Professional Documents
Culture Documents
risk factor for nephrotoxicity highlights the need for latter study.14 Because of a greater emphasis on achieving
additional studies to assess current recommendations for higher vancomycin levels (target trough levels of 1520
vancomycin dosing for ICU patients with pneumonia. mg/L) in recent guidelines,13 we believe additional stud-
(Clin Ther. 2012;34:149 157) 2012 Published by ies are warranted to assess the potential nephrotoxic risks
Elsevier HS Journals, Inc. of increased vancomycin exposure.
Key words: intensive care, nephrotoxicity, nosoco- To evaluate the risk of nephrotoxicity in ICU pa-
mial pneumonia, vancomycin. tients with pneumonia treated with broad-spectrum em-
piric therapy including vancomycin, we performed a ret-
rospective analysis of patients enrolled in IMPACT-HAP
INTRODUCTION (Improving Medicine Through Pathway Assessment of
Hospital-acquired pneumonia (HAP), ventilator-asso- Critical Therapy in Hospital-Acquired Pneumonia).
ciated pneumonia (VAP), and health careassociated IMPACT-HAP is a multicenter performance improve-
pneumonia (HCAP) are important causes of morbidity ment project initiated soon after publication of the ATS/
and mortality in intensive care units (ICUs), despite IDSA guidelines and aimed at improving the manage-
advances in antimicrobial therapy and the use of better ment of ICU patients with nosocomial pneumonia,
supportive care modalities. The American Thoracic So- details of which have been recently published.15 In the
ciety (ATS) and the Infectious Diseases Society of current study, our primary objective was to report the
America (IDSA) published an updated guideline for the incidence of nephrotoxicity and its associated risk factors
management of HAP, VAP, and HCAP in 2005,1 in ICU patients who received vancomycin for the treat-
which emphasized early, appropriate antibiotics in ad- ment of HAP, VAP, and HCAP.
equate doses. These guidelines recommend that patients
with risk factors for infection with multidrug-resistant METHODS
pathogens should receive broad-spectrum empiric ther- Study Design
apy with activity against gram-negative pathogens, in- This was a retrospective analysis of data collected
cluding Pseudomonas aeruginosa, and an antibiotic with from a multicenter, observational study of ICU pa-
activity against methicillin-resistant Staphylococcus au- tients with a diagnosis of HAP, VAP, or HCAP treated
reus (MRSA). The guidelines indicate that vancomycin at 4 academic medical centers in the United States: the
should be dosed to achieve target trough levels of 15 to 20 University of Louisville (Louisville, Kentucky), The
mg/L.1 The same vancomycin trough levels are also rec- Ohio State University Medical Center (Columbus,
ommended for serious infections due to S aureus and Ohio), the Henry Ford Health System (Detroit, Mich-
MRSA (including pneumonia) in a consensus review of igan), and the University of Miami/Jackson Memorial
therapeutic monitoring of vancomycin by the American Hospital (Miami, Florida). The performance improve-
Society of Health-System Pharmacists, the Society of In- ment project, IMPACT-HAP, has been described in
fectious Diseases Pharmacists, and the IDSA2 and in the detail previously.15 Patients included in this study were
recently published IDSA Clinical Practice Guidelines for treated from February 2006 through July 2007. Local
the treatment of MRSA infections.3 institutional review board approval was obtained in
Nephrotoxicity is uncommon when vancomycin is each participating hospital with waiver of consent for
used at conventional dosages (eg, 1 g every 12 data collection and analysis. Data were collected on
hours).2,4 6 The risk, however, may increase when case-report forms, entered into a Web-based database,
vancomycin is administered concomitantly with other and transferred electronically to the IMPACT-HAP
nephrotoxic drugs or at the higher dosages needed to Data and Statistical Coordinating Center at the Uni-
achieve target trough levels for patients with HAP, versity of Louisville. The center validated the quality of
VAP, and HCAP.7 In early studies, vancomycin nephro- data by checking for discrepancies and inconsistencies.
toxicity was confined to patients receiving concomitant Upon validation, the cases were available for analysis.
aminoglycoside therapy.2,6 More recent studies indicate
that vancomycin trough levels 15 mg/L8 13 and high Patient Population and Inclusion Criteria
daily dosages (ie, 4 g)14 are independently associated Adults in participating ICUs were eligible for inclu-
with an increased risk of nephrotoxicity. ICU patients sion in the analysis if they met ATS/IDSA definitions
had a 3-fold higher risk than non-ICU patients in the for HAP, VAP, or HCAP1; received treatment with
broad-spectrum empiric therapy that included vanco- or the Fisher exact test, and continuous variables were
mycin; had 1 vancomycin trough level collected compared using the Student t test and the nonparamet-
within 96 hours of vancomycin therapy; and had a ric Wilcoxon rank sum test when appropriate.19
baseline serum creatinine level 2 mg/dL. Patients To identify factors independently associated with
were excluded if they had a baseline serum creatinine nephrotoxicity, multivariate logistic regression analy-
level 2 mg/dL, no serum creatinine recorded at study ses were conducted.19 Variables associated with neph-
entry, or known history of end-stage renal disease or rotoxicity in the bivariate analysis were considered for
dialysis at baseline. We collected data on patient demo- inclusion in the models, requiring P 0.20 for each
graphic and baseline characteristics; severity of illness, term to be included. Kaplan-Meier analyses were used
including the Acute Physiology and Chronic Health Eval- to examine time to nephrotoxicity according to vanco-
uation (APACHE) II score, which provides a general mycin trough levels, with patients stratified into 4
measure of severity of disease by assigning points based groups according to initial vancomycin trough level as
on initial values of 12 routine physiologic measurements, follows: 10, 10 to 15, 15 to 20, and 20 mg/L.
age, and previous health status16; diagnostic procedures;
and treatment, including all antibiotics received from the
time of diagnosis of pneumonia. Patients were followed RESULTS
up until hospital discharge, death, or 28 days after pneu- IMPACT-HAP enrolled 449 ICU patients with HAP,
monia diagnosis, whichever occurred first. Laboratory HCAP, or VAP. We excluded 209 patients from anal-
values were collected during the index hospitalization, ysis because they had no baseline serum creatinine re-
including serum creatinine and vancomycin trough levels. corded (n 38), had a baseline serum creatinine 2
It was recommended that blood for trough concentra- mg/dL (n 79), had a known history of end-stage
tions be drawn 1 hour before planned dosing. As part renal disease or dialysis at baseline (n 6), or did not
of the standard of care at each institution, clinical phar- receive treatment with vancomycin (n 86). These
macists were actively involved in the care of ICU patients criteria were applied hierarchically; although it is pos-
and assisted with appropriate dosing of antibiotics. sible some patients had multiple exclusion criteria,
they were only counted once (Figure 1).
Study Definitions Of 240 evaluable patients, 188 were treated with
Baseline serum creatinine was defined as the mean vancomycin and had sufficient clinical and laboratory
of the values recorded on days 1 and 0, with day 0 follow-up information for analysis. In these 188 pa-
being day of pneumonia diagnosis and, in general, ini- tients, 63% were male; the mean (SD) age was 58.5
tiation of antibiotic therapy. Nephrotoxicity was de- (17.2) years; and the mean APACHE II score was 19.4
fined as an increase in serum creatinine 0.5 mg/dL or (6.4). Nephrotoxicity during the period from initiation of
50% above baseline, whichever was greater, in at least 2 vancomycin therapy to 72 hours after completion of ther-
consecutive measurements during the period from initia- apy occurred in 29 of 188 vancomycin-treated patients
tion of vancomycin therapy to 72 hours after completion (15.4%). The demographic and clinical variables signifi-
of therapy.2,14 Because vancomycin is mainly eliminated cantly associated with the occurrence of nephrotoxicity
by glomerular filtration, any change in renal function can in bivariate analysis were higher median vancomycin
affect vancomycin serum concentrations. To account for trough level, initial vancomycin trough level 15 mg/L,
this potential confounder, we limited our analysis of van- concomitant aminoglycoside administration, and shorter
comycin trough levels to those recorded within the first ICU stay before diagnosis of pneumonia (Table I).
96 hours of initiation of therapy.17 All vancomycin In the multivariate logistic regression analysis, vari-
trough levels documented in the medical record were col- ables independently associated with nephrotoxicity in
lected, and the highest concentration in the first 96 hours vancomycin-treated patients were initial vancomycin
was used in the analysis. trough level 15 mg/L (odds ratio [OR], 5.2 [95% CI,
1.9 13.9]; P 0.001), concomitant administration of
Statistical Analysis aminoglycosides (OR, 2.67 [95% CI, 1.09 6.54]; P
Statistics were calculated using SAS 9.2 (SAS Insti- 0.03), and duration of vancomycin therapy as a con-
tute Inc, Cary, North Carolina).18 For bivariate analy- tinuous variable (OR for each additional treatment
ses, categorical variables were compared using 2 test day, 1.12 [95% CI, 1.021.23]; P 0.02; Table II).
Figure 1. Flow of patients through analysis. ESRD end-stage renal disease; IMPACT-HAP Improving Medicine
Through Pathway Assessment of Critical Therapy in Hospital-Acquired Pneumonia.
A relationship was observed between vancomycin ences in mortality at 28 days were not significant
trough levels and the occurrence of nephrotoxicity. (33.3% vs 25.3%; P 0.48).
Nephrotoxicity significantly increased as a function of In an effort to address reverse causality (ie, the
the initial vancomycin serum trough concentration, potential confounding effect of acute renal injury
rising from 7.0% at a trough 10 mg/L to 34.0% at already present at pneumonia diagnosis), the bivari-
20 mg/L (P 0.001; Figure 2). Kaplan-Meier analysis ate and multivariate analyses were repeated after
revealed a significant difference in mean time to nephro- eliminating those patients with evidence of acute re-
toxicity when patients were stratified according to initial nal dysfunction on study day 0. This excluded 3
vancomycin trough level (P 0.0003; Figure 3). Mean patients presenting with an increase in serum creat-
time to nephrotoxicity decreased from 8.8 days at vanco- inine 0.5 mg/dL above their previously known
mycin trough levels 15 mg/L to 7.4 days at 20 mg/L. baseline, 10 patients with a 50% creatinine in-
Patients who developed nephrotoxicity had a longer crease above baseline, and 21 patients for both rea-
ICU stay (median [interquartile range (IQR)], 17 [9 sons. In this subgroup, nephrotoxicity was observed
26] vs 12 [6 20] days; P 0.03) and seemed to have a in 18 of 154 patients (11.7%). Demographic and
longer hospital stay (median [IQR], 20 [14 30] vs 15 clinical characteristics were similar to those of the
[9 26] days; P 0.06) after initiation of antibiotics for 188 vancomycin-treated patients. In these 154 pa-
pneumonia than those patients without nephrotoxic- tients, 63% were male and the mean age was 58.4
ity, although the difference in hospital stay did not (17.2) years. Because APACHE II includes points for
reach statistical significance. Between-group differ- renal dysfunction, the mean scorenot unexpectedly
Nephrotoxicity No Nephrotoxicity
Characteristic (n 29) (n 159) P
IQR interquartile range; CPIS Clinical Pulmonary Infection Score; APACHE II Acute Physiology and Chronic Health
Evaluation II; NP nosocomial pneumonia; ICU intensive care unit.
*All percentages were based on number of evaluable patients (ie, excludes patients with missing data).
The following characteristics were included in the bivariate model but are not shown above because P 0.2: race, type of
pneumonia, renal disease, cardiac disease, cardiosystem dysfunction, and mechanical ventilation.
was slightly lower in the patients without acute nephrotoxicity was duration of vancomycin therapy
nephrotoxicity at baseline (18.3 [6.0] vs 19.4 [6.4]; (OR, 1.15 [95% CI, 1.031.28]; P 0.01). The OR
P 0.01). In multivariate logistic regression analy- for vancomycin trough 15 mg/L was 2.93 (95%
sis, the only variable independently associated with CI, 0.96 8.92; P 0.06).
Table II. Multivariate logistic regression model for the occurrence of nephrotoxicity in vancomycin-treated
patients.
DISCUSSION
Nephrotoxicity is a frequent complication in ICU pa-
tients. Even modest decreases in renal function are as-
sociated with negative outcomes in critically ill pa-
tients, including increased mortality, hospital length of
stay, duration of mechanical ventilation, and hospital
costs.20 22 The recent recommendations in guideline
documents1,3 and an expert review2 to maintain higher
vancomycin trough levels when this antibiotic is used
as part of broad-spectrum empiric therapy for pneu-
monia stimulated our interest in examining the poten-
tial outcomes and consequences of implementing this
practice in ICU patients with pneumonia.
We found that nephrotoxicity occurred in 15.4% of Figure 3. Kaplan-Meier analysis of time to nephro-
188 ICU patients who received vancomycin for the toxicity stratified according to initial van-
treatment of HAP, VAP, or HCAP. The frequency of comycin trough values (P 0.0003).
nephrotoxicity increased as a function of initial vanco-
sistent with that in our study. There are 2 outlying based on changes in serum creatinine and is similar
articles that merit further consideration. Matsko et al25 to risk level in the RIFLE (Risk, Injury, and Failure;
reported the lowest incidence (7% in 299 patients in a and Loss, and End Stage Kidney Disease) criteria28 and
240-bed government teaching hospital). Although the Stage I in the Acute Kidney Injury Network crite-
their meeting abstract provided no additional details ria.29 By limiting our analysis to patients initial van-
about the patient population, they also found a signif- comycin trough values, we improved our capacity to
icant relationship between initial vancomycin troughs determine whether a causal exposureresponse rela-
and nephrotoxicity. Jeffres et al9 reported the highest tionship exists. To the best of our knowledge, this is the
incidence (43% in 102 patients with HCAP due to largest study to date describing incidence of nephro-
MRSA in a 1200-bed urban teaching hospital), which toxicity and the role of vancomycin in development of
was attributed to aggressive vancomycin dosing and nephrotoxicity in ICU patients with HAP, VAP, and
prolonged vancomycin administration. HCAP.
Importantly, others have reported that vancomycin Our study also has important limitations. IMPACT-
was an independent risk factor for nephrotoxicity, es- HAP was an observational performance improvement
pecially when analyzed according to increased serum project, not a randomized controlled trial. As such,
concentrations as trough 15 mg/L8 13 or 22.5 mg/ IMPACT-HAP did not dictate prescribing practice;
L,25 steady-state concentration 28 mg/L,24 highest however, vancomycin trough levels were recom-
trough,23 mean trough,17,23 and duration of ther- mended by the study team in accordance with the
apy.12,13,23,25 Additional independent risk factors, all guidelines and managed locally as part of routine care
potentially present in our IMPACT-HAP population, by clinical pharmacists in participating ICUs. Al-
included ICU residence11,17 and concomitant use of though this was a retrospective analysis, investigators
aminoglycosides24 or other nephrotoxic agents.11,13,23 completed data-collection forms and validated the in-
Collectively, these studies may have important im- formation locally before transferring it via the Internet
plications for practical implementation of the current to the IMPACT-HAP coordinating center, where it un-
ATS/IDSA guideline.1 Our results and those of others derwent a second validation. Even with the relatively
question whether vancomycin should be dosed to large study group, some subsets were too small for
achieve target trough levels of 15 to 20 mg/L when detailed analysis, such as a more thorough evaluation
used in ICU patients with HAP, VAP, or HCAP. Since of patients receiving concurrent vancomycin and ami-
the ATS/IDSA guideline was published, Jeffres et al26 noglycoside therapy. The use of inclusion and exclu-
reported that higher mean vancomycin trough values sion criteria may limit the generalizability of our re-
and higher mean AUC values did not have favorable sults. Our patients were adults in multiple ICUs who
effects on survival in patients with HCAP due to had HAP, VAP, or HCAP, an inherently complex
MRSA. In a subsequent study,9 the same investigators group for analysis; however, they were a more homog-
concluded that aggressive dosing strategies for vanco- enous group than those in previous studies that in-
mycin may not offer any advantages in clinical efficacy cluded patients with mixed infections in widely varied
and that alternative agents should be considered. Based settings.8,17,23,24 Although we collected detailed infor-
on our data and those of others, the benefit of increased mation on antibiotic use, we did not have information
vancomycin dosing to achieve higher troughs should on exposure to all nephrotoxic agents, such as intrave-
be weighed against the risk of nephrotoxicity. nous contrast dye. Similarly, although we excluded pa-
Our study has several strengths, including a well- tients with evidence of acute renal dysfunction at diag-
characterized study population with clinical and lab- nosis, we did not include detailed data on shock and
oratory information available for analysis.15,27 For other ICU-related risk factors for nephrotoxicity.
consistency with other studies, we used a nephrotox-
icity definition that is a reasonable composite from CONCLUSIONS
the literature and matches the definition for vanco- Our study provides evidence that nephrotoxicity may
mycin-induced nephrotoxicity used in the 2009 con- be common among ICU patients with HAP, VAP, or
sensus statement by the American Society of Health- HCAP who receive broad-spectrum antibiotic therapy
System Pharmacists, the IDSA, and the Society of that includes vancomycin. An exposureresponse rela-
Infectious Diseases Pharmacists.2 This definition is tionship exists between initial vancomycin trough level
and occurrence and mean time to nephrotoxicity. A conflicts of interest with regard to the content of the
vancomycin trough level 15 mg/L may be an inde- article.
pendent risk factor for nephrotoxicity in ICU pneumo-
nia patients. Our findings suggest the need for additional
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ACKNOWLEDGMENTS
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Funding for this study was provided by Pfizer Inc, US
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Impact of mild acute kidney injury Address correspondence to: Daniel H. Kett, MD, Division of Pulmonary
(AKI) on outcome after open repair and Critical Care Medicine, the Miller School of Medicine at the University
of aortic aneurysms. Ren Fail. 2008; of Miami, Jackson Memorial Hospital, 1611 NW 12th Avenue, C455A,
30:287296. Miami, FL 33156. E-mail: dkett@med.miami.edu