Linezolid is an antibiotic that is commonly used in clinical practice to treat drug-resistant Gram-positive bacterial infections, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and certain strains of Streptococci.
It is effective in treating skin and soft tissue infections, pneumonia and other respiratory tract infections. Linezolid works by inhibiting bacterial protein synthesis through binding to the 23S ribosomal RNA of the bacterial ribosome. It is a member of the oxazolidinone class of antibiotics and has a unique mechanism of action compared to other antibiotics.
Linezolid and serotonin
Linezolid has been found to have weak, reversible monoamine oxidase (MAO) inhibitory activity, which can lead to increased serotonin levels when used concurrently with other serotonergic agents. It is contraindicated within the product license when concurrently prescribed with other serotonergic agents due to the risk of serotonin toxicity.
Serotonin toxicity can have serious consequences, with reported mortality rates ranging from 2 to 12 percent. At present, many prescribers avoid linezolid prescribing in patients with concurrent serotonergic agents due to this risk limiting our treatment options for patients with complex Gram-positive infections.
In this article, we report on a critical appraisal from the Pharmacy Infection Journal Club held in August 2023 of a systematic review which aimed to evaluate the evidence linking linezolid to serotonin toxicity when used as monotherapy (i.e. without other serotonergic agents) or in combination with other serotonergic agents.
A systematic review of linezolid-associated serotonin toxicity
The review analysed a total of 84 studies to determine the prevalence and resolution of serotonin toxicity associated with linezolid therapy.
The authors conducted a systematic literature search using PubMed, IDWeek meetings, the European Congress of Clinical Microbiology and Infectious Disease Annual Meetings, and the American College of Clinical Pharmacy meetings. They included case reports, case series, retrospective, cohort and prospective studies that reported linezolid use and screened for or developed serotonin toxicity.
In randomised controlled trials, the incidence of serotonin toxicity with linezolid monotherapy was 0.0 – 0.04%, and was no different to comparator antibiotics. When linezolid was combined with other serotonergic agents, there was no significant difference in risk of serotonin toxicity compared to other antibiotics combined with other serotonergic agents.
In observational studies, the incidence of serotonin toxicity with linezolid monotherapy was found to be 0.0050%, while the incidence with linezolid combination therapy was 0.0134%. In cases where linezolid and serotonergic agents were discontinued at the onset of toxicity, symptom resolution was observed, with 75% of cases reporting resolution within 24 to 48 hours after discontinuation.
Based on the data collected, the authors of this systematic review concluded that linezolid therapy should not be deferred due to the risk of serotonin syndrome. The review revealed a low prevalence of serotonin toxicity in both linezolid monotherapy and linezolid used concurrently with other serotonergic agents. Additional monitoring of high-risk patients is advised and discontinuation of linezolid and serotonergic agents at the onset of toxicity led to rapid resolution of symptoms recommended.
The study’s design, limitations and implications were critiqued during the journal club review.
The study’s strength was its literature review. It included a wide range of studies including case reports, case series, and retrospective and prospective studies. This comprehensive approach enhances the reliability and generalizability of the findings.
However, while the review reports the incidence of serotonin toxicity with linezolid combination therapy, it does not provide detailed information on the specific serotonergic agents used in combination. This lack of specificity limits the applicability of the findings to clinical practice. In addition, the review does not mention any assessment of the quality or risk of bias in the included studies. This omission raises concerns about the potential influence of bias on the reported findings.
Participants of the journal club discussed the following points:
It was noted that local practices regarding co-prescribing linezolid and serotonergic agents varied, with some institutions having strict guidelines and precautions in place to minimise the risk of serotonin toxicity, while others relied on individual patient assessment and close monitoring. Chelsea & Westminster NHS Trust and Imperial Trust have developed local prescribing policies to advised and guide on the safe combined use of linezolid and serotonergic agents.
The participants discussed whether the systematic review had the potential to change clinical practice. It was acknowledged that the review provided valuable evidence suggesting a low prevalence of serotonin toxicity with linezolid therapy. However, some participants expressed the need for further research and larger studies to confirm these findings and provide more robust evidence.
Monitoring of high-risk patients
In-hospital monitoring allows for early recognition of serotonin syndrome in patients at risk. However, the risk of toxicity continues for many days post exposure and therefore there remains a risk of serotonin syndrome developing in patients discharged on linezolid. The group discussed the need for risk-assessing patients on discharge and the role for a Patient Information Leaflet for discharged patients highlighting this risk.
Use of linezolid in high-risk populations
The participants also discussed the use of linezolid in populations with expected higher serum levels (e.g. renal dysfunction, low body weight and in those receiving 600mg TDS dosing) and whether this poses an increased risk of serotonin toxicity. The impact of dosing of linezolid and/or serum concentrations on the risk of serotonin syndrome is unknown at present due to the paucity of data. It is conceivable that patients with higher serum levels may risk greater toxicity. Some colleagues have explored linezolid TDM but this is not widely adopted across practice at present.
Overall, the journal club review highlighted the systematic review’s findings that linezolid therapy, when used optimally, should not be deferred due to the risk of serotonin syndrome. The low prevalence of serotonin toxicity observed in the included studies suggests that linezolid can be used safely, both as monotherapy and in combination with other serotonergic agents. However, the participants emphasised the importance of individual patient assessment, close monitoring, and adherence to local guidelines to minimise the risk of serotonin toxicity.
The opinions expressed in this article are those of the authors. They do not purport to reflect the opinions or views of the UKCPA or its members. We encourage readers to follow links and references to primary research papers and guidance.
Competing interest statement:
The authors declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years.
SH has consulted for/received speaker fees from the following companies: Shionogi (2021–22); BowMed (2021); Eumedica (2022-23); Kent Pharma (2021); Gilead (2021–22); Baxter (2022) and Pfizer (2020–2023), and received research grants from the CW + Charity (2021–2023).