International Journal of Mental Health & PsychiatryISSN: 2471-4372

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Short Article, Int J Ment Health Psychiatry Vol: 5 Issue: 1

Bupropion with Linezolid: A Review

Divya Periasamy and Sachidanand Peteru*

Jamaica Hospital Medical Center, NY, USA

*Corresponding Author : Selvan T
MD, Jamaica Hospital Medical Center, 8900 Van Wyck Expy, Richmond Hill, NY 11418, USA,
Tel: 718-206-7135
E-mail: [email protected]

Received: December 26, 2018 Accepted: February 13, 2019 Published: February 19, 2019

Citation: Periasamy D, Peteru S (2019) Bupropion with Linezolid: A Review. Int J Ment Health Psychiatry 5:1. doi: 10.4172/2229-4473.1000225

Abstract

Introduction: Linezolid (Zyvox) is an antibiotic, which belongs to the class of oxazolidinone. FDA approved it in 1998 to treat gram-positive drug-resistant enterococcus, staphylococcus, and pneumococcus infections in adults (MRSA and VRE). Bupropion (Welbutrin) is a medication primarily used as an antidepressant and smoking cessation aid. FDA first approved it in 1985. Both these medications are well known for causing serotonin syndrome when combined with serotonergic agents or administered along with tyramine-rich foods. Case: A 50-year old male patient was admitted to the hospital with right leg cellulitis and was treated with linezolid. The patient also had a history of depression and anxiety and was stable on bupropion for the past two years. Our C and L team was consulted for medication reconciliation and possible drug-drug interaction. On an extensive literature search, we came across just one case of hypertensive crisis when treated with linezolid and bupropion simultaneously. Hypertensive crisis from other confounding factors is unknown. We recommended continuing the prescribed bupropion on the patient along with his linezolid medication after explaining the risks and benefits. The patient completed his treatment and there were no symptoms suggestive of serotonin syndrome or hypertensive crisis. Conclusion: Bupropion was continued in a patient who was simultaneously treated with linezolid and pt completed the treatment without any symptoms of serotonin syndrome or hypertensive crisis. However, clinicians should be vigilant about drug-drug interactions and should make decisions on a case by case basis.

Keywords: Linezolid; Bupropion; MAO inhibitor; SSRI; SNRI; DNRI; Serotonin syndrome; Hypertensive crisis; FAERS; Neuroleptic malignant syndrome

Introduction

Linezolid (Zyvox) is an antibiotic, which belongs to the class of oxazolidinone. It was approved in 1998 by the FDA to treat gram-positive drug-resistant enterococcus, staphylococcus, and pneumococcus infections in adults (MRSA and VRE). Linezolid disrupts bacterial growth by inhibiting the initiation process through protein synthesis, 23S RNA. It is also a nonselective, reversible, weak MAO inhibitor. This increases the levels of dopamine, serotonin, and norepinephrine in the body, which in turn increases the potential for drug-drug interactions, food-drug interactions, and side effects.

In patients who take linezolid and serotonin agonists simultaneously, there is a documented risk of developing serotonin syndrome [1]. Sternbach described serotonin syndrome in 1991. Serotonin syndrome is caused by excessive serotonin in circulation in both the central and peripheral nervous systems. The 5HT receptors agonize through elevated synaptic concentrations of serotonin. The mild serotonin syndrome case is mediated by 5-HT1A receptors and 5-HT2A mediates the severe cases [2]. It presents with confusion, agitation, headache, tachycardia, and loss of muscle coordination, blood pressure fluctuations, temperature changes, tremors, and shivering. A severe serotonin syndrome presents with very high fever, seizures, irregular heart rate, and unconsciousness. Symptoms develop within 6 hours of adding or modifying medications that increase serotonin levels. Unfortunately, there are no lab tests to determine serotonin syndrome [3,4].

Bupropion (Welbutrin) is an antidepressant, which is a relatively weak inhibitor of the neuronal uptake of nor epinephrine and dopamine and does not inhibit monoamine oxidase or the re-uptake of serotonin [5]. Bupropion is used to treat depression, ADHD, smoking cessation, seasonal affective disorder. Bipolar (depression phase) and anxiety associated with depression.

We are presenting a case who was admitted to the hospital with right leg MRSA positive cellulitis for which linezolid was started. The patient also had depression and anxiety, which was well controlled with the help of bupropion. The C and L team was consulted for possible risk of drug-drug interactions and switching to other antidepressants.

We recommended continuing the medications, as there is not enough evidence to support, though there is a possible drug-drug interaction. Our patient was stable on meds and agreed to continue on bupropion after explaining the risks and benefits of continuing it. We offered emergent interventions to treat hypertensive crisis or serotonin syndrome, should it happen and the patient did well.

Methods

The case was thoroughly reviewed and discussed with the surgical and medical team. An intensive literature search was done on PUBMED, FDA, and PDR to formulate the discussion. Serotonin syndrome with linezolid was looked up and we found 67 articles. Out of these articles, serotonin syndrome due to drug interactions especially with antidepressants had similar signs and symptoms, was treated alike and was already reported many times. Hence these articles were eliminated. When we searched for bupropion causing serotonin syndrome we came across 58 articles. In every article bupropion was not the only drug and hence it was not certain that it was the cause for serotonin syndrome in those patients. On vigilant search, we came across one case reported for serotonin syndrome with simultaneous use of linezolid and bupropion.

Case Vignette

A 50-year old male patient was admitted to the hospital with right leg cellulitis, post skin graft surgery due to a motor vehicle accident. The cellulitis was not getting better, multiple antibiotics were tried and eventually, linezolid was recommended. Patient has a history of depression and anxiety and was stable on bupropion for the past two years. Our C and L team was consulted for medication reconciliation and possible drug-drug interaction. On an extensive literature search, we came across just one case of hypertensive crisis in which the patient was treated with linezolid and bupropion simultaneously.

Hypertensive crisis from other confounding factors is unknown. As per our knowledge, there are no other reports of a hypertensive crisis with bupropion, we recommended continuing the prescribed bupropion on the patient along with his linezolid medication after explaining the risks and benefits. The patient completed his treatment and there were no symptoms suggestive of serotonin syndrome or hypertensive crisis. The patient continued doing well even after 3 months post discharge.

Discussion

According to FDA, linezolid has a total number of 4829 adverse events reported since 1998 while bupropion has 8076 events since 1988. 690 deaths were reported for linezolid and 3566 deaths were reported for bupropion. For linezolid, the total events, reported for drug interactions were 211 (4.4% of the total). The number of cases with serotonin syndrome reported was 137 cases (2.86% of the total cases reported) out of which serotonin syndrome reportedly caused 16 deaths (11.6%). In addition, there were 6 cases of hypertensive crisis and 3 cases of neuroleptic malignant syndrome (NMS) (Figure 1) [6].

Figure 1: The number of adverse effect cases reported on the FDA website for Linezolid [5].

Linezolid is a weak MAO inhibitor, which causes various psych manifestation even in non-psych patients – see Table 1.

Symptoms No. of Cases Symptoms No. of Cases
Feeling abnormal 56 Nervousness 12
Prosthesis 55 Altered mental status 11
Insomnia 47 Paranoia 11
Hallucinations 44 Tinnitus 11
Delirium 36 Irritable 11
Anxiety 30 Myoclonus 11
Lethargy 30 Aggression 10
Palpitations 23 Epilepsy 8
Depression 23 Cognitive 7
Glossodynia 23 Cold sweat 6
Sweating 17 Mental disorder 6
Chest discomfort 17 Stress 4
Eating disorder 15 Crying 4
    Thinking abnormal 4

Table 1: Psychiatry symptoms associated with Linezolid.

Bupropion the total events, reported for drug interactions were 324 (4.0% of the total). The number of cases of serotonin syndrome reported was 216 cases (2.6% of the total cases reported) out of which serotonin syndrome reportedly caused 8 deaths (3.7%). There are 33 cases of NMS reported and 6 cases of hypertensive crisis (Figure 2).

Figure 2: The number of adverse effect cases reported on the FDA website for Bupropion [3].

Serotonin syndrome or serotonin toxicity is excessive serotonin in the nerve cells causing a collection of symptoms. The contributing factors that cause serotonin syndrome are kidney diseases, pulmonary diseases, and liver diseases. To facilitate a diagnosis the symptoms should be categorized into three: 1) Cognitive effects: headache, agitation, hypomania, mental confusion, hallucinations, coma 2) Autonomic effects: shivering, sweating, hyperthermia, vasoconstriction, tachycardia, nausea, and diarrhea. 3) Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), and tremor. Severe serotonin syndrome, which is potentially fatal, presents with high fever, seizures, irregular heartbeat, and unconsciousness.

• Spontaneous clonus

• Inducible clonus and agitation or diaphoresis

• Ocular clonus and agitation or diaphoresis

• Tremor and Hyperreflexia

• Hypertonic

• Temperature above 38 degree Celsius and ocular clonus or inducible clonus

This rule has greater accuracy and we are less likely to miss the mild and moderate serotonin syndrome [7].

The key principles in managing serotonin syndrome are-Stop the serotonergic agent; provide supportive care to normalize the vital signs; sedate with benzodiazepines; administer serotonin antagonists (cyproheptadine); assess the need to restart serotonin agents after the symptoms resolve. Serotonin syndrome generally resolves in 24 hours after initiating treatment. Both mild and moderate serotonin syndrome recover within 24 hours to a few days. The time will depend on the half-life of the drug. Drugs like fluoxetine take much longer. A single serotonergic medication can be started after symptoms have resolved. MAO inhibitors have the greatest risk, and symptoms can persist for several days. Antipsychotics like olanzapine and chlorpromazine are also considered antidote for serotonin syndrome but their efficacy has not been proven and hence not recommended [4,8].

The differential diagnosis for serotonin syndrome is neuroleptic malignant syndrome (NMS), anticholinergic toxicity, malignant hyperthermia, and intoxication from sympathomimetic agents, sedative-hypnotic withdrawal, meningitis, and encephalitis [8].

Conclusion

On prescriber’s digital reference (pdr.net), bupropion is contraindicated in the use of linezolid. In case linezolid has to be started on a patient on bupropion, bupropion has to be stopped immediately and the patient has to be monitored for a hypertensive crisis for 2 weeks post or 24 hours of the last dose of linezolid whichever comes first. Bupropion can be re-initiated 24 hours after the last dose of linezolid, but with our patient, he was simultaneously on bupropion and linezolid and did not develop any adverse events during the hospital stay. Pt has been doing well 3 months later on follow up visits.

However, clinicians should be vigilant about drug-drug interactions and decide on case by case basis. More research is needed regarding antibiotics for the treatment of MRSA/VRE infections that causes lesser drug-drug interactions and side effects.

References

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