Linezolid modestly increases blood pressure response to oraltyramine, and as a consequence patients receiving linezolidshould not consume excessive amounts of tyramine-rich foods anddrinks. The bioavailability of linezolid is not affected by enteralfeeds or food.
Clinical evidence,mechanism, importance and management
A study in healthy subjects found that plasma levels following a single 375mg oral dose of linezolid as a tablet were 23 % higher when given to fasted subjects than when it was taken immediately after a high-fat meal. However, AUCs were not significantly different, indicating that extent of absorption was not affected by food (See reference number 2). Another study in healthy subjects found that food delayed rate but not extent of absorption and distribution of linezolid into tissues (See reference number 3).
In a pharmacodynamic study in healthy subjects, dose of oral tyramine required to raise systolic blood pressure by 30 mmHg was decreased by a factor of about 3.5 (from a range of 300 to 600mg without linezolid to 100 to 200mg with linezolid) when subjects were pretreated with linezolid 625mg twice daily for 4 to 7 days. This increase in pressor response to tyramine was similar to that seen with moclobemide 150mg three times daily (See reference number 4). Further, another placebo-controlled study in healthy subjects found that single doses of linezolid 600mg and moclobemide 300mg also caused similar increases in pressor response to intravenous tyramine as measured by amount of tyramine required to raise systolic blood pressure by 30 mmHg (See reference number 5).
Linezolid is a weak,non-selective inhibitor of MAO. As a consequence, it can inhibit breakdown of tyramine by MAO in gut, and can also potentiate effect of tyramine at nerve endings, therefore causing an increase in blood pressure (see Mechanism, under ‘MAOIs or RIMAs
+ Tyramine-rich foods’). However, extent of this rise was similar to that for moclobemide, which is much less than that seen with classical MAOIs.
The manufacturers of linezolid recommend that patients should avoid large amounts of tyramine-rich foods and drinks(See reference number 6,7)and should not consume more than 100mg of tyramine per meal (See reference number 7). For a list of possible tyramine-content of various foods and drinks, see table 1 below,, table 2 below, and table 3 below,. This is in line with dietary restrictions recommended for RIMAs rather than more stringent dietary recommendations required in patients taking non-selective MAOIs.
Nguyen M,Beringer P, Wong-Beringer A, Louie S, Gill M, Gurevitch A. Effect of continuousenteral feedings (TF) on oral bioavailability (F) of linezolid (LZD) in hospitalized patients. Abstracts of the 43(See reference number rd) Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, Il, 2003, 43, 36.
Welshman IR,Sisson TA, Jungbluth GL, Stalker D, Hopkins NK. Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Dispos (2001) 22, 91–7.
Islinger F,Dehghanyar P, Sauermann R, Burger C, Kloft C, Muller M, Joukhader C. The effectof food on plasma and tissue concentrations of linezolid after multiple doses. Int J Antimicrob Agents (2006) 27, 108–12.
Antal EJ,Hendershot PE, Batts DH, Sheu W-P, Hopkins NK, Donaldson KM. Linezolid, anovel oxazolidinone antibiotic: assessment of monoamine oxidase inhibition using pressor response to oral tyramine. J Clin Pharmacol (2001) 41, 552–62.
Cantarini MV,Painter CJ, Gilmore EM, Bolger C, Watkins CL, Hughes AM. Effect of oral linezolid on the pressor response to intravenous tyramine. Br J Clin Pharmacol (2004) 58, 470–5.
Zyvox (Linezolid). Pharmacia Ltd. UK Summary of product characteristics,July 2007.
Zyvox (Linezolid). Pharmacia & Upjohn. US Prescribing information,March 2007.
| Table 1 The tyramine-content of some drinks | ||
|---|---|---|
| Tyramine content (mg/L) | Refs | |
| Ales, beers and lagers | ||
| Beer (Canada) | 0 to 11.2, 27.1, 29.5, 112.9 | 1,2 |
| Beer (Former Czechoslovakia) | 10.4, 47 to 60 | 3 |
| Beer (Germany) | 1 | 3 |
| Beer (Ireland) | 0.5 to 4, 54 | 2,3 |
| Beer (Netherlands) | 1 | 3 |
| Beer (UK) | 0.3 to 1.34 | 2-4 |
| Beer (USA) | 0.7 to 4.4 | 2,3,5 |
| Low-alcohol beers | 0 to 10 | 2,6 |
| Wines | ||
| Chianti (Italy) | ||
| Governo process | 1.8 to 10.4, 25.4 | 1, 5 |
| Newer process | 0.0 to 4.7 | 3,4,7,8 |
| Champagne | 1, 13.7 to 18 | 3,9 |
| Wine, red (Canada, France, Italy, Spain, USA) | 0 to 8.6 (mean 5.2) | 9 |
| Wine, white (France, Germany, Italy, Portugal, Spain, Former Yugoslavia) | 0.4 to 6.5 | 4,5,9 |
| Fortified wines and spirits | ||
| Gin | 0 | 8 |
| Port | Less than 0.2 (undetectable) | 5 |
| Sherry | 0.2 to 3.6 | 1,3,5,8 |
| Vodka | 0 | 8 |
| Whiskey | 0 | 8 |
| Table 2 The tyramine-content of some foods | ||
|---|---|---|
| Food | Tyramine content (mg/kg or mg/L) | Refs |
| Avocado | Higher in ripe fruit, 23, 0 | 1-3 |
| Banana peel | 52, 65 | 2,4 |
| Banana pulp | 7, 0 | 2-4 |
| Caviar (Iranian) | 680 | 5 |
| Cheese – see table 3 below, and Pizza toppings, below | ||
| Country cured ham | not detectable | 6 |
| Farmer salami sausage | 314 | 6 |
| Genoa salami sausage | 0 to 1237 (average 534) | 6 |
| Hard salami | 0 to 392 (average 210) | 6 |
| Herring (pickled) | 3030 | 7 |
| Lebanon bologna | 0 to 333 (average 224) | 6 |
| Liver-chicken | 94 to 113 | 8 |
| Liver-beef | 0 to 274 | 9 |
| Orange pulp | 10 | 2 |
| Pepperoni sausage | 0 to 195 (average 39) | 6 |
| Pizza toppings (cheese and pepperoni) | 0 to 3.6 (0 to 0.38mg on half a medium pizza) | 10 |
| Plum, red | 6 | 2 |
| Sauerkraut | 55 | 4 |
| Soy sauce | 0 to 878 | 4,10-12 |
| Soya bean curd (tofu) | 0.6 to 16 | 10 |
| Soya beans, fermented | 713 | 12 |
| Soya bean paste, fermented | 206 | 12 |
| Smoked landjaeger sausage | 396 | 6 |
| Summer sausage | 184 | 6 |
| Tomato | 4, 0 | 2,3 |
| Thuringer cervelat | 0 to 162 | 6 |
| Yeast extracts | ||
| Bovril | 200 to 500 | 13 |
| Bovril beef cubes | 200 to 500 | 13 |
| Bovril chicken cubes | 50 to 200 | 13 |
| Marmite (UK product) | 500 to 3000 | 3,4,13 |
| Oxo chicken cubes | 130 | 14 |
| Red Oxo cubes | 250 | 14 |
| Yoghurt | 0 to 4 | 3,4,15 |
| Table 3 The tyramine content of some cheeses This table is principally intended to show the extent and the variation that can occur | |||
|---|---|---|---|
| Variety of cheese | Tyramine content (mg/kg) | Approximate mg/60g portion | Refs |
| American processed | 50 | 3 | 1 |
| Argenti | 188 | 11 | 2 |
| Blue | 31 to 997 | 2 to 60 | 2-4 |
| Boursault | 1116 | 67 | 3 |
| Brick | 194 | 12 | 2 |
| Brie | 3 to 473 | 0.2 to 28 | 1,4,5 |
| Cambozola Blue Vein | 18 | 1 | 4 |
| Camembert | 3 to 519 | 0.2 to 31 | 1–3,5 |
| Cheddar | 8 to 1530 | 0.5 to 92 | 2-6 |
| Cheshire | 24 to 418 | 1.4 to 25 | 5 |
| Cream cheese | undetectable (less than 0.2), 9 | 0 to 0.5 | 1,4 |
| Cottage cheese | undetectable (less than 0.2), 5 | 0 to 0.3 | 1,5 |
| Danish Blue | 31 to 743 | 2 to 45 | 3-5 |
| d’Oka | 158, 310 | 9.5, 19 | 2 |
| Double Gloucester | 43 | 2.6 | 5 |
| Edam | 100, 214 | 6, 13 | 2 |
| Emmental | 11 to 958 | 0.7 to 57 | 1,4,5 |
| Feta | 5.8, 20, 76 | 0.3 to 4.6 | 4-6 |
| Gorgonzola | 56 to 768 | 3.4 to 46 | 4,5 |
| Gouda | 54, 95 | 3.2, 5.7 | 2 |
| Gouda type (Canadian) | 20 | 1.2 | 3 |
| Gourmandise | 216 | 13 | 3 |
| Gruyere | 64 to 516 | 3.8 to 31 | 1,4,5,7 |
| Kashar | 44 (mean of seven samples) | 2.6 | 7 |
| Liederkrantz | 1226, 1683 | 74, 101 | 2 |
| Limburger | 44 to 416 | 2.6, 25 | 2,5 |
| Mozzarella | 17 to 410 | 1 to 25 | 3-6 |
| Munster | 87 to 110 | 5.2 to 6.6 | 2,4,5 |
| Mycella | 1340 | 80 | 3 |
| Parmesan | 4 to 290 | 0.2 to 17 | 3-5 |
| Provolone | 38 | 2.3 | 3 |
| Red Leicester | 41 | 2.5 | 5 |
| Ricotta | 0 | 0 | 4 |
| Romano | 4, 197, 238 | 0.2 to 14 | 2,3,6 |
| Roquefort | 13 to 520 | 0.8 to 31 | 2,3,5 |
| Stilton | 359 to 2170 | 28 to 130 | 1,3-5 |
| Tulum | 208 (mean of seven samples) | 12.5 | 7 |
| White (Turkish) | 17.5 (mean of seven samples) | 1 | 7 |