Department of Clinical Neuropharmacology (DCNP), Pioneer Valley Private Hospital, PO Box 8183, Mount Pleasant, Queensland 4740, Australia
Keywords: oxazolidinones , interactions , selective serotonin reuptake inhibitors , SSRIs
Sir,
The report of Jones et al.1 concerning serotonin syndrome (SS) with linezolid follows several other reports (referenced by the authors), one of which I have already commented on.2
Recent advances have improved our understanding of SS [better called serotonin toxicity (ST)3]. Professor Whyte's group at the Hunter Area Toxicology Service (HATS) have published their seminal studies of a large number of overdoses, many (>500 cases) involving serotonergic drugs. Their papers on ST46 define the features and reinforce the value and importance of the spectrum concept.7,8 It is a complex subject: up-to-date and comprehensive information can be accessed in my web update9 [particularly, a list of drugs that are significant serotonin reuptake inhibitors (SRIs)].
The important conclusion from Whyte's work is that ST is a spectrum and potentially fatal ST only occurs when monoamine oxidase inhibitors (MAOIs) are mixed with SRIs. If general physicians understand which drugs are SRIs and exercise caution if they have to be combined with linezolid (which may possibly be an MAOI of significant clinical potency) then they are unlikely to encounter serious clinical problems. SRIs that may not be readily identified as such include some of the narcotic analgesics (tramadol, pethidine), dual action antidepressants like duloxetine, venlafaxine and milnacipran (and the similar drug sibutramine), as well as the anti-histamines chlorpheniramine and brompheniramine.
The usual features of ST6,8 are:
It may be noted that the reported case is atypical and exhibits mild ST signs; this may be attributed to increased susceptibility due to old age and organic brain disease. Venlafaxine produces greater ST than the selective SRIs (SSRIs)4 and can give rise to severe serotonergic side effects by itself in therapeutic doses, and ST in overdose. This is where the spectrum concept is useful. All the SSRIs can produce ST; HATS data show that it occurs in 15% of cases where an overdose has been taken.4 Case reports of exaggerated serotonergic side effects and ST from monotherapy with serotonergic antidepressants (in therapeutic dose) are well documented and have been reviewed.10
Case reports like this cannot therefore be taken as evidence that linezolid is involved in ST of only mild to moderate severity. If it is able to produce clinically significant monoamine oxidase inhibition then there will be a risk of severe and life-threatening ST if it is co-administered with any SRI. The pressor response of linezolid to oral tyramine is similar to that of moclobemide.11 Moclobemide frequently causes serious ST, and sometimes deaths, but only when combined with SRIs. The MAOI activity of linezolid may possibly reach levels sufficient to precipitate serious ST, so continued vigilance is advisable despite the absence of ST with SRIs in the small Phase 3 study.12
Ceasing only the venlafaxine may have been an option in this case because, like moclobemide, linezolid alone will not cause ST, but venlafaxine alone does. Dissemination of accurate information about ST will assist treatment decisions about linezolid, and improve understanding and risk estimation of ST.
Footnotes
* Tel: +61-7-4942-1883; Fax: +61-7-4942-8283; Email: kg{at}matilda.net.au
References
1
.
Jones, S. L., Athan, E. & O'Brien, D. (2004). Serotonin syndrome due to co-administration of linezolid and venlafaxine. Journal of Antimicrobial Chemotherapy 54, 28990.
2 . Gillman, P. K. (2003). Linezolid and serotonin toxicity. Clinical Infectious Diseases 37, 12745.[CrossRef][ISI][Medline]
3 . Gillman, P. K. (1998). Serotonin syndrome: history and risk. Fundamental and Clinical Pharmacology 12, 48291.[ISI][Medline]
4
.
Whyte, I. M., Dawson, A. H. & Buckley, N. A. (2003). Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants. Quarterly Journal of Medicine 96, 36974.
5 . Isbister, G., Hackett, L., Dawson, A. et al. (2003). Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity. British Journal of Clinical Pharmacology 56, 44150.[CrossRef][ISI][Medline]
6
.
Dunkley, E., Isbister, G., Sibbritt, D. et al. (2003). The Hunter Serotonin Toxicity Criteria: a simple and accurate diagnostic decision rules for serotonin toxicity. Quarterly Journal of Medicine 96, 63542.
7 . Gillman, P. K. & Whyte, I. M. (2004). Serotonin syndrome. In Adverse Syndromes and Psychiatric Drugs (Haddad, P., Dursun, S. & Deakin, B., Eds). Oxford University Press, Oxford, UK.
8 . Whyte, I. M. (2004). Serotonin toxicity (syndrome). In Medical Toxicology, 3rd edn (Dart, R. C., Ed.), pp. 1036. Lippincott Williams & Wilkins, Baltimore, MD, USA.
9 . Gillman, P. K. (2004) Serotonin toxicity (serotonin syndrome): a current analysis. [Online.] www.psychotropical.com/SerotoninToxicity.doc, Psychopharmacology Update Notes (July 2004, date last accessed).
10 . Gillman, P. K. & Hodgens, S. (1998). Serotonin syndrome following SSRI mono-therapy. Human Psychopharmacology 13, 5256.[CrossRef][ISI]
11
.
Antal, E. J., Hendershot, P. E., Batts, D. H. et al. (2001). Linezolid, a novel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine. Journal of Clinical Pharmacology 41, 55262.
12 . Perry, C. M. & Jarvis, B. (2001). Linezolid: a review of its use in the management of serious Gram-positive infections. Drugs 61, 52551.[ISI][Medline]