Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis

Abstract

Purpose: To characterize the post-marketing reporting of serotonin syndrome (SS) due to drug-drug interactions (DDIs) with linezolid and investigate the relationship with pharmacokinetic/pharmacodynamic (PK/PD) properties of serotonergic agents.

Methods: We queried the worldwide FDA Adverse Event Reporting System to extract SS records due to DDIs where linezolid was reported as suspect. For each serotonergic agent concomitantly reported, proportion of SS reports and mean number of DDIs were calculated and three different "SS reporting zones" were created. Relevant PK (peak concentration, area under plasma concentration curve, volume of distribution (V_D), and lipophilicity) and PD (values of binding affinity (Ki) and IC₅₀ for serotonin reuptake transporter (SERT) and 5-HT_2A) parameters were extracted for each serotonergic agent, and relevant PK/PD indexes were calculated to assess correlation with mean number of DDIs (PV index).

Results: Six hundred sixty-nine reports of SS mentioning linezolid were found, being linezolid-citalopram (N = 69; 10.3%) the most frequently DDI reported. Citalopram and methadone showed respectively the highest proportion of SS reports (0.28%) and the lowest mean number of DDIs (1.41). Citalopram, escitalopram, and methadone emerged as red (i.e., alert)-zone medications: they exhibited high lipophilicity and large V_D (proxies of excellent central nervous system penetration) coupled with high potency. Among PK/PD indexes, a significant correlation with PV index was found for V_D/Ki SERT ratio (p = 0.05).

Discussion: Our integrated approach suggests that linezolid is more likely to cause SS when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. Proper management of SS should be tailored on a case-by-case basis.

Keywords: Drug-drug interactions; Infectious disease “dilemma”; Linezolid; Pharmacovigilance-pharmacokinetic/pharmacodynamic approach; Serotonin syndrome.

Fig. 1

Examples of clinical scenarios posing a “dilemma” to the infectious disease consultant regarding the use of linezolid in patients on serotonergic agents (MRSA, methicillin-resistant Staphylococcus aureus; NSTI, necrotizing soft tissue infection; HAP, hospital-acquired pneumonia; OCD, obsessive-compulsive disorder; ICU, intensive care unit; ID, infectious disease; PK, pharmacokinetic; SS, serotonin syndrome)

Fig. 2

Scatterplot showing the relationship between the proportion of SS reports (on x-axis) and the mean number of DDIs (on y-axis) for each serotonergic agent. Threshold values of ≥ 0.1% and ≤ 1.5 were respectively selected for proportion of SS reports and mean number of DDIs, identifying three different SS risk zones (red-zone, high-risk medications; yellow-zone, intermediate-risk medications; green-zone, low-risk medications)

Fig. 3

Scatterplot showing the relationship between VD/Ki SERT ratio (PK/PD index; x-axis) and mean number of DDIs (PV index; y-axis). A significant correlation was found (ρ = − 0.53; p = 0.05)