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143（ 1 ）Risk factors associated with unexpectedly high troughconcentration and the occurrence of nephrotoxicity inpatients with vancomycin treatment
Yoshiko Takahashi1,*, Sumiyo Tatsumi1,*, Shingo Takubo1,
Takeshi Kimura1 and Yoshio Takesue2
12

Department of Pharmacy, Hospital of Hyogo College of Medicine
Department of Infection Prevention and Control, Hyogo College of Medicine(Received for publication February 15, 2017)

Objectives: The purpose of this study was to identify clinically important risk
factors that may predispose patients with appropriate vancomycin dosing to an
unexpectedly-high trough concentration (Cmin) and the occurrence of nephrotoxicity.
Methods: Patients treated with vancomycin and who were performed therapeutic
drug monitoring were included in the study. Nephrotoxicity was deﬁned as anincrease of ＞0.5 mg/dL or a 50% increase in serum creatinine over the baseline.
Multivariate analysis was performed to identify independent risk factors for Cmin of≥20 μg/mL and deterioration of renal function.
Results: One hundred and ninety-seven patients were analyzed. Nephrotoxicity
occurred in 16.8% of patients during vancomycin therapy. Cmin of ≥20 μg/mL wasdemonstrated in 17.8% of patients. Twenty-ﬁve of 35 patients demonstrated a Cmin of≥20 μg/mL at multiple TDM. Cmin of ≥20 μg/mL and deterioration of renal function
were closely correlated with one another. Additionally, an independent risk factor
identiﬁed to be associated with Cmin of ≥20 μg/mL was the administration ofdiuretics [odds ratio (OR) 3.21, 95% conﬁdence interval (CI) 1.30–7.90]. Use ofnon-steroidal anti-inﬂammatory drugs (NSAIDs) (OR 3.22, 95% CI 1.09–9.57) andmanagement with total parenteral nutrition (OR 3.64, 95% CI 1.33–10.00) wereindependent factors associated with nephrotoxicity during vancomycin therapy.
Conclusions: NSAIDs, diuretic drug use and total parenteral nutrition (TPN) wereindependent risk factors for a high Cmin or nephrotoxicity. Limited use of these drugs
is preferable to prevent adverse events during vancomycin therapy.

*: Equal contribution

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1. Introduction
Many studies have demonstrated a positive association between the risk of nephrotoxicity
and higher vancomycin doses, ranging from 12 to 42.7% of patients1–4). The risk increases withhigher vancomycin maximum trough levels, longer duration of vancomycin use, and concomitant
use of other nephrotoxic agents as well as in patients who are critically ill or have previously
compromised renal function5). The occurrence of nephrotoxicity signiﬁcantly increased as the initial trough concentration (Cmin) increased. Several reports have shown that Cmin of ≥20 μg/mL hada signiﬁcantly higher incidence of nephrotoxicity than those of ＜20 μg/mL3,4,6).
Because vancomycin is mainly eliminated by glomerular ﬁltration, a decrease in renal function, whatever the cause, will increase the vancomycin concentration. As the elevated concentrations of vancomycin may represent an effect, rather than a cause, of nephrotoxicity, the association between maximum Cmin during vancomycin therapy and the occurrence of nephrotoxicity
should be assessed with caution. Although several studies aimed to identify the risk factors fornephrotoxicity in patients receiving vancomycin therapy, to our knowledge, no study has deﬁnitively determined the risk factors causing unexpectedly high vancomycin concentration, such as
trough levels of ≥20 μg/mL. If such risk factors are identiﬁed, they will have important implication for clinical practice. Alternative antimicrobial agents should be considered not only in patients with risk factors for nephrotoxicity, but also in patients who have factors that may cause atrough level of ≥20 μg/mL to prevent the occurrence of vancomycin-induced nephrotoxicity. The
primary endpoint of the study was to identify the risk factors causing a trough level of ≥20 μg/mL
during vancomycin therapy, which was managed by a certiﬁed pharmacist, and the secondary
endpoint was to determine the risk factors associated with vancomycin-induced nephrotoxicity.

2. Material and Methods
A retrospective study was conducted among patients who received vancomycin for suspected or diagnosed Gram-positive infection between January 2011 and December 2011 in the
Hyogo College of Medicine hospital (1,006 beds). This study was approved by the institutional
review board at Hyogo College of Medicine. Patients who were treated with a certiﬁed pharmacist in the Department of Infection Control and Prevention were included in the analysis if they(i) were ＞17 years old, (ii) received vancomycin for at least 72 h (iii) had a vancomycin troughlevel measurement within 96 h after starting administration, and at least once every week thereafter. Exclusion criteria consisted of patients with hemodialysis, vasopressor support during therapy, concomitant administration of aminoglycosides or amphotericin B, use of contrast media
during therapy, and a history of receiving vancomycin for at least 72 h in the 14 days prior to inclusion.

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145（ 3 ）Vancomycin was administered at a dose of 15–20 mg/kg every 12 h to patients with normal
renal function, and the dosing regimen was adjusted based on the creatinine clearance (which was
calculated by the Cockcroft-Gault formula based on serum creatinine, age, and body weight) inpatients with decreased renal function using a nomogram. Vancomycin concentration was measured using a commercial reagent kit (Vanc Flex; Siemens Healthcare Diagnostics Inc., Tokyo,
Japan). This is a particle-enhanced turbidimetric inhibition immunoassay (PETINIA), which uses
a Dimension Xpand analyzer. Predicted Cmin value was calculated using analysis-supporting simulation software (VCM-TDM on EXCEL Ver.2.01, Shionogi & Co., LTD.). Targeted Cmin was
10–15 μg/mL during the study period.
Deterioration of renal function (nephrotoxicity) was deﬁned as an increase in serum creatinine of 0.5 mg/dL, or a ≥50% increase from the baseline serum creatinine level before start ofvancomycin. A certiﬁed pharmacist ordered therapeutic drug monitoring (TDM) during thecourse of vancomycin therapy, and the vancomycin dosage was adjusted according to the Cmin.
Initial and maximum Cmin during vancomycin therapy were used in the analysis of the association
between vancomycin concentration and occurrence of nephrotoxicity.
Twenty-one variables were analyzed as possible risk factors associated with a Cmin of≥20 μg/mL and nephrotoxicity: age ≥65 years, sex (male), body weight ＜50 kg, comorbid disease (diabetes mellitus, liver cirrhosis/chronic hepatitis, chronic renal failure, cardiac disease, hypertension, carcinoma, or inﬂammatory bowel disease), surgery within 1 month, administration of
concomitant drugs (diuretic drug, non-steroidal anti-inﬂammatory drugs (NSAIDs), immunosuppressive agents, or steroids), laboratory data (albumin ＜2.5 g/dL or serum creatinine ≥1.0 mg/dL)at the start of vancomycin treatment, and prolonged duration of vancomycin therapy (longer thanthe median value). Additionally, because the elevated concentrations of vancomycin may represent not only an effect, but also a cause of nephrotoxicity, deterioration of renal function was included in the analysis of risk factors for a trough level of ≥20 μg/mL, and a trough level of≥20 μg/mL was analyzed as a possible risk factor for nephrotoxicity.
The variables selected by univariate analysis (P＜0.2) were subjected to multivariate analysis. Statistical analysis was performed as follows: categorical variables were compared by theχ2 test with Yatesʼs correction or Fisherʼs exact probability test when necessary (chi-squareprocedures by Yatesʼs correction can be legitimately applied only if all values are ≥5), using Microsoft Excel 2003. To calculate the correlation between each category of Cmin (＜20, 20–25, and≥25 μg/mL) and the incidence of nephrotoxicity, the Cochran-Armitage test was used. The levelof statistical signiﬁcance was set at P＜0.05. SPSS ver. 16 (SPSS Inc., Chicago, IL, USA) wasused to perform these analyses.

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3. Results
During the study period, vancomycin was administered to 225 patients, and 197 patientswere evaluable. Clinical characteristics were demonstrated in Table 1. Of the 197 evaluable patients, 71 were deemed to have documented methicillin-resistant Staphylococcus aureus (MRSA)
infections. Initial and maximal trough concentrations were demonstrated in Table 2. Thirty-threepatients (16.8%) met the deﬁnition of nephrotoxicity. All cases of nephrotoxicity were reversible,
with short-term dialysis required in ﬁve patients. Incidence of nephrotoxicity was 7.4% (12/162
patients) in patients consistently with a maximum trough level of ＜20 μg/mL, 44.4% (8/18
Table 1. Clinical characteristic in patients who received vancomycin for suspected or diagnosed
Gram-positive infection

Table 2. Trough level in patients who received vancomycin

Table 3. Comparison of trough level, renal function, and dosing and duration of vancomycin therapy between patients demonstratinga trough level of ≥20 μg/mL and those consistently ＜20 μg/mL

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147（ 5 ）Table 4. Risk factors associated with a trough level of ≥20 μg/mL (univariate analysis)

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June 2017Table 5. Risk factors associated with deterioration of renal function during vancomycin therapy (univariate analysis)

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patients) in those demonstrating a maximum trough level of 20–25 μg/mL, and 76.5% (13/17
patients) in those with ≥25 μg/mL.
Cmin, renal function and vancomycin therapy in patients demonstrating a Cmin of ≥20 μg/mL
and those consistently with ＜20 μg/mL (Table 3). There was no signiﬁcant difference in serum
creatinine at the start of vancomycin therapy between these two groups. Creatinine at the time of
TDM prior to the TDM demonstrating a Cmin of ≥20 μg/mL was 0.63±0.23 mg/dL. On average, aCmin of ≥20 μg/mL was ﬁrst observed after 3.2±2.5 performances of TDM. Twenty-ﬁve of 35
patients demonstrated a Cmin of ≥20 μg/mL at multiple TDM performances. The average Cminmeasured at the TDM prior to the one demonstrating the maximum Cmin ≥20 μg/mL was
13.8±4.6 μg/mL, and a dose increase was performed in 2 of the 25 patients according to the Cminof the TDM prior to the TDM demonstrating the maximum Cmin ≥20 μg/mL. The vancomycin
daily dosage was 1.72±0.56 g, and the predicted Cmin value was 10.82±4.52 μg/mL at the TDM
prior to demonstrating a Cmin of ≥20 μg/mL. The actual Cmin was 29.09±10.67 μg/mL.
Univariate analysis of risk factors associated with a Cmin of ≥20 μg/mL and those associatedwith deterioration of renal function during vancomycin therapy are shown in Tables 4 and 5, respectively. Diuretic drug use, deterioration of renal function during vancomycin therapy, total
parenteral nutrition and male were selected for multivariate analysis of the risk factors for a Cminof ≥20 μg/mL, and NSAIDs, management of total parenteral nutrition, Cmin of ≥20 μg/mL, surgery, enteral nutrition and diuretic drug use were selected for multivariate analysis of the risk factors for deterioration of renal function.
In multiple logistic regression analysis, diuretics use (adjusted odds ratio (OR): 3.21, 95%
conﬁdence interval (CI): 1.30–7.91) and deterioration of renal function during vancomycin therapy (adjusted OR: 16.39, 95% CI: 6.24–43.07) were found to be signiﬁcantly associated with amaximum Cmin of ≥20 μg/mL (Table 6). In addition, a Cmin of ≥20 μg/mL (adjusted OR: 17.95,

Table 6. Independent risk factors associated with a trough level of ≥20 μg/mL (multivariate
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151（ 9 ）Table 7. Independent risk factors associated with deterioration of renal function during
vancomycin therapy (multivariate analysis)

95% CI: 6.67–48.33), NSAIDs (adjusted OR: 3.22, 95% CI: 1.09–9.57), and total parenteral nutrition (TPN) (adjusted OR: 3.64, 95% CI: 1.33–10.00) were found to be independent risk factors
associated with the occurrence of nephrotoxicity (Table 7).

4. Discussion
The associations between vancomycin exposure and nephrotoxicity were largely attributed
to baseline differences in disease severity and concomitant nephrotoxin. In patients with elevatedbaseline risk of nephrotoxicity independent of vancomycin exposure, the risk is ampliﬁed substantially by the addition of vancomycin therapy. Induction of mild renal dysfunction prior to elevation of vancomycin concentration, and the resulting high serum concentration of vancomycin
due to decrease of renal clearance may further cause deterioration of renal function (Lodise etal.5)).
However, in the present study, baseline serum creatinine and serum creatinine prior to the
TDM that demonstrated a high trough level did not differ between patients who experienced aCmin of ≥20 μg/mL and those consistently with a Cmin of ＜20 μg/mL. The daily dose of vancomycin at the time of TDM prior to the TDM demonstrating a Cmin of ≥20 μg/mL was 1.72 g, andthere was no signiﬁcant difference compared with that at the time of the TDM demonstrating
the maximum Cmin in patients with a Cmin consistently ＜20 μg/mL. Duration of vancomycin
therapy was 8.6 days in patients with Cmin of ≥20 μg/mL and 7.6 days in patients with Cmin of＜20 μg/mL. Hence, neither overdosing, longer duration of vancomycin therapy, nor low renal152（ 10 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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function should have caused a high Cmin in patients with a Cmin of ≥20 μg/mL. Similarly, Hidayat
et al.7) demonstrated that duration of vancomycin therapy and baseline serum creatinine values
did not differ between those who attained high (15–20 μg/mL) vs low trough levels (＜15 μg/mL).
Anticipation of high trough level or deterioration of renal function during vancomycin therapy is important to prevent the occurrence of adverse events due to vancomycin. As mentioned
above, deterioration of renal function and a Cmin of ≥20 μg/mL occurred simultaneously. Excluding these, independent risk factors for Cmin of ≥20 μg/mL was diuretic drug use, and independentrisk factors for deterioration of renal function during vancomycin therapy were NSAIDs and
TPN. Risk factors associated with nephrotoxicity, other than vancomycin exposure, have been
demonstrated by several authors8). Elyasi et al.9) reported that there are a number of different risk
factors which could accelerate or potentiate the occurrence of vancomycin-induced nephrotoxicity, with the most documented risk factors being high trough vancomycin level (especially≥20 μg/mL) or dose (＞4 g/day), concomitant treatment with nephrotoxic agents, prolonged therapy (even more than 7 days), and admittance to an intensive care unit (especially prolonged stay).
Concomitant nephrotoxic agents can increase the incidence of vancomycin-associated nephrotoxicity by up to 35%10). Most patients with drug-induced nephrotoxicity received amphotericin
B, tobramycin or tacrolimus with vancomycin7,11,12). Concomitant vasopressor and intravenous
contrast media agents were also reported as risk factors of vancomycin-induced nephrotoxicity5,13). Hidayat et al.7) also reported that concomitant nephrotoxic agents remain the most signiﬁcant predictor of the development of nephrotoxicity by multivariate analysis. Possible nephrotoxic agents were radiopaque dye, aminoglycosides, amphotericin B, cyclosporine A, tacrolimus,
angiotensin-converting enzyme inhibitors and angiotensin receptor blocking agents and NSAIDs
and COX-2 inhibitors are known to raise serum creatinine. To prevent the impact of these apparent risk factors for nephrotoxicity, we excluded patients with hemodialysis, vasopressor support
during therapy, concomitant administration of aminoglycosides or amphotericin B, and use ofcontrast media during therapy. However, due to the frequent use, we included patients who wereconcomitantly administered NSAIDs.
Malnourished patients may represent a subgroup of critically ill patients for whom the clinician may consider initiating TPN. TPN is indicated for patients in whom enteral nutrition or oral
intake are not feasible. The administration of oral or enteral nutrition in patients with sepsis has
potential physiologic advantages related to the maintenance of gut integrity and prevention of intestinal permeability, dampening of the inﬂammatory response, and modulation of metabolic responses14). These might cause deterioration of renal function in patients with TPN during vancomycin therapy.
In our study, diuretic drug use were selected for multivariate analysis of the risk factors for a
Cmin of ≥20 μg/mL. McKamy et al.15) reported that nephrotoxicity occurred in patients with targeted troughs of ≥15 μg/mL, in the intensive care unit, and receiving furosemide. Furosemide isJune 2017

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153（ 11 ）not a direct nephrotoxin, but its use may cause dehydration, in which the addition of vancomycin
may further increase developing nephrotoxicity. Jeffres et al.6) reported that a loop diuretic waspresent in 63% of adult patients who had nephrotoxicity during vancomycin therapy. Cappelletty
et al.16) reported that furosemide use, hypertension, and vancomycin Cmin ≥16.2 μg/mL were eachassociated with nephrotoxicity during vancomycin therapy. Ingram et al.17) reported that use ofaminoglycosides or loop diuretics, and vancomycin Cmin of ≥28 μg/mL were independent risk
factors. From these, we hypothesized that concomitant use of nephrotoxic agents such as NSAIDs
and dehydration caused by a diuretic drug induces mild renal dysfunction prior to elevation of
vancomycin concentration, and the high serum concentration of vancomycin occurring as a resultof decreased renal clearance causes further deterioration of renal function.
Our analyses have some limitations. First, degree of severity of infection was not assessed.
Hemodynamic instability might cause renal dysfunction during vancomycin therapy, and enlargement of volume of distribution caused by extravasation have an impact on the serum vancomycin
concentration18). Second, recent guidelines recommend Cmin of 15–20 μg/mL in serious infection19). However initial Cmin remaied 9.56±5.87 μg/mL in our study. Third, although we investigated the risk factors for deterioration of renal function and a Cmin of ≥20 μg/mL individually, it is
difﬁcult to determine which occurred ﬁrst and caused the other.
In conclusion, considerably high incidence of nephrotoxicity and high Cmin was observed,
even in patients receiving treatment with adequate dosing of vancomycin, and in those without
lower renal function at baseline. NSAIDs, diuretic drug use, and TPN were independent risk factors for high Cmin or nephrotoxicity. Limited use of these drugs is preferable to prevent adverse
events during vancomycin therapy.
Acknowledgement
This study was awarded the 9th award in the category of clinical research conferred by the director of the west Japan branch of the Japanese Society of Chemotherapy.
Conﬂict of interest
Yoshio Takesue has received support grant from Shionogi & Co., Ltd. and Meiji Seika
Pharma Co., Ltd. and payment for lectures from Pﬁzer Japan Inc., MSD K.K., Astellas PharmaInc., Dainippon Sumitomo Pharma, Meiji Seika Pharma Co., Ltd., Taisho Toyama Pharmaceutical Co., Asahi Kasei Pharma Co., Ltd. and the Japanese Association for Infectious Diseases. Allother authors: none to declare.

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