Linezolid is a prozolidinone with pronounced activity against S. aureus and enterococci. This antimicrobial drug is used mainly for the treatment of skin and soft tissue infections, nosocomial pneumonia. The increased use of linezolid has highlighted the interaction of drugs with serotonergic agents, such as selective serotonin reuptake inhibitors (SSRIs).

Linezolid is a weak, reversible, non-selective monoamine oxidase (MAO) inhibitor, capable of interacting with serotonergic substances that cause serotonin syndrome (SS). In studies of healthy volunteers with linezolid, there was no effect on blood pressure, heart rate or temperature when used as monotherapy or in combination with dextromethorphan. In phase II and III tests, there was also no case of SS with the co-administration of linezolid and serotonergic agents. However, since the advent of linezolid on the market, 7 reports have been published on the development of SS in 8 patients following the use of linezolid and one of the SSRIs. Among them, citalopram (3 cases), sertraline (2 cases), fluoxetine (1 case), venlafaxine (1 case) and one case with paroxetine, which was discontinued 3 days before the appointment of linezolid. In six patients, symptoms of SS resolved successfully after discontinuation of linezolid; 2 cases were fatal. The interaction of linezolid and SSRIs is now classified as a “large” drug interaction (important and with supporting documentation).

Serotonin syndrome results from an increase in the concentration of serotonin in the intrasynaptic space and from overstimulation of 5-HT receptors, especially 5-HT1A and 5-HT2. This can lead to cognitive and behavioral symptoms, such as autonomous instability. SS is usually the result of increasing the dose or prescribing additional serotonergics to a stable therapy regimen. SS should be suspected if the patient has three of the following symptoms: agitation (excitement), change of mental state (confusion, hypomania), myoclonus, tremors, tremors, hyperreflexia, ataxia, diarrhea, or facial heat soon after adding linezolid to an SSRI stable regimen or vice versa. Patients may also suffer from sweating, trismus, parasthesis, discoordination and contractions of the head; however, these symptoms do not determine the diagnosis of CC. The severity of the symptoms is determined by the degree to which the serotonin level increases and how long it lasts.

Symptoms of serotonin syndrome usually occur within 24 hours of taking these drugs and may increase if the interaction is not recognized and the drugs are not canceled. This distinguishes serotonin syndrome from malignant antipsychotic syndrome, which usually occurs after 7 days or more of treatment with psychotropic drugs.

There is no proven method for treating serotonin syndrome, except patient care. However, withdrawal of the responsible drugs is mandatory and the symptoms usually go away on their own after 24 to 48 hours. Cyproheptadine at a dose of 20 to 30 mg may be effective if the patient has severe autonomous instability.

Interaction mechanism. Serotonin released into the synaptic space is eliminated by recapture pumps for re-accumulation in the vesicles or degradation of MAO. It is assumed that competitive use of SSRIs and linezolid can lead to serotonin syndrome due to the dual action on the synaptic kinetics of serotonin. SSRIs are capable of inhibiting re-uptake pumps, while linezolid can inhibit the breakdown of serotonin, causing excess mediator in neurons and excessive stimulation of serotonin receptors.

Drug interaction control. It is a therapeutic dilemma. Drug interaction monitoring programs suggest stopping SSRI therapy 14 days before linezolid is given. However, this route may not be a practical solution for patients receiving treatment who require treatment with linezolid. A more acceptable approach may be the appointment of linezolid in the context of a stable SSRI regimen and the vigilance of the doctor and the patient regarding the first symptoms of serotonin syndrome (changes in psyche and behavior, autonomous instability). If the patient has any of these symptoms, linezolid should be discontinued and alternative antibacterial therapy should be initiated.