out in practice. Cautious use of dual aminoglycoside þ colistimethate therapy may therefore be possible if necessitated clinically. Vancomycin is another antibiotic frequently linked with possible renal adverse effects. Similar to aminoglycosides, none of the studies reviewed that examined vancomycin associations isolated additional nephrotoxicity risk with concomitant colistimethate.6-8,9-11,13 Therefore, avoidance of vancomycin and utilization of alternative agents for gram-positive coverage in those patients receiving colistimethate would seemingly not be substantiated according to the examined literature. Five of the considered studies adequately examined the relationship between IV contrast and nephrotoxicity rates during colistimethate therapy. Exact types and quantities of IV contrast received were predominantly not defined. Four of these investigations did not reveal a correlation between receipt of contrast agents and higher risk of nephrotoxicity.6-8,10 However, Doshi et al did note a statistically significant association with IV contrast material.13 Diuretics may show an association with colistimethate nephrotoxicity according to some reviewed studies. Deryke et al reported a statistically significant association with diuretics (class of diuretic not defined) and renal toxicity while on colistimethate in univariate analysis.6 However, when patients receiving pressors were excluded from the analysis, such a relationship did not exist. Low numbers of patients in this study prevented a multivariate analysis from being performed. Pogue et al similarly found a statistically significant relationship with loop diuretics upon univariate analysis, although the same relationship was not reported upon multivariate analysis.5 In the study performed by Sorli et al, loop diuretic use was not found to be associated with colistimethate nephrotoxicity at day 7 of therapy on univariate analysis, but an association was significant at the end of therapy.9 In similar vein to the study by Pogue et al, multivariate analysis did not uncover any statistically significant relationships. Other reviewed studies adequately examining this potential association did not yield any statistically significant results.7,8,10,13 Pressor agents were sufficiently examined for potentiation of nephrotoxicity in 5 studies, although only the analysis of DeRyke et al found a significant association with colistimethate nephrotoxicity.5-7,10,13 Use of ACE inhibitor or ARB was suitably analyzed in 3 studies, none of which found a correlation with renal adverse effects on colistimethate therapy.6,10,13 Four studies inspected possible links between NSAID use and nephrotoxicity of colistimethate. Of these, 3 studies found no relationship, while the study by Sorli et al found a significant association at the end of therapy on univariate
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analysis although not at the earlier point of day 7 of therapy or upon multivariate analysis.8-10,13 Calcineurin inhibitors were only examined in 2 reports.8,10 The study by Kwon et al discovered a statistically compelling relationship with colistimethate nephrotoxicity in both univariate and multivariate analyses.8 However, Gauthier et al uncovered no such relationship.10 A discussion of which calcineurin inhibitor agents were predominantly utilized in the study was not provided. Only the study by Doshi et al reported specifically on the possibility of an amphotericin B association, although no statistical correlation was isolated.13 Additionally, and while not traditionally considered a nephrotoxic agent, Pogue et al unearthed upon multivariate analysis that concomitant rifampin administration was associated with colistimethate nephrotoxicity (although the same relationship was not seen during univariate analysis of variables).5 Although many of the above-mentioned pharmacologic agents did not appear to have a relationship with colistimethate nephrotoxicity individually, exposure to multiple potential nephrotoxins with inclusion of colistimethate did appear to yield significant associations in 4 studies where this was examined. Pogue et al discovered upon multivariate analysis that receipt of 3 potentially renal toxic agents concomitantly was associated with colistimethate nephrotoxicity.5 Of note, vancomycin exposure was not considered in this study, as the authors felt that its nephrotoxic nature was still debatable based on the current literature. Collins et al isolated upon multivariate analysis that receipt of one or more concurrent nephrotoxins was significantly associated with colistimethate renal toxicity.12 Vancomycin and loop diuretics represented the largest exposures to potentially nephrotoxic drugs in this study, with >50% of study patients having received concomitant therapy with at least one of these agents, while >10% of study patients had also received an aminoglycoside or IV contrast dye. Relationships with individual agents were not reported. Doshi et al found that receipt of 2 additional potential nephrotoxins was significantly linked with colistimethate nephrotoxicity on multivariate analysis.13 Sorli et al displayed in their report that coadministration of 2 additional potentially nephrotoxic agents was significantly correlated with colistimethate nephrotoxicity.9
Additional Risk Factors Beyond the impact of dosing and concurrent nephrotoxic agents, other associations have at times been reported with various patient-specific factors and disease states. However, the variables analyzed have been assorted and frequently dissimilar among investigations. Two of the most commonly considered or isolated items across the studies examined were age and hyperbilirubinemia. Several studies have suggested some association with increasing age and propensity for colistimethate-induced kidney injury6,10,12 although at the same time others have not yielded such results.5,7,8,11,13 The majority of all patients across these investigated studies were in the sixth to seventh decade of life, with the exception of the study by Hartzell et al, which featured predominantly patients in their third decade of life by way of studying a younger population through a military institution.7
Two studies that analyzed total bilirubin as a variable elucidated a statistically significant relationship with colistimethate nephrotoxicity.8,11 It is worth noting that both of these studies examined populations of Korean patients. In one study,11 patients manifesting acute kidney injury had a higher total bilirubin than those who did not (2.6 mg/dL vs 1.0 mg/dL, P < .05). Additionally, within the nephrotoxicity group, those with early injury occurring within 7 days had a significantly higher bilirubin than those developing toxicity later in the course (3.3 mg/ dL vs 0.6 mg/dL, P < .05). In the other study,8 statistically more patients in the group developing nephrotoxicity had hyperbilirubinemia, defined as a total bilirubin >5 mg/dL, than those who did not (P ¼ .026). However, in the study by Gauthier et al, no association was revealed with utilizing the same total bilirubin threshold.10 This study featured patients in the United States, although it is worth noting that the overall size of the cohort was smaller (n ¼ 42 vs 70). None of the other analyzed studies examined any associations with bilirubin. It would appear that further study of hyperbilirubinemia as a possible risk factor is warranted, particularly in non-Korean populations, as a component of genetic interplay cannot be ruled out. The exact mechanism responsible for this relationship between higher total bilirubin levels and renal toxicity of colistimethate has also not been determined, but a similar relationship has been reported in the context of aminoglycoside nephrotoxicity.21-24
Severity and Time Course of Nephrotoxicity All the examined studies, through utilization of RIFLE criteria, provided descriptive information regarding severities of renal toxicity encountered.5-13 The percentage of patients developing nephrotoxicity falling into the Risk category ranged from 15% to 44% across studies and varied from 5% to 47% for those falling into the Injury category. The largest differential occurred in the Failure category, with reported rates spanning between 13% and 80%. Taking into account the reported quantities of patients developing nephrotoxicity while on colistimethate therapy across all of the examined studies, approximately 30%, 30%, and 40% progressed to the Risk, Injury, and Failure categories of RIFLE criteria, respectively. Of note, the majority of all patients in the considered studies had normal baseline renal function, frequently owing to exclusion criteria for significant renal dysfunction utilized within many of the analyses. Some patients developing nephrotoxicity while on colistimethate therapy have required renal replacement therapy. This was reported across many of the reviewed investigations.8,10-12 The rate of patients with acute kidney injury requiring such modalities approached 20% and varied between 0% and 28% across the studies examined. Few patients in the reviewed studies were documented as having persistence in nephrotoxicity as defined by Loss and End Stage Renal Disease (ESRD) categorizations of RIFLE criteria. This may be somewhat indicative of the reversibility of colistimethate-induced renal toxicity. However, limitations may exist in the data accrued due to the nature of how Loss and ESRD criteria are defined (ie, Loss criteria being defined at >4
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weeks and ESRD criteria being defined at >3 months). Lack of adequate follow-up information within these time frames could either owe to patient mortality or postdischarge status. When acute kidney injury occurred, the time of onset was most frequently within the first 5 to 7 days of therapy. Pogue et al reported that approximately 78% of their patient cohort with nephrotoxicity had occurrence within the first 7 days of therapy.5 Ko et al had similar results with 71% of the observed nephrotoxicity occurring within the first week of colistimethate exposure, while Sorli et al found approximately 49% of acute kidney insult occurring within that time frame.9,11 In the review by Kwon et al, a median onset of 7.5 days to acute kidney injury was elucidated.8 The patient cohort analyzed by Gauthier et al had median onset of 5 days to the appearance of renal injury, while DeRyke et al had all 10 patients developing nephrotoxicity on colistimethate do so within 5 days of therapy initiation.6,10 Considering the totality of the information examined and presented, acute kidney injury that may develop while on colistimethate therapy most often appears to be mild to moderate in magnitude. It is also more often than not reversible in nature and frequently not requiring more invasive measures such as dialysis. Given these traits, higher tolerance for occurrence of renal adverse effects may be reasonable in order to maintain the potential for positive infection-related outcomes with continuation of therapy in the face of toxicity.
Relative Nephrotoxicity Traits of Colistimethate and Polymyxin B As can be seen from the preceding discussion, overall nephrotoxicity rates with colistimethate according to RIFLE criteria have been variable and in the range 31% to 55%,5-13 with a weighted average of approximately 47% based on the sample sizes in the respective studies. Less studies specifically utilizing RIFLE criteria are present to assess polymyxin B-induced acute kidney injury although some have been reported in the literature. Kubin et al retrospectively examined 73 patients having received polymyxin B in an attempt to characterize risk factors for nephrotoxicity as described by RIFLE criteria.25 Median dose received was 1.8 mg/kg/d (18 000 units/kg/d) and was reported to have been calculated on total (actual) body weight. Intermittent dosing was utilized with the bulk of patients receiving every 12 hours (Q12H; 52%) or Q24H (40%) dosing. Upon multivariate analysis of data, patients with BMI 25 kg/m2 displayed significantly higher rates of acute kidney injury than those with lower BMI (P ¼ .045), although comparative weight-based dosing between the 2 groups was found to be statistically similar at 1.7 mg/kg/d (17 000 units/kg/d) and 1.9 mg/kg/d (19 000 units/kg/ d), respectively (P ¼ .551). While not examined via multivariate regression, the median cumulative dose of polymyxin B was found to be significantly higher in the group experiencing acute kidney injury (1578 vs 800 mg, P ¼ .02). Concomitant vancomycin exposure was also found to confer additional risk of nephrotoxicity on polymyxin B therapy (P ¼ .03), although use of other individual potential nephrotoxins (aminoglycosides, IV contrast, diuretics, calcineurin inhibitors, amphotericin B) did not yield such an
association. Use of ACE inhibitor/ARB was not assessed, and no patients received NSAIDs. Age was not found to confer additional risk, and hyperbilirubinemia was not assessed statistically. Median time to onset of renal toxicity was 4 days. Of those developing nephrotoxicity, approximately 55% were categorized as Injury or Failure per RIFLE criteria. Of those developing acute renal adverse effects, 16% required renal replacement therapy, and the overall rate of nephrotoxicity in this study was 60%. In 2013, Akajagbor et al reported nephrotoxicity characteristics on a retrospective cohort of patients having received either polymyxin B or colistimethate at their institution during the time period 2008 to 2010.26 In patients with normal renal function, polymyxin B was dosed at 15 000 to 25 000 units/kg/d as a continuous infusion, while colistimethate was dosed intermittently but by way of a variety of strategies (5 mg/kg/d IBW, 5 mg/kg/ d ABW or a fixed dose of 150 mg Q12H). It was not specified as to what weight polymyxin B was dosed upon. Presumably, dosing occurred based on ABW, as data available in a supplement to the article indicate mean calculated doses based on IBW were closer to 22 000 units/kg/d in the study. A total of 173 patients were included in the analysis, with 89% being an ICU-based population. Overall, nephrotoxicity developed in 41.8% and 60.4% of patients receiving polymyxin B and colistimethate, respectively (P ¼ .02), with a median onset of approximately 4 days and a mean time to peak serum creatinine of approximately 7 days. Patients in both the polymyxin B and the colistimethate groups fell into the RIFLE criteria categories in a relatively similar distribution to that mentioned previously regarding colistimethateonly studies, although numerically higher percentages of polymyxin B patients were in the Risk and Injury subsets, while larger percentages of colistimethate patients fell into more advanced divisions of renal injury. Of 64 patients, 7 (11%) experiencing acute kidney injury on colistimethate were categorized in the Loss designation, while only 1 patient in the colistimethate group progressed to end-stage kidney disease (ESKD). Of note, no patients in the polymyxin B group progressed to Loss or ESKD categories as defined by RIFLE criteria. Proportions of patients requiring renal replacement therapy were not specifically described. On multivariate analysis of the entire cohort, age 31 to 60 years old (P ¼ .022) and colistimethate use (P ¼ .002) were independently associated with nephrotoxicity. Concomitant nephrotoxins were not noted to significantly potentiate renal toxicity, with at least 25% of patients having received one or more of the following: aminoglycosides, vancomycin, IV contrast, diuretics, and pressors. Hyperbilirubinemia was not assessed as a possible risk factor. It was reported that average daily and cumulative doses were comparable for those developing and not developing nephrotoxicity in both the polymyxin B and the colistimethate groups. However, it was noted that nephrotoxicity rates tended to increase for colistimethate based on dose according to IBW (54.5%, 62.3%, and 65% for doses of 5 mg/kg/d, respectively). Mean calculated doses of colistimethate received in the study were approximately 2.9 mg/kg/d IBW (3.9 mg/kg/d ABW) per the supplemental data provided. Similar results were found in another recent retrospective cohort review of 225 patients by Phe et al.27 In that study, the
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prevalence of nephrotoxicity based on RIFLE criteria was higher with colistimethate than with polymyxin B in a matched cohort review (55.3% vs 21.1%, P ¼ .003). The onset of nephrotoxicity was also significantly earlier in patients administered colistimethate (P ¼ .003). In the intention-to-treat analysis, rates of acute kidney injury for colistimethate and polymyxin B were 33.9% and 23.1% (P ¼ .08), respectively. In patients without cystic fibrosis, respective rates were 48.2% and 23.1% (P < .001). Examining stratification according to RIFLE categories, and in contrast to the analysis by Akajagbor and colleagues, numerically larger percentages of colistimethate patients were in Risk and Injury groupings and a greater percentage of polymyxin B patients reached the Failure designation (although the only statistically significant differential occurred in the Risk category, with a substantially larger portion of colistimethate patients: 14% vs 4.8%, P ¼ .02). Upon multivariate analysis, duration of therapy was found to be a significant risk factor for nephrotoxicity for both colistimethate and polymyxin B (P ¼ .02 for each). Daily dose based on ideal body weight was also found to be a significant risk factor for colistimethate (P ¼ .02), although daily doses were not found to be for polymyxin B. Interestingly, cystic fibrosis was found to be a protective factor against acute renal toxicity for colistimethate upon the multivariate analysis (P ¼ .04). Such analysis was not permitted for polymyxin B as no patients with cystic fibrosis were present in that cohort. Age was also found to be an independent risk factor for acute kidney injury in the colistimethate group (P ¼ .03), although not for polymyxin B. Of note, patients in the colistimethate cohort were substantially younger than patients in the polymyxin B cohort (mean 46.4 years vs 71.4 years, P < .001). Hyperbilirubinemia was not assessed as a risk factor in this analysis. Mean doses utilized in this study were 1.8 mg/kg/d IBW (18 000 units/kg/d IBW) for polymyxin B and 4.6 mg/kg/d IBW for colistimethate. Based on ABW, respective mean doses were 1.5 mg/kg/d (15 000 units/kg/d) and 4.1 mg/kg/d. Cumulative doses were not reported.
discontinuation of colistimethate treatment—that is, balancing the generally reversible nature of its nephrotoxicity, along with potentially deleterious effects of withholding antimicrobial therapy, versus attempts to mitigate further insult to the kidney. In the setting of continued treatment with colistimethate, sufficient dose reduction based on estimated glomerular filtration rate according to published recommendations is imperative. This is particularly true in light of the possible correlations between dose and renal toxicity presented earlier.
Conclusion Given the growing amount of current literature on the subject, in addition to the variability in definitions applied, an attempt was made to describe the renal injury characteristics of colistimethate (and secondarily for polymyxin B as well) in terms of studies utilizing a standardized definition in the RIFLE criteria. At dosing strategies currently used, and in prevailing clinical contexts, unacceptably high rates of nephrotoxicity are still seen with colistimethate therapy. However, the magnitude of kidney toxicity often encountered and the frequently reversible nature do not rule out therapy and are reassuring on some level. The finding of inconsistent associations between use of concomitant nephrotoxins and renal adverse effects may also add an element of confidence in some therapeutic scenarios. Although data are limited, the findings of comparatively lower nephrotoxicity rates with polymyxin B are intriguing and warrant further study—ideally in the form of prospective studies versus colistimethate. Given the complexities of colistimethate pharmacokinetics, in addition to clinical experience with safety and efficacy thus far in contemporary settings, such investigations would be of value. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
Treatment of Nephrotoxicity No definitive treatment modalities for colistimethate-induced nephrotoxicity have been isolated. Care is predominantly supportive in nature. Renal replacement therapy is occasionally required as noted previously. Maintaining adequate hydration is advisable. Avoiding continued administration of concomitant nephrotoxins when possible would appear to be intuitive while noting the previously described data that the relationship between colistimethate-induced kidney injury and accompanying nephrotoxic agents has frequently not been established. Discontinuation of colistimethate therapy, with use of alternative antibiotic options available, may be advisable when therapeutically feasible. However, given the typical clinical circumstances under which colistimethate therapy is employed, the presence of other treatment modalities may be minimal or nonexistent. Therefore, clinical decisions must be made regarding overall risks and benefits of continuation versus
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Supplemental Material The online [appendices/data supplements/etc] are available at http:// jpp.sagepub.com/supplemental.
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4. Bellomo R, Ronco C, Kellum J, et al. Acute renal failure- definition, outcome measures, animal models, fluid therapy and information technology needs: the second international consensus conference of the acute dialysis quality initiative (ADQI) group. Crit Care. 2004;8(4):R204-R212. 5. Pogue J, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis. 2011;53(9):879-884. 6. DeRyke C, Crawford A, Uddin N, et al. Colistin dosing and nephrotoxicity in a large community teaching hospital. Antimicrob Agents Chemother. 2010;54(10):4503-4505. 7. Hartzell J, Neff R, Ake J, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis. 2009;48(12):1724-1728. 8. Kwon J, Lee J, Huh W, et al. Predictors of acute kidney injury associated with intravenous colistin treatment. Int J Antimicrob Agents. 2010;35(5):473-477. 9. Sorli L, Luque S, Grau S, et al. Trough colistin plasma level is an independent risk factor for nephrotoxicity: a prospective observational cohort study. BMC Infect Dis. 2013;13:380. 10. Gauthier T, Wolowich W, Reddy A, et al. Incidence and predictors of nephrotoxicity associated with intravenous colistin in overweight and obese patients. Antimicrob Agents Chemother. 2012; 56(5):2392-2396. 11. Ko H, Jeon M, Choo E, et al. early acute kidney injury is a risk factor that predicts mortality in patients treated with colistin. Nephron Clin Pract. 2011;117(3):c284-8. 12. Collins J, Haynes K, Gallagher J. Emergent renal dysfunction with colistin pharmacotherapy. Pharmacotherapy. 2013;33(8):812-816. 13. Doshi N, Mount K, Murphy C. Nephrotoxicity associated with intravenous colistin in critically ill patients. Pharmacotherapy. 2011;31(12):1257-1264. 14. Spapen H, Jacobs R, Van Gorp V, et al. Renal and neurological side effects of colistin in critically ill patients. Ann Intensive Care. 2011;1(1):14.
15. Falagas M, Kasiakou S. Use of international units when dosing colistin will help decrease confusion related to various formulations of the drug around the world. 2006;50(6):2274-2275. 16. Coly-mycin M injection [package insert]. JHP Pharmaceuticals, LLC, Rochester, Michigan; 2013. 17. Colistimethate injection [package insert]. X-GEN Pharmaceuticals, Inc., Big Flats, New York; 2012. 18. Colistimethate injection [package insert]. Paddock Laboratories, Inc., Minneapolis, Minnesota; 2012 19. Colistimethate injection [package insert]. Fresenius Kabi USA, LLC., Lake Zurich, Illinois; 2013. 20. Colistimethate injection [package insert]. Heritage Pharmaceuticals, Inc. Eatontown, New Jersey; 2014. 21. Cortes J, Gamba G, Contreras A, et al. Amikacin nephrotoxicity in patients with chronic liver disease. Rev Invest Clin. 1990; 42(2):93-98. 22. Oliveira J, Silva C, Barbieri C, et al. Prevalence and risk factors for aminoglycoside nephrotoxicity in intensive care units. Antimicrob Agents Chemother. 2009;53(7):2887-2891. 23. Desai T, Tsang T. Aminoglycoside nephrotoxicity in obstructive jaundice. Am J Med. 1988;85(1):47-50. 24. Lucena M, Andrade R, Cabello M, et al. Aminoglycosideassociated nephrotoxicity in extrahepatic obstructive jaundice. J Hepatol. 1995;22(2):189-196. 25. Kubin C, Ellman T, Phadke V, et al. Incidence and predictors of acute kidney injury associated with intravenous polymyxin B therapy. J Infect. 2012;65(1):80-87. 26. Akajagbor D, Wilson S, Shere-Wolfe K, et al. Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin b in critically ill patients at a tertiary care medical center. Clin Infect Dis. 2013;57:1300-1303. 27. Phe K, Lee Y, McDaneld P, et al. Comparison of nephrotoxicity rates associated with colistimethate versus polymyxin B therapy: in vitro assessment and a multicenter cohort study. Antimicrob Agents Chemother. 2014;58(5):2740-2746.
Continuing Education Credit The New York State Council of Health-system Pharmacists (NYSCHP) is pleased to provide you with the opportunity to obtain continuing education credit for this article online at HealthSystemCE.org (http://www.healthsystemce.org); login using your email address and HSCE password; then click the ‘‘Journal CE’’ tab. There is no charge to NYSCHP members. If you are not a member of NYSCHP, call 1-518-456-8819 to pay the $15 fee to access the quiz and obtain the password necessary to access the Journal’s CE article. In lieu of this fee, a completed membership application with your dues may be submitted. A grade of 70% or above is required to earn the CE credit. Repeat examinations will be permitted once for a grade below 70%. AN ¼ The NYSCHP is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity provides 1.4 contact hours (0.14 CEUs) of continuing education. The Universal Activity Number is 0134-0000-14-156-H01-P. Submission of exam for CE credit expires October 31, 2017.
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