Linezolid has been prescribed to treat pulmonary infections, skin and soft tissue infections, and intra-abdominal infections caused by multidrug-resistant Gram-positive bacteria because of its strong antibacterial activity. Since the hepatic microsomal CYP450 oxidation system was previously thought not to be involved in linezolid metabolism [7, 31], it is considered that hepatic impairment will not cause changes in the pharmacokinetic characteristics of linezolid. However, some studies have reported that patients with hepatic impairment who received standard doses of linezolid were at greater risk of Cmin above the upper limit of the therapeutic concentration range [17, 19]. The fact that we concentrated on individuals with hepatic impairment who received standard doses of linezolid to assess the impact of liver function on Cmin and the relationship between linezolid overexposure and thrombocytopenia, which is the study's biggest strength. Furthermore our findings have challenged the idea that dose optimization of linezolid is unnecessary for patients with hepatic impairment.
A study on pharmacokinetics of linezolid in healthy volunteers found that participants received linezolid 625 mg orally or intravenously every 12 hours, the steady-state Cmin was 8.02 mg/L and 3.84 mg/L, respectively [32]. The mean trough concentration of linezolid in our study was 10.42 mg/L, which was significantly higher than it in healthy population. Similar results have been found in other published studies. Luque et al. conducted a 1:1 case-control study of cirrhotic patients receiving a standard dose of linezolid, and found a significantly higher Cmin of linezolid in the case group compared with the control group (20.6 mg/L vs 2.7 mg/L, P < 0.01)[17]. Another study included only four patients with cirrhosis, but all of whom showed high linezolid trough concentrations of 32.5, 36.4, 40.8, 45.4 mg/L, respectively [19]. We also found that the median Cmin of linezolid in patients with severe hepatic impairment was significantly higher than in patients with mild (20.65 mg/L vs 5.51 mg/L, P < 0.001) and moderate (20.65 mg/L vs 6.70 mg/L, P = 0.001) hepatic impairment.
As is known to all, linezolid is cleared from the body through the renal or non-renal pathway. According to pharmacokinetic studies, 30% of linezolid is excreted unchanged via the kidney, and 65% dose is metabolized into two carboxylic acid metabolites (PNU-142586 and PNU-142300) by oxidation of its morpholine ring [7, 33]. Wynalda et al. found that linezolid is metabolized to 2-hydroxylinezolid in liver microsomes, which severs as the precursor of the two major metabolites mentioned above [31]. Another study published this year found that CYP2J2, CYP1B1, and CYP4F2 catalyze the 2-hydroxylation of linezolid, especially CYP2J2 [34]. As a result, non-renal clearance of linezolid in patients with hepatic impairment may be decreased, which may be the primary cause of greater trough concentrations in these patients who received standard doses of linezolid. Based on these findings, the prevention of linezolid overexposure appears to require therapeutic medication monitoring and dose modification for patients with hepatic impairment.
High trough concentrations of linezolid were known to cause adverse drug events, conversely low trough concentrations were associated with treatment failure. Previous studies have identified the desired therapeutic concentration range for linezolid, with the lower limit of the range being 2 mg/L and the upper limit of the range varied from 6 to 10 mg/L due to the inclusion of different populations of patients [8, 12, 17, 23, 26, 27]. The therapeutic concentration range of linezolid in present study was chosen to be 2–8 mg/L, which is consistent with the majority of investigations. Notably, patients with varying degrees of hepatic impairment had significantly different incidences of Cmin > 8 mg/L (P = 0.013), while the percentage of patients with Cmin < 2 mg/L was similar. And we found that severe hepatic impairment was the only predictor of Cmin > 8 mg/L, which was similar to the results of another study[17]. Furthermore, in one prospective study designed to determine the association between high plasma concentrations of linezolid and adverse drug reactions, multiple linear regression was used to look into factors potentially influencing Cmin, and the findings revealed that adding cirrhosis as a potential risk factor to the regression model would improve the accuracy of the final model [14]. These findings added to the body of research showing that hepatic impairment raised the risk of linezolid overexposure.
Age and renal function have been demonstrated to alter linezolid exposure levels in prior researches. Some studies have reported that linezolid overexposure was significantly associated with Ccr ≤ 40 mL/min [8, 23, 30], and Cattaneo et al. found that older adults had a higher incidence of linezolid overexposure (Cmin > 8 mg/L) [16]. However, similar results were not found in our study. The main reason may be that the number of patients in this study was limited, only 10 of them were older than 65 years old, and no discernible changes were seen in the distribution of Ccr in patients with various levels of medication exposure. In addition, co-medication with proton pump inhibitors, amiodarone, and amlodipine also enhance the risk of linezolid overexposure, due to their tendency to interfere metabolism of linezolid as P-glycoprotein inhibitors [35]. However, we couldn’t draw definitive conclusions based on the small number of patients who took the three drugs in combination with linezolid.
The incidence of thrombocytopenia increased with the aggravation of hepatic impairment in our study, although there was a statistical difference only between patients with severe hepatic impairment and the other two groups. It has been reported by Zhang et al. reported that patients with hepatic impairment are more likely to develop thrombocytopenia caused by linezolid than those with normal liver function[36]. In another study of patients with infection caused methicillin-resistant Staphylococcus aureus after they received the digestive surgery, the researchers found that patients with chronic liver disease tended to have a higher incidence of thrombocytopenia [37]. We also found that patients with Cmin > 8 mg/L had a risk 11.4 times higher of thrombocytopenia than patients with Cmin ≤ 8 mg/L. And in a prospective study, the researchers found that the prevalence of thrombocytopenia was significantly lower (P = 0.012) in both group A (Cmin fell within the desired range of 2–8 mg/L) and subgroup B1 (The initial Cmin value was higher than 8 mg/L and returned to the desired range after prospective TDM) than in subgroup B2 (Cmin was maintained at > 8 mg/L throughout the study period) [21]. In addition, a significant increase in plasma levels of linezolid was found to be associated with hepatic impairment both in our and previous studies. Therefore, we recommended that patients with hepatic impairment should be provided linezolid at a lower dosage rather than a conventional one without any modifications.
There were some shortcomings in this study. Firstly, due to the retrospective design, the possibility of confounding clinical conditions could not be completely excluded. Secondly, the limited number of cases included in the study prevented us from observing the impact of other factors such as age, Ccr, and drug-drug interactions on linezolid exposure. In addition, we didn’t investigate the efficacy of linezolid, which was attributed to a lack of efficacy information for some patients. We recommended that linezolid doses be optimized for patients with hepatic impairment, especially in patients who are diagnosed with severe hepatic impairment. Therefore, further prospective studies with larger samples are needed to determine the treatment regimen of linezolid in patients with different degrees of hepatic impairment.