Case analysis of hepatotoxicity caused by vancomycin

doi:10.21203/rs.3.rs-1873168/v1

Objective: To analyze the characteristics and clinical manifestations of liver injury caused by vancomycin, and to provide reference for clinical medication.

Methods: Patients with liver function injury who received vancomycin treatment in the Third Xiangya Hospital of Central South University and Hunan Maternal and Child Health Hospital from 2016 to 2021 were selected for retrospective analysis of their general situation, course of vancomycin, dose, liver function index, severity of liver injury, combined medication, etc.

Results: Of the 4562 patients who received vancomycin, 17 patients were finally included, with an incidence rate of 0.37%. There were 12 males (70.6%) and 5 females (29.4%); age 17-84, average 45.41±20.405. All patients were evaluated with Naranjo’s score, score ≥3. The dosage, time and plasma concentration of vancomycin in patients were analyzed, 9 patients (52.94%) had abnormal liver function when they received vancomycin at the initial dose of 1g Q12h. 14 patients (82.35%) with liver injury were combined with 2 ~ 4 drugs, and severe liver injury occurred in patients who combined with 2 drugs. Occurrence time of liver injury was 2-12 days after the initiation of vancomycin, average 4.53±2.401 days, 16 patients (94.1%) showed abnormal liver function within 7 days after medication, and 2 patients with grade 3-4 liver injury all showed abnormal within 3 days after medication. Only 4 of the 17 patients (23.53%) had vancomycin blood concentration within the normal range, and no correlation was found between blood concentration and severity of liver injury. The correlation between the severity of liver injury and vancomycin was analyzed, none of the patients had allergies such as rash, 2 patients (11.76%) had jaundice and fatigue occurred in 5 patients (29.41%); the remaining 10 patients (58.82%) had no symptoms related to liver injury. All 17 patients showed abnormal AST/ALT, and 9 patients also showed abnormal bilirubin; 15 patients (88.24%) liver injury severity was grade 1, indicating mild hepatic impairment, and no correlation between liver injury severity and creatinine was observed. Among the 17 patients, 1 patient received no intervention, 4 patients stopped taking vancomycin after developing liver damage, and 1 patient reduced dose; 11 patients (64.7%) were treated with hepatinica.

Conclusion: Although the study concluded that the incidence of liver injury was not high, the liver toxicity of vancomycin should still be paid attention to and the liver function indicators should be monitored during the clinical use of vancomycin.

vancomycin

liver toxicity

liver injury

abnormal liver function

blood concentration

case analysis

Vancomycin is a glycopeptide antibiotic, which mainly has antibacterial effect on Gram-positive bacteria, such as Glucococcus aureus, Streptococcus, Clostridium, Actinomycetes, Enterococcus, Listeria, etc. No cross-resistance with other antibiotics. It mainly exerts antibacterial effects through three aspects: 1) inhibit the synthesis of bacterial cell wall glycopeptides; 2) change the permeability of the bacterial cell membrane and destroy its barrier function; 3) selectively inhibit the biosynthesis of bacterial RNA so that the bacteria cannot reproduce^{[1, 2]}. Studies have reported that the incidence of adverse events in the vancomycin group was 12.5%, and the most common adverse reactions were nephrotoxicity, ototoxicity, red-man syndrome, allergic reactions, and abnormal liver function indicators, which was mainly manifested as abnormal AST, ALT and AFP indicators^[3]. Attributable to the excretion of more than 80% of vancomycin in the urine in the form of prototype^[4], its nephrotoxicity has also received widespread attention. Although the correlation between liver toxicity and vancomycin is very low, abnormal liver function indicators such as elevated AST, ALT, AFP, and jaundice have been observed in the use of vancomycin. A meta-analysis of 20 RCT studies from 1950 to 2010 showed that of 4699 patients treated with vancomycin, 321 patients (6.83%) had liver function abnormalities, mainly a mild to moderate increase in serum transaminase^[5]. In order to further study the clinical characteristics of vancomycin's liver toxicity, we analyzed the clinical data of patients with liver injury caused by vancomycin.

1.1 Data source A total of 4562 inpatients who received vancomycin treatment in the Third Xiangya Hospital from 2016 to 2021 were selected. According to the inclusion and exclusion criteria, 17 patients were finally included. Inclusion criteria: 1. receive vancomycin treatment during hospitalization; 2. blood concentration of vancomycin was monitored during medication; 3. meet the correlation evaluation criteria of the Naranjo’s Adverse Reaction Assessment Scale, score ≥3. Exclusion criteria: Patients who did not meet the above inclusion criteria.

1.2 Methods Retrospective research methods were used to read and sort out the patient records, and to extract information such as gender, age, infection site, vancomycin dosage, blood concentration, adverse reaction time, symptoms, indicators, treatment measures, and outcomes.

1.3 Observation indicators The purpose to use vancomycin in enrolled patients; time of adverse reactions; symptoms; liver function indicators: AST, ALT, direct bilirubin, indirect bilirubin; renal function index: creatinine; plasma concentration; Outcomes; concurrent diseases and medication; and other information for statistical analysis.

1.4 Statistical methods SPSS 22.0 was used for statistical analysis.

2.1 General situation

A total of 17 patients with liver injury were included, with an incidence rate of 0.37%, including 12 males (70.6%) and 5 females (29.4%); aged 17-84 years, average 45.41±20.405. Among the 17 patients, 1 patient had a history of cholecystectomy, 1 patient had a history of hepatitis B and 1 patient had a history of alcohol consumption. 6 patients had aggravated liver injury, and the remaining 11 patients had new-onset liver dysfunction. All patients were evaluated with Naranjo’s score, score ≥3. 10 patients were likely to be related and 7 patients were likely to be related. The general information of the patients is shown in Table 1, and the basic information of the patients is shown in Table 2.

Table 1 Patient Characteristics

Characteristics	Stratification	Cases(n=17)	No.(%)
Age（years）
	＜18	1	5.88
	≥18-＜41	8	47.06
	≥41-＜66	5	29.41
	≥66	3	17.65
Site of infection
	Lung	11	64.71
	Intracranial	1
	Urinary Tract	1
	Postoperative prevention	1
	Pulmonary infection with bacteremia	1
	Intracranial infection with bacteremia	1
Concomitant disease (species)
	1-3	12	70.59
	4-6	4	23.53
	7-9	1	5.88
Purpose of medication
	surgical prophylaxis	1	5.88
	empiric medication	14	82.35
	targeted treatment	2	11.77
Knott's score
	3	1	5.88
	4	6	35.30
	5	6	35.30
	6	4	23.53

a：Is there any liver disease in the past:，such as hepatitis; b: Blood concentrationb of vancomycin :standard value:10-15; c: Whether to stop and protect liver treatment drugs;

2.2 Analysis of dosage, time and plasma concentration of vancomycin in patients with liver injury

2.2.1 Vancomycin dosage and treatment course

Among the 17 patients, 9 patients (52.94%) received vancomycin at a dose of 1 g Q12h, among which 4 patients had vancomycin blood concentration higher than the upper limit of normal, and 1 patient had liver injury severity of grade 4; and the severity of liver injury was grade 1 in 3 cases which were lower than normal. 4 patients (23.53%) were given 1g Q8h after the initial 1g Q12h administration, among the 4 patients, the blood concentration of vancomycin was higher than the normal value in 1 patient, 2 patients were lower than the normal range; and 1 case was in the normal range with the severity of liver injury was grade 3. The dose adjustment of all patients was made after the determination of blood drug concentration of vancomycin. The administration time of vancomycin was 3-15 days, average 6.82±3.264d. There were 4 patients (23.53%) who received vancomycin for 3-6 days, of which 1 patient had grade 4 liver injury, and 6 patients (35.28%) were 6-9 days, of which 1 case had grade 3 liver injury (Table 3).

2.2.2 Concomitant medication

Analyses the effect of drug combination of 17 patients, 14 patients (82.35%) used 2 to 4 drugs at the same time (Table 3). Of which 5 patients (29.41%) used 2 drugs, 5 patients (29.41%) used 3 drugs, 4 cases(23.53%) of 4 drugs; 2 patients with grade 3-4 liver injury were treated with 2 drugs at the same time.

2.2.3 The time of liver damage after medication

The time of liver damage occurrence in 17 patients was analyzed. Abnormal liver function indexes occurred 2-12 days after vancomycin was started, average 4.41±2.293d. 16 patients (94.1%) showed abnormal liver function within 7 days after drug administration (Table 3). Among them, 8 patients (47.1%) developed liver injury on 3 days, 4 patients (23.5%) on 4 days, 2 patients (11.8%) on 5 days, 1 patient on 6 days and 7 days, respectively. 1 patient developed on 12 days, and 2 cases of grade 3-4 liver injury occurred on 3 days.

Table 3 Analysis of vancomycin use in patients with liver injury

Results	Stratification	Cases(n=17)	No.(%)
Dosage
	1g Q12h	9	52.94
	1g Q12h→1g Q8h	4	23.53
	1g Q8h→0.5g Q12h	1
	1g Q12h→0.5g Q8h→0.5g Q12h	1
	0.5g Q12h	1
	0.5g Q8h→1.0g Q8h	1
Dosing days (d)
	≤3	3	17.65
	3＜days≤6	4	23.53
	6＜days≤9	6	35.28
	9＜days≤12	2	11.77
	12＜days≤15	2	11.77
Concomitant medication (types)
	1	2	11.77
	2	5	29.41
	3	5	29.41
	4	4	23.53
	5	1	5.88
Time to Liver Damage After Medication（d）
	3d inside	8	47.1
	3-7d	8	47.1
	＞7d	1

2.2.4 Vancomycin plasma concentration

After vancomycin administration, blood concentration of all patients was determined. The blood drug concentration range was 1.20-37.19μg/ml, average 14.8906±11.21257μg/ml. Among them, 6 patients (35.29%) did not reach effective blood concentration. 7 patients (41.18%) beyond the normal range. Among the 7 patients with vancomycin beyond the normal range, Naranjo’s score of 6 patients (85.71%) is possible, and 1 case is probable. But only 1 patient with grade 3-4 liver function damage has blood drug concentration above the upper limit of normal, which is grade 4 liver function damage, suggesting that there may be no correlation between severity and plasma concentration.

2.3 Correlation analysis between the severity and vancomycin

2.3.1 Whether there is Dress syndrome

Dress syndrome, also known as drug hypersensitivity syndrome, and drug eruption syndrome with eosinophilia and systemic symptoms. It has been reported that the typical clinical manifestations of Dress syndrome induced by vancomycin include extensive rash, fever, eosinophilia and multiple organ function involvement, of which rash and fever are the main clinical manifestations ^[6]. In this study, 13 patients developed fever, which was considered to be caused by infection, but none of them developed clinical manifestations related to allergy such as rash.

2.3.2 Changes of liver and kidney function and severity of liver injury

Among the 17 patients, 2 (11.76%) showed yellow skin staining, including 1 patient with multiple organ failure, and 5 patients (29.41%) showed fatigue. The remaining 10 patients (58.82%) had no liver function damage. All 17 patients had abnormal liver function indexes, mainly including increased AST/ALT and increased direct/indirect bilirubin. 17 patients had abnormal AST/ALT, and 14 patients (82.35%) had AST/ALT increased at the same time, only 2 patients had elevated AST, 1 patients with elevated ALT, Abnormal bilirubin in 9 patients (52.94%) at the same time, 4 cases (23.53%) patients with abnormal AST/ALT and bilirubin. Among the 17 patients, 7 patients (41.18%) had AST/ALT≤3ULN, 2 patients (11.76%) had 3ULN < AST/ALT≤5ULN, 7 patients (41.18%) had 5ULN < AST/ALT≤20ULN, and 1 patient (5.88%) had ≥20ULN.

4 of 17 patients (23.53%) had elevated creatinine, including 3 patients with AST/ALT in the range of 5-20ULN, and 1 patient with >20ULN; 3 patients had grade 1 liver injury. And 1 patient had 3 Grade liver injury, the AST/ALT of 5-20ULN. No correlation between the severity and creatinine was observed. According to drug-induced liver injury severity classification standard ^[7], and to assess function of liver, 15 patients (88.24%) with severity for grade 1, 2 patients occurred 3-4 grade showed skin jaundice, only 1 patient with grade 4 liver function injury had blood drug concentration of vancomycin exceeding the normal range.

2.4 Interventions and Outcomes

Among the 17 patients, 1 patient received no intervention, 4 patients stopped vancomycin after liver injury, 1 patient was given vancomycin reduction, and 11 patients (64.7%) were treated with hepatinica. Among the patients receiving treatment,7 patients were treated with reduced glutathione, 3 patients were treated with 2 kinds of hepatinica, phosphatidylcholine + adenosylmethionine, magnesium isoglycyrrhizinate + reduced glutathione, reduced glutathione + polyene phosphatidylcholine.1 patient was treated with 3 kinds of hepatinica (reduced glutathione, enephosphatidylcholine, adenosylmethionine). 11 patients (64.71%) were treated for 3-29 days, average 12.27±9.76d. Among all patients, 12 patients (70.59%) had improved liver function after intervention, of which 8 patients (47.06%) returned to the normal level of liver function index, and 4 patients (23.53%) had continued decline, but did not return to the normal level during hospitalization. 2 patients (11.76%) were asked to be discharged from hospital by their family members without improvement, and there was no follow-up examination data; 3 patients (17.65%) died, including 2 patients with respiratory failure and 1 patient with acute cardiac failure, all of which died due to multiple organ failure caused by the progression of the primary disease.

After intravenous administration, vancomycin can be officially distributed in most tissues and body fluids of the body, and can reach effective bactericidal concentrations in serum, pleural fluid, pericardial fluid, ascites, urine, and atrium, but cannot reach it in bile. effective concentration. At the same time, the drug is not metabolized in the body and is eventually excreted in the form of prototype in the urine. For patients with renal dysfunction, the excretion of vancomycin will be weakened, but studies have shown that abnormal liver function affects the pharmacokinetics of vancomycin. No effect. Pharmacokinetic results from earlier years indicated that vancomycin concentrations in liver tissue and bile were at or below the detection limit^[8]. A Japanese study prepared vancomycin-conjugated monoclonal antibodies to target vancomycin molecules in the kidney and liver of rats, and used immunohistochemistry to monitor the uptake of vancomycin in the kidney and liver of rats. The study showed that Vancomycin is not metabolized by the liver^[9].

Although the correlation between hepatotoxicity and vancomycin was low, abnormal liver function markers such as AST, ALT, AFP elevations, and jaundice were observed with vancomycin use. Results of a meta-analysis of 20 RCTs between 1950 and 2010 showed that patients who received vancomycin had a significantly higher incidence of abnormal liver function, especially serum transaminases, than patients who did not receive vancomycin. Levels are elevated, but most are mild to moderate^[10]. In a retrospective cohort study of patients with hepatic impairment receiving vancomycin, the pharmacokinetics of 237 patients with no or mild hepatic dysfunction and 171 patients with moderate to severe hepatic dysfunction were compared. Dysfunction patients had higher mean trough concentrations, lower clearance rates, longer half-lives, and higher rates of acute kidney injury, with significantly different results^[11]. Another study also demonstrated that liver function has an important influence on vancomycin pharmacokinetics^[12] and is associated with poorer survival in patients with acute or chronic liver failure^[13]. At present, the cause of abnormal liver function indexes caused by vancomycin is not clear, but for patients with hepatic insufficiency, timely use of regular doses of vancomycin may also lead to increased blood concentration^[14]. In this study, through a detailed retrospective analysis of the case data of patients with hepatotoxicity caused by vancomycin, the characteristics of vancomycin hepatotoxicity including occurrence time, blood concentration, intervention measures and liver function indicators were described in detail. In this study, 0.37% of the patients had liver function damage. Similar to previous studies, most of the patients had mild liver damage, mainly manifested as mild to moderate transaminase abnormalities; however, no liver injury was observed in our study. There is a correlation between the severity of functional impairment and blood drug concentration and renal injury. To further verify whether there is a correlation, we used SPSS 22.0 to analyze the liver function indicators including AST/ALT and direct/indirect bilirubin in 17 patients, which were compared with Vangu. Correlation analysis was performed on the administration time, total dose, and blood drug concentration of mycin, and the results showed that there was no correlation between the increase in liver function indexes and the number of days of administration, total dose and blood drug concentration, which may be related to the small sample size, so further research is needed.

Similar to nephrotoxicity, the mechanism of hepatotoxicity is also related to oxidative stress and malignant mitochondrial damage^[15]. different types. The nephrotoxicity of vancomycin mainly acts on renal tubule mitochondria, thereby causing renal cell damage; while most drugs need to be transported by transmembrane transporters into mitochondria. Current studies have shown that the expression of Oat1/3 and Oct2 was observed in the rat vancomycin kidney injury model, which may play an important role in the transport of vancomycin to the renal proximal tubule cells. At the same time, vancomycin may inhibit the expression of Oat1, Oat3, and Oct2, resulting in decreased transport of endogenous toxins and increased renal damage^[16]. In the liver, OAT family members related to vancomycin transport are less expressed, which may be the main reason for the difference between nephrotoxicity and hepatotoxicity. At the same time, studies have shown that the therapeutic dose of vancomycin given to rats, although vancomycin can be detected in the hepatic sinusoidal endothelial cells of the liver for up to 8 days after injection, but on the surface of hepatocytes and bile capillaries. It was not detected, indicating that vancomycin cannot pass through the cells and cannot enter the liver^[9], which further proves that the vancomycin-related transporter is missing from the surface of the liver cell membrane. At the same time, some studies have shown that Oat and OCT genes are expressed in some rat hepatocytes^[17], which may be related to the occurrence of vancomycin hepatotoxicity.

In this study, 17 patients with liver injury after using vancomycin were studied. The general condition, severity of liver injury, liver function indexes (AST/ALT, direct bilirubin/indirect bilirubin) and liver injury The correlation between the degree and vancomycin was analyzed. In all patients, the type of liver injury was mainly asymptomatic abnormal liver function indicators, 2 patients developed jaundice, and eventually died of systemic multi-organ failure due to concurrent disease progression. The dosage, time and blood concentration were analyzed, 9 patients (52.94%) had abnormal liver function when they initially used vancomycin with a conventional dose of 1g Q12h; most patients were used 2-4 drugs in combination, and severe liver injury occurred in patients who used 2 drugs; patients developed abnormal liver function within 7 days after the drug is 94.1%. In 76.47% of the patients, the blood concentration was not within the effective blood concentration range. Among the 7 patients exceeding the normal value, the patients with a Naranjo’s score was probably related is 85.71%, suggesting that higher blood concentration may lead to the occurrence of abnormal liver function, but no linear relationship between blood concentration and liver injury was found. Most of the patients have 1-3 complication, and they are treated with 2-4 drugs at the same time, which may aggravating the hepatotoxicity, including antibacterial drugs, antiviral drugs, antihypertensive drugs, and a few patients using antitumor drugs. In the clinical should focus on the liver toxicity of vancomycin, and the liver function indicators of patients should be monitored. In this study, liver toxicity induced by vancomycin was described in detail, and patient data were analyzed to provide a reference for clinical use of vancomycin. However, due to the small amount of data and large differences among patients, more data are needed for further analysis.

Author information

Authors and Affiliations

Department of Pharmacy, Tianjin Medical University General Hospital，Tianjin，China

Jiayao Wu

[email protected]

Department of Pharmacy, Hunan Provincial Maternal and Child Health Hospital，Changsha，China

Yulu Zhou

[email protected]

Authors' contributions Jiayao Wu drafted the manuscript and prepared figures. Yulu Zhou carefully revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy.

Ethical Approval Given the observational and retrospective nature of the study, and the anonymity of all patients whom clinical data were used, approval by the ethics committee was not requested.

Research involving human participants and/or animals This observational study was conducted retrospectively from electronic data exclusively obtained for clinical purposes.

Consent to Participate Consent is not required because of the retrospective and observational nature of study, because the information is anonymized, and the submission does not include data or images that may identify the people.

Consent to Publish Not applicable.

Competing interests The authors have no competing interests to declare that are relevant to the content of this article.

Funding The authors did not receive support from any organization for the submitted work.

Availability of data and materials All data generated or analysed during this study are included in this published article.

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Table 2 is available in the Supplementary Files section

No competing interests reported.

Table2.docx

Case analysis of hepatotoxicity caused by vancomycin

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Abstract

Introduction

1 Materials And Methods

2 Results

3 Discussion

Declarations

References

Table

Additional Declarations

Supplementary Files

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