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• Response to Van den Eynde and Gillman's letter
  Maria de Castro Julve, Roser Vives, Sara Ortonobes Roig, Paula Miralles Albors, Luis Falgueras and Mònica Gómez-Valent
  Published on: 20 March 2020
• A critical appraisal
  Vincent Van den Eynde, Peter K Gillman
  Published on: 6 March 2020

• Published on: 20 March 2020

  Response to Van den Eynde and Gillman's letter

  • Maria de Castro Julve, Hospital pharmacist Parc Taulí Hospital Universitari. Sabadell. Barcelona
  • Other Contributors:
    • Roser Vives, Pharmacologist
    • Sara Ortonobes Roig, Hospital pharmacist
    • Paula Miralles Albors, Hospital pharmacist
    • Luis Falgueras, Infectious Diseases specialist
    • Mònica Gómez-Valent, Hospital pharmacist

  I) We agree with Dr. Van den Eynde that since tedizolid is a more potent inhibitor than linezolid, it is administered at lower doses. Thus, the MAO inhibition would be lower. This is probably the reason why there have been no reports regarding serotoninergic toxicity. However, the possibility of MAO inhibition cannot be ruled out, especially when tedizolid is administered together with serotoninergic drugs. We would like to emphasize that the spontaneous reporting of suspected adverse reactions is useful to identify potential signals that suggest a causal association between a medicinal product and a previously unknown reaction. Whether this suspected adverse reaction is a signal, it should be confirmed by further reports.

  II) In our article we do not affirm that it is a serotonin syndrome or a serotonin toxicity, since, in fact, we do not have enough clinical information to confirm it. We only discuss the possibility that the hypertensive crisis could be related to the co-administration of tedizolid and other serotoninergic drugs. Our position is well defined in the following paragraph of the article: “The causality of hypertension as an adverse drug reaction due to the co-administration of tedizolid and other serotonergic treatments was evaluated using the algorithm of Naranjo et al, obtaining a final score of 3. According to this value, the relationship between tedizolid and the hypertensive crisis should be classified as possible, as we were not able to rule ou...

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  I) We agree with Dr. Van den Eynde that since tedizolid is a more potent inhibitor than linezolid, it is administered at lower doses. Thus, the MAO inhibition would be lower. This is probably the reason why there have been no reports regarding serotoninergic toxicity. However, the possibility of MAO inhibition cannot be ruled out, especially when tedizolid is administered together with serotoninergic drugs. We would like to emphasize that the spontaneous reporting of suspected adverse reactions is useful to identify potential signals that suggest a causal association between a medicinal product and a previously unknown reaction. Whether this suspected adverse reaction is a signal, it should be confirmed by further reports.

  II) In our article we do not affirm that it is a serotonin syndrome or a serotonin toxicity, since, in fact, we do not have enough clinical information to confirm it. We only discuss the possibility that the hypertensive crisis could be related to the co-administration of tedizolid and other serotoninergic drugs. Our position is well defined in the following paragraph of the article: “The causality of hypertension as an adverse drug reaction due to the co-administration of tedizolid and other serotonergic treatments was evaluated using the algorithm of Naranjo et al, obtaining a final score of 3. According to this value, the relationship between tedizolid and the hypertensive crisis should be classified as possible, as we were not able to rule out the involvement of other factors.”

  References

  1. Flanagan S, Bartizal K, Minassian SL, et al. In vitro, in vivo, and clinical studies of tedizolid to assess the potential for peripheral or central monoamine oxidase interactions. Antimicrob Agents Chemother 2013;57:3060–6.

  2. Moore N, Berdaï D, Blin P, Droz C. Pharmacovigilance - The next chapter. Therapie. 2019 Dec;74(6):557-567.

  3. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45.

  4. de Castro Julve M, Miralles Albors P, Ortonobes Roig S, et al. Hypertensive crisis following the administration of tedizolid: possible serotonin syndrome. Eur J Hosp Pharm 2018;0:1-3.

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  Conflict of Interest:
  None declared.

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• Published on: 6 March 2020

  A critical appraisal

  • Vincent Van den Eynde, Independent Researcher None
  • Other Contributors:
    • Peter K Gillman, Clinical Neuropharmacologist

  We note, upon critical appraisal of this case report, two shortcomings:
  (I) the authors provide a one-sided and inaccurate extrapolation to clinical practice from the literature data on tedizolid;
  (II) the authors do not adhere to well-established ‘diagnostic decision rules for serotonin toxicity’: the Hunter criteria.<1>
  I. In gauging the MAO-inhibiting potential of both antibiotics, de Castro Julve et al. rightly note that ‘tedizolid appears to be a more potent inhibitor in vitro of MAO-A than linezolid’ <2>– but neglect to mention (a) that tedizolid is also four to sixteen (or – depending on the source – ‘two to eight’)<3> times more potent than linezolid at treating most gram-positive infections;<4> and (b) that tedizolid is therefore administered at a lower dose than is linezolid (200mg/day vs. 600mg/12 hours).<3> This likely leads, in practice, to less tedizolid-induced (vs. linezolid-induced) MAO-inhibition<3>, as evidenced by the clinically insignificant potentiation of the tyramine pressor response (TYR30)<2>, and to less potential for serotonergic drug interactions<5>, as further evidenced by the fact that no changes in the murine head twitch response occur, even at plasma tedizolid concentrations which exceed – ‘by up to ~25-fold’ – the Cmax observed in humans at the clinical dose of 200mg/day.<3>
  II. The detection in their patient of a hypertensive crisis ‘suspected to be an adverse r...

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  We note, upon critical appraisal of this case report, two shortcomings:
  (I) the authors provide a one-sided and inaccurate extrapolation to clinical practice from the literature data on tedizolid;
  (II) the authors do not adhere to well-established ‘diagnostic decision rules for serotonin toxicity’: the Hunter criteria.<1>
  I. In gauging the MAO-inhibiting potential of both antibiotics, de Castro Julve et al. rightly note that ‘tedizolid appears to be a more potent inhibitor in vitro of MAO-A than linezolid’ <2>– but neglect to mention (a) that tedizolid is also four to sixteen (or – depending on the source – ‘two to eight’)<3> times more potent than linezolid at treating most gram-positive infections;<4> and (b) that tedizolid is therefore administered at a lower dose than is linezolid (200mg/day vs. 600mg/12 hours).<3> This likely leads, in practice, to less tedizolid-induced (vs. linezolid-induced) MAO-inhibition<3>, as evidenced by the clinically insignificant potentiation of the tyramine pressor response (TYR30)<2>, and to less potential for serotonergic drug interactions<5>, as further evidenced by the fact that no changes in the murine head twitch response occur, even at plasma tedizolid concentrations which exceed – ‘by up to ~25-fold’ – the Cmax observed in humans at the clinical dose of 200mg/day.<3>
  II. The detection in their patient of a hypertensive crisis ‘suspected to be an adverse reaction to tedizolid’<2> on the fourth day of treatment, is not a valid diagnostic criterion for even a tentative assessment of ‘serotonin syndrome’ – note, furthermore, that this nomenclature is increasingly considered outmoded: serotonin surplus occurs on a toxicity spectrum<1>, and is preferably consistently referred to as ‘serotonin toxicity’. The absence of observed spontaneous/inducible/ocular clonus or hyperreflexia in the patient, precludes – by all recognized criteria – a diagnosis of possible serotonin toxicity.<1>
  Van den Eynde Vincent (first author) has nothing to disclose.
  Gillman Peter Kenneth (second/corresponding author: ken.psychotropical@gmail.com) has nothing to disclose.
  ---
  Bibliography (<endnotes>):
  1 Dunkley ECJ, Isbister GK, Sibbritt D, et al. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Q J Med 2003;96:635-42.
  2 de Castro Julve M, Miralles Albors P, Ortonobes Roig S, et al. Hypertensive crisis following the administration of tedizolid: possible serotonin syndrome. Eur J Hosp Pharm 2018;0:1-3.
  3 Rybak JM, Roberts K. Tedizolid Phosphate: a Next-Generation Oxazolidinone. Infect Dis Ther 2015;4:1-14.
  4 Flanagan S, Bartizal K, Minassian SL, et al. In Vitro, In Vivo, and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions. Antimicrob Agents Chemother 2013;57:3060-6.
  5 Burdette SD, Trotman R. Tedizolid: The First Once-Daily Oxazolidinone Class Antibiotic. Clin Infect Dis 2015;61:1315-21.

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  Conflict of Interest:
  None declared.

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