Can a patient receive linezolid if already taking an antidepressant and methadone? What is the risk of serotonin syndrome?

Comment by InpharmD Researcher

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents, including antidepressants and methadone. The incidence and risk of serotonin syndrome when linezolid is used with other serotonergic drugs is not fully known. However, a systematic review and meta-analysis observed an incidence rate of 12.3 per 1,000 patients for serotonin toxicity in patients administered linezolid plus one serotonergic agent compared to 11 per 1,000 in patients receiving linezolid monotherapy. Notably, the incidence was fivefold higher when patients received concomitant linezolid combined with multiple serotonergic agents. Conversely, retrospective studies have found no significant difference in the incidence of serotonin syndrome between linezolid monotherapy and a combination of linezolid and other serotonergic medications, though these studies are limited by small sample sizes and potential underreporting. Per an FDA warning, linezolid should not be administered to patients taking serotonin reuptake inhibitors, tricyclic antidepressants, bupropion, buspirone, serotonin 5-HT1 receptor agonists (triptans), or opioids (including meperidine).

Background

A 2009 review on linezolid and serotonin syndrome discussed the use of linezolid and SSRIs simultaneously or within close temporal relation to each other to concurrently manage resistant nosocomial infections and depressive disorder in U.S. hospitals. Serotonin toxicity from adverse interactions between linezolid and SSRIs may be potentially fatal, but its true incidence is rare. It was recommended to separate the administration of linezolid from SSRIs by two weeks (or by five weeks in case of fluoxetine due to its long half-life); however, given linezolid’s status as a weak MAO inhibitor with potent antibiotic efficacy, the use of linezolid with SSRIs should be determined based on informed clinical judgment. The authors proposed that the initiation of linezolid to treat a new infection should not be delayed to wash out the SSRI. SSRI-treated patients should be closely monitored for emerging signs and symptoms of toxicity for at least three weeks in case of a new initiation of linezolid. Whether to maintain the patient on SSRIs or not following linezolid initiation should depend on the cost-/risk-benefit analysis of the clinical situation. [1]

A 2023 systematic review and meta-analysis evaluated the incidence of serotonin toxicity associated with drug-drug interactions between concomitant linezolid and serotonergic agents compared to linezolid alone. A total of 5 relevant studies were ultimately included, all of which were retrospective and observational in study design. Included articles compared linezolid combined with serotonergic agents versus linezolid alone, or compared linezolid and one serotonergic agent to linezolid plus multiple serotonergic agents. Based on pooled data from 4 studies (n= 6,025 patients), a statistically significant difference was observed in incidence of serotonin toxicity in linezolid monotherapy versus linezolid plus a serotonergic agent (OR 1.78; 95% CI 1.04 to 3.02; I2= 49%; low GRADE certainty assessment), translating to an estimated incidence rate of 12.3 per 1,000 patients in the linezolid plus serotonergic agent group versus 11 per 1,000 patients receiving linezolid monotherapy. However, based on data from 4 studies (n= 2,501 patients), concomitant use of linezolid plus more than 1 serotonergic agent was associated with approximately a five-fold increased risk compared to linezolid plus a single serotonergic agent (OR 5.18; 95% CI 1.05 to 25.49; I2= 44.87%; moderate GRADE certainty assessment), translating to an estimated pooled incidence rate of 14.5 per 1,000 patients versus 3.4 per 1,000 patients for linezolid plus multiple serotonergic agents and linezolid plus 1 serotonergic agent, respectively. Overall, results suggest that linezolid can be used safely in patients receiving a single concomitant serotonergic agent, if benefits are deemed to outweigh risks, as incidence of serotonin toxicity was observed to be low in this comparison. However, the incidence was notably higher when patients received concomitant linezolid combined with multiple serotonergic agents. [2]

Another 2023 systematic review included a total of 84 studies to evaluate the association between linezolid and serotonin toxicity when using linezolid as monotherapy or concomitantly with other serotonergic agents. Data were pooled from 15 randomized controlled trials, 57 case reports, 10 retrospective/observational studies, and 2 abstracts. Linezolid monotherapy was described in both randomized trials as well as retrospective observational studies. Based on 14 randomized trials (n= 7,174 patients) the incidence of serotonin toxicity in patients receiving short courses of linezolid, ranging from 5 to 14 days, was presented as a 95% confidence interval ranging from 0.0 to 0.04%. The incidence was reported to be no different than controls. Based on data from 5 retrospective observational studies that evaluated incidence of serotonin syndrome with linezolid monotherapy, the total incidence rate was 0.0050% (3 of 598 patients). When evaluating incidence of serotonin syndrome in patients receiving linezolid in combination with at least one other serotonergic agent, none of the 2,208 patients in the included randomized trials experienced serotonin toxicity. In the 11 retrospective observational studies, however, 15 of 1,170 patients (0.0128%) were documented with signs or symptoms consistent with serotonin toxicity. Similar to most other studies, the authors concluded an overall low prevalence of serotonin toxicity in scenarios of both linezolid monotherapy and concomitant use with other serotonergic agents. [3]

A 2023 single-center, retrospective cohort study examined adult patients who received at least 1 dose of linezolid with or without concurrent serotonergic agents during their hospitalization. A total of 1,743 patients during the period from 2014 to 2021 were included in the analysis. Dose categories for concurrent agents were classified as low (dose <33%), moderate (33-66%), or high (>66% of maximum daily dose). Of patients receiving linezolid, 67% were on at least one serotonergic agent, with most patients receiving moderate- or high-dose serotonergic agents. Ultimately, only two patients (0.1%) were identified as potentially experiencing serotonin toxicity throughout their treatment. The first patient received a seven-day course of linezolid with moderate-dose escitalopram and low-dose trazodone, and although they reportedly experienced mental status change and agitation, they did not meet the full Sternbach criteria to establish serotonin toxicity. The second patient received linezolid with three serotonergic agents (moderate-dose duloxetine, moderate-dose vilazodone, and low-dose metoclopramide) and met the full criteria for serotonin toxicity as well as experiencing diaphoresis, diarrhea, and fever. A physician’s note described potential serotonin toxicity post-linezolid discontinuation, and the three serotonergic agents were removed from the patient’s regimen. Although the patient died four days later, death was attributed to acute respiratory distress syndrome secondary to influenza pneumonia. Based on the Sternbach criteria, serotonin toxicity occurred in this cohort at a rate of 0.06%. Neither patient met the conditions under the Hunter criteria for serotonin toxicity. As this study was retrospective in nature, it may be subject to missing data or inaccurate reporting. Additionally, the mean duration of linezolid given was short in nature, and longer courses with concurrent serotonergic agents may have captured toxicity reports. [4]

A 2021 pharmacovigilance analysis characterized the post-marketing reporting of serotonin syndrome due to drug-drug interactions (DDIs) with linezolid and investigated the relationship with pharmacokinetic/pharmacodynamic properties of serotonergic agents. Serotonin syndrome records from the FDA Adverse Event Reporting System were analyzed for linezolid-related DDIs. Proportions of serotonin syndrome report and mean DDIs were calculated for each co-reported serotonergic agent, leading to creation of three “serotonin syndrome reporting zones. The “red-zone” has high serotonin report rates and low DDI means, the “yellow-zone” has high serotonin syndrome report rates and high or low DDI means, and the “green-zone” has low serotonin syndrome report rates and high DDI means. Citalopram has the highest serotonin syndrome report proportion (0.277%) and methadone the lowest mean DDI count. These two, along with escitalopram, were classified as red-zone medications as they showed high lipophilicity and large volume of distribution coupled with high potency. The findings suggest that linezolid is more likely to cause serotonin syndrome when co-administered with citalopram, escitalopram, and methadone, as inferred from their pharmacological properties. [5]

References:

[1] Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry. 2009;11(6):353-356. doi:10.4088/PCC.09r00853
[2] SanFilippo S, Turgeon J, Michaud V, Nahass RG, Brunetti L. The Association of Serotonin Toxicity with Combination Linezolid-Serotonergic Agent Therapy: A Systematic Review and Meta-Analysis. Pharmacy (Basel). 2023;11(6):182. Published 2023 Nov 20. doi:10.3390/pharmacy11060182
[3] Elbarbry F, Moshirian N. Linezolid-associated serotonin toxicity: a systematic review. Eur J Clin Pharmacol. 2023;79(7):875-883. doi:10.1007/s00228-023-03500-9
[4] Kufel WD, Parsels KA, Blaine BE, Steele JM, Seabury RW, Asiago-Reddy EA. Real-world evaluation of linezolid-associated serotonin toxicity with and without concurrent serotonergic agents. Int J Antimicrob Agents. 2023;62(1):106843. doi:10.1016/j.ijantimicag.2023.106843
[5] Gatti M, Raschi E, De Ponti F. Serotonin syndrome by drug interactions with linezolid: clues from pharmacovigilance-pharmacokinetic/pharmacodynamic analysis. Eur J Clin Pharmacol. 2021;77(2):233-239. doi:10.1007/s00228-020-02990-1
Relevant Prescribing Information

Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Therefore, linezolid has the potential for interaction with adrenergic and serotonergic agents.

Contraindications
Linezolid should not be used in patients taking any medicinal product which inhibits monoamine oxidases A or B (e.g., phenelzine, isocarboxazid) or within two weeks of taking any such medicinal product. [6]

Postmarketing Experience
The following adverse reactions have been identified during postapproval use of linezolid. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Serotonin Syndrome
Spontaneous reports of serotonin syndrome including fatal cases associated with the co-administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been reported. [6]

Unless clinically appropriate and patients are carefully observed for signs and/or symptoms of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions, linezolid should not be administered to patients with carcinoid syndrome and/or patients taking any of the following medications: serotonin re-uptake inhibitors, tricyclic antidepressants, bupropion, buspirone, serotonin 5-HT1 receptor agonists (triptans), or opioids, including meperidine. [6]

In some cases, a patient already receiving a serotonergic antidepressant or buspirone may require urgent treatment with linezolid. If alternatives to linezolid are not available and the potential benefits of linezolid outweigh the risks of serotonin syndrome or NMS-like reactions, the serotonergic antidepressant should be stopped promptly and linezolid administered. The patient should be monitored for two weeks (five weeks if fluoxetine was taken) or until 24 hours after the last dose of linezolid, whichever comes first. Symptoms of serotonin syndrome or NMS-like reactions include hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes that include extreme agitation progressing to delirium and coma. The patient should also be monitored for discontinuation symptoms of the antidepressant (see package insert of the specified agent(s) for a description of the associated discontinuation symptoms). [6]

References:

[6] Zyvox (linezolid). Prescribing information. Pharmacia & Upjohn Company LLC; 2024.
Literature Review

A search of the published medical literature revealed 8 studies investigating the researchable question:

Can a patient receive linezolid if already taking an antidepressant and methadone? What is the risk of serotonin syndrome?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-8 for your response.

 

Association of Linezolid With Risk of Serotonin Syndrome in Patients Receiving Antidepressants

Design

Retrospective, population-based, cohort study

N= 1,134

Objective

To examine the incidence of serotonin syndrome in patients receiving oral linezolid and how concomitant antidepressant treatment changes this risk

Study Groups

Antidepressants (n= 215)

No antidepressants (n= 919)

Inclusion Criteria

 Older adults (aged ≤ 65 years) who were dispensed linezolid during the study period; followed up with for 30 days after linezolid therapy

Exclusion Criteria

 None reported

Methods

This was a retrospective analysis of the Ontario Drug Benefit database, which captures outpatient prescription medications dispensed to persons older than 65 years old in Ontario, Canada. Patients who were prescribed linezolid were separated into those who were also taking concurrent antidepressants or not. 

The antidepressants included (1) selective serotonin reuptake inhibitors (SSRIs): paroxetine, fluvoxamine, fluoxetine, sertraline, citalopram, and escitalopram; (2) serotonin-norepinephrine reuptake inhibitors (SNRIs): venlafaxine, desvenlafaxine, and duloxetine; (3) tricyclic antidepressants: clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, protriptyline, doxepin, and trimipramine; (4) monoamine oxidase (MAO)-inhibitors: isocarboxazid, phenelzine, selegiline, tranylcypromine, and moclobemide; (5) norepinephrine and dopamine reuptake inhibitors: bupropion; and (6) other: trazodone, mirtazapine, buspirone, amoxapine, maprotiline, and nefazodone.

Data was also recorded on the use of other serotonergic medications: lithium, 5HT3 receptor antagonists (dolasetron, granisetron, ondansetron, and palonosetron), metoclopramide, methylphenidate, dexmethylphenidate, fentanyl, meperidine, methadone, oxycodone, tramadol, triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan), ergot derivatives (dihydroergotamine, ergotamine, and methylergonovine), dextromethorphan, chlorpheniramine, cyclobenzaprine, carbamazepine, valproic acid, tryptophan, dextroamphetamine, rasagiline, and ritonavir.

Duration

 October 1, 2014 to January 1, 2021

Outcome Measures

Primary: clinically significant serotonin syndrome based on a physician's diagnosis, Sternbach criteria, or the Hunter Serotonin Toxicity Criteria within 30 days of starting oral linezolid treatment

Secondary: altered mental status, hospitalization, or death within 30 days of starting linezolid

Baseline Characteristics

  

Antidepressants (n= 215)

No antidepressants (n= 919)

  

Age, years

66-69

70-79

≥80

 

22.3%

38.6%

39.1%

 

19.3%

42.4%

38.3%

  

Female

54.4% 45.9%  

Mean days of linezolid treatment

 11.7 ± 7.2 10.3 ± 6.2  

Number of concurrent antidepressants

 1.2 ± 0.5 0  

Taking other serotonergic drugs

 8.8% 5.1%  

Results

There were fewer than 6 cases of serotonin syndrome reported overall. The exact numbers were not reported per the data policy of the database due to potentially identifiable patient information. Based on fewer than 6 events, the possible risk difference for serotonin syndrome ranged from -0.5% to 2.3%. The number of serotonin syndrome cases were fewer in the antidepressant group.

Using propensity-score matching, the adjusted risk of serotonin syndrome was lower in the antidepressant group (adjusted risk difference, -1.2%; 95% confidence interval, -2.9% to 0.5%; p= 0.50). Per this data, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which is equivalent to a number needed to harm of 200.
  Antidepressants (n= 215) No antidepressants (n= 919) p-value

Secondary endpoints within 30 days of linezolid

Altered mental status/confusion

Hospitalization

Death from any cause

 

11.6%

42.8%

7.4%

 

6.9%

43.3%

4.8%

 

0.02

0.93

0.13

Adverse Events

 N/A

Study Author Conclusions

In this cohort study, concomitant antidepressants did not significantly increase the risk of serotonin syndrome in patients taking linezolid. Within the 95% CI, the worst-case scenario would be a 0.5% increase in the risk of serotonin syndrome due to antidepressants, which would be a number needed to harm of 200. As such, it is likely safe to prescribe linezolid in patients taking antidepressants, and antidepressants should not be an absolute contraindication for linezolid.

InpharmD Researcher Critique

Inherent limitations of this retrospective, database analysis include the possibility of confounding variables and incomplete data sets. For the primary endpoint, serotonin syndrome was diagnosed retrospectively based on a constellation of diagnosis codes, which did not match perfectly with the diagnostic criteria. Additionally, the small number of events seen limit the analysis and accuracy of the results.



References:

Bai AD, McKenna S, Wise H, Loeb M, Gill SS. Association of Linezolid With Risk of Serotonin Syndrome in Patients Receiving Antidepressants. JAMA Netw Open. 2022;5(12):e2247426. doi:10.1001/jamanetworkopen.2022.47426

 

Incidence of Serotonin Syndrome With Combined Use of Linezolid and Serotonin Reuptake Inhibitors Compared With Linezolid Monotherapy

Design

Retrospective, single-center, case-control study

N= 348

Objective

To compare the incidence of serotonin syndrome when linezolid was administered alone and in combination with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs)

Study Groups

Combination therapy (n= 87)

Linezolid monotherapy (n= 261)

Inclusion Criteria

Adult inpatients who received at least 1 dose of linezolid while admitted; use of an SSRI or SNRI during linezolid or within 14 days before linezolid

Exclusion Criteria

 None reported

Methods

This was a retrospective study from a single academic medical center in Iowa. Patient records were screened for an SSRI or SNRI administration during or within the 14 days preceding treatment with linezolid. Any patient with at least 1 inpatient administration of an SSRI or SNRI simultaneously with or up to 2 weeks before an inpatient dose of linezolid was included in the combination therapy group.

Patients who did not receive an inpatient dose of an SSRI or SNRI with or within the 2 weeks before linezolid were eligible for inclusion in the linezolid monotherapy group as long as the patient did not also have any outpatient administrations of an SSRI or SNRI in the 2 weeks before linezolid, as determined by medication histories before admission and discharge medication lists.

Duration

 January 2010 to December 2014

Outcome Measures

Diagnosis of serotonin syndrome, including the presence of at least 3 Sternbach criteria or 1 Hunter criterion

Baseline Characteristics

  

Combination therapy (n= 87)

Linezolid monotherapy (n= 261)

 p-value

Age, years

 53.8 ± 17.5 53.9 ± 17.6 0.965

Male

 47.1% 47.1% 1.000

Median length of stay, days

 18 14 0.236

ICU admission

Median ICU length of stay, days

60.9%

2

59.4%

2

0.801

0.587

Median linezolid doses

 14 15 0.627

Received other serotonergic agents*

Tricyclic antidepressants

Other antidepressants

Analgesics

Antiemetics

Migraine therapy

94.3%

3.4%

37.9%

65.5%

67%

3.4%

88.1%

5.4%

22.6%

55.9%

57.1%

0

0.104

0.578

0.005

0.117

0.050

0.015

Of the patients who received a concurrent SSRI or SNRI, citalopram was the most common agent (41.4%).

Additionally, 23% of patients receiving combination therapy had the SSRI or SNRI discontinued before linezolid use

ICU: intensive care unit

*Agents other than SSRIs or SNRIs

Results

 

Combination therapy (n= 87)

Linezolid monotherapy (n= 261)

p-value

Possible serotonin syndrome diagnosis

Met at least 3 Sternbach criteria

Met at least 1 Hunter criterion

 

12 (13.8%)

1 (1.1%)

 

35 (13.4%)

5 (1.9%)

 

0.928

0.533

Documented serotonin syndrome diagnosis

 1 (1.1%) 1 (0.4%) 0.438

No significant difference was seen in the incidence of serotonin syndrome between the combination therapy and monotherapy groups (relative risk, 3.00; 95% confidence interval, 0.19 to 47.45).

Adverse Events

 N/A

Study Author Conclusions

 There was no significant difference in the incidence of serotonin syndrome when linezolid was used alone or in combination with an SSRI or SNRI, and the overall incidence of serotonin syndrome was low.

InpharmD Researcher Critique

 Inherent limitations of this retrospective review include the possibility of confounding variables and reliance on accurate medical documentation. The groups were not evenly matched and the overall incidence of serotonin syndrome was low. 



References:

Karkow DC, Kauer JF, Ernst EJ. Incidence of Serotonin Syndrome With Combined Use of Linezolid and Serotonin Reuptake Inhibitors Compared With Linezolid Monotherapy. J Clin Psychopharmacol. 2017;37(5):518-523. doi:10.1097/JCP.0000000000000751

 

Linezolid and Serotonergic Drug Interactions: a Retrospective Survey

Design

Retrospective chart review

N= 72

Objective

To determine the frequency, significance, and risk factors for serotonergic drug interactions between linezolid and selective serotonin reuptake inhibitors (SSRIs) or venlafaxine in inpatients at the Mayo Clinic (Rochester, MN)

Study Groups

Concomitant linezolid and SSRI (n= 52)

Linezolid and SSRI within 14 days (n= 20)

Inclusion Criteria

Received linezolid and an SSRI or venlafaxine either concomitantly or within 14 days of each other

Exclusion Criteria

N/A

Methods

Information was collected from inpatient medical records. Sternbach criteria and Boyer algorithm for diagnosis of serotonin syndrome were used to identify indicative clinical features. Patients with a suspected diagnosis were stratified by low or high probability of having experienced serotonin syndrome based on clinical features. 

Low probability was described as meeting at least 3 Sternbach criteria, any Boyer criteria, and symptoms did not progress with continued therapy of if concomitant therapy was stopped but symptoms did not resolve. High probability was described as meeting three or more Sternbach criteria or any Boyer criteria with no clear alternative explanations or reversal of symptoms with discontinuation of therapy. 

Duration

April 2000 - November 2004

Outcome Measures

Probability of serotonin syndrome

Baseline Characteristics

 Not reported

Results

Endpoint

Concomitant linezolid and SSRI (n= 52)

Linezolid and SSRI within 14 days (n= 20)

Probability of serotonin syndrome

High

Low

 

2 (4%)

1 (2%) 

 

0

1 (5%) 

Two patients had a high probability of serotonin syndrome. Only one patient had serotonin syndrome listed as a diagnosis on their medical records. This patient was a 30-year-old female who received concomitant linezolid and sertraline, as well as trazodone and fentanyl. The patient was documented as having four Sternbach clinical criteria: agitation (anxiety), myoclonus, diaphoresis, and shivering, as well as two Boyer criteria: spontaneous clonus and inducible clonus with either agitation or diaphoresis. 

The second patient with high probability of serotonin syndrome did not have a diagnosis documented in the medical record. This 81-year-old female received concomitant therapy with linezolid and venlafaxine, followed by citalopram. Six Sternbach clinical criteria were met: mental status changes, agitation, myoclonus, hyperreflexia, tremor, and incoordination and four Boyer criteria were met: tremor and hyperreflexia, spontaneous clonus, muscle rigidity with a body temperature of 138􏰁 °C and ocular or inducible clonus, and ocular clonus with either agitation or diaphoresis. 

Adverse Events

N/A

Study Author Conclusions

If the clinical situation warrants use of linezolid in a patient receiving an SSRI, linezolid may be used concomitantly with SSRIs, without a 14-day washout period and with careful monitoring for signs and symptoms of serotonin syndrome. Serotonergic agents should be promptly discontinued if serotonin syndrome is suspected.

InpharmD Researcher Critique

Many of the patients (65 of 72) in this study received a serotonergic medication other than linezolid or an SSRI, increasing the risk for signs and symptoms of serotonin syndrome. The accuracy of information assessed by this study was limited to what was documented in patient medical records and clinical judgment of healthcare providers present when symptoms occurred. 

 

References:

Taylor JJ, Wilson JW, Estes LL. Linezolid and serotonergic drug interactions: a retrospective survey. Clin Infect Dis. 2006;43(2):180-187. doi:10.1086/504809

 

Risk of serotonin syndrome in acutely ill patients receiving linezolid and opioids concomitantly: a retrospective cohort study

Design

Retrospective observational cohort study

N= 106

Objective

To establish whether combining linezolid with opioids will increase the incidence of serotonin syndrome in acutely ill patients

Study Groups

Full cohort (N= 106)

Inclusion Criteria

 Age ≥ 18 years old, acutely-ill, hospitalized, received concomitant linezolid and opioids

Exclusion Criteria

Received linezolid for less than one day

Methods

Patient data were compiled via review of electronic medical records at Hamad Medical Corporation in Qatar. Opioid treatment may have included morphine, fentanyl, remifentanil, or tramadol.

Duration

Patients admitted between March 2020 to September 2020

Follow-up: 2 weeks after start of linezolid administration

Outcome Measures

Incidence of serotonin syndrome (defined according to Hunter's criteria)

Baseline Characteristics

  

All patients (N= 106)

Age, years

 53 ± 16.2

Male

 91.5%

Comorbidities

Diabetes

Hypertension

Chronic kidney disease

Chronic liver disease

Chronic respiratory disease

Malignancy

 

51.9%

44.3%

19.8%

4.7%

17.9%

8.5%

ICU admission

Required invasive mechanical ventilation

88.67%

53.8%

30-day mortality

36.8%

Route of linezolid administration

Oral/nasogastric tube

Intravenous

Oral/nasogastric tube/intravenous

 

33%

65.1%

1.9%

Number of serotonergic medications received concomitantly with linezolid

0

1

2

3

 

35.8%

40.6%

16%

7.5%

Concomitant medications

Any opioid

Morphine

Fentanyl

Dextromethorphan

Remifentanil

Ondansetron

Amitriptyline

 

56.6%

37.7%

34%

10.4%

10.4%

1.9%

0.9%
All patients who received concomitant linezolid and opioids were in the intensive care unit.

Results

Endpoint

All patients (N= 106)

Incidence of serotonin syndrome

 1 (1.6%)*

* In this single patient, serotonin syndrome symptoms manifested as spontaneous clonus. However, the patient developed spontaneous clonus post-cardiac arrest, making the association between serotonin syndrome and concomitant linezolid-opioids treatment less likely.

Adverse Events

 N/A

Study Author Conclusions

According to these results, the incidence of serotonin syndrome among acutely ill patients who received concomitant opioids and linezolid was very low, and the use of this combination is probably safe. Further prospective studies with a larger sample size are needed to confirm these findings.

InpharmD Researcher Critique

Like most other relevant studies, the current study is limited by its retrospective observational design. Additionally, the study employed a very limited sample size, decreasing the likelihood of accurately detecting more rare events, such as serotonin syndrome.



References:

Mitwally H, Saad MO, Alkhiyami D, et al. Risk of serotonin syndrome in acutely ill patients receiving linezolid and opioids concomitantly: a retrospective cohort study. IJID Reg. 2022;5:137-140. Published 2022 Sep 24. doi:10.1016/j.ijregi.2022.09.008

 

A Cross-sectional Analysis of Linezolid in Combination with Methadone or Buprenorphine as a Cause of Serotonin Toxicity

Design

Retrospective, single-center, cross-sectional analysis

N= 383 patients (494 encounters)

Objective

To evaluate the incidence of and risk factors for serotonin toxicity among hospitalized adults treated with linezolid + methadone or linezolid + buprenorphine

Study Groups

All encounters (n = 494)

Inclusion Criteria

Order for linezolid administered within 24 hours of an order for buprenorphine or methadone

Exclusion Criteria

Not stated

Methods

Pharmacy records for all medication administration of linezolid, methadone, and buprenorphine at the institution were evaluated. The medical record of these encounters underwent close review, with each one further categorized by two physician authors. Encounters were categorized as "noncase" if there were no concerns for serotonin toxicity in the clinical record or when the suspected episode occurred before the coadministration of linezolid + methadone or linezolid + buprenorphine. If serotonin toxicity was considered but not confirmed by the clinical team, encounters were classified as "possible case." "Definite cases" were those with confirmed serotonin toxicity diagnoses. Both authors applied Hunter diagnostic criteria to possible and definite cases based on available information. Disagreements were resolved by consensus.

Duration

November 2015 to October 2019 

Outcome Measures

 Cases of serotonin toxicity

Baseline Characteristics

  

All cases (n = 494) 

 

  

Age, years

 42.5     

Female

 52.4%    

Methadone only

 411 (83%)     
Buprenorphine only 78 (16%)    
Both 5 (1%)    
Encounter duration, d 15.7    

In a subgroup of the 106 encounters with prolonged (≥3 days) overlap of linezolid + methadone or linezolid + buprenorphine, the demographics were similar, except for longer hospital duration (15.7 vs. 33.6).

Results

Endpoint

Methadone 

Buprenorphine

Both

Overlap Duration <3 Days

No

Possible

Definite

 

321

0

0 

 

63

0

0 

 

4

0

0 

Overlap Duration ≥3 Days

No

Possible

Definite

 

88

2*

0 

 

15

0

0

 

1

0

0
Possible cases of serotonin toxicity occurred in 0.40% of all encounters (upper 1-sided 95% confidence interval [CI], 0.87%) and 1.89% of encounters with ≥3 days of overlap (upper 1-sided 95% CI, 4.06%).
* In the first case, a 28-year-old man experienced tachycardia, hyperreflexia, and ankle clonus on linezolid and trazodone, alongside methadone 10 mg three times daily. Symptoms resolved after trazodone cessation, but Hunter criteria were not met due to clonus ambiguity. In the second case, a 56-year-old man showed encephalopathy and tremor on linezolid, methadone 30 mg three times daily, and bupropion. Symptoms resolved after discontinuing linezolid and methadone, with Hunter criteria not met due to absent hyperreflexia. Both cases had prolonged linezolid + methadone overlap and multiple serotonergic medications compared to noncases. Case #1 had 48.5 days of overlap, exceeding noncase averages, while Case #2 had 8.0 days of overlap, above average but below the upper bounds for noncases with similar overlaps. The average doses of methadone orders in both cases were below noncase averages.

Adverse Events

See result

Study Author Conclusions

Serotonin toxicity occurring during the administration of linezolid in combination with methadone and/or buprenorphine occurred rarely among 494 hospital encounters, including 106 encounters with ≥3 days of overlap. Limitations include potential missed diagnoses of serotonin toxicity and short durations of overlap. Further study evaluating the short-term risk of this combination is needed.

InpharmD Researcher Critique

The study faces limitations in standardizing the clinical diagnosis of serotonin syndrome, with retrospective application of diagnostic criteria often inconclusive due to missing clinical data. Subjective classification of cases as probable or definite was mitigated by independent adjudication by two physicians. Additionally, the duration of concurrent administration was often shorter than typical for linezolid courses, potentially underestimating overlap duration, while the low number of identified cases and short overlap duration limited statistical comparisons of risk factors, thus constraining the findings' applicability to clinical care. 



References:

Traver EC, Heil EL, Schmalzle SA. A Cross-sectional Analysis of Linezolid in Combination with Methadone or Buprenorphine as a Cause of Serotonin Toxicity. Open Forum Infect Dis. 2022;9(7):ofac331. Published 2022 Jul 1. doi:10.1093/ofid/ofac331

 

A Case Series on Serotonin Syndrome from Concomitant use of linezolid With Methadone, Buprenorphine, and/or Dextroamphetamine

Design

Single-center retrospective review

N= 194 encounters

Objective

 To assess the prevalence of serotonin syndrome (SS) as a result of concomitant use of linezolid plus at least one of the following agents: methadone, buprenorphine, dextroamphetamine at Massachusetts General Hospital (MGH)

Study Groups

All encounters (n = 194)

Inclusion Criteria

 Adults ≥18 years admitted and prescribed linezolid concomitantly with at least one of the following agents: methadone, buprenorphine, and/or dextroamphetamine

Exclusion Criteria

 Patients who had interacting medications ordered for an as-needed frequency only or were ordered interacting medications that were not administered

Methods

Chart reviews assessed medication doses and concomitant therapy duration, categorized as ≤24 hours, 25-48 hours, and ≥72 hours. Data collected included age, gender, linezolid therapy length, concurrent medications, and doses. Confirmed SS cases were verified by ICD-10 codes or meeting Hunter Serotonin Toxicity Criteria (HSTC) symptoms. Symptoms included clonus, agitation, diaphoresis, tremor, hyperreflexia, and hypertonicity with fever. Patients without ICD-10 diagnoses but meeting HSTC symptoms were considered possible SS cases. Interacting medication doses were categorized as low, medium, or high.

Duration

April 2016 to June 2022

Outcome Measures

 Characterizing prescribing preferences and prevalence of confirmed and possible serotonin syndrome

Baseline Characteristics

  

All encounters

(n = 194)

  

 

  

Age, years

 47       

Female

 40%       

Methadone

Low dose

Medium dose

High dose

133 (65.8%)

63 (47.4%)

48 (36.1%)

22 (16.5%)

      

Buprenorphine

Low dose

Medium dose

High dose

45 (23.2%)

7 (15.6%)

30 (66.7%)

8 (17.8%)

      

Dextroamphetamine

Low dose

Medium dose

High dose

23 (11.9%)

14 (60.9%)

8 (34.8%)

1 (4.3%)

      

>1 agent *

7 (3.6%)

      

Mean duration of overlap with linezolid, days

Methadone

Buprenorphine

Dextroamphetamine

 

4.6

3.3

7

      

Patients on methadone with buprenorphine (n = 4), methadone with dextroamphetamine (n = 2), buprenorphine and dextroamphetamine (n = 1). 

Results

Endpoint

Total (n = 194)

 ≤24 h overlap with linezolid

25-48 h overlap with linezolid

≥72 h overlap with linezolid
Cases of definitive SS 1 (0.5%) 0 0 1*
Cases of possible SS 2 (1.0%) 1** 1** 0
*Confirmed SS: A 37-year-old female, taking 85 mg of methadone daily, switched from vancomycin to linezolid due to intravenous antibiotic refusal. After 72 hours on linezolid, right leg clonus was observed, resolving upon discontinuation of linezolid and switch to trimethoprim-sulfamethoxazole. Despite lacking mention of clonus type, its resolution with linezolid cessation led the investigators to classify this as definitive serotonin syndrome as a precaution.
**Two possible cases: In the first scenario, a 22-year-old male, taking buprenorphine and bupropion, experienced sudden confusion, agitation, hypertension, and tachycardia after receiving a dose of linezolid. His urine test showed amphetamines, raising uncertainty about whether his symptoms were due to drug use or SS. Linezolid was switched to doxycycline as a precaution. Although no symptoms met the criteria for SS, the team documented this as a potential case due to concern.

In the second scenario, a 44-year-old female on methadone demonstrated altered mental status, high fevers, and abnormal EEG readings suggesting seizure activity. A lumbar puncture revealed pleocytosis. While neurology and infectious diseases teams were not highly concerned about SS, linezolid was discontinued as a precaution. Although the patient didn't show clonus, cases of SS have manifested as febrile encephalopathy with pleocytosis, prompting the classification of this case as possible SS.

Adverse Events

See Results

Study Author Conclusions

Linezolid may be considered in patients who are concomitantly on methadone, buprenorphine, and/or dextroamphetamine. In our analysis of 194 encounters, one definitive case and two possible cases of SS were identified. Additional real-world studies are necessary to identify if exposure and/or duration may be correlated with an increased risk of serotonin syndrome.

InpharmD Researcher Critique

 Due to the study's small sample size, statistical power is limited, requiring larger studies for robust conclusions. Additionally, the exclusion of patients using alternative stimulants and reliance solely on ICD-10 codes may have led to missed cases of SS, compounded by overlapping features with other conditions like neuroleptic malignant syndrome. Moreover, post-discharge cases in inaccessible medical records were not evaluable, despite attempts to minimize missed cases through extensive chart review. 

 

References:

Huang J, Edrees H, Lee G. A Case Series on Serotonin Syndrome from Concomitant use of linezolid With Methadone, Buprenorphine, and/or Dextroamphetamine. J Pharm Pract. 2024;37(3):780-785. doi:10.1177/08971900231182772

 

Serotonin Syndrome Due to Concomitant Use of Linezolid and Methadone

Design

 Case report 

Case presentation

A 60-year-old man, with a history of drug addiction, bipolar disorder, and mental disability, was admitted to the hospital's poisoning department with dizziness, nausea, and vomiting. He had low blood pressure, high heart rate, low respiratory rate, and meiotic pupils. His medical history included lithium, clonazepam, valproate sodium, perphenazine, and methadone (dose unknown) use. Upon admission, he was unconscious with a Glasgow coma scale score of 7. Laboratory findings indicated elevated white blood cell count, creatinine, potassium, CPK, and lactic acidosis. Serum drug levels showed toxic levels of lithium and valproate sodium, and urine test was positive for methadone and benzodiazepines and negative for tramadol and cannabinoids. Hemodialysis was performed, correcting electrolyte imbalance. All medications were place on hold except for methadone. He was intubated and transferred to the ICU.

On the third day, he developed a fever and chest imaging revealed pneumonia. Empirical antibiotics were started (ceftriaxone 1000 mg twice a day intravenously and clindamycin 600 mg three times a day intravenously), but sputum culture showed Staphylococcus aureus resistant to initial antibiotics. Linezolid 600 mg twice a day intravenously was initiated but after 2 days, resulted in fever, agitation, tremor, spontaneous clonus movements in the hands, and tachycardia, prompting suspicion of sepsis. The chest X-ray remained unchanged, urine analysis was normal, and electroencephalogram (EEG) showed no seizure activity. Brain CT scan was normal. Serotonin syndrome was diagnosed based on Hunter's criteria. Linezolid was stopped, and vancomycin initiated. Treatment included hydration, metoclopramide, cyproheptadine, and benzodiazepines. Symptoms improved within 48 hours, but consciousness marginally improved. Extubation occurred after 3 days, with improved consciousness and communication. After 1 week, transferred to the ward in stable condition.

Study Author Conclusions

 The diagnosis of serotonin syndrome was difficult in the patient who presented with tremors, agitation, and clonus movement. Discontinuation of reference agents and treatment of symptoms is compelling. This syndrome must be prevented by educating patients to avoid self‐medication and limiting drug combinations. 

 

References:

Masbough F, Roshanzamiri S, Rahimi M, Sahraei Z, Evini PET. Serotonin syndrome due to concomitant use of linezolid and methadone. Clin Case Rep. 2022;10(11):e6341. Published 2022 Nov 5. doi:10.1002/ccr3.6341

 

Serotonin syndrome due to co-administration of linezolid and methadone

Design

 Case report 

Case presentation

A 39-year-old drug addict male presented with fever (up to 39.5°C), abdominal and musculoskeletal pain, fatigue, hypotension, and oliguria. He had a history of sciatica and underwent a surgery for iliac-femoral arterial bypass. He was on methadone 40 mg/day maintenance therapy and antiretroviral treatment (lamivudine 300 mg daily, tenofovir 245 mg daily and darunavir 800 mg /ritonavir 100 mg daily). On admission, he was dehydrated with high fever, tachycardia, and respiratory distress. Laboratory findings showed leukocytosis, elevated CRP, and renal impairment. Imaging revealed bilateral pulmonary infiltrates, muscle abscesses, and pyomyositis. Blood cultures were positive for MRSA. Initial treatment with ceftriaxone and amoxicillin-clavulanate was later changed to linezolid 600 mg twice daily plus clindamycin 600 mg four times daily intravenously due to MRSA sensitivity. Despite treatment, he developed confusion, agitation, and autonomic instability, suggestive of serotonin syndrome. Linezolid was stopped, and supportive care with rehydration, steroids, and benzodiazepines was initiated, leading to improvement. Later, he was transitioned to ciprofloxacin and rifampicin, resulting in clinical improvement and resolution of abscesses.

Study Author Conclusions

The present case suggests that clinicians should be aware of the potential drug interaction between linezolid and some opioids that have serotonergic activity as methadone, to avoid the risk of life-threatening serotonin toxicity which may result from this drugs combination.

 

References:

Mastroianni A, Ravaglia G. Serotonin syndrome due to co-administration of linezolid and methadone. Infez Med. 2017;25(3):263-266.