High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid

Hangzhou, China

High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid

Yi-Min Zhang, Wei Yu, Ning Zhou, Jian-Zhou Li, Li-Chen Xu, Zhong-Yang Xie, Ying-Feng Lu and Lan-Juan Li

Hangzhou, China

BACKGROUND: Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of thrombocytopenia in patients with acute-on-chronic liver failure (ACLF) who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocytopenia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients.

METHODS: Thirty-fve patients with ACLF who had been subjected to intravenous administration of 600 mg linezolid every 12 hours for more than 7 days were categorized as a ACLF treatment (ACLF-T) group, 72 patients without ACLF treated with the same dosage of linezolid were recruited as a non-ACLF treatment (NACLF-T) group, and 70 patients with ACLF without linezolid treatment served as an ACLF control (ACLF-C) group. The incidences of thrombocytopenia in different groups were compared at day 14. Risk factors were investigated using logistic regression analysis.

RESULTS: The incidence of thrombocytopenia at day 14 was signifcantly higher in the ACLF-T group than in the ACLF-C group (20/35 vs 24/70,P=0.025) and in the NACLF-T group (20/35 vs 9/72,P<0.001). Multivariate analysis showed that the ratio of platelet count (day 7/day 0) <1 (OR=10.021;P=0.012)and the baseline platelet count (OR=0.985;P=0.036) were independent risk factors of thrombocytopenia at day 14 of linezolid therapy.

CONCLUSIONS: The benefts of linezolid treatment should outweigh the risk of thrombocytopenia in patients with ACLF. Moreover, it is necessary to closely monitor the platelet count during linezolid therapy especially in the patients with decreased platelet count at day 7 of linezolid therapy.

(Hepatobiliary Pancreat Dis Int 2015;14:287-292)

acute-on-chronic liver failure; linezolid; thrombocytopenia

Introduction

Linezolid is the frst oxazolidinone antibiotic reagent that is effective for treating Gram-positive bacterial infections including drug-resistant Grampositive bacteria.[1,2]According to the early report,[3]patients with liver failure were prone to bacterial infection, including Gram-positive bacteria. Drug-resistant Grampositive bacteria remain a large challenge in patients with severe liver dysfunction.[4-6]In this situation, linezolid is a reasonable choice for patients with proven or highly suspected drug-resistant Gram-positive bacterial infection.

However, data on linezolid treatment in patients with acute-on-chronic liver failure (ACLF) are unavailable. To date, the most common side effect associated with linezolid is thrombocytopenia,[7,8]which can lead to discontinuation of linezolid therapy. The recommended linezolid treatment duration is more than 7 days.[9]This retrospective cohort study was to investigate whether the incidence of thrombocytopenia is higher in patients with ACLF treated with linezolid over 7 days compared with non-ACLF patients treated with linezolid. Furthermore,risk factors of thrombocytopenia in patients treated with linezolid for more than 7 days were investigated using logistic regression analysis.

Methods

Patients and linezolid therapy

We analyzed the records of patients admitted to the Department of Infectious Diseases, the First Affliated Hospital, Zhejiang University School of Medicine from January 2011 to May 2014. A total of 35 ACLF patients with proven or highly suspected drug-resistant Grampositive bacterial infection and received linezolid therapy over 7 days were enrolled in a ACLF treatment (ACLF-T) group. Seventy-two patients without ACLF at the same period who underwent linezolid therapy for more than 7 days were recruited in a non-ACLF treatment (NACLF-T) group. Another 70 patients with ACLF without linezolid treatment were randomly selected as 2：1 ratio of ACLF-T patients and served as a control (ACLF-C) group. The criteria of ACLF were adopted according to the Chinese Guidelines for Diagnosis and Treatment of Liver Failure.[10]Each patient in the ACLF-T and NACLF-T groups received 600 mg of linezolid administrated intravenously every 12 hours. Concomitant anti-Gram-negative bacteria or antifungal therapy was allowed if necessary. No patients received any blood perfusion or medication such as interferon, rifampin and quinidine that have side effect of decreasing platelet count.

The study protocol was approved by the ethics committee of the First Affliated Hospital, Zhejiang University School of Medicine. No further informed consent was required for reviewing medical records and images because of the nature of the retrospective study.

Defnition of thrombocytopenia and ratio of platelet count

The ratio of platelet count (day 7/day 0 or day 14/day 0) was used to monitor the platelet change. The ratio of platelet count (day 7/day 0) refers to the ratio between the platelet count at day 7 (±1 day) and the baseline. The platelet count ratio (day 14/day 0) represents the ratio between the platelet count at day 14 (±2 days) and baseline. Baseline means the platelet count of a patient before linezolid treatment or when hospital admission without linezolid treatment. Thrombocytopenia was defned as platelet count <100×109/L and a decrease of platelet≥ 25% (ratio of platelet count ≤0.75).

Data collection and comparison

Data were collected from an electronic database. The demographic and baseline characteristics of both groups were compared. The incidences of thrombocytopenia at day 14 were compared between the ACLF-T group and the other two groups.

The patient characteristics including age, gender, presence of diabetes mellitus, presence of chronic liver disease, linezolid treatment duration, baseline parameters such as platelet, hemoglobin, white blood cell (WBC), neutrophil, C reactive protein (CRP), creatinine, total bilirubin, alanine aminotransferase (ALT), albumin, international normalized ratio (INR), hepatic encephalopathy grade, ascites grade, esophageal varices grade, model for end-stage liver disease (MELD) score and the ratio of platelet count (day 7/day 0) <1 were analyzed. Our aim was to fnd risk factors in patients who developed thrombocytopenia at day 14 of linezolid therapy.

Statistical analysis

Statistical analysis was performed by SPSS (version 17.0, Chicago, IL, USA). Parametric variables were expressed as mean±SEM, except for statements, and compared by Student'sttest. Nonparametric variables were compared by the Chi-square test or Fisher's exact test. APvalue <0.05 (two-tailed) was considered statistically signifcant. The variables at level ofP<0.05 in univariate analysis were compared in multivariate analysis.

Results

Demographic and characteristics of patients in the three groups

The baseline characteristics of patients in the three groups are described in Table 1. The CRP (68.1±9.8 vs 7.2 ± 0.4 mg/L,P<0.001), WBC (12.1±1.8 vs 5.1 ±0.3 ×109/L,P=0.001), and neutrophil (9.2±1.6 vs 4.5 ±0.3×109/L,P=0.007) were signifcantly higher in the ACLF-T group than in the ACLF-C group. However, there was no signifcant difference in age, gender, presence of diabetes mellitus, baseline platelet count, hemoglobin, INR, total bilirubin, albumin, ALT, creatinine, hepatic encephalopathy grade, ascites grade, esophageal varices grade, MELD score and presence of chronic liver disease between the ACLF-T group and ACLF-C group.

The baseline platelet count (113.4±13.6 vs 219.3± 17.8×109/L,P<0.001), hemoglobin (92.6±4.8 vs 108.2± 4.1 g/L,P=0.024) and albumin (29.3±1.1 vs 32.4±0.7 g/L,P=0.022) were signifcantly lower in the ACLF-T group than in the NACLF-T group; whereas baseline INR (1.91 ± 0.15 vs 1.12±0.02,P<0.001), total bilirubin (209.1±13.8 vs 14.4±1.1 µmol/L,P<0.001), ALT (183.5±22.8 vs 30.3± 3.6 U/L,P<0.001) and MELD score (20.8±2.4 vs 5.4±1.1,P<0.001) were signifcantly higher in the ACLF-T group than in the NACLF-T group. Moreover, the percentage of the presence of chronic liver disease, ascites grade and esophageal varices grade were signifcantly higher in the ACLF-T group than in the NACLF-T group (P<0.001).

Table 1.Demographic and baseline characteristics of patients in the three groups

Fig.Incidence of thrombocytopenia at day 14 in the ACLF-T, ACLF-C and NACLF-T groups.

Comparison of the incidence of thrombocytopenia at day 14

At day 14, 20 of 35 (57.1%) patients in the ACLF-T group experienced thrombocytopenia, whereas 9 of 72 (12.5%) patients in the NACLF-T group and 24 of 70 (34.3%) patients in the ACLF-C group experienced thrombocytopenia. The incidence of thrombocytopenia was signifcantly higher in the ACLF-T group than in the NACLF-T group (P<0.001) at day 14. Moreover, the incidence of thrombocytopenia at day 14 was signifcantly higher in the ACLF-T group than in the ACLF-C group (P=0.025) (Fig.).

Risk analysis of thrombocytopenia at day 14 of linezolid therapy

Thrombocytopenia at day 14 occurred in 29/107 (27.1%) patients who accepted linezolid therapy. The characteristics of patients were compared between those who experienced thrombocytopenia at day 14 and those who did not. Univariate analysis showed that baseline INR (1.7±0.2 vs 1.2±0.1,P=0.001), platelet count (122.8 ± 12.5 vs 207.5±17.7 ×109/L,P<0.001), total bilirubin (150.2± 32.5 vs 52.0±18.2 µmol/L,P=0.007), ratio of platelet count (day 7/day 0) <1 (24/29 vs 30/78,P<0.001), MELD score (23.5±2.7 vs 5.6±0.9,P<0.001), presence of chronic liver disease (24/29 vs 41/78,P=0.007), esophageal varices grade (P<0.001) and ascites grade (P<0.001) were predictors for thrombocytopenia at day 14 (Table 2). Other factors such as age, gender, presence of diabetes mellitus, CRP, WBC, neutrophil, hemoglobin, ALT, treatment duration, creatinine and hepatic encephalopathy grade were not signifcantly different between the two groups. These factors at a level ofP<0.05 in univariate analysis were analyzed using multivariate logistic regression, baseline platelet count (OR=0.985;P=0.036) and ratio of platelet count (day 7/day 0) <1 (OR=10.021;P=0.012) were independent risk factors of thrombocytopenia at day 14 of linezolid therapy (Table 3).

Table 2.Univariate analysis of predictors associated with thrombocytopenia at day 14 of linezolid therapy

Table 3.Multivariate analysis of independent risk factors for thrombocytopenia at day 14 of linezolid therapy (n=107)

Discussion

The most frequent adverse effect of linezolid therapy is thrombocytopenia.[7,8,11]However, the incidence of thrombocytopenia is controversial. Radunz et al[12]reported that linezolid is safe and effective for the treatment of adult liver transplant patients with Grampositive infections; linezolid does not cause severe thrombocytopenia. However, Orrick et al[13]reported that thrombocytopenia, which was defned as a decrease of 30% in platelet count, occurred in 23 of 48 patients after linezolid administration. Attassi et al[14]found a 47% incidence of linezolid-related thrombocytopenia, and Niwa et al[15]reported a 16.7% (7/42) incidence of thrombocytopenia. The wide variation in the incidence of linezolid-related thrombocytopenia may be due to the adoption of different defnitions of thrombocytopenia and the enrollment of different baseline characteristics of patients in different studies. We defned thrombocytopenia as a decrease in platelet count of ≥ 25% or a fnal count of <100×109/L, which is similar to the defnition adopted by Niwa et al.[15]The incidence of thrombocytopenia at day 14 of linezolid therapy (27.1%, 29/107) was lower than that reported elsewhere,[13,14]which may be attributed to the restricted defnition of thrombocytopenia we used. The ratio of thrombocytopenia was higher in the present study than that reported by Niwa et al,[15]which may be ascribed to the different proportion of patients with severe liver dysfunction.

Ikuta et al[16]reported that chronic liver disease increases the risk of linezolid-related thrombocytopenia in methicillin-resistantStaphylococcus aureusinfected patients after digestive surgery; they also noticed that indocyanine green retention at 15 minutes was related to thrombocytopenia. The present study compared the ratio of thrombocytopenia between the ACLF-T and ACLF-C groups (57.1% vs 34.3%) which indicated a high risk of linezolid-related thrombocytopenia in ACLF patients. The beneft of linezolid therapy and risk of thrombocytopenia in ACLF patients should be weighted.

The mechanisms of linezolid-related thrombocytopenia require further studies. Pharmacokinetic studies demonstrated that linezolid readily distributes to wellperfused tissues and with a distribution volume of 30-50 L in healthy adults. Non-renal clearance accounts for approximately 65% of the total clearance of linezolid and the plasma elimination half-life ranges from 4 to 6 hours.[17]One of the possible mechanisms of thrombocytopenia is linezolid's direct toxicity toward hematopoietic cells.[7]Sasaki et al[11]reported a marked decrease in linezolid clearance (approximately 50% decrease) in severe cirrhotic patients (Child-Pugh grade C). They speculated that it is related to the hindrance in the formationof possible major metabolite of linezolid, PNU-142586, and the inhibition of active transfer of linezolid to hepatocyte. PNU-142586 was formed in liver microsomes through nonenzymatic routes such as reactive oxygen species (ROS).[18]PNU-142586 formation is blocked in severe liver-insuffcient patients especially those with advanced fbrosis because of the downgrading of hepatic ROS protein.[19]Therefore, we suggested that the low linezolid clearance in patients with ACLF causes linezolid accumulation in blood and the decrease of platelet count.

Univariate analysis in our study showed that baseline characteristics such as platelet count, INR, total bilirubin, ascites grade, esophageal varices grade, MELD score and presence of chronic liver disease were related to the risk of thrombocytopenia at day 14 of linezolid therapy. These results indicated that linezolid-related thrombocytopenia is increased in ACLF patients.Another study[20]demonstrated that the duration of linezolid treatment is a risk factor for thrombocytopenia. However, this was not shown in our study because the enrolled patients received linezolid therapy for more than 7 days. Grau et al[21]reported that the low value of baseline platelet count increased the risk of thrombocytopenia, which was also found in our study. The association of chronic liver diseases was also found in our study as one of the risk factors of linezolid-related thrombocytopenia.[16]Multivariate analysis in our study showed that baseline platelet count and ratio of platelet count (day 7/day 0) <1 were independent risk factors of thrombocytopenia at day 14 of linezolid therapy. Therefore, we suggested that linezolid-related thrombocytopenia may occur more frequently in patients with a low platelet level, and the incidence of thrombocytopenia at day 14 may be predicted early at day 7 of linezolid therapy.

This study has two limitations. First, we did not measure the serum concentrations of linezolid during the treatment and therefore, the pharmacokinetics and pharmacodynamics were inconclusive. Second, the retrospective nature of the study might introduce bias in patient selection.

In conclusion, this study indicated that the benefts of linezolid treatment should be considered to outweigh the risk of thrombocytopenia in ACLF patients and the platelet count should be monitored closely during linezolid treatment in patients with ACLF.

Contributors:LLJ designed the study, YW, ZN, LJZ, XLC, XZY and LYF collected the data. ZYM collected and analyzed the data, and drafted the paper. All authors contributed to the design and interpretation of the study and to further drafts. LLJ is the guarantor.

Funding:This study was supported by grants from the China National Science and Technology Major Project (2012ZX10002004 and 2013ZX10002001) and Zhejiang CTM Science and Technology Project (2011ZB061).

Ethical approval:This study was approved by the ethics committee of the First Affliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Competing interest:No benefts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received November 1, 2014

Accepted after revision March 6, 2015

AuthorAffliations:State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, the First Affliated Hospital, Zhejiang University School of Medicine (Zhang YM, Yu W, Zhou N, Li JZ, Xu LC, Xie ZY, Lu YF and Li LJ); Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhang YM, Lu YF and Li LJ), Hangzhou 310003, China

Lan-Juan Li, MD, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affliated Hospital, Zhejiang University School of Medicine; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, No.79 Qingchun Road, Hangzhou 310003, China (Tel/Fax： +86-571-87236755; Email： ljli@zju.edu.cn) © 2015, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(15)60379-4

Published online May 21, 2015.