Be aware of serotonin syndrome when giving linezolid

December 2004

Linezolid (Zyvox, Pfizer) is an oxazolidinone with excellent activity against Staphylococcus aureus and Enterococcus species. Linezolid is gaining popularity for use in skin and skin structure infections and health care–associated pneumonia. The increasing use of linezolid has brought to light the drug interaction with serotonergic agents, such as the selective serotonin reuptake inhibitors (SSRIs).

Linezolid is a weak reversible nonselective inhibitor of monoamine oxidase (MAOI) and has the potential to interact with serotonergic agents causing serotonin syndrome (J Antimicrob Chemother. 2003;51[suppl S2]:ii45-ii53). In phase-1 studies, linezolid did not show any effects on blood pressure, heart rate or temperature when used alone or in combination with dextromethorphan. When linezolid was administered with tyramine, doses of more than 100 mg of tyramine were required to raise blood pressure. This dose of tyramine is more than what is found in normal dietary intake. In phase-2 and -3 clinical trials, there were no reported cases of serotonin syndrome with the coadministration of linezolid and serotonergic agents (J Antimicrob Chemother. 2003;51[suppl S2]:ii45-ii53). However, since the release of linezolid there have been seven reports in the literature involving eight patients who experienced serotonin syndrome associated with the use of linezolid and SSRIs. The SSRIs involved were citalopram (Celexa, Forest) with three cases, sertraline (Zoloft, Pfizer) with two cases, fluoxetine with one case, venlafaxine (Effexor, Wyeth) with one case, and paroxetine with one case that was discontinued three days prior to initiating linezolid. Six patients had resolution of their symptoms upon discontinuation of linezolid and two cases were fatal. The interaction with linezolid and the SSRIs is now classified as a “major” drug interaction (interaction that is significant and has supportive documentation) by most of the vendors of drug interaction screening programs used by inpatient and outpatient pharmacies. However, the clinical question remains: “How can I best manage this drug interaction?”

What is serotonin syndrome?

Simply, serotonin syndrome is a result of increased serotonin in the intrasynaptic space resulting in overstimulation of the 5-HT receptors, specifically 5-HT_1A and 5-HT₂ (Pain Med. 2003;4:63-74). This may result in cognitive and behavioral symptoms as well as autonomic instability. Serotonin syndrome typically results from increases in dosage or addition of a serotonergic agent to an established medication regimen. Serotonin syndrome should be suspected when a patient exhibits three of the following: agitation, mental status changes (confusion, hypomania), myoclonus, shivering, tremor, hyperreflexia, ataxia, diarrhea or fever in the face of linezolid being added to a stable SSRI regimen or visa versa. Patients may also experience diaphoresis, trismus, parasthesias, uncoordination and head twitching; however, these symptoms are not required for diagnosis of serotonin syndrome (Pain Med. 2003;4:63-74). The severity of symptoms is dependent on the degree of elevation of serotonin and its duration of elevation (Fundam Clin Pharmacol. 1998;12:482-491).

Symptoms of serotonin syndrome usually begin within 24 hours after the addition of the offending agent. The symptoms may increase and become more severe if the interaction is not recognized and offending agent discontinued. This differs from neuroleptic malignant syndrome, which typically occurs after seven or more days of therapy of the offending agents. There is no proven treatment of serotonin syndrome other than supportive care. However, discontinuation of the offending agents is imperative, and symptoms will typically resolve within 24 to 48 hours. Case reports have suggested that cyproheptadine 20 mg to 30 mg may be of benefit if the patient is experiencing severe autonomic instability (J Psychopharmacol. 1999;13:100-109).

The mechanism of the interaction

It is estimated that the body has approximately 10 mg of serotonin, which is present in the gastric and intestinal mucosa, platelets and central nervous system. Serotonin synthesis begins when ingested tryptophan crosses the blood brain barrier to be hydrolyzed and subsequently decarboxylized to serotonin. After serotonin is released into the synaptic space, it is removed from the cleft by reuptake pumps for repackaging in storage vesicles or degradation by monoamine oxidase. Monoamine oxidase A preferentially metabolizes serotonin, while monoamine oxidase B metabolizes catecholamines (Pain Med. 2003;4:63-74).

One would postulate that the concurrent use of SSRIs and linezolid might lead to serotonin syndrome by the dual actions on serotonin. The SSRIs will inhibit the serotonin reuptake pumps while linezolid will inhibit the degradation of serotonin, resulting in an overabundance of serotonin in the neurons, causing the overstimulation of the serotonin receptors.

Management of linezolid and SSRI drug interaction

The management of the linezolid and SSRI drug interaction has become a treatment dilemma. The drug interaction screening programs suggest that the SSRI be discontinued for 14 days prior to linezolid being started. However, this may not be a practical solution to treating patients who require linezolid therapy. A more practical approach may be to begin linezolid to a stable SSRI regimen and for the prescriber and patient to be alert to the early symptoms of serotonin syndrome (cognitive and behavioral changes and autonomic instability). If the patient exhibits any of these symptoms, linezolid should be discontinued and alternative antibacterial therapy started.

For more information:

• French G. Safety and tolerability of linezolid. J Antimicrob Chemother. 2003;51(suppl S2):ii45-ii53.
• Enger RA, Meglathery SB, van Decker WA, Gallagher RM. Serotonin syndrome and other serotonergic disorders. Pain Med. 2003;4:63-74.
• Gillman PK. Serotonin syndrome: history and risk. Fundam Clin Pharmacol. 1998;12:482-491.
• Gillman PK. The serotonin syndrome and its treatment. J Psychopharmacol. 1999;13:100-109.

• Marianne Billeter, PharmD, BCPS, Clinical Pharmacology Specialist, Infectious Diseases, Ochsner Clinic Foundation, New Orleans.