Serotonin Syndrome Due to Co-Administration of Linezolid and Methadone

Le Infezioni in Medicina, n. 3, 263-266, 2017 CASE REPORT 263

Serotonin syndrome due to co-administration of linezolid and methadone

Antonio Mastroianni1, Gianfranco Ravaglia2 1U.O. Malattie Infettive, Presidio Ospedaliero, “G.B. Morgagni - L. Pierantoni”, Forlì, Italy; 2U.O. Farmacia, Presidio Ospedaliero “G.B. Morgagni - L. Pierantoni”, Forlì, Italy

SUMMARY

Serotonin syndrome (SS), a potentially life-threatening verity from mild to life-threatening. To our knowledge, adverse drug reaction caused by excessive serotoner- we present the first reported case of SS associated with gic agonism in central and peripheral nervous system linezolid and methadone with a brief review of the lit- serotonergic receptors, may be caused by a single drug erature. or a combination of drugs with serotonergic activity. The syndrome results in a variety of mental, autonom- Keywords: serotonin syndrome, linezolid, methadone, ic and neuromuscular changes, which can range in se- methicillin-resistant Staphylococcus aureus.

n INTRODUCTION methadone. This serious adverse interaction between linezolid and methadone inducing SS was erotonin syndrome (SS) is a toxic state caused reported in a drug-addict HIV-positive man with Smainly by excessive serotonergic activity in sepsis, osteomyelitis and multiple muscle abscess- the nervous system, nearly always caused by a es and metastatic skin abscesses caused by meth- drug interaction involving two or more “seroto- icillin-resistant Staphylococcus aureus (MRSA), un- nergic” drugs [1]. These include serotonin pre- der combined antibiotic treatment. cursors, serotonin agonists, serotonin releasers, serotonin reuptake inhibitors, monoaminoxidase inhibitors (MAOIs) and some herbal medicines. n CASE REPORT Linezolid is a weak, nonselective, reversible inhibitor of MAOIs, and potentially may interact A 39-year-old drug-addict male was admitted to with MAOIs and adrenergic and serotonergic our department with fever (up to 39.5°C) and a agents. SS has been reported in patients receiving deterioration of the general conditions associat- linezolid concomitantly with serotonergic drugs ed with pain in the abdomen, the dorsal and lum- [2]. Methadone is a serotonin re-uptake inhibitor bar-sacral spine, and lower limbs two months which may be involved in serotonin toxicity reac- duration, with fatigue, hypotension and oliguria tions [3]. during the last 24 hours reported by his family. To the best of our knowledge, we present the first In previous months, for the persistence of a sciat- reported case of SS associated with linezolid and ica he had taken anti-inflammatory therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids, with a self-administration. The Corresponding author patient had a remarkable medical history be- Antonio Mastroianni cause of a surgery for right iliac-femoral arterial E-mail: [email protected] bypass about 1 year ago. The patient assumed 264 A. Mastroianni, et al.

methadone 40 mg/day, as maintenance therapy right arm were positive for MRSA. On the basis for opioid dependence. Antiretroviral therapy of blood and pus cultures, on the fifth day of hos- included lamivudine 300 mg daily, tenofovir 245 pitalization antibiotic treatment was changed to mg daily and darunavir 800 mg / ritonavir 100 linezolid 600 mg twice daily plus clindamycin mg daily. 600 mg four times daily intravenously, suspend- On admission, clinical examination revealed a ing the previous antibiotic combination, while dehydrated patient with high fever, blood pres- repeated surgical drainage of the muscle abscess- sure of 90/50 mmHg, heart rate 125/min, and es was performed during his hospital stay. How- respiratory rate 35/min, as well as the presence ever, the patient was febrile (39°C) and sweating of multiple erythematous and tender swellings and three days after the introduction of new anti- over the right elbow and arm, left side of the biotic therapy has become increasingly confused, chest wall, and abdomen. Respiratory examina- disoriented and agitated. His pulse fluctuated tion revealed bilateral coarse crepitations. The between 95 and 120 beats/minute, and his blood neurological examination was negative, the pa- pressure between 110/70 and 100/60 mm Hg. tient was collaborative, oriented and responsive He had a score of 10 on the Glasgow Coma Scale even if very suffering. Laboratory findings in- and was unable to sustain conversation; he had cluded: hematocrit 37.6%, white blood cell count generalised abdominal tenderness. Neurological 15.15×109/l, platelet count 95×109/l, C-reactive examination revealed dilated reactive pupils, an protein 340 mg/l, and creatinine 1.2 mg/dl. The increased tone in both legs, with brisk reflexes chest X-ray displayed bilateral opacities, while and clonus at both ankles but no meningism. In- computed tomography (CT) revealed the pres- vestigations revealed a white cell count of 21.1 x ence of multiple cavitated nodular infiltrates in 109/l, predominantly neutrophils, and a C-reac- both pulmonary fields. Ultrasound of the swell- tive protein of 15 mg/dl. Chest and abdominal ings showed the presence of fluid attenuation X-rays and urine were normal. into the muscles. A transthoracic echocardio- An urgent evaluation raised the suspicion of a gram was negative for endocarditis. Supportive serotonin syndrome and after a neurological con- care, including aggressive rehydration with nor- sultation linezolid was immediately suspended; mal saline and empiric antibiotics (ceftriaxone 2 the patient was subjected to rehydration therapy, g once daily intravenously and amoxicillin and steroids and benzodiazepines, with a progressive potassium clavulanate 1000 mg/200 mg every 8 improvement in the next 48 hours. The patient’s hours daily intravenously) was initiated imme- clinical condition gradually improved and a dif- diately. ferent antibiotic therapy including ciprofloxacin, A CT scan of the abdomen showed multiple mus- 400 mg twice daily intravenously, and rifampi- cle abscesses and a pyomyositis of the left psoas cin 600 mg daily intravenously was reintroduced muscle. The kidneys showed some hypodense on the twelfth day of hospitalization. A repeat- areolas with lamellar morphology, the largest in ed CT of the chest (day 20) showed a significant the middle third of the left kidney (finding com- improvement of the infiltrates, while the muscle patible with areas of initial pyelonephritis). There abscesses had reduced in size. The patient was was also evidence of edematous imbibitions of followed up at the clinic; he received ciproflox- subcutaneous and adipose tissue of the left lower acin 750 mg twice daily plus oral rifampin 600 limb tissue, multifocal dorsal-lumbar chronic os- mg daily for three months, with disappearance teomyelitis and a bilateral abscess in suprapatel- of the muscle abscesses (40 days after his dis- lar recess. Blood cultures obtained on admission charge). were positive for MRSA sensitive to daptomy- cin (MIC<0.25 mg/L), levofloxacin (MIC<=0.12 mg/L), linezolid (MIC<1 mg/L), teicoplanin n DISCUSSION (MIC<=0.5 mg/L), tigecycline (MIC<=0.12 mg/L), rifampicin (MIC<=0.03 mg/L) and van- SS, a potentially life-threatening adverse drug re- comycin (MIC<1 mg/L). Cultures obtained from action caused by excessive serotonergic agonism the blood and the purulent material aspirated in central and peripheral nervous system seroto- after guided drainage from the swelling of the nergic receptors, may be caused by a single or a Serotonin syndrome, linezolid and methadone 265

combination of drugs with serotonergic activity, the oxazolidinone class with weak, nonspecific and it results in a variety of mental, autonomic inhibitor of monoamine oxidase enzymes. Con- and neuromuscular changes, which can range in comitant therapy with an adrenergic or seroto- severity from mild to life-threatening [4,5]. nergic agent or consuming tyramine (>100 mg/ A variety of single or a combination of drugs day) may induce SS [12]. with excessive serotonergic agonism on central In a recent critical review serotonergic agent dose nervous system and peripheral serotonergic re- and duration of coadministration with linezolid ceptors can be involved as a cause of SS, includ- did not appear to influence the occurrence of ing MAOIs, tricyclic antidepressants, selective SS. The Authors stated that time of onset ranges serotonin reuptake inhibitors (SSRIs), opiate an- from <1 to 20 days, and effect resolves in <1 to algesics, over-the-counter cough medicines, an- 5 days after discontinuation of offending agents tibiotics, weight-reduction agents, antiemetics, [3]. SS in a chronic-pain patient receiving concur- antimigraine agents, drugs of abuse, H2-antag- rent methadone, ciprofloxacin, and venlafaxine onist and herbal products) can be involved as a has been reported [13]. cause of SS [5]. In our case report we hypothesized the patient Most cases will involve either an SSRIs or an has suffered from a SS due to the interaction MAOIs and at least one other medication. Most between linezolid and methadone, blocking se- reported cases of SS are in patients using multi- rotonin reuptake and the serotonin presynaptic ple serotonergic drugs or who have had consid- release, causing increased levels of serotonin in erable exposure to a single serotonin-augment- the central nervous system (CNS). ing drug [6]. As a matter of fact, mental, autonomic and neu- Most cases of SS are mild and may be treated romuscular symptoms resolved after discon- by withdrawal of the offending agent and sup- tinuation of linezolid and the administration of portive care; however, critically ill patients may benzodiazepines. We ruled out the possibility of require neuromuscular paralysis, sedation, and other CNS pathology or other drug interaction. intubation [6]. In recent years, some opioid an- The case reported is the first report of SS associ- algesics including phenylpiperidine series opi- ated with linezolid and methadone without the oids, pethidine (meperidine), tramadol, metha- co-administration of other serotonergic agents. done and dextromethorphan and propoxyphene The present case suggests that clinicians should appearead to be weak serotonin re-uptake inhib- be aware of the potential drug interaction be- itors and may infrequently precipitate dose-de- tween linezolid and some opioids that have sero- pendent serotonin toxicity reactions with mono- tonergic activity as methadone, to avoid the risk amine oxidase inhibitor (MAOIs) drugs [3, 7]. of life threatening serotonin toxicity which may Methadone, a synthetic piperidine opioid, is a result from this drugs combination. racemic mixture of R/S methadone enantiomers. We can therefore predict that combination of It exerts its analgesia through opioid receptor linezolid with methadone, a weak serotonin agonism by R enantiomer and N-methyl-D-as- re-uptake inhibitor, might possibly precipitate partate antagonism by S enantiomer, it is metab- serious serotonin toxicity. olized by hepatic enzymes and it is a CYP2D6 A knowledge of the properties of these drugs enzyme inhibitor [3, 8]. may help to ensure that serious reactions can be In vitro studies of methadone show a greater avoided in methadone-maintained people. tendency toward serotonin reuptake inhibition compared with other opiates, which may explain methadone-mediated precipitation of SS [7]. A n REFERENCES case of SS has been associated with methadone overdose and with fentanyl and methadone use [1] Alusik S., Kalatova D., Paluch Z. Serotonin syndrome. Neuro. Endocrinol. 35, 4, 265-273, 2014. in a burn injury [9, 10]. [2] Ramsey T.D., Lau T.T., Ensom M.H. Serotonergic and A patient was seen on the palliative care service adrenergic drug interactions associated with linezolid: at Buffalo General Hospital who developed SS a critical review and practical management approach. and mutism associated with methadone use [11]. Ann. Pharmacother. 47, 4, 543-560, 2013. Linezolid is a synthetic antimicrobial agent of [3] Rastogi R., Swarm R., Patel T. A. Case scenario: opi- 266 A. Mastroianni, et al.

oid association with Serotonin Syndrome: implications [9] Martinez T.T., Martinez D.N. A case of serotonin to the practitioners. Anesthesiology 115, 6, 1291-1298, 2011. syndrome associated with methadone overdose. Proc. [4] Boyer E.W., Shannon M. The serotonin syndrome. West. Pharmacol. Soc. 51, 42-44, 2008. N. Engl. J. Med. 352, 11, 1112-1120 2005. [10] Hillman A.D., Witenko C.J., Sultan S.M., Gala G. [5] Dvir Y., Smallwood P. Serotonin syndrome: a com- Serotonin syndrome caused by fentanyl and metha- plex but easily avoidable condition. Gen. Hosp. Psychia- done in a burn injury. Pharmacotherapy 35, 1, 112-117, try 30, 3, 284-287, 2008. 2015. [6] Ables A.Z., Nagubilli R. Prevention, recognition, [11] Bush E., Miller C., Friedman I. Case of serotonin and management of serotonin syndrome. Am. Fam. syndrome and mutism associated with methadone. J. Physician. 81, 9, 1139-1142, 2010. Palliat. Med. 9, 6, 1257-1259, 2006. [7] Gillman P.K. Monoamine oxidase inhibitors, opioid [12] Kulkarni R.R., Kulkarni P.R. Linezolid-induced analgesics and serotonin toxicity. Br. J. Anaesth. 95, 4, near-fatal serotonin syndrome during escitalopram 434-441, 2005. therapy: case report and review of literature. Indian J. [8] Pilgrim J.L., Gerostamoulos D., Drummer O.H. Psychol. Med. 35, 4, 413-436, 2013. Review: Pharmacogenetic aspects of the effect of cyto- [13] Lee J., Franz L., Goforth H.W. Serotonin syndrome chrome P450 polymorphisms on serotonergic drug me- in a chronic-pain patient receiving concurrent metha- tabolism, response, interactions, and adverse effects. done, ciprofloxacin, and venlafaxine. Psychosomatics 50, Forensic Sci. Med. Pathol. 7, 2, 162-184, 2011. 638-639, 2009.