Linezolid, a Novel Oxazolidinone Antibiotic: Assessment of Monoamine Oxidase Inhibition Using Pressor Response to Oral Tyramine

Abstract

The primary objective of this study was to compare the effects of oral linezolid with moclobemide and placebo on the pressor response to oral tyramine. Secondary objectives were to determine possible mechanisms of the effect based on changes in the pharmacokinetics of tyramine and to evaluate alternative methods for quantifying the pressor effect. Subjects received linezolid (625 mg bid orally), moclobemide (150 mg tid orally), or placebo for up to 7 days. Using the oral tyramine dose producing a >30 mmHg increase in systolic blood pressure (SBP) (PD>30), a positive pressor response was defined as a PD>30 index (pretreatment/treatment ratio of PD>30) of > or = 2. There were 8/10, 11/11, and 1/10 responders with linezolid, moclobemide, and placebo, respectively. Responses returned to baseline within 2 days of drug discontinuation. The ratio of mean greatest SBP and heart rate at the time of greatest SBP (GSBP/HR) increased linearly with tyramine dose both pretreatment and during treatment with linezolid and moclobemide. During treatment, responses to tyramine when subjects took linezolid or moclobemide were significantly different from placebo. Both drugs significantly decreased tyramine oral clearance compared with placebo. Urinary excretion of catecholamines and metabolites was consistent with MAOI activity of the drugs, but results were variable. The MAOI activity of linezolid is similar to that of moclobemide, a drug used clinically without food restrictions. Restrictions to normal dietary intake of tyramine-containing foods are not warranted when taking linezolid.

In Vitro , In Vivo , and Clinical Studies of Tedizolid To Assess the Potential for Peripheral or Central Monoamine Oxidase Interactions

“…The dose of tyramine required to elicit an increase in systolic blood pressure of Ն30 mmHg (TYR 30 ) was used to evaluate potential MAO interactions (16,30). In each of 2 sequential cohorts, subjects were randomized to receive oral placebo or 200 mg tedizolid phosphate per day during the first treatment period (up to 14 days), with a 2-day minimum washout, followed by treatment with the opposite intervention for up to 14 days.…”

“…Treatment effects were assessed in the subset of subjects achieving TYR 30 in both treatment periods; the tyramine sensitivity factor was calculated as the ratio of placebo TYR 30 to tedizolid TYR 30 . A tyramine sensitivity factor of Ն2 is considered a clinically relevant increase in tyramine sensitivity (16).…”

“…Almost all subjects (29/ 30) experienced at least 1 adverse event during one or both treat- (16,30,32). All 7 subjects who achieved a TYR 30 with both tedizolid phosphate and placebo treatments reported palpitations.…”

“…The pressor-enhancing effect of linezolid has been documented in rats (15) and in humans (16,17). Postmarketing reports identified rare episodes of serotonin toxicity, resulting from high intrasynaptic concentrations of serotonin and serotonin receptor 2A overstimulation in the central nervous system (13).…”

“…Among all interactions tested, Ͼ50% binding or activity inhibition was detected only for MAO-A and MAO-B, prompting evaluation of in vitro MAO inhibitor activity and potential relevant consequences in vivo. Established methods (10,12,16,17,24,25) were used to assess MAO inhibitor activity of tedizolid in vitro and evaluate the impact of tedizolid phosphate on MAO-related effects in human and animal models.…”