The potential risk factors of nephrotoxicity during vancomycin therapy in Chinese adult patients

Abstract

Objective

To evaluate potential risk factors that may make patients susceptible to nephrotoxicity in those concomitantly receiving vancomycin in the hospital.

Methods

This was a single-centre retrospective analysis of patients treated with vancomycin for gram-positive or mixed infections in the Renmin Hospital of Wuhan University from January 2017 to May 2018. All of them were treated for ≥48 hours and had no kidney disease. Nephrotoxicity refers to acute kidney diseases and disorders after the use of vancomycin, and includes acute kidney injury. Univariate analysis and binary logistic regression analysis with the forward stepwise method were used to assess the risk factors associated with nephrotoxicity.

Results

Of the 790 patients treated with vancomycin, only 257 patients met the inclusion criteria, and 40 (15.6%) subjects developed nephrotoxicity. Significant differences (p<0.05) were seen in the number of combined antimicrobials (p=0.012), dose adjustment (p<0.001), more than three antimicrobials (p=0.015), monitoring trough concentrations (p=0.001), furosemide (p<0.001), torasemide (p<0.001), cefoperazone sodium tazobactam sodium (p=0.039), voriconazole (p=0.012) and ganciclovir (p=0.008). Regression analysis further indicated that furosemide (OR 7.983, p<0.001) and torasemide (OR 3.496, p<0.001) were risk factors for vancomycin nephrotoxicity. Diabetes mellitus (OR 3.062, p=0.035), voriconazole (OR 3.515, p=0.020) and fluconazole (OR 3.326, p=0.018) might be also risk factors.

Conclusion

Fluconazole and voriconazole might be potential risk factors for vancomycin nephrotoxicity, besides furosemide and torasemide. It is not recommended to use imipenem cilastatin sodium and vancomycin at the same time. If necessary, meropenem may be safer. Appropriate combination drugs, cautious initial dose or timely dose adjustment might reduce the occurrence of nephrotoxicity when using vancomycin.

Introduction

Vancomycin is a glycopeptide antibiotic that has been used in clinical practice for more than 60 years. It was first reported to be sensitive to most gram-positive cocci and to be particularly valuable in the treatment of infections caused by penicillin-resistant staphylococci in 1956.¹ After many years, the use of vancomycin has become widespread, but the adverse reactions it causes cannot be ignored. This drug is not the first-choice agent owing to its adverse effects, and it is not as effective as methicillin for non-methicillin-resistant strains.² Vancomycin is eliminated by glomerular filtration, with 80–90% of an administered dose appearing in the urine within 24 hours.³ Therefore, it may cause nephrotoxicity during the administration process. Recent studies have shown that the incidence of vancomycin use in adults with nephrotoxicity is 18–43%.^4–6 Some studies identified high vancomycin trough levels, prolonged duration of vancomycin therapy and intensive care unit (ICU) stay, and concomitant treatment with nephrotoxic agents, in particular, aminoglycosides or furosemide, as independent risk factors for nephrotoxicity. Patient factors and health conditions that can induce kidney damage include female gender, advancing age, body mass index, smoking, reduced kidney function, sepsis/shock, diabetes mellitus, cardiovascular disease and hypertension.^4–9 The increase of the valley concentration in the target exposure is considered to increase the likelihood of concentration-related adverse effects, including nephrotoxicity.¹⁰ Additionally, studies have shown that just one serum vancomycin concentration peak or trough can predict nephrotoxicity.¹¹ Therefore, this study is a retrospective analysis to further explore the risk factors related to its nephrotoxicity in the hospital and provide reasonable references to doctors when vancomycin is applied.

Methods

Patients and data collection

The medical records of 790 patients receiving vancomycin at Renmin Hospital of Wuhan University from January 2017 to May 2018 were collected. A retrospective analysis of 257 patients was finalised according to the inclusion and exclusion criteria below. Patients enrolled in the study met three conditions: (1) the duration of administration was ≥48 hours; (2) patients were ≥19 years old; (3) there was no kidney disease: estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m² for <3 months with stable serum creatinine (SCr).¹² Patients were also excluded if they had undergone kidney transplantation or had a single kidney, atrophy, kidney stones or kidney stones after surgery.

The study laboratory used the IDMS traceable enzymatic assay (Creatinine Plus Ver. 2, Roche Diagnostics) for SCr. The CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation was used to calculate the eGFR.¹³ The CKD-EPI equation is: GFR (in mL/min per 1.73 m²)=141×min(SCr/κ, 1)^α×max(SCr/κ, 1)^-1.209×0.993^Age×1.018 (if female)×1.159 (if black), where SCr is serum creatinine (in mg/dL), κ is 0.7 for females and 0.9 for males, and α is −0.329 for females and −0.411 for males.

The study was approved by the Renmin Hospital Ethics Committee of Wuhan University. In view of the retrospective and observational nature of the study with no interventions performed, the need for informed consent was waived. The information was recorded from the electronic medical records of the hospital. The following patient information and laboratory values were included: age, gender, weight, serum creatinine values, eGFR, trough concentration, duration and length of stay. Additionally, data were collected on concomitant exposure to potential nephrotoxic drugs (shown in table 1) and underlying risk factors (diabetes, hypertension, ICU and surgery) for nephrotoxicity.

Table 1.

Summary of nephrotoxic and non-nephrotoxic groups

Variable	Total	Nephrotoxicity	Non-nephrotoxicity	P value
	(n=257)	(n=40, 15.6%)	(n=217, 84.4%)
Continuous variable
Age, years	54	57	54	0.153
Duration of vancomycin therapy, days	8	8	8	0.704
Vancomycin dose, g/12 hours	1	1	1	0.866
Number of combined antimicrobials, n	2	2	2	0.012
Duration of hospital stay, days	29	33	29	0.414
Binary variable, n (%)
Gender, male	169 (65.8)	29 (17.2)	140 (82.8)	0.328
Dose adjustment	230 (89.5)	28 (12.2)	202 (87.8)	<0.001
>3 antimicrobials	69 (26.8)	17 (24.6)	52 (75.4)	0.015
Monotherapy	27 (10.5)	3 (11.1)	24 (88.9)	0.500
Microbiological test	246 (95.7)	39 (15.9)	207 (84.1)	0.545
Monitoring trough concentrations	47 (18.3)	15 (31.9)	32 (68.1)	0.001
Comorbid conditions, n (%)
Hypertension	56 (21.8)	7 (12.5)	49 (87.5)	0.474
Diabetes mellitus	24 (9.3)	7 (29.2)	17 (70.8)	0.054
ICU	53 (20.6)	12 (22.6)	41 (77.4)	0.111
Surgery	206 (80.2)	36 (17.5)	170 (82.5)	0.089
MRSA	35 (13.6)	5 (14.3)	30 (85.7)	0.822
Concomitant diuretics, n (%)
Furosemide	63 (24.5)	23 (36.5)	40 (63.5)	<0.001
Torasemide	42 (16.3)	14 (33.3)	28 (66.7)	<0.001
Hydrochlorothiazide	17 (6.6)	5 (29.4)	12 (70.6)	0.103
Spironolactone	13 (5.1)	2 (15.4)	11 (84.6)	0.985
Concomitant antibacterials, n (%)
Meropenem	105 (40.9)	14 (13.3)	91 (86.7)	0.412
Imipenem sistatin sodium	56 (21.8)	13 (23.2)	43 (76.8)	0.074
Aminoglycoside	36 (14)	2 (5.6)	34 (94.4)	0.074
Cefoperazone sodium sulbactam sodium	36(14)	9 (25)	27 (75)	0.092
Cefoperazone sodium tazobartan sodium	23 (8.9)	7 (30.4)	16 (69.6)	0.039
Fluconazole	29 (11.3)	8 (27.6)	21 (72.4)	0.058
Voriconazole	24 (9.3)	8 (33.3)	16 (66.7)	0.012
Ganciclovir	23 (8.9)	8 (34.8)	15 (65.2)	0.008
Levofloxacin	12 (4.7)	2 (16.7)	10 (83.3)	0.914
Rifampicin	6 (2.3)	0	6 (100)	0.287
Other concomitant medication, n (%)
NSAIDs	26 (10.1)	2 (7.7)	24 (92.3)	0.243
ACEI	8 (3.1)	3 (37.5)	5 (62.5)	0.082
ARB	7 (2.7)	1 (14.3)	6 (85.7)	0.925
Anaesthetics	148 (57.6)	24 (16.2)	124 (83.8)	0.737
Psychotropics	174 (67.7)	31 (17.8)	143 (82.2)	0.149

ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor antagonist; ICU, intensive care unit; MRSA, methicillin-resistant Staphylococcus aureus; NSAIDs, non-steroidal anti-inflammatory drugs.

Evaluation of nephrotoxicity

Based on actual research, patient biochemical indicators, and the latest definitions of acute kidney injury (AKI) and acute kidney diseases and disorders (AKD), we established nephrotoxicity as AKD during the study. AKD can be defined by a GFR <60 mL/min/1.73 m² for <3 months, a decrease in GFR by ≥35% for <3 months, or an increase in SCr by >50% for <3 months.¹² AKI can be defined as: an increase in SCr by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; an increase in SCr to ≥1.5 times baseline within the previous 7 days; and urine volume ≤0.5 mL/kg/h for 6 hours.^{14 15}

Statistical analysis

SPSS 24.0 was used for statistical analyses. The categorical variables were subject to χ² test, the unidirectional ordered data was subject to Mann-Whitney test of independent samples, and the bidirectional ordered data was subject to the κ consistency test. In the χ² test, the exact method adopted the progressive-only method. If the number of cells whose expected count was less than five was >25%, Fisher's exact probability method was used to re-test. A bilateral p value <0.05 was considered statistically significant. All patient factors with a p value of 0.05±0.005 in the univariate analysis were considered for inclusion in the multivariate analysis. A multivariate analysis of risk factors for vancomycin nephrotoxicity was performed using logistic regression with a forward conditional method, and Homos-Lemeshow test was used to evaluate the goodness of fit. Patient characteristics hypothesised to be strong predictors of nephrotoxicity and variables that were significantly associated with nephrotoxicity in bivariate analyses were included. The threshold of nephrotoxicity at different concentrations of vancomycin in serum was studied by using the receiver operating characteristic (ROC) curve, and the time of administration and the combination were also analysed. The Youden index was used to determine the optimal threshold for maximising sensitivity and specificity under specific thresholds.

Results

Of the 790 patients, some patients had been excluded because they did not meet the age criteria (297), or they had incomplete serum creatinine levels (135), or they had chronic kidney disease or other factors (101). For the remaining 257 patients, 40 (15.6%) subjects developed nephrotoxicity. All patients were given vancomycin intravenously after sodium chloride injection or glucose injection was mixed. Table 1 summarises differences in clinical and demographic variables between patients who did and did not develop nephrotoxicity during the treatment with vancomycin. Median age was 54.0 years with 65.8% male (169/257). The median duration of vancomycin therapy was 8 days, and the median hospital stay was 29 days. In addition, the median dose of vancomycin was 1 g every 12 hours, and the median number of combined antimicrobials was two.

As shown in table 1, patients were divided into two groups based on the presence (n=40) or absence (n=217) of nephrotoxicity. Age, gender, duration of vancomycin therapy, vancomycin dose, and duration of hospital stay did not differ between the two groups. Monotherapy on treatment infection (p=0.500) and microbiological testing (p=0.545) seemed to have no effect on the occurrence of nephrotoxicity, respectively. However, the number of combined antibacterials appeared to be related to nephrotoxicity (p=0.012). In the light of following antibacterial drug thresholds, we classified the number of antibiotics and found out whether more than three antimicrobials could affect nephrotoxicity. The results showed the nephrotoxic proportion of patients with more than three types of antibacterials was significantly higher than that of patients with less than three types of antibacterials (24.6% vs 12.2%, p=0.015, 17/69 vs 23/188). The incidence of nephrotoxicity was higher in patients who needed to be monitored for trough concentration (31.9% vs 11.9%, p=0.001, 15/47 vs 25/210), while the incidence of nephrotoxicity was significantly reduced to 12.2% after dose adjustment (p<0.001). 13.6% of patients (35/257) were identified as methicillin-resistant Staphylococcus aureus (MRSA) positive, and 20.6% of patients (53/257) were in the ICU. Of the 257 patients, 56 patients (21.8%) had hypertension and 24 patients (9.3%) had diabetes mellitus. The nephrotoxic group and non-nephrotoxic group in this study were not significantly different in these comorbidities. Nevertheless, patients with diabetes mellitus had a significantly higher proportion of nephrotoxicity when compared with those patients without diabetes mellitus (29.2% vs 14.2%, p=0.054, 7/24 vs 33/233).

In both groups, a comparable number of potentially nephrotoxic agents were used concomitantly with vancomycin. Previous literature has shown that furosemide is a risk factor for kidney injury.⁴ In this study, other diuretics were also included. Interestingly, the data showed that there was no significant difference in nephrotoxicity between patients treated with hydrochlorothiazide or spironolactone and those not treated with hydrochlorothiazide or spironolactone. However, furosemide (p<0.001) and torsemide (p<0.001) can increase the risk of nephrotoxicity. Table 1 also lists the top 10 antibacterials. For example, 40.9% of patients used meropenem combined with vancomycin, and 21.8% of patients used imipenem. Although both of them were not statistically significant in terms of nephrotoxicity, patients treated with imipenem had a higher proportion of nephrotoxicity (23.2% vs 13.4%, p=0.074, 13/56 vs 27/201) relative to those subjects treated without imipenem. Furthermore, it could be seen that the proportions of nephrotoxicity in patients taking cephalosporins, azoles or ganciclovir were obviously higher than the mean proportion (15.4%), respectively, while the proportions of nephrotoxicity in patients treated with cefoperazone sodium tazobactam sodium (p=0.039), voriconazole (p=0.012) or ganciclovir (p=0.008) combined were statistically significant relative to those subjects treated without these concomitant drugs, respectively. Among the other concomitant drugs, patients taking angiotensin-converting enzyme inhibitors had a relatively high proportion of nephrotoxicity (37.5%), while non-steroidal anti-inflammatory drugs, angiotensin II receptor antagonist, psychotropic drugs, and anaesthetics had no effect on the occurrence of nephrotoxicity.

On the basis of the above results, regression analysis included not only the factors of p<0.05 in the single factor test, but also the possible influencing factors. For example, diabetes mellitus, dose adjustment, furosemide, torasemide, imipenem-cilastatin sodium, cefoperazone sodium sulbactam sodium, cefoperazone sodium tazobactam sodium, fluconazole, voriconazole, ganciclovir, more than three antimicrobials, monitoring trough concentrations, and number of combined antimicrobials were included in the regression analysis. We chose forward conditional for binary logistic regression analyses. After these variables were filtered for three times, three variables were introduced into the final model. The significance of the omnibus test of the model coefficient in step 3 was 0.000, indicating that at the significance level of 0.1, the partial regression coefficient of at least one independent variable was not 0. The significance value of the Homos-Lemeshow test was 0.769, meaning that the model adequately fits the observation data. The accuracy rate of prediction using binary logistic regression was 85.2%, indicating that the fitting effect was excellent. As shown in table 2, in the logistic regression analyses, furosemide and torasemide were independently associated with nephrotoxicity while receiving vancomycin therapy. Therefore, those patients with furosemide therapy (OR 7.983, 95% CI 3.578 to 17.813; p<0.001) or torasemide therapy (OR 3.496, 95% CI 1.448 to 8.439; p=0.005) were more likely to have nephrotoxicity. On the other hand, dose adjustment (OR 0.174, 95% CI 0.065 to 0.463; p<0.001) was the protective factor for nephrotoxicity of vancomycin.

Table 2.

Logistic regression equation variables for nephrotoxicity

Variable	B	P	OR	95% CI
Furosemide	2.077	<0.001	7.983	3.578 to 17.813
Torasemide	1.251	0.005	3.496	1.448 to 8.439
Dose adjustment	−1.748	<0.001	0.174	0.065 to 0.463
Constant	−0.309	0.655	0.734

B>0, OR >1, risk factors; B<0, OR <1, protective factors; B=0, OR=1, not affected.

In this study, there were only 47 patients who were monitored for trough concentration. The ROC curve was drawn on the data of these 47 patients, and then judged the threshold of the analysis factor according to the Youden index. The data we collected was generally half an hour after the fourth maintenance dose, which was the valley concentration of vancomycin. As shown in table 3, the p values of trough concentrations and number of combined antimicrobials are <0.05, respectively, their areas under the curve are 0.833 and 0.875, respectively, and their thresholds are 15.475 and 3.5, respectively. Therefore, in order to reduce nephrotoxicity, the trough concentration of vancomycin should be <15.475 mg/L, and the number of combined antimicrobials should not exceed three antibacterial drugs.

Table 3.

The area under the ROC curve

Variable	Subcurvilinear region	P value	Threshold value
Duration of vancomycin therapy, days	0.382	0.469	13.5
Vancomycin trough concentration, mg/L	0.833	0.041	15.475
Weight, kg	0.306	0.233	53.25
Number of combined antimicrobials, n	0.875	0.022	3.5

ROC, receiver operating characteristic.

In addition, when the variables furosemide and torsemide were removed, further logistic regression analysis showed that diabetes mellitus (OR 3.062, 95% CI 1.082 to 8.667; p=0.035), monitoring trough concentrations (OR 2.411, 95% CI 1.031 to 5.638; p=0.042), voriconazole (OR 3.515, 95% CI 1.215 to 10.172; p=0.020) and fluconazole (OR 3.326, 95% CI 1.230 to 8.993; p=0.018) might also be risk factors for nephrotoxicity, while dose adjustment (OR 0.213, 95% CI 0.082 to 0.551; p=0.001) might be a protective factor.

Discussion

Vancomycin is the first-line antibiotic treatment for infections caused by MRSA and is often used for the treatment of other gram-positive infections. In this study, the results showed that furosemide therapy added to patients receiving vancomycin increased the odds of developing nephrotoxicity by 7.983-fold, which is consistent with previous studies.^{4 16} On the one hand, diuretics add extra stress on the renal tubules and force unnatural duress of excess fluid. On the other hand, since the kidneys are already under unnatural stress from the diuretic, they appear to be more prone to acute damage from vancomycin.⁴ In the meantime, vancomycin is eliminated mainly by glomerular filtration, with 80–90% of an administered dose appearing in the urine within 24 hours.³ Therefore, we still further analysed the other diuretics, such as torasemide, hydrochlorothiazide and spironolactone, but the results showed that there was no statistically significant nephrotoxicity whether hydrochlorothiazide and spironolactone were used or not. In other words, they had no or minimal effect on nephrotoxicity of vancomycin. However, torasemide was also a risk factor for nephrotoxicity of vancomycin, which was similar to furosemide. The result indicated that furosemide increased the risk of kidney damage by 7.983-fold, and torsemide increased the risk of kidney damage by 3.496-fold. This difference might be related to their diuretic mechanism and efficacy.

Both furosemide and torsemide have a therapeutic effect on kidney disease,¹⁷ and our statistical combination of drugs was during the vancomycin administration, which may lead to the above results. In addition, we further obtained the results in table 4 by removing two risk factors (furosemide and torsemide) from the regression analysis. It is well known that diabetes can cause kidney disease, and some studies have indicated that the survival rate of diabetic nephropathy patients is much lower than in those without it.¹⁸ Therefore, diabetic patients with nephrotoxic drugs may be more likely to cause nephrotoxicity.

Table 4.

Logistic regression equation variables when furosemide and torsemide were removed

Variable	B	P	OR	95% CI
Voriconazole	1.257	0.020	3.515	1.215 to 10.172
Fluconazole	1.202	0.018	3.326	1.230 to 8.993
Diabetes mellitus	1.119	0.035	3.062	1.082 to 8.667
Monitoring trough concentrations	0.880	0.042	2.411	1.031 to 5.638
Dose adjustment	−1.546	0.001	0.213	0.082 to 0.551
Constant	−4.742	0.024	0.009

B>0, OR >1, risk factors; B<0, OR <1, protective factors; B=0, OR=1, not affected.

The principal molecular target of azole antifungals is cytochrome P450–Erg11p or Cyp51p and it can be coordinated with the haemoglobin prosthetic Fe of other P450 enzymes in the human body.¹⁹ The hepatic cytochrome P450 (CYP450) enzyme system has been well studied, and several CYP450 enzyme gene polymorphisms are associated with reduced metabolism and subsequent end-organ toxicity. The kidney also possesses CYP450 enzymes that participate in drug metabolism.²⁰ Previous studies have shown that hepatotoxicity of azole drugs looks more obvious,²¹ but its mechanism of action implies that azole antifungals can be risk factors for kidney injury. From table 4, our study results support the idea that azole antifungals, such as fluconazole and voriconazole, are risk factors for nephrotoxicity.

Plasma determinations showed that after renal damage, vancomycin could persist at high levels for a long time in the patient, with the possibility that this long exposure could cause more renal damage.²² There is a positive correlation between the body clearance of vancomycin and renal function.²³ According to vancomycin instruction and vancomycin individualised dosing clinical guidelines, the old patients should be 500 mg every 12 hours or 1 g every 12 hours. Among the patient information we collected, the average daily dose for the elderly was 1.88 g. Patients who need monitoring trough concentrations of vancomycin are those who received vancomycin/aminoglycoside combinations, or infrequent doses of vancomycin undergoing haemodialysis, or higher doses of vancomycin.²⁴ These studies might explain why monitoring trough concentrations of vancomycin was a risk factor for nephrotoxicity, and indicated that doctors should reduce the dose directly according to renal function indexes and carry out trough concentration monitoring, so as to avoid more severe renal damage caused by a large dose of vancomycin. However, it is reported that a higher trough concentration of vancomycin may improve outcomes in patients with complicated MRSA bacteraemia.²⁵ Therefore, we recommend that a slightly higher daily dose but still <2 g should be given to patients with poor renal function or the elderly when it is determined to be an MRSA infection. This can maintain a high trough concentration such as 15–20 mg/L for patients with renal dysfunction associated with complex MRSA infection, so as to improve the therapeutic effect.

There was an increased risk of vancomycin-associated nephrotoxicity in patients with trough concentrations >15 mg/L independently of other known risk factors for renal injury.²⁶ Some studies have suggested that vancomycin nephrotoxicity was associated with the levels of trough concentration.²⁷ Based on the statistical valley concentration data, we simulated the ROC curve to obtain the Jouden index, and according to the Jouden index the trough concentration of vancomycin should not exceed 15.475 mg/L. At the same time, we found that no more than three antibacterial agents in combination with vancomycin should be applied to avoid nephrotoxicity.

Some studies have suggested that ceftaroline was effective and safe for MRSA bloodstream infection when given as monotherapy or in combination with other MRSA-active antibiotics.²⁸ Reduced susceptibility of MRSA to vancomycin has been a major medical concern. Prolonged use and suboptimal dosing of vancomycin may possibly lead to the emergence of MRSA strains with reduced susceptibility.²⁹ Vancomycin is not the first choice for the non-methicillin-resistant strains. If vancomycin is selected, the response rate will be lower than that of methicillin or cephalosporin, and the cure time may be prolonged.² In the study, the incidence of vancomycin-associated nephrotoxicity in adults is 15.6%, but the total adverse reaction incidence of vancomycin in adults is 33%, including allergy, hepatotoxicity, leucopenia and thrombocytopenia. Therefore, vancomycin is not recommended as the preferred drug if there are other options, considering the many adverse reactions that are caused.

There are some limitations in the study. First, the available data are not enough or completely dependent on the case record. Second, in the regression analysis, the final analysis results may have a slight deviation due to the limited sample size or the inclusion of other unknown influential factors. Third, other drugs that may cause or aggravate nephrotoxicity can be ignored.

Conclusion

Fluconazole and voriconazole might be potential risk factors for nephrotoxicity of vancomycin besides furosemide and torasemide. It is not recommended to use imipenem cilastatin sodium and vancomycin at the same time. If necessary, meropenem may be safer. The monitoring trough concentration of vancomycin should not exceed 15.475 mg/L and the number of combined antimicrobials should not exceed three antibacterial drugs, under normal circumstances, and the duration of vancomycin therapy should not exceed 2 weeks.

What this paper adds.

What is already known on this subject

• Vancomycin use is often associated with nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible, as numerous potential risk factors for nephrotoxicity frequently coexist.

• Concurrent nephrotoxic agents, in particular, aminoglycosides or furosemide, are risk factors for nephrotoxicity of vancomycin.

What this study adds

• Unlike furosemide, hydrochlorothiazide and spironolactone had no or very little effect on vancomycin nephrotoxicity.

• Some azole antifungals might be potential risk factors for vancomycin nephrotoxicity.

• The monitoring trough concentration of vancomycin should not exceed 15.475 mg/L.

• The number of combined antimicrobials should not exceed three antibacterial drugs, under normal circumstances, and the duration of vancomycin therapy should not exceed 2 weeks.

Data availability statement

No data are available.

Ethics statements

Patient consent for publication

Not required.