CLINICALLY SPEAKING
Linezolid-Associated Serotonin Syndrome A Report of Two Cases Robert G. Frykberg, DPM, Scott Gordon, Edward Tierney, Jaminelli Banks,
MPH* DPM* DPM* DPM*
Linezolid, a mild monoamine oxidase inhibitor, is a commonly used antibiotic drug for the treatment of complicated skin and skin structure infections, including diabetic foot infections. Use of linezolid has been associated with serotonin syndrome, a potentially life-threatening condition typically caused by the combination of two or more medications with serotonergic properties, due to increased serotonin release. The goals of this article are to highlight the risk factors associated with the development of serotonin syndrome related to the use of linezolid and to aid in its prevention and early diagnosis. In this case series we report on two hospitalized patients who, while being treated with linezolid for pedal infections, developed serotonin syndrome. Both individuals were also undergoing treatment with at least one serotonergic agent for depression and had received this medication within 2 weeks of starting the antibiotic drug therapy. In these individuals, we noted agitation, confusion, tremors, and tachycardia within a few days of initiation of linezolid therapy. Owing to the risk of serotonin toxicity, care should be taken when prescribing linezolid in conjunction with any other serotonergic agent. Although serotonin syndrome is an infrequent complication, it can be potentially life threatening. Therefore, risks and benefits of therapy should be weighed before use. (J Am Podiatr Med Assoc 105(3): 244-248, 2015)
Serotonin syndrome is a potentially fatal condition with a wide spectrum of severity that has been associated with the use of linezolid when combined with serotonergic agents.1 The incidence of serotonin toxicity is between 0.54% and 18.2%.2 The diagnosis of serotonin toxicity has been reported to be based on clinical manifestations after initiation of linezolid therapy and abrupt resolution on withdrawal of the precipitating medications.3 Linezolid-associated serotonin toxicity is associated with an increase in serotonergic activity in the central nervous system. It is most commonly seen in association with therapeutic use of selective serotonin reuptake inhibitors (SSRIs), inadvertent medication interactions, and self-poisoning.4 Serotonin has activity in both the central and peripheral nervous systems. In the central nervous system it The views expressed herein are those of the authors and do not represent the views of the US Department of Veterans Affairs or the US Government. *Department of Podiatry, Carl T. Hayden VA Medical Center, Phoenix, AZ. Corresponding author: Robert G. Frykberg, DPM, MPH, Carl T. Hayden VA Medical Center, 650 E Indian School Rd, Phoenix, AZ 85012. (E-mail: [email protected])
244
acts to modulate attention, behavior, and thermoregulation. In the peripheral nervous system it is produced mainly by intestinal enterochromaffin cells and is mainly involved in regulating gastrointestinal motility, vasoconstriction, uterine contraction, and bronchoconstriction, and it has some effect on platelet aggregation.5 The serotonin syndrome is often described as a clinical triad of hyperthermia, mental status changes, and autonomic hyperactivity with neuromuscular abnormalities. This can include agitation, diaphoresis, mydriasis, hyperthermia (temperature as high as 1048–1068F), tachycardia, hypertension, diarrhea, akathisia, tremor, and muscular rigidity, but not all of these findings are consistently present in all of the patients with the disorder.6 The onset of symptoms is rapid, within minutes of initial administration, and they usually resolve within 24 hours of discontinuation of the precipitating drugs and supporting care, some requiring treatment with 5hydroxytryptamine 2A antagonists such as cyproheptadine. Benzodiazepines have been recommended for agitation control and neuromuscular paraly-
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sis and for orotracheal intubation with sedation for more severe cases.4,6,7 Serotonin syndrome may result from any drug combination that has the effect of increasing the net amount of serotonergic neurotransmission in the body.8 Along with SSRIs, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and multiple other medications can result in net increases of serotonin in the body. Receptor stimulation of the postsynaptic 5-hydroxytryptamine 1A and 2A receptors has been implicated in conjunction with serotonin syndrome, but no single receptor is known to be solely responsible.4,9 Linezolid, a reversible monoamine oxidase inhibitor antibiotic drug, was developed as an antidepressant agent but was marketed as an antibiotic drug after it was found to be effective against methicillin-resistant Staphylococcus aureus (MRSA) and other infections.10 This oxazolidinone antimicrobial agent is commonly used to treat complicated skin and skin structure infections caused by gram-positive multidrug-resistant organisms. It has been increasingly used to treat inpatient and outpatient MRSA infections and is indicated for the treatment of diabetic foot infections. Linezolid also exhibits monoamine oxidase type A and B inhibitory effects, which, if administered concomitantly with other monoamine oxidase inhibitors, SSRIs, or similar serotonergic drugs, can increase serotonin concentrations and potentiate serotonin toxicity.11 The US Food and Drug Administration (FDA) has recently issued a warning stating that serious central nervous system reactions are possible if linezolid is given in conjunction with certain psychotropic medications and has advised clinicians to monitor patients for signs and symptoms of serotonin syndrome when using a combination of linezolid and SSRIs (Table 1).6,12 In this article, we report on two individuals who developed serotonin syndrome while they were being treated with linezolid for MRSA foot infections. Both individuals were also receiving treatment with a concomitant serotonergic agent for an unrelated diagnosis of anxiety and depression.
Case Reports Case 1 A 70-year-old man with a history of human immunodeficiency virus (HIV), congestive heart failure, peripheral neuropathy, a recent left foot transmetatarsal amputation, and depression was
Table 1. Medications with Serotonergic Activity Generic Name
Found in Trade Name(s)
Selective serotonin reuptake inhibitors Paroxetine
Paxil, Paxil CR, Pexeva
Fluvoxamine
Luvox, Luvox CR
Fluoxetine
Prozac, Sarafem, Symbyax
Sertraline
Zoloft
Citalopram
Celexa
Escitalopram
Lexapro
Serotonin-norepinephrine reuptake inhibitors Venlafaxine
Effexor, Effexor XR
Desvenlafaxine
Pristiq
Duloxetine
Cymbalta
Tricyclic antidepressants Amitriptyline
Amitid, Amitril, Elavil, Endep, Etrafon, Limbitrol, Triavil
Desipramine
Norpramin, Pertofrane
Clomipramine
Anafranil
Imipramine
Tofranil, Tofranil PM, Janimine, Pramine, Presamine
Nortriptyline
Pamelor, Aventyl hydrochloride
Protriptyline
Vivactil
Doxepin
Sinequan, Zonalon, Silenor
Trimipramine
Surmontil
Monoamine oxidase inhibitors Isocarboxazid
Marplan
Phenelzine
Nardil
Selegiline
Emsam, Eldepryl, Zelapar
Tranylcypromine
Parnate
Other psychiatric medications Amoxapine
Asendin
Maprotiline
Ludiomil
Nefazodone
Serzone
Trazodone
Desyrel, Oleptro, Trialodine
Bupropion
Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Aplenzin
Buspirone
Buspar
Vilazodone
Viibryd
Mirtazapine
Remeron, Remeron Soltab
Adapted from the Food and Drug Administration precautions for linezolid.12,13
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admitted to the Carl T. Hayden VA Medical Center (Phoenix, Arizona) for cellulitis at the left transmetatarsal amputation site and right second digit. Along with multiple medications for the treatment of HIV (including the antiretroviral drug ritonavir), the patient was also taking citalopram to treat his depression. Empirical treatment with intravenous vancomycin and piperacillin/tazobactam was initiated for his infection. Wound cultures demonstrated MRSA, and the piperacillin/tazobactam was discontinued. Four days after initiation of therapy, venous access was lost, and the patient refused any additional venous access. The MRSA grown from his wound was shown to be susceptible to trimethoprim/sulfamethoxazole (TMP/SMX) and linezolid but resistant to clindamycin and tetracycline. The decision was made to initiate oral therapy with TMP/SMX because the pateint was currently taking citalopram to treat his depression. On the second day of treatment with TMP/SMX the patient developed acute renal insufficiency (45% increase in the serum creatinine level) that was believed to be secondary to the sulfa antimicrobial agent, and it was discontinued. He was then given oral linezolid, 600 mg twice daily, and his citalopram therapy was placed on hold. After 1.5 days of linezolid therapy, the patient began noting tremors, tachycardia, palpations, diaphoresis, disorientation, and ‘‘threats of impending doom.’’ Serotonin syndrome, as a potential adverse reaction to linezolid, was suspected on clinical grounds alone, and the linezolid administration was promptly discontinued. The patient was also given lorazepam to aid with his symptoms. We did not obtain serotonin levels for this patient because he rather quickly responded to the cessation of linezolid therapy. A peripherally inserted central catheter was placed, and vancomycin therapy was again initiated. Once stable, the patient was discharged from the hospital taking intravenous vancomycin several days later without sequelae. Case 2 In 2007, a 62-year-old man with a medical history significant for coronary artery disease, type 2 diabetes, an allergy to penicillin, peripheral neuropathy, and peripheral vascular disease was admitted to the hospital for continued cellulitis of the left foot after a hallux amputation for gangrene performed 1 month earlier. Cultures taken at admission grew multiple gram-negative organisms as well as MRSA. He was administered empirical therapy that includ-
246
ed intravenous clindamycin and oral ciprofloxacin. He was also being treated for his neuropathy with amitriptyline. Initially, his infection responded to the antibiotic drug therapy, but he did have some recalcitrant cellulitis. Accordingly, the decision was made to switch to linezolid for more effective coverage of the MRSA and to continue with the ciprofloxacin. Amitriptyline use was discontinued, and gabapentin therapy was started in its place. Two days after initiation of linezolid therapy the patient became confused overnight. Early in the morning he became agitated, and his confusion continued; he began to run a fever (temperature of 101.58F), with a pulse rate of 118/min. Serotonin syndrome was suspected, and lorazepam was administered concurrent with discontinuation of linezolid. A short time later the patient assaulted a nurse with a clipboard, causing a fracture and laceration to her left chin. He subsequently required restraints. Linezolid, gabapentin, and all narcotics were discontinued, and the patient was administered intravenous vancomycin. His agitation and confusion quickly resolved. Although it was universally agreed that this episode represented an acute serotonin syndrome, it was unfortunate that no serotonin serum levels were available to corroborate the clinical diagnosis.
Discussion No randomized controlled studies or cohort studies for the examination of linezolid-associated serotonin syndrome where known to be in print at the time of this report, but in 2006 Lawrence et al11 examined more than 2,000 cases of serotonin poisoning that were reported to the FDA’s Adverse Event Reporting System. They found 29 patients with linezolid-associated serotonin toxicity. Of the 29 patients, 13 required hospitalization.11 The most commonly occurring causative drugs in these patients were SSRIs. However, a 2005 review of serotonin syndrome also listed a potential drug interaction between linezolid and ritonavir, an antiretroviral agent used for the treatment of HIV.4 Nonetheless, there have thus far been no definitive case reports of serotonin syndrome indicating a direct link between linezolid and ritonavir. In 2013, Woytowish and Maynor2 performed a literature review search for relevant case reports, retrospective studies, and review articles published on linezolid-associated serotonin toxicity. Their review identified 32 documented cases, including three fatalities. Most of the cases reported were in patients concurrently receiving SSRIs, with onset
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and resolution of symptoms varying from hours to days. The authors concluded that based on their review, the reported incidence of serotonin toxicity with the use of linezolid is rare.2 Consistent with previous reports, Butterfield and colleagues13 revealed low rates of potential serotonin toxicity in patients receiving linezolid and comparators when applying either the Sternbach criteria or the Hunter Serotonin Toxicity Criteria for serotonin toxicity. Lodise et al14 concluded that the potential for serotonin toxicity should not preclude the use of linezolid in patients receiving another medication with serotonergic activity and reported that they were not able to detect any increased risk of serotonin toxicity with linezolid relative to vancomycin. Although the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk seems to be low. In the cases presented herein, one drug associated with the adverse event was an SSRI and the other was a tricyclic antidepressant. The latter, although not an SSRI, is known to inhibit serotonin reuptake. In the same patient, this agent had been replaced with gabapentin, also not previously associated with serotonin syndrome. There is a lack of specific evidence-based treatment for serotonin syndrome. Removal of the precipitating drugs is the most important step in the management of this condition.7,15 Samartzis et al16 recommend supportive care after withdrawal of the predisposing drugs. Cyproheptadine is an H1 histamine receptor antagonist and a nonspecific serotonin receptor antagonist.1,17 A recommendation from the 2005 DRUGDEX System indicates that the combined use of venlafaxine, a strong serotonergic agent, and linezolid is contraindicated.18 On the other hand, Packer and Berman19 report that combining linezolid with antidepressant agents is not contraindicated. The authors further state that if infection cannot be controlled with other antimicrobial agents, antidepressant drugs are occasionally withdrawn proactively, if deemed safe. The FDA suggested that a 14-day washout period be used before initiation of therapy with either agent. However, it may not always be possible to delay treatment of infection; hence, clinicians must closely monitor each individual patient receiving linezolid combined with a serotonergic agent and weigh its risks and benefits.2 Taylor et al20 suggest that continuation of a single SSRI with close observation for any signs of serotonin toxicity is an acceptable alternative to complete cessation of the medication. Early detection is, therefore, essential, and clinical features of this condition must be
recognized. There are several studies that have been shown to assist in the diagnosis of serotonin syndrome. The Sternbach criteria21 state that the patient must have the presence of at least three clinical features coincident with the addition of or an increase in a known serotonergic agent. These clinical features include mental status changes, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever. The Boyer and Shannon criteria4 were adapted from the Hunter criteria and are more recent and provide more specific clusters of clinical features that include tremor and hyperreflexia, spontaneous clonus, muscle rigidity, a body temperature greater than 388C, either ocular clonus or inducible clonus, ocular clonus and either agitation or diaphoresis, and inducible clonus and either agitation or diaphoresis. The presence of any of these clusters of symptoms should raise the clinical suspicion for serotonin syndrome. Laboratory tests for serotonin syndrome have not been found to be of use in aiding with its diagnosis.4
Conclusions Linezolid is a commonly used antibiotic drug for the treatment of complicated infections, including MRSA, but reports of serotonin toxicity with this agent are uncommon. It is also only one of three antimicrobial agents currently indicated for diabetic foot infections. Linezolid is generally well tolerated, and its oral bioavailability characteristics make it a popular choice for inpatient and outpatient treatment. Linezolid, as with other medications, has many precautions and contraindications, but none may be as overlooked as that of the possibility of serotonin toxicity when given in combination with other serotonergic agents. Owing to the risk of serotonin toxicity and in light of the warning issued by the FDA, care should be taken when prescribing linezolid in conjunction with any other serotonergic agent. If possible, a 14day washout period should be used before taking this antibiotic agent. Based on these reports, linezolid is not contraindicated in combination with serotonergic agents. Although the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk seems to be low. However, the risks and benefits of therapy should be weighed before use, and close monitoring for the symptoms of serotonin toxicity is warranted.
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Financial Disclosure: None reported. Conflict of Interest: None reported.
References 1. KULKARNI RR, KULKARNI PR: Linezolid-induced near-fatal serotonin syndrome during escitalopram therapy: case report and review of literature. Indian J Psychol Med 35: 413, 2013. 2. WOYTOWISH MR, MAYNOR LM: Clinical relevance of linezolid-associated serotonin toxicity. Ann Pharmacother 47: 388, 2013. 3. MCCLEAN M, WALSH JC, CONDON F: Serotonin syndrome in an orthopaedic patient secondary to linezolid therapy for MRSA infection. Ir J Med Sci 180: 285, 2011. 4. BOYER EW, SHANNON M: The serotonin syndrome. N Engl J Med 352: 1112, 2005. 5. MASON PJ, MORRIS VA, BALCEZAK TJ: Serotonin syndrome: presentation of 2 cases and review of the literature. Medicine (Baltimore) 79: 201, 2000. 6. MORRISON EK, ROWE AS: Probable drug-drug interaction leading to serotonin syndrome in a patient treated with concomitant buspirone and linezolid in the setting of therapeutic hypothermia. J Clin Pharm Ther 37: 610, 2012. 7. GUPTA V, KARNIK ND, DESHPANDE R, ET AL: Linezolidinduced serotonin syndrome. BMJ Case Rep 2013: pii, 2013. 8. DE ROOS F: Drug interactions: combinations that can kill your patients. Paper presented at: American College of Emergency Physicians Scientific Assembly, Washington, DC, September 26, 2005. 9. MACKAY FJ, DUNN NR, MANN RD: Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract 49: 871, 1999. 10. PACKER S, BERMAN SA: Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid. Am J Psychiatry 164: 346, 2007.
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11. LAWRENCE KR, ADRA M, GILLMAN PK: Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 42: 1578, 2006. 12. US FOOD AND DRUG ADMINISTRATION: FDA Drug Safety Communication: updated information about the drug interaction between linezolid (Zyvox) and serotonergic psychiatric medications. Available at: http://www.fda. gov/drugs/drugsafety/ucm276251.htm. Accessed March 17, 2015. 13. BUTTERFIELD JM, LAWRENCE KR, REISMAN A, ET AL: Comparison of serotonin toxicity with concomitant use of either linezolid or comparators and serotonergic agents: an analysis of Phase III and IV randomized clinical trial data. J Antimicrob Chemother 67: 494, 2012. 14. LODISE TP, PATEL N, RIVERA A, ET AL: Comparative evaluation of serotonin toxicity among veterans affairs patients receiving linezolid and vancomycin. Antimicrob Agents Chemother 57: 5901, 2013. 15. GILLMAN PK: The serotonin syndrome and its treatment. J Psychopharmacol 13: 100, 1999. 16. SAMARTZIS L, SAVVARI P, KONTOGIANNIS S, ET AL: Linezolid is associated with serotonin syndrome in a patient receiving amitriptyline, and fentanyl: a case report and review of the literature. Case Rep Psychiatry 2013: 617251, 2013. 17. PERRY PJ, WILBORN CA: Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management. Ann Clin Psychiatry 24: 155, 2012. 18. KLASKO R: DRUGDEX System, Thomson Micromedex, Greenwood Village, CO, 2005. 19. PACKER S, BERMAN S: Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid. Am J Psychiatry 164: 346, 2007. 20. TAYLOR JJ, ESTES LL, WILSON JW: Linezolid and serotonergic drug interactions. Clin Infect Dis 43: 1371, 2006. 21. STERNBACH H: The serotonin syndrome. Am J Psychiatry 148: 705, 1991.
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Linezolid-Associated Serotonin Syndrome A Report of Two Cases Robert G. Frykberg, DPM, Scott Gordon, Edward Tierney, Jaminelli Banks,
MPH* DPM* DPM* DPM*
Linezolid, a mild monoamine oxidase inhibitor, is a commonly used antibiotic drug for the treatment of complicated skin and skin structure infections, including diabetic foot infections. Use of linezolid has been associated with serotonin syndrome, a potentially life-threatening condition typically caused by the combination of two or more medications with serotonergic properties, due to increased serotonin release. The goals of this article are to highlight the risk factors associated with the development of serotonin syndrome related to the use of linezolid and to aid in its prevention and early diagnosis. In this case series we report on two hospitalized patients who, while being treated with linezolid for pedal infections, developed serotonin syndrome. Both individuals were also undergoing treatment with at least one serotonergic agent for depression and had received this medication within 2 weeks of starting the antibiotic drug therapy. In these individuals, we noted agitation, confusion, tremors, and tachycardia within a few days of initiation of linezolid therapy. Owing to the risk of serotonin toxicity, care should be taken when prescribing linezolid in conjunction with any other serotonergic agent. Although serotonin syndrome is an infrequent complication, it can be potentially life threatening. Therefore, risks and benefits of therapy should be weighed before use. (J Am Podiatr Med Assoc 105(3): 244-248, 2015)
Serotonin syndrome is a potentially fatal condition with a wide spectrum of severity that has been associated with the use of linezolid when combined with serotonergic agents.1 The incidence of serotonin toxicity is between 0.54% and 18.2%.2 The diagnosis of serotonin toxicity has been reported to be based on clinical manifestations after initiation of linezolid therapy and abrupt resolution on withdrawal of the precipitating medications.3 Linezolid-associated serotonin toxicity is associated with an increase in serotonergic activity in the central nervous system. It is most commonly seen in association with therapeutic use of selective serotonin reuptake inhibitors (SSRIs), inadvertent medication interactions, and self-poisoning.4 Serotonin has activity in both the central and peripheral nervous systems. In the central nervous system it The views expressed herein are those of the authors and do not represent the views of the US Department of Veterans Affairs or the US Government. *Department of Podiatry, Carl T. Hayden VA Medical Center, Phoenix, AZ. Corresponding author: Robert G. Frykberg, DPM, MPH, Carl T. Hayden VA Medical Center, 650 E Indian School Rd, Phoenix, AZ 85012. (E-mail: [email protected])
244
acts to modulate attention, behavior, and thermoregulation. In the peripheral nervous system it is produced mainly by intestinal enterochromaffin cells and is mainly involved in regulating gastrointestinal motility, vasoconstriction, uterine contraction, and bronchoconstriction, and it has some effect on platelet aggregation.5 The serotonin syndrome is often described as a clinical triad of hyperthermia, mental status changes, and autonomic hyperactivity with neuromuscular abnormalities. This can include agitation, diaphoresis, mydriasis, hyperthermia (temperature as high as 1048–1068F), tachycardia, hypertension, diarrhea, akathisia, tremor, and muscular rigidity, but not all of these findings are consistently present in all of the patients with the disorder.6 The onset of symptoms is rapid, within minutes of initial administration, and they usually resolve within 24 hours of discontinuation of the precipitating drugs and supporting care, some requiring treatment with 5hydroxytryptamine 2A antagonists such as cyproheptadine. Benzodiazepines have been recommended for agitation control and neuromuscular paraly-
May/June 2015 Vol 105 No 3 Journal of the American Podiatric Medical Association
sis and for orotracheal intubation with sedation for more severe cases.4,6,7 Serotonin syndrome may result from any drug combination that has the effect of increasing the net amount of serotonergic neurotransmission in the body.8 Along with SSRIs, monoamine oxidase inhibitors, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and multiple other medications can result in net increases of serotonin in the body. Receptor stimulation of the postsynaptic 5-hydroxytryptamine 1A and 2A receptors has been implicated in conjunction with serotonin syndrome, but no single receptor is known to be solely responsible.4,9 Linezolid, a reversible monoamine oxidase inhibitor antibiotic drug, was developed as an antidepressant agent but was marketed as an antibiotic drug after it was found to be effective against methicillin-resistant Staphylococcus aureus (MRSA) and other infections.10 This oxazolidinone antimicrobial agent is commonly used to treat complicated skin and skin structure infections caused by gram-positive multidrug-resistant organisms. It has been increasingly used to treat inpatient and outpatient MRSA infections and is indicated for the treatment of diabetic foot infections. Linezolid also exhibits monoamine oxidase type A and B inhibitory effects, which, if administered concomitantly with other monoamine oxidase inhibitors, SSRIs, or similar serotonergic drugs, can increase serotonin concentrations and potentiate serotonin toxicity.11 The US Food and Drug Administration (FDA) has recently issued a warning stating that serious central nervous system reactions are possible if linezolid is given in conjunction with certain psychotropic medications and has advised clinicians to monitor patients for signs and symptoms of serotonin syndrome when using a combination of linezolid and SSRIs (Table 1).6,12 In this article, we report on two individuals who developed serotonin syndrome while they were being treated with linezolid for MRSA foot infections. Both individuals were also receiving treatment with a concomitant serotonergic agent for an unrelated diagnosis of anxiety and depression.
Case Reports Case 1 A 70-year-old man with a history of human immunodeficiency virus (HIV), congestive heart failure, peripheral neuropathy, a recent left foot transmetatarsal amputation, and depression was
Table 1. Medications with Serotonergic Activity Generic Name
Found in Trade Name(s)
Selective serotonin reuptake inhibitors Paroxetine
Paxil, Paxil CR, Pexeva
Fluvoxamine
Luvox, Luvox CR
Fluoxetine
Prozac, Sarafem, Symbyax
Sertraline
Zoloft
Citalopram
Celexa
Escitalopram
Lexapro
Serotonin-norepinephrine reuptake inhibitors Venlafaxine
Effexor, Effexor XR
Desvenlafaxine
Pristiq
Duloxetine
Cymbalta
Tricyclic antidepressants Amitriptyline
Amitid, Amitril, Elavil, Endep, Etrafon, Limbitrol, Triavil
Desipramine
Norpramin, Pertofrane
Clomipramine
Anafranil
Imipramine
Tofranil, Tofranil PM, Janimine, Pramine, Presamine
Nortriptyline
Pamelor, Aventyl hydrochloride
Protriptyline
Vivactil
Doxepin
Sinequan, Zonalon, Silenor
Trimipramine
Surmontil
Monoamine oxidase inhibitors Isocarboxazid
Marplan
Phenelzine
Nardil
Selegiline
Emsam, Eldepryl, Zelapar
Tranylcypromine
Parnate
Other psychiatric medications Amoxapine
Asendin
Maprotiline
Ludiomil
Nefazodone
Serzone
Trazodone
Desyrel, Oleptro, Trialodine
Bupropion
Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Aplenzin
Buspirone
Buspar
Vilazodone
Viibryd
Mirtazapine
Remeron, Remeron Soltab
Adapted from the Food and Drug Administration precautions for linezolid.12,13
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admitted to the Carl T. Hayden VA Medical Center (Phoenix, Arizona) for cellulitis at the left transmetatarsal amputation site and right second digit. Along with multiple medications for the treatment of HIV (including the antiretroviral drug ritonavir), the patient was also taking citalopram to treat his depression. Empirical treatment with intravenous vancomycin and piperacillin/tazobactam was initiated for his infection. Wound cultures demonstrated MRSA, and the piperacillin/tazobactam was discontinued. Four days after initiation of therapy, venous access was lost, and the patient refused any additional venous access. The MRSA grown from his wound was shown to be susceptible to trimethoprim/sulfamethoxazole (TMP/SMX) and linezolid but resistant to clindamycin and tetracycline. The decision was made to initiate oral therapy with TMP/SMX because the pateint was currently taking citalopram to treat his depression. On the second day of treatment with TMP/SMX the patient developed acute renal insufficiency (45% increase in the serum creatinine level) that was believed to be secondary to the sulfa antimicrobial agent, and it was discontinued. He was then given oral linezolid, 600 mg twice daily, and his citalopram therapy was placed on hold. After 1.5 days of linezolid therapy, the patient began noting tremors, tachycardia, palpations, diaphoresis, disorientation, and ‘‘threats of impending doom.’’ Serotonin syndrome, as a potential adverse reaction to linezolid, was suspected on clinical grounds alone, and the linezolid administration was promptly discontinued. The patient was also given lorazepam to aid with his symptoms. We did not obtain serotonin levels for this patient because he rather quickly responded to the cessation of linezolid therapy. A peripherally inserted central catheter was placed, and vancomycin therapy was again initiated. Once stable, the patient was discharged from the hospital taking intravenous vancomycin several days later without sequelae. Case 2 In 2007, a 62-year-old man with a medical history significant for coronary artery disease, type 2 diabetes, an allergy to penicillin, peripheral neuropathy, and peripheral vascular disease was admitted to the hospital for continued cellulitis of the left foot after a hallux amputation for gangrene performed 1 month earlier. Cultures taken at admission grew multiple gram-negative organisms as well as MRSA. He was administered empirical therapy that includ-
246
ed intravenous clindamycin and oral ciprofloxacin. He was also being treated for his neuropathy with amitriptyline. Initially, his infection responded to the antibiotic drug therapy, but he did have some recalcitrant cellulitis. Accordingly, the decision was made to switch to linezolid for more effective coverage of the MRSA and to continue with the ciprofloxacin. Amitriptyline use was discontinued, and gabapentin therapy was started in its place. Two days after initiation of linezolid therapy the patient became confused overnight. Early in the morning he became agitated, and his confusion continued; he began to run a fever (temperature of 101.58F), with a pulse rate of 118/min. Serotonin syndrome was suspected, and lorazepam was administered concurrent with discontinuation of linezolid. A short time later the patient assaulted a nurse with a clipboard, causing a fracture and laceration to her left chin. He subsequently required restraints. Linezolid, gabapentin, and all narcotics were discontinued, and the patient was administered intravenous vancomycin. His agitation and confusion quickly resolved. Although it was universally agreed that this episode represented an acute serotonin syndrome, it was unfortunate that no serotonin serum levels were available to corroborate the clinical diagnosis.
Discussion No randomized controlled studies or cohort studies for the examination of linezolid-associated serotonin syndrome where known to be in print at the time of this report, but in 2006 Lawrence et al11 examined more than 2,000 cases of serotonin poisoning that were reported to the FDA’s Adverse Event Reporting System. They found 29 patients with linezolid-associated serotonin toxicity. Of the 29 patients, 13 required hospitalization.11 The most commonly occurring causative drugs in these patients were SSRIs. However, a 2005 review of serotonin syndrome also listed a potential drug interaction between linezolid and ritonavir, an antiretroviral agent used for the treatment of HIV.4 Nonetheless, there have thus far been no definitive case reports of serotonin syndrome indicating a direct link between linezolid and ritonavir. In 2013, Woytowish and Maynor2 performed a literature review search for relevant case reports, retrospective studies, and review articles published on linezolid-associated serotonin toxicity. Their review identified 32 documented cases, including three fatalities. Most of the cases reported were in patients concurrently receiving SSRIs, with onset
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and resolution of symptoms varying from hours to days. The authors concluded that based on their review, the reported incidence of serotonin toxicity with the use of linezolid is rare.2 Consistent with previous reports, Butterfield and colleagues13 revealed low rates of potential serotonin toxicity in patients receiving linezolid and comparators when applying either the Sternbach criteria or the Hunter Serotonin Toxicity Criteria for serotonin toxicity. Lodise et al14 concluded that the potential for serotonin toxicity should not preclude the use of linezolid in patients receiving another medication with serotonergic activity and reported that they were not able to detect any increased risk of serotonin toxicity with linezolid relative to vancomycin. Although the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk seems to be low. In the cases presented herein, one drug associated with the adverse event was an SSRI and the other was a tricyclic antidepressant. The latter, although not an SSRI, is known to inhibit serotonin reuptake. In the same patient, this agent had been replaced with gabapentin, also not previously associated with serotonin syndrome. There is a lack of specific evidence-based treatment for serotonin syndrome. Removal of the precipitating drugs is the most important step in the management of this condition.7,15 Samartzis et al16 recommend supportive care after withdrawal of the predisposing drugs. Cyproheptadine is an H1 histamine receptor antagonist and a nonspecific serotonin receptor antagonist.1,17 A recommendation from the 2005 DRUGDEX System indicates that the combined use of venlafaxine, a strong serotonergic agent, and linezolid is contraindicated.18 On the other hand, Packer and Berman19 report that combining linezolid with antidepressant agents is not contraindicated. The authors further state that if infection cannot be controlled with other antimicrobial agents, antidepressant drugs are occasionally withdrawn proactively, if deemed safe. The FDA suggested that a 14-day washout period be used before initiation of therapy with either agent. However, it may not always be possible to delay treatment of infection; hence, clinicians must closely monitor each individual patient receiving linezolid combined with a serotonergic agent and weigh its risks and benefits.2 Taylor et al20 suggest that continuation of a single SSRI with close observation for any signs of serotonin toxicity is an acceptable alternative to complete cessation of the medication. Early detection is, therefore, essential, and clinical features of this condition must be
recognized. There are several studies that have been shown to assist in the diagnosis of serotonin syndrome. The Sternbach criteria21 state that the patient must have the presence of at least three clinical features coincident with the addition of or an increase in a known serotonergic agent. These clinical features include mental status changes, agitation, myoclonus, hyperreflexia, diaphoresis, shivering, tremor, diarrhea, incoordination, and fever. The Boyer and Shannon criteria4 were adapted from the Hunter criteria and are more recent and provide more specific clusters of clinical features that include tremor and hyperreflexia, spontaneous clonus, muscle rigidity, a body temperature greater than 388C, either ocular clonus or inducible clonus, ocular clonus and either agitation or diaphoresis, and inducible clonus and either agitation or diaphoresis. The presence of any of these clusters of symptoms should raise the clinical suspicion for serotonin syndrome. Laboratory tests for serotonin syndrome have not been found to be of use in aiding with its diagnosis.4
Conclusions Linezolid is a commonly used antibiotic drug for the treatment of complicated infections, including MRSA, but reports of serotonin toxicity with this agent are uncommon. It is also only one of three antimicrobial agents currently indicated for diabetic foot infections. Linezolid is generally well tolerated, and its oral bioavailability characteristics make it a popular choice for inpatient and outpatient treatment. Linezolid, as with other medications, has many precautions and contraindications, but none may be as overlooked as that of the possibility of serotonin toxicity when given in combination with other serotonergic agents. Owing to the risk of serotonin toxicity and in light of the warning issued by the FDA, care should be taken when prescribing linezolid in conjunction with any other serotonergic agent. If possible, a 14day washout period should be used before taking this antibiotic agent. Based on these reports, linezolid is not contraindicated in combination with serotonergic agents. Although the potential exists for serotonin toxicity to occur with concomitant use of linezolid and serotonergic agents, the risk seems to be low. However, the risks and benefits of therapy should be weighed before use, and close monitoring for the symptoms of serotonin toxicity is warranted.
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Financial Disclosure: None reported. Conflict of Interest: None reported.
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