Are there any antidepressants that may be used concomitantly with linezolid and don't require a washout period?

Comment by InpharmD Researcher

There is a paucity of literature evaluating the safety of specific antidepressants when used concomitantly with linezolid without a washout period. Case reports involving certain antidepressants can be located in Table 1. According to the package insert for linezolid, a serotonergic antidepressant can be stopped promptly if urgent treatment with linezolid is required (i.e., vancomycin-resistant enterococcus faecium, nosocomial pneumonia, or complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus) and benefits of immediate administration outweigh the potential risk of serotonin syndrome or neuroleptic malignant syndrome.

  

PubMed: linezolid antidepressant washout = 3 results (1 relevant)

Background

According to a U.S. Food and Drug Administration drug safety communication, conditions that may be life-threatening or require urgent treatment with linezolid include when it is being used to treat vancomycin-resistant Enterococcus faecium (VRE), nosocomial pneumonia, or complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus (MRSA). In these emergencies, directions for serotonergic antidepressant treatment from the package insert should be followed. [1]

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 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, 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. [2]

A 2006 review discusses reports of serotonin syndrome to determine relevant drug interactions with linezolid. A summary of these reports and the specific dosage of antidepressant used in each case when linezolid administration was required can be found in Table 1. [3]

References:

[1] U.S. Food and Drug Administration (FDA). FDA Drug Safety Communication: Serious CNS reactions possible when linezolid (Zyvox) is given to patients taking certain psychiatric medications. Available https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-linezolid-zyvox-given-patients. Updated December 14, 2017. Accessed November 9, 2021.
[2] Quinn DK, Stern TA. Linezolid and serotonin syndrome. Prim Care Companion J Clin Psychiatry. 2009;11(6):353-356. doi:10.4088/PCC.09r00853
[3] Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26(12):1784-1793. doi:10.1592/phco.26.12.1784
Relevant Prescribing Information

Linezolid: Serotonin Syndrome
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 neuroleptic malignant syndrome (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. [4]

References:

[4] Linezolid [prescribing information]. East Windsor, NJ: AuroMedics Pharma LLC; 2021
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Are there any antidepressants that may be used concomitantly with linezolid and don't require a washout period?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-2 for your response.

Case Reports of Serotonin Syndrome with Concomitant Administration of Linezolid and Serotonin Agonists

Condition requiring linezolid 

 Sex Age, years Serotonin Agonist, mg/day Onset of serotonin syndrome, days  Mental status changes and Sternbach Criteria  Resolution, days

MSSA wound

 F 56 Paroxetinea

1 to 2

 Agitation, tremor 2b

Severe burns

 F 4 Fluoxetine 5 2 Agitation, myoclonus 2

Osteomyelitis

 M 67 Mirtazapine 30 28 Mental status change only Unknownc

Cystic fibrosis

 F 38 Venlafaxine 300 4 Hyperreflexia, tremor 9d

MRSA hip infection

 M 85 Venlafaxine 150 20 Agitation, fever, myoclonus 2

Urinary VREF infection

 F 56 Citalopram 20, mirtazapine 30 4

Agitation, fever, high blood pressure

 2e

Multiple myeloma

 M 37 Citalopram 40 3 Tremor, diaphoresis, high blood pressure 9

Osteomyelitis

 M 81 Citalopram 40 7 to 21 Tremor, fever N/Af 

Staphylococcus aureus infection

 F 85 Citaloprama Unknown   Tremor, hyperreflexia  3

Stem cell transplant

 F 56 Citalopram 20 2 to 7  Tremor, incoordination, high blood pressure 9 

Lymphoma

 M 36 Sertraline 50 5  Agitation, fever, high blood pressure 2 

Decubitus ulcer

 M 45 Sertraline 200 10  Tremor, fever, myoclonus 2 

MRSA pneumonia  

 F 39 Fluoxetinea 1 to 2  Agitation, myoclonus 2 

In all of the adults, the dosage of linezolid was 600 mg BID given orally or intravenously.

MSSA = methicillin-susceptible Staphylococcus aureus; MRSA = methicillin-resistant S. aureus; VREF = vancomycin-resistant Enterococcus faecium; N/A = not applicable.

a Dose not specified; b Paroxetine was tapered 72 hours before linezolid was started; c Patient self-discontinued then restarted mirtazapine therapy;   
d Dose of venlafaxine was reduced on day 8; e Patient was admitted with citalopram 40 mg, which was discontinued when linezolid was started. Citalopram was restarted at 20 mg because of anxiety. f Patient died.
References:

Huang V, Gortney JS. Risk of serotonin syndrome with concomitant administration of linezolid and serotonin agonists. Pharmacotherapy. 2006;26(12):1784-1793. doi:10.1592/phco.26.12.1784

 

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 diagnosis on their medical records. This patient was a 30-year-old female who received concomitant linezolid and sertraline, as well as trazdone and fentanyl. 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 judgement 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