Application of vancomycin in patients with augmented renal clearance

Abstract

Objective

To analyse the influence of factors on the steady-state trough concentration (C_trough) of vancomycin, especially in patients with augmented renal clearance, and to provide a reference for clinical application.

Methods

Data on patient demographics, routine blood examination, hepatic function and kidney function were collected from May 2013 to October 2016. A total of 292 patients were enrolled and correlations between C_troughof vancomycin and other test indices were analysed by SPSS software.

Results

The patients with augmented renal clearance were significantly younger with relatively lower C_trough values and higher weight, ALB and PLT compared to others. And age was the most important factor of C_troughamong subgroups of ARC.

Conclusions

Inpatients with augmented renal clearance, vancomycin C_trough was mainly affected by age. Clinicians and pharmacists should adjust the dosage regimen in a timely manner based on therapeutic drug monitoring and these influencing factors.

Introduction

Vancomycin has been used clinically for 60 years, since its approval by the FDA in 1958.^{1 2} In recent years, bacterial infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE) have increased. Vancomycin is commonly used worldwide as the first choice of treatment for MRSA, leading to bacterial resistance and a gradually rising treatment failure rate, so a rational dosage regimen is particularly required.^3–5

Many research studies have shown that the steady-state trough concentration (C_trough) of vancomycin has a good correlation with the treatment failure rate and the incidence of nephrotoxicity, so adequate exposure to vancomycin to achieve the expected serum level is necessary. Many guidelines have recommended that the target trough concentrations of vancomycin should reach 10–20 µg/mL or at least >10 µg/mL in order to ensure clinical efficacy and avoid resistance.^6–9 In addition, the C_trough of vancomycin is easy to monitor, so therapeutic drug monitoring of the trough concentration is also recommended. However, the phenomenon of augmented renal clearance (ARC) causes unexpectedly lower concentrations of vancomycin leading to suboptimal drug exposure and treatment failure.^10–12

In this study more data were collected and analysed based on previous studies to further investigate the factors affecting the C_trough of vancomycin in patients with ARC, with the aim of providing a reference for the clinical application of vancomycin.

Materials and methods

Eligibility criteria

Inclusion criteria were: (a) suspected or documented Gram-positive infections; (b) dosage regimen 1000 mg every 12 hours; (c) monitoring of vancomycin C_trough.

Exclusion criteria were: (a) demographic information or test index not obtained; (b) patients receiving renal replacement therapy; (c) pregnant or lactating women; (d) diagnosis of abscess fibrosis.

Enrolment and data collection

315 sets of data from 292 patients (194 male, 98 female) aged 12–90 years hospitalised in the First Affiliated Hospital of China Medical University from May 2013 to October 2016 were enrolled in the study. The demographics and characteristics including age, weight, gender, blood cell analysis and clinical biochemistry tests such as white blood cells (WBCs), red blood cells (RBCs), serum creatinine concentration (S_cr), blood urea nitrogen (BUN), serum albumin (ALB), haemoglobin (HGB) and platelet count (PLT), neutrophils (NE), lymphocytes (LY), monocytes (MONO), cystatin C (Cys-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), glutamyltransferase (GGT), vancomycin dosage and vancomycin C_trough of all patients were collected from the medical records.

The serum samples were analysed by homogeneous enzyme immunoassay using Siemens Viva-E instrument.¹³

Patient groups

In our study, patients were divided into three groups and three subgroups based on creatinine clearance (CL_cr) as follows: Group A (CL_cr <80 mL/min), Group B (CL_cr 80–130 mL/min), Group C (CL_cr >130 mL/min). Group C was further divided into three subgroups according to different indices (subgroups I–III). The Cockcroft–Gault formula was used to calculate the CL_cras shown below^{14 15}:

CL_cr=(140−age)×weight/(0.818×S_cr) for males

CL_cr=0.85 × (140−age)×weight/(0.818×S_cr) for females

where S_cr is serum creatinine (µmol/L).

Statistical analysis

SPSS software version 22.0 was used for statistical analyses. Continuous variables were expressed as median (interquartile range). After normality assessment with one sample Kolmogorov–Smirnov test, Kruskal–Wallis, χ² and logistics regression were applied for data analysis.

Results

The main demographics and characteristics of the patients enrolled in the different groups are shown in table 1. Sixty patients were enrolled in Group A, 69 patients in group B and 186 patients in Group C. The results in the table show that C_trough, age, weight, CL_cr, ALB and PLT had statistically significant differences among groups (P<0.05). Compared with Groups A and B, the patients with ARC in Group C were significantly younger with significantly lower C_troughvalues and relatively higher weight, ALB and PLT.

Table 1.

Demographics and characteristics of patients enrolled in the study

Item	Group A n=60	Group B n=69	Group C n=186	P values
Gender (M/F)	39/21	40/29	134/52	0.091
Ctrough (μg/mL)	23.50 (16.93–31.65)	11.40 (8.15–16.25)	7.70 (4.50–12.63)	0.000
Age (years)	68.00 (56.25–75.00)	56.00 (49.00–63.00)	45.00 (33.00–57.25)	0.000
Weight (kg)	62.50 (55.00–70.75)	64.00 (55.00–72.75)	71.50 (62.00–80.00)	0.000
CLcr (mL/min)	50.25 (38.95–71.20)	109.00 (97.95–120.75)	180.50 (152.95–207.35)	0.000
ALB (g/L)	22.95 (20.00–27.50)	27.40 (21.70–30.30)	28.50 (25.18–33.60)	0.000
PLT (109/L)	106.00 (51.50–222.00)	173.00 (45.50–266.75)	239.00 (134.00–386.00)	0.000

Group A: CL_cr <80 mL/min; Group B: 80–130 mL/min; Group C: >130 mL/min.

ALB, serum albumin; CL_cr, creatinine clearance; C_trough, steady-state trough concentration of vancomycin; PLT, platelet count.

Numerical variables summarised as median (IQR)

The vancomycin C_trough values in each group are shown in figure 1. The median C_troughof vancomycin was 23.5 µg/mL in Group A, 11.40 µg/mL in Group B and 7.70 µg/mL in Group C at the therapeutic dose of 1000 mg every 12 hours. The results showed that C_troughvalues of patients in Group A were all >10 µg/mL of which 33.33% were 10–20 µg/mL and 66.67% were >20 µg/mL). The percentage of patients reaching a concentration of 10–20 µg/mL was 40.58% in Group B and 32.80% in Group C. The data of Group C indicated more than 60% of patients having C_trough <10 µg/mL and only 2.69% having C_trough >20 µg/mL.

Figure 1.

Box plot of steady-state trough vancomycin concentrations in each group (black squares mean values, horizontal lines in boxes 50th percentiles, ends of boxes 25th and 75th percentiles). Group A (creatinine clearance (CL_cr) <80 mL/min), Group B (CL_cr 80–130 mL/min), Group C (CL_cr >130 mL/min).

In this study, patients in Group C (CL_cr > 130 mL/min) were defined as having ARC and further divided into three subgroups according to different indices (subgroups I–III). The results are shown in table 2 and figure 2. As the results show, only age and CL_cr had a statistically significant difference among subgroups (P<0.05).

Table 2.

Characteristics of patients in each of the subgroups

Item		Median (IQR) Ctrough	P values
Age (n=186)	Subgroup I: <40 years (n=60)	5.90 (3.70–13.88)	0.000
	Subgroup II: 40–60 years (n=97)	7.70 (4.25–10.90)
	Subgroup III: >60 years (n=29)	13.10 (7.50–16.60)
Weight (n=186)	Subgroup I: <55 kg (n=16)	7.00 (3.75–10.10)	0.382
	Subgroup II: 55–75 kg (n=105)	7.50 (4.05–12.15)
	Subgroup III: >75 kg (n=65)	8.40 (4.80–13.00)
CLcr (n=186)	Subgroup I: 130–150 mL/min (n=43)	9.50 (7.30–14.30)	0.015
	Subgroup II: 150–180 mL/min (n=48)	7.35 (4.50–11.40)
	Subgroup III: >180 mL/min (n=95)	6.80 (3.50–13.30)
PLT (n=156)	Subgroup I: <125 ×109/L (n=34)	7.50 (3.70–12.73)	0.486
	Subgroup II: 125–350×109/L (n=73)	8.40 (4.90–15.55)
	Subgroup III: >350×109/L (n=49)	8.10 (5.25–13.00)
ALB (n=158)	Subgroup I: <40 g/L (n=84)	7.70 (4.84–11.40)	0.054
	Subgroup II: 40–55 g/L (n=68)	8.90 (4.50–14.90)
	Subgroup III: >55 g/L (n=6)	5.10 (1.80–6.70)

ALB, serum albumin; CLcr, creatinine clearance; Ctrough, steady-state trough concentration of vancomycin; PLT, platelet count.

Figure 2.

Box plot of steady-state trough vancomycin concentrations in each group in each subgroup according to different indices. Age (subgroup I: <40 years, subgroup II: 40–60 years, subgroup III: >60 years); serum albumin (ALB) (subgroup I: <40 g/L, subgroup II: 40–55 g/L, subgroup III: >55 g/L); creatinine clearance (CL_cr) (subgroup I: 130–150 mL/min, subgroup II: 150–180 mL/min, subgroup III: >180 mL/min); PLT (subgroup I: <125×10⁹/L, subgroup II: 125–350×10⁹/L, subgroup III: >350 ×10⁹/L), weight (subgroup I: <55 kg, subgroup II: 55–75 kg, subgroup III: >75 kg).

Logistic regression was further used to analyse the influence of age and CL_cr on C_trough. As the result, parallelity assumptions were accepted and no multicollinearity between independent variables. As shown in table 3, age was the most important factor of C _troughamong subgroups of ARC.

Table 3.

The parameter estimation of influencing factors in the patients with CL_cr more than 130 mL/min

	Effect	Wald	SE	B	95%CI	P
Age		5.980	0.011	0.027	0.005, 0.048	0.014
CLcr	Subgroup Ⅰ	1.866	0.385	0.526	−0.229, 1.280	0.172
	Subgroup II	0.502	0.398	−0.282	−1.062, 0.498	0.479
	Subgroup III	–	–	0a	–	–

a: The parameter is set to 0.

Discussion

Vancomycin is a time-dependent antibiotic and a lot of research has shown that the C_trough, which is easy to monitor, has a good correlation with treatment and nephrotoxicity.^{8 16} In our study, 292 patients (194 male and 98 female) were enrolled and 315 datasets were collected for analysis. The dosage of all patients included in the study was consistent (1000 mg every 12 hours), C_troughwas monitored and SPSS software was used to analyse the relationship between C_trough and the test results, especially for patients with ARC. The results showed that the C_trough of vancomycin could be affected by many factors.

In this study we observed that patients with a higher weight had a relatively lower C_trough of vancomycin than those with a lower weight, as the weight of patients in Groups A and B was similar but the weight of patients in Group C (median 71.5 kg) was significantly higher than that in the first two groups, which may be due to their increased glomerular filtration rate.^{17 18} We also found that when a certain high body weight was reached, the C_troughof vancomycin was at a relatively constant level or slightly lower. Han et al proposed that obese patients had higher drug clearance than non-obese patients and that the drug clearance had a linear relationship with ideal body weight, but not with total body weight.¹⁹ Since the height data were incomplete, the ideal body weight was not obtained and correlation analysis was not performed with C_trough.

With the decrease in ALB, the lower protein binding rate of vancomycin resulted in an increase in free drug and more drug was needed for excretion by the kidneys. It might also lead to tissue oedema and leakage of protein to the tissues resulted in an increase in the apparent volume of distribution and a longer elimination half-life.^{20 21} Especially for patients with impaired renal function, vancomycin could not be removed effectively which led to a relatively higher C_trough. The changes in PLT might also be associated with adverse reactions with vancomycin, which need further study and verification.

In this study, ARC was defined as CL_cr >130 mL/min²² and all patients were grouped according to CL_cr. It was clear that patients with ARC had a lower C_trough than non-ARC patients. As vancomycin is not metabolised in vivo and 90% is excreted via the kidneys, the renal function of patients could affect the clearance of vancomycin and further affect its serum concentration; thus, in the group with higher CL_cr a lower C_trough was observed. Particularly in Group C, the percentage of patients with C_trough <10 µg/mL was more than 60%. CL_cr also gradually declined with age, especially in older patients. In Group A the median age was 68 years and more than 67.21% of patients were aged >60 years, but the median age in Group C was only 45 years. The results of our previous published research showed that CL_cr and C_troughof vancomycin exhibited a logarithmic correlation.²³ Further study in patients with ARC in this study has shown that the effect of age on C_trough was more significant than CL_cr.

Our study has described the factors influencing the C_troughof vancomycin, especially for patients with ARC. According to our results, ARC might result in suboptimal exposure and unexpectedly low steady-state serum levels of vancomycin which probablely cause treatment failure. Therefore, in clinical anti-infective treatment, patients with ARC should be identified as early as possible and routine therapeutic drug monitoring is also required for these patients according to the individual renal function status to increase the initial dose and adjust the dosage regimen in a timely manner to reach the effective serum concentration in order to improve the clinical efficacy. We hope that this study will provide a reference for the clinical use of vancomycin and we will continue this work on a larger scale for further study.

What this paper adds.

What is already known on this subject

• Vancomycin is commonly used worldwide as the first-choice drug for the treatment of MRSA, leading to bacterial resistance and a gradually rising treatment failure rate.

• Many studies have reported that the dosage of vancomycin should be adjusted according to the patient’s creatinine clearance (CL_cr) to achieve an effective serum concentration range (10–20 mg/L).

• In therapeutic drug monitoring of vancomycin, it was found that there were still many patients whose serum concentration did not reach the effective concentration range if only adjusted according to patient’s CL_cr, especially for patients with augmented renal clearance.

What this study adds

• By analysing the factors influencing the steady-state trough concentration (C_trough) of vancomycin, it was found that many factors can affect C_trough.

• For patients with augmented renal clearance, vancomycin C_troughwas mainly affected by age.