Highlights
- •Associations between vancomycin treatment and nephrotoxicity were evaluated retrospectively in 90 patients in the northwest of China.
- •Fourteen (15.6%) patients developed nephrotoxicity, with serum creatinine elevated significantly from mean (standard deviation) 90.0 (18.8) μmol/l to 133.8 (63.2) μmol/l (p = 0.015).
- •Drug dosing >38 mg/kg/day and a serum trough level >20 mg/l were identified as risk factors of nephrotoxicity.
- •The renal function of critically ill patients receiving vancomycin should be monitored closely.
Summary
Objective
To identify specific risk factors of vancomycin-induced nephrotoxicity in China, as the relationship between vancomycin therapy (dosing and trough concentration monitoring) and nephrotoxicity has been the subject of critical debate.
Methods
The cases of 90 critically ill patients who received vancomycin therapy in Xijing Hospital in the northwest of China between March 2014 and January 2015 were reviewed retrospectively. Vancomycin dosing, blood serum trough concentration, and other independent risk factors associated with nephrotoxicity were evaluated in a multivariable model.
Results
Among the 90 critically ill patients, 59 were males; mean age was 46.3 years. The indications for vancomycin use were methicillin-resistant Staphylococcus aureus-associated pneumonia, central nervous system infection, and bacteremia. Clinical pharmacists prescribed weight-based dosing, ranging from 20 to 45 mg/kg/day. Fourteen (15.6%) patients developed nephrotoxicity, with serum creatinine elevated significantly from a mean (standard deviation) of 90.0 (18.8) μmol/l to 133.8 (63.2) μmol/l (p = 0.015). It was found that those with a vancomycin dosage >38 mg/kg/day (50.0% vs. 11.3%, p = 0.004) and a vancomycin serum trough concentration >20 mg/l (57.1% vs. 12.0%, p = 0.01) were more likely to develop nephrotoxicity.
Conclusion
The data from this study indicate that a vancomycin dosage >38 mg/kg/day and a serum trough level >20 mg/l are both independent factors associated with the development of nephrotoxicity, suggesting that renal function should be monitored closely during vancomycin treatment.
Keywords
1. Introduction
Vancomycin is a tricyclic glycopeptide antibiotic that is commonly used for the treatment of severe infections caused by Gram-positive bacteria. It is especially indicated for methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant pneumococci, and for patients who are allergic to penicillins and cephalosporins.
1
, 2
, - Gould F.K.
- Brindle R.
- Chadwick P.R.
- Fraise A.P.
- Hill S.
- Nathwani D.
- et al.
MRSA Working Party of the British Society for Antimicrobial Chemotherapy. Guidelines (2008) for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the United Kingdom.
J Antimicrob Chemother. 2009; 63: 849-861
3
However, there is controversy regarding vancomycin dosing, infusion methods, and serum concentration monitoring. On the one hand, the treatment of infections in the central nervous system (CNS) and skin require higher blood concentrations because of the poor penetration of vancomycin into these tissues. This pushes the effective blood concentrations close to toxic levels, and the incidence of vancomycin-related nephrotoxicity varies widely between 5% and 35%.4
, 5
In addition, pharmacokinetic studies have generated conflicting evidence on the association between serum concentration, efficacy, and nephrotoxicity.6
, - Hall R.G.
- 2nd
- Hazlewood K.A.
- Brouse S.D.
- Giuliano C.A.
- Haase K.K.
- Frei C.R.
- et al.
Empiric guideline-recommended weight-based vancomycin dosing and nephrotoxicity rates in patients with methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study.
BMC Pharmacol Toxicol. 2013; 14: 12
7
, 8
, 9
, - Rybak M.
- Lomaestro B.
- Rotschafer J.C.
- Moellering Jr., R.
- Craig W.
- Billeter M.
- et al.
Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
Am J Health Syst Pharm. 2009; 66: 82-98
10
On the other hand, inadequate drug dosing and low serum concentrations (<10 mg/l) might promote an increase in the vancomycin minimum inhibitory concentration (MIC) for bacteria, resulting in the development of vancomycin-resistant strains.11
, 12
, 13
Indeed, a gradual increase in vancomycin MIC in MRSA isolates has been demonstrated, which has pushed the vancomycin dosing to a higher level.14
According to the Infectious Diseases Society of America, clinicians can target the vancomycin serum trough concentration at a range of 15–20 mg/l for complicated infections to improve penetration and efficacy. Further, body weight-based vancomycin dosages of less than 30 mg/kg/day seldom cause severe nephrotoxicity.
9
However, previous evidence has indicated that a serum trough concentration >15 mg/l might be associated with increased nephrotoxicity.- Rybak M.
- Lomaestro B.
- Rotschafer J.C.
- Moellering Jr., R.
- Craig W.
- Billeter M.
- et al.
Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
Am J Health Syst Pharm. 2009; 66: 82-98
15
, 16
A vancomycin dosing nomogram to achieve high trough concentrations has been assessed in Taiwanese patients.17
In China, the patients receiving vancomycin are usually critically ill and their drug clearance rate may be altered drastically, making them more susceptible to nephrotoxicity. However, data regarding the associations between serum trough concentrations, efficacy, and toxicity in the northwest of China are lacking. Therefore, the goal of the present study was to evaluate the risk factors of nephrotoxicity in these critically ill patients receiving vancomycin therapy, including the drug dosing regimen, serum trough concentration, age, body weight, and incidence of nephrotoxicity. The results of this study will provide new useful evidence to guide vancomycin treatment in China.
2. Patients and methods
2.1 Patients
A retrospective cohort study was conducted in Xijing Hospital of the Fourth Military Medical University between March 2014 and January 2015. Adult patients who received vancomycin for at least 48 h were identified. Patients with renal dysfunction (receipt of dialysis or creatinine clearance <30 ml/min), those treated with vancomycin during the same hospital stay, those receiving concomitant nephrotoxins (aminoglycosides, amphotericin B, radiocontrast dye, and vasopressors), and those without available laboratory data were excluded from the evaluation.
For all patients included in this study, the following data were collected: age, gender, actual body weight, diagnosis, type of infection, intensive care unit (ICU) admission, concurrent medication, vancomycin dosing, vancomycin trough concentration, and laboratory measurements. Their medical records and related documents were obtained with informed consent from the central database of Xijing Hospital.
2.2 Design and data collection
Clinicians prescribed vancomycin in accordance with the guidelines and recommendations of the Infectious Diseases Society of America when severe MRSA infections were confirmed. Actual body weight-based dosing ranged from 20 to 45 mg/kg/day. The most frequently used dosing in the study hospital was 1.5–2 g every day. Vancomycin was administered by intermittent intravenous infusion.
Blood samples for the measurement of the vancomycin trough concentration were obtained within 30 min before the administration of the fifth dose of vancomycin. This trough level represents the stable serum trough concentration of the following period. Renal function was monitored constantly, before and during vancomycin therapy.
No severe side effects that required the discontinuation of vancomycin therapy occurred in this study. When the vancomycin trough concentration was higher than 25 mg/l, the vancomycin dosage was adjusted according to the patient's condition. If no methicillin-resistant strain was detected, the chemotherapy was de-escalated to a beta-lactam antibiotic.
2.3 Definitions
Renal function was assessed by measuring the urinary production and the serum concentration of creatinine, urea nitrogen, and cystatin. Nephrotoxicity was defined as an increase in serum creatinine (SCr) >0.5 mg/dl (44.2 μmol/l), or an increase in SCr >50% from the baseline level for at least 2 days.
18
- Bellomo R.
- Ronco C.
- Kellum J.A.
- Mehta R.L.
- Palevsky P.
Acute Dialysis Quality Initiative workgroup
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.
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: R204-R212
2.4 Statistical analysis
Univariate analysis was used to compare patients who developed nephrotoxicity with those who did not develop nephrotoxicity in regard to the age, body weight, and other basic characteristics. Data were analyzed with the Chi-square test. Multivariate analysis was used to identify independent risk factors of vancomycin-associated nephrotoxicity. IBM SPSS Statistics version 20.0 (IBM Corp., Armonk, NY, USA) was used for the analysis of significant differences.
Data were presented as the mean and standard deviation (SD). A p-value of 0.05 or less indicated a statistically significant difference.
3. Results
3.1 Patient characteristics
Among 172 courses of vancomycin identified, 90 patients met the inclusion criteria. The cohort consisted of 59 men and 31 women. Their mean (SD) age was 46.3 (15.6) years and their mean (SD) body weight was 62.4 (9.4) kg. The sources of MRSA infection were bloodstream (52.2%), pulmonary (18.9%), CNS (14.4%), skin/soft tissue (4.4%), genitourinary (4.4%), gastrointestinal (2.2%), osteomyelitis (2.2%), and endocarditis (1.1%).
3.2 Administration of vancomycin
The median length of vancomycin therapy was 9 days. The mean (SD) dosage was 31.3 (5.4) mg/kg/day. Thirty-four patients were given vancomycin dosages between 20 and 30 mg/kg/day (25.5 ± 2.8), and 46 patients were given doses between 30 and 38 mg/kg/day (33.2 ± 2.3). Ten patients were given >38 mg/kg/day (40.4 ± 1.6). The mean (SD) vancomycin serum concentration was 10.1 (5.4) mg/l. Fifty-eight patients had a mean concentration between 5 and 10 mg/l (6.9 ± 1.7), and 25 patients had a mean concentration between 10 and 20 mg/l (13.5 ± 3.0). Seven patients had a concentration higher than 20 mg/l (23.9 ± 2.1). There were two deaths due to multiple organ failure. All other patients achieved clinical cure by the time of discharge from the hospital.
3.3 Incidence of nephrotoxicity
Among 90 patients, there were two mortalities due to multiple organ failure. A total of 14 (15.6%) patients developed nephrotoxicity while receiving vancomycin therapy. None of these patients showed severe symptoms or needed dialysis. Their renal dysfunction was transient and laboratory measurements returned to normal levels before hospital discharge.
The mean (SD) SCr of all patients prior to vancomycin treatment was 78.9 (23.8) μmol/l. The calculated baseline mean (SD) creatinine clearance rate was 94.8 (53.5) ml/min. After the initiation of vancomycin treatment, the mean (SD) SCr increased significantly to 86.8 (38.5) μmol/l (p < 0.05). Although both figures were within the normal range, statistically significant changes were observed when patients with and without nephrotoxicity were evaluated separately.
With regard to the 14 patients who developed nephrotoxicity, their mean (SD) baseline SCr was 90.0 (18.8) μmol/l. During vancomycin treatment, this figure increased significantly to 133.8 (63.2) μmol/l (p = 0.015). For the other 76 patients without nephrotoxicity, there was no significant change in SCr prior to and after treatment: 76.9 (24.1) μmol/l and 78.2 (24.1) μmol/l, respectively (p = 0.41).
The actual body weight and dosing showed significant differences between patients with and without nephrotoxicity. However, in terms of the age, gender, length of vancomycin treatment, vancomycin serum trough concentrations, and baseline SCr levels, there were no significant differences. The results are presented in Table 1.
Table 1Characteristics of patients with and without nephrotoxicity (N = 90)
| Characteristic | No nephrotoxicity (n = 76) | Nephrotoxicity (n = 14) | p-Value |
|---|---|---|---|
| Age, years | 48.6 (15.1) | 51.4 (19.1) | 0.701 |
| Body weight, kg | 52.9 (9.5) | 57.1 (6.7) | 0.006 |
| Treatment length, days | 10.6 (4.7) | 10.5 (3.1) | 0.969 |
| Dosage, mg/kg/day | 30.6 (5.2) | 34.9 (4.9) | 0.007 |
| Trough level, mg/l | 10.7 (4.9) | 14.5 (6.3) | 0.184 |
| Baseline SCr, μmol/l | 76.9 (24.1) | 90 (18.8) | 0.065 |
| SCr during treatment, μmol/l | 78.2 (24.1) | 133.8 (63.2) | 0.009 |
SCr, serum creatinine.
a Results are presented as the mean (standard deviation).
Multivariable data analysis showed that a vancomycin dosage >38 mg/kg/day and a vancomycin serum trough level >20 mg/l were both independent predictors of renal toxicity. The results are shown in Table 2.
Table 2Multivariable analysis of independent risk factors for nephrotoxicity (N = 90)
| Variable | OR | 95% CI | p-Value |
|---|---|---|---|
| Sex female | 0.903 | 0.623–1.308 | 0.764 |
| Age ≥60 years | 1.105 | 0.778–1.570 | 0.503 |
| Body weight ≤55 kg | 1.361 | 0.428–4.333 | 0.406 |
| Dosage ≥38 mg/kg/day | 1.474 | 0.994–2.185 | 0.004 |
| Duration of therapy ≥15 days | 1.621 | 0.72–3.359 | 0.152 |
| Vancomycin trough ≥20 mg/l | 1.345 | 0.963–1.879 | 0.010 |
| ICU admission | 1.013 | 0.804–1.277 | >0.99 |
OR, odds ratio; CI, confidence interval; ICU, intensive care unit.
4. Discussion
In this retrospective study, 15.6% of 90 critically ill patients developed nephrotoxicity during vancomycin treatment. It was demonstrated that patients receiving weight-based dosages higher than 38 mg/kg/day and with a serum trough concentration greater than 20 mg/ml were more likely to develop nephrotoxicity. It was also noticed that the incidence of nephrotoxicity was higher than in previous studies that have reported standard vancomycin dosing (30 mg/kg/day), in which this caused around 5% of patients to develop nephrotoxicity.
4
, 5
This might be due to the fact that 11.1% of patients were receiving dosages around 40 mg/kg/day and all patients were in a critical state.The relationships between vancomycin dosing, serum trough concentrations, and efficacy or nephrotoxicity have been documented by other authors.
4
, 19
, 20
, 21
Vancomycin prescribed at a high dose and an extended duration of use appear to be the risk factors for developing nephrotoxicity.22
, 23
Larger doses and increased vancomycin trough concentrations have been shown to be involved in the occurrence of renal injury.8
, 24
, 25
For instance, vancomycin-induced nephrotoxicity occurred when the dosing regimen maintained the trough concentration between 15 and 20 mg/l.15
, 16
Han et al. also reported that a trough concentration over 12.1 mg/l was a major risk factor for nephrotoxicity in patients undergoing therapeutic vancomycin monitoring.26
The nephrotoxicity might also be a particular matter in high-dose vancomycin therapy for MRSA infections.27
, 28
, 29
Obviously, regular monitoring of vancomycin dosing is critical for the prevention of nephrotoxicity.30
, 31
The increased dosing of vancomycin treatment was supposed to counter the gradual creeping of the vancomycin MIC in MRSA isolates.
1
, 14
Although weight-based vancomycin dosing has been recommended in the guidelines,6
, - Hall R.G.
- 2nd
- Hazlewood K.A.
- Brouse S.D.
- Giuliano C.A.
- Haase K.K.
- Frei C.R.
- et al.
Empiric guideline-recommended weight-based vancomycin dosing and nephrotoxicity rates in patients with methicillin-resistant Staphylococcus aureus bacteremia: a retrospective cohort study.
BMC Pharmacol Toxicol. 2013; 14: 12
7
, 9
the association between different dosing and nephrotoxicity is yet to be clarified, especially in the northwest area of China. From the authors’ observations, aggressive dosages are more likely to cause nephrotoxicity. Evidence suggests that a solution to this problem might be the use of continuous infusion, which could replace the fluctuating concentrations with a plateau concentration of 20–25 mg/l. This could also maximize treatment efficacy and reduce nephrotoxicity. Studies performed by DiMondi and Rafferty- Rybak M.
- Lomaestro B.
- Rotschafer J.C.
- Moellering Jr., R.
- Craig W.
- Billeter M.
- et al.
Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists.
Am J Health Syst Pharm. 2009; 66: 82-98
32
and Hutschala et al.33
have shown that continuous infusion results in a lower rate of nephrotoxicity developing compared with intermittent infusion.32
, 33
Moreover, previous evidence has shown that the incidence of vancomycin-induced nephrotoxicity may also be related to patient age,
34
, 35
, 36
, 37
the severity of illness,38
, 39
chronic kidney disease, and methicillin-resistant pneumonia.40
, 41
In the present study, the incidence of nephrotoxicity of 15.6% also implies that a critically ill state might be a risk factor for renal toxicity with vancomycin therapy. Among the 14 patients who developed nephrotoxicity, 10 were male and four were female, suggesting that there may also be a gender difference in relation to the incidence of nephrotoxicity.The possible mechanisms of vancomycin-induced nephrotoxicity have also been investigated previously.
42
For instance, oxidative stress from mitochondrial superoxide production might contribute to vancomycin-related renal injury,43
, 44
while the manipulation targeting superoxide dismutase to renal tubule cells has been shown to improve the vancomycin-induced nephrotoxicity in rodents.45
The serum neutrophil gelatinase-associated lipocalin could also influence renal function in patients on vancomycin treatment,46
and the functional state of the kidney in children might lead to susceptibility to vancomycin toxicity.47
- Matson K.L.
- Shaffer C.L.
- Beck G.L.
- Simonsen K.A.
Assessment of initial serum vancomycin trough concentrations and their association with initial empirical weight-based vancomycin dosing and development of nephrotoxicity in children: a multicenter retrospective study.
Pharmacotherapy. 2015; 35: 337-343
This study has several limitations. First, this was a retrospective investigation of MRSA patients in only one institution. An observation bias of the data cannot be excluded. Second, the patients receiving vancomycin in the northwest of China were mostly critically ill patients. Their vancomycin distribution and clearance status could be significantly altered, making them more susceptible to nephrotoxicity. Last, loading doses and pharmacokinetic monitoring of vancomycin have not yet been adopted in the study institution. Multicenter controlled studies with a larger sample are still needed to clarify the associations between dosing, serum trough concentrations, and nephrotoxicity. This would benefit these critically ill patients by ensuring efficacy and safety during vancomycin therapy.
In conclusion, the present results suggest that vancomycin dosing higher than 38 mg/kg/day and trough concentrations greater than 20 mg/ml might be associated with an increased risk of developing nephrotoxicity. These data may provide useful evidence to instruct clinicians for evaluating the vancomycin regimen in China.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81272346) and the National Basic Research Program of China (2012CB525002; 2013BA106B04)
Ethical approval: The study was approved by the Research Ethics Committee of Xijing Hospital, the Fourth Military Medical University, China.
Conflict of interest: None.
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Article Info
Publication History
Published online: July 06, 2015
Accepted:
June 30,
2015
Received in revised form:
June 26,
2015
Received:
April 7,
2015
Corresponding Editor: Eskild Petersen, Aarhus, Denmark.Identification
Copyright
© 2015 The Authors. Published by Elsevier Inc.
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