Adverse drug events associated with linezolid administration: a real-world pharmacovigilance study from 2004 to 2023 using the FAERS database

Abstract

Introduction: Linezolid is an oxazolidinone antibiotic that is active against drug-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis. Real-world studies on the safety of linezolid in large populations are lacking. This study aimed to determine the adverse events associated with linezolid in real-world settings by analyzing data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: We retrospectively extracted reports on adverse drug events (ADEs) from the FAERS database from the first quarter of 2004 to that of 2023. By using disproportionality analysis including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), along with the multi-item gamma Poisson shrinker (MGPS), we evaluated whether there was a significant association between linezolid and ADE. The time to onset of ADE was further analyzed in the general population and within each age, weight, reporting population, and weight subgroups. Results: A total of 11,176 reports of linezolid as the "primary suspected" drug and 263 significant adverse events of linezolid were identified, including some common adverse events such as thrombocytopenia (n = 1,139, ROR 21.98), anaemia (n = 704, ROR 7.39), and unexpected signals that were not listed on the drug label such as rhabdomyolysis (n = 90, ROR 4.33), and electrocardiogram QT prolonged (n = 73, ROR 4.07). Linezolid-induced adverse reactions involved 27 System Organ Class (SOC). Gender differences existed in ADE signals related to linezolid. The median onset time of all ADEs was 6 days, and most ADEs (n = 3,778) occurred within the first month of linezolid use but some may continue to occur even after a year of treatment (n = 46). Conclusion: This study reports the time to onset of adverse effects in detail at the levels of SOC and specific preferred term (PT). The results of our study provide valuable insights for optimizing the use of linezolid and reducing potential side effects, expected to facilitate the safe use of linezolid in clinical settings.

Keywords: FAERS; adverse drug event; disproportionality analysis; linezolid; pharmacovigilance; real-world analysis.

FIGURE 1

A flowchart of the whole study.

FIGURE 2

The main findings of this study. After data cleaning, we detected the signal strength of ADEs at the SOC and PT levels. Moreover, we performed gender-based subgroup analysis and conducted detailed calculations and comparisons of TTO. ADEs, adverse drug events; SOC, System Organ Class; PT, preferred term; TTO, time to onset.

FIGURE 3

Signals detection at the SOC level. (A) Distribution of ADEs of linezolid from 2004 to the first quarter of 2023 (2023 Q1). (B) The bar chart displays the reported cases of ADEs at each SOC level. (C) Signals detection at the SOC level. The ROR values and their 95% confidence intervals (95% CI) are visualized. We label the SOCs with positive signal values to make a distinction. FAERS, Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS); ADEs, adverse drug events; SOC, System Organ Class; ROR, reporting odds ratio.

FIGURE 4

Signals detection at the PT level. (A) SOC attribution and number of 263 PTs that simultaneously satisfy the 4 methods of disproportionality analysis with positive signal values. (B) We selected PTs with a minimum of 20 cases and displayed the ROR and corresponding 95% CI using a forest plot. The blue arrows signify that the lower limit of the 95% confidence interval of the ROR exceeds 25.PTs, preferred terms; SOC, System Organ Class; PTs, preferred terms; CI, confidence interval; ROR, reporting odds ratio.

FIGURE 5

Analysis of gender-differentiated risk signals in linezolid. (A) Reporting odds ratios (ROR) with 95% CI for all positive gender-related ADEs. (B) Gender-differentiated risk signal volcano plot for linezolid. The horizontal coordinate shows the log2 ROR value and the vertical coordinate indicates the adjusted p-value after -log10 conversion. Significant signals are highlighted and annotated in prominent colors. The p-value is adjusted with false discovery rate (FDR) method.

FIGURE 6

Time to onset (TTO) analysis (counted in days) of linezolid-related ADEs at the overall level. The frequency bar chart illustrates the distribution of TTO reports across various time periods.

FIGURE 7

Time to onset (TTO) analysis of ADEs at the SOC and PT levels. (A) Box plot of the TTO at the SOC level for linezolid. Bold bar within the stick: median TTO; Lower end of the stick: 1/4 quantile of the TTO; Upper end of the stick: 3/4 quantile of the TTO. (B) Specific comparison of TTO in PTs at eight different SOC levels. SOC, System Organ Class; PTs, preferred term.