Pharmacy Blog – Dr Vibore

Aluminium/magnesium hydroxide and aluminium hydroxide donot significantly affect bioavailability of amoxicillin or amoxicillin with clavulanic acid (co-amoxiclav). Antacids may reducethe absorption of hydrochloride salt of pivampicillin

Clinical evidence,mechanism, importance and management

The pharmacokinetics of amoxicillin 1 g, and both amoxicillin and clavulanic acid (given as co-amoxiclav 625 mg), were not significantly altered by 10 doses of aluminium/magnesium hydroxide (Maalox) 10 mL, with last dose given 30 minutes before amoxicillin (See reference number 1). Another study found that four 40mg doses of aluminium hydroxide (Aludrox) given at 20 minute intervals had no effect on pharmacokinetics of either amoxicillin or clavulanic acid (given as co-amoxiclav 750mg with second dose of antacid) (See reference number 2).

There would seem to be no reason for avoiding concurrent use of antacids and amoxicillin or co-amoxiclav

The UK manufacturers(See reference number 3)used to recommend that,because antacids may decrease pivampicillin absorption, concurrent use should be avoided. This warning relates to a hydrochloride salt formulation, which needs acidic conditions for optimal absorption, whereas basic salt formulation should not be affected by any pH change (See reference number 4).

Deppermann K-M,Lode H, Höffken G, Tschink G, Kalz C, Koeppe P. Influence of ranitidine,pirenzepine, and aluminium magnesium hydroxide on the bioavailability of various antibacterials, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid. Antimicrob Agents Chemother (1989) 33, 1901–7.

Staniforth DH,Clarke HL, Horton R, Jackson D, Lau D. Augmentin bioavailability followingcimetidine, aluminum hydroxide and milk. Int J Clin Pharmacol Ther Toxicol (1985) 23, 145–

7.

Pondocillin (Pivampicillin). Leo Laboratories Ltd. ABPI Compendium of Datasheets andSummaries of Product Characteristics,1998–99, 625–6.

Leo Laboratories Limited. Personal communication,March 1995.

An isolated report describes acute dystonia in one patient,whichwas attributed to an interaction between metronidazole and chloroquine.

Clinical evidence,mechanism, importance and management

A patient was given a 7-day course of metronidazole and ampicillin,following a laparoscopic investigation. She developed acute dystonic reactions (facial grimacing,coarse tremors, and an inability to maintain posture) on day 6, within 10 minutes of being given chloroquine phosphate (equivalent to 200mg of base) and intramuscular promethazine

25 mg. The dystonic symptoms started to subside within 15 minutes of being given diazepam 5mg intravenously,and had completely resolved within 2 hrs (See reference number 1).

The authors of report attribute dystonia to an interaction between metronidazole and chloroquine as she had taken both drugs alone without adverse effect. However, they do not fully assess possible contribution of promethazine, which is known to cause dystonias. It is therefore possible that reaction seen was an adverse effect of promethazine, or perhaps even an interaction between promethazine and chloroquine. No general recommendations can therefore be made from this single report.

1. Achumba JI,Ette EI, Thomas WOA, Essien EE. Chloroquine-induced acute dystonic reactionsin the presence of metronidazole. Drug Intell Clin Pharm (1988) 22, 308–10.

Acute psychoses and confusion can be caused by concurrentuse of metronidazole and disulfiram

Clinical evidence,mechanism, importance and management

In a double-blind study in 58 hospitalised chronic alcoholics taking disulfiram,29 patients were also given metronidazole 750mg daily for a month, then 250mg daily thereafter. Six of 29 subjects in group receiving metronidazole developed acute psychoses or confusion. Five of 6 had paranoid delusions and in 3 visual and auditory hallucinations were also seen. The symptoms persisted for 2 to 3 days after drugs were withdrawn, but disappeared at end of a fortnight and did not reappear when disulfiram alone was restarted (See reference number 1). Similar reactions have been described in two other reports (See reference number 2,3).

The reason for this interaction is not understood,but it appears to be established. Concurrent use should be avoided or very well monitored.

Rothstein E,Clancy DD. Toxicity of disulfiram combined with metronidazole. N Engl J Med (1969) 280, 1006–7.

Goodhue WW. Disulfiram-metronidazole (well-identified) toxicity. N Engl J Med (1969) 280,1482–3.

Scher JM. Psychotic reaction to disulfiram. JAMA (1967) 201,1051.

Prednisone modestly decreases AUC of metronidazole

Clinical evidence,mechanism, importance and management

In 6 patients with Crohn’s disease AUC of metronidazole 250mg twice daily was reduced by 31 % by prednisone 10mg twice daily for 6 days, probably because prednisone induces metabolism of metronidazole by liver enzymes (See reference number 1).

Information appears to be limited to this report and interaction is probably of only limited clinical importance

1. Eradiri O,Jamali F, Thomson ABR. Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn’s disease. Biopharm Drug Dispos (1988) 9, 219–

27.

Rifabutin and azithromycin seem not to affect serum levels ofeach other, but a very high incidence of neutropenia was seen inone study of combination. Both rifabutin and rifampicinmarkedly reduce serum levels of clarithromycin. Clarithromycin increases serum levels of rifabutin and combinationis associated with an increased risk of uveitis and neutropenia. Rifampicin (rifampin) greatly reduces telithromycin levels and concurrent use is not recommended.

Neutropenia. A study in 12 healthy subjects was designed to investigate safety and possible interactions between rifabutin 300mg daily, and azithromycin 250mg daily or clarithromycin 500mg twice daily, for a course of 14 days. The subjects were matched against 18 healthy controls who received either of macrolides or rifabutin alone. The study had to be abandoned after 10 days because 14 patients developed neutropenia; 2 taking rifabutin alone,and all 12 of those taking rifabutin with a macrolide. Eight subjects developed a fever,5 required colony simulating factors, and 3 required hospitalisation (See reference number 1).

Pharmacokinetics. In a study(See reference number 2) investigating a possible regimen for prophylaxis of Mycobacterium avium complex (MAC) disease, 12 HIV-positive patients were treated with clarithromycin 500mg daily, to which rifabutin 300mg daily was added on day 15. By day 42 clarithromycin AUC had fallen by 44%, and levels of metabolite, 14-hydroxyclarithromycin, had risen by 57%. A related study(See reference number 2) in 14 patients given clarithromycin 500 mg every 12 hrs and rifabutin 300mg daily found that after 28 days AUC of rifabutin had increased by 99%, and AUC of active metabolite, 25-O-desacetyl-rifabutin, had increased by 375%. Another group of patients with lung disease due to MAC were treated with clarithromycin 500mg twice daily. When rifabutin 600mg was added clarithromycin levels fell by 63 % (from 5.4 to 2 micrograms/mL) (See reference number 3). Limited information from a randomised study in healthy subjects found similar results (See reference number 1,4). Fluconazole appears to further increase effects of clarithromycin on rifabutin (See reference number 4). One study suggests that there is no pharmacokinetic interaction between azithromycin and rifabutin (See reference number 1).

Uveitis or arthralgias. Uveitis,and in some cases pseudojaundice, aphthous stomatitis and an arthralgia syndrome have been described in patients treated with both clarithromycin 1 to 2 g daily and rifabutin 300 to 600mg daily (See reference number 5-8). The presence of fluconazole does not appear to affect development of uveitis in patients taking clarithromycin with rifabutin,(See reference number 6,7,9)but it has been suggested that this was because only small doses (50 mg) were used (See reference number 7). Reports suggest that uveitis develops between 27 to 370 days after taking combination (See reference number 6,7). The reaction appears to be dose-dependent. In patients taking rifabutin 600mg with clarithromycin incidence of uveitis was 14 % in patients weighing more than 65 kg, 45 % in those weighing between 55 and 65 kg and 64 % in those weighing less than 55 kg. The risk of developing uveitis was reduced from a mean of 43 % to 13 % when dose of rifabutin was reduced to 300mg daily (See reference number 9). Uveitis did not develop in 8 patients taking rifabutin and azithromycin 500 mg daily,(See reference number 7)although cases of uveitis have been reported in patients taking rifabutin,fluconazole, and azithromycin 1.2 g weekly but they have been attributed to an interaction between rifabutin and fluconazole (See reference number 10). See Azoles + Rifabutin interaction.

Patients with lung disease due to MAC were treated with clarithromycin 500 mg twice daily. When rifampicin 600mg daily was added, mean serum levels of clarithromycin fell by almost 90 % (from 5.4 to

The manufacturer notes that rifampicin reduces AUC and maximum

serum levels of telithromycin by 86 % and 79%,respectively (See reference number 12). Two cases of cholestatic jaundice have been reported in patients taking

Both rifabutin and rifampicin are known enzyme inducers, which can increase metabolism of other drugs by liver, thereby reducing their serum levels. Rifampicin is recognised as being more potent inducer. Rifabutin is also a substrate for cytochrome P450 isoenzyme CYP3A4. Both clarithromycin and fluconazole are inhibitors of CYP3A4 and it is probable that clarithromycin and fluconazole exert additive effects resulting in greater inhibition of rifabutin metabolism than occurs with either drug alone (See reference number 4).

The reason for uveitis is not known, but based on animal studies it has been suggested that it is associated with effective treatment of MAC and is due to release of a mycobacterial protein, rather than a toxic effect of drugs (See reference number 15). It has been suggested that lower body weight and concurrent clarithromycin may result in toxic rifabutin serum levels,although concurrent fluconazole which increases levels does not appear to be a fac

Direct information appears to be limited to reports cited but interactions would appear to be established. What is not entirely clear is whether these interactions result in treatment failures because of potentially subtherapeutic clarithromycin serum levels. Because of lack of information, be alert for evidence of reduced efficacy if clarithromycin and rifampicin are used.

Although rifabutin can lower clarithromycin levels, efficacy of this combination for MAC infection is established, although not without risk, see Uveitis, below. Clarithromycin raises rifabutin levels and therefore increases risks of adverse effects. Concurrent use may therefore be desirable,but monitoring for adverse effects is necessary.

Due to a pharmacokinetic interaction UK manufacturers recommend that telithromycin should not be given during and for 2 weeks after use of rifampicin (See reference number 12)

Information regarding neutropenia with macrolides and rifamycins is very limited but what is known suggests that white cell counts should be monitored closely if rifabutin is given with azithromycin or clarithromycin. Rifabutin is known to cause polyarthritis on rare occasions,but in conjunction with clarithromycin it appears to happen at much lower doses (See reference number 8). Careful monitoring is necessary.

The CSM in UK has warned about need to be aware of increased risk of uveitis with clarithromycin and rifabutin(See reference number 16) and of raised rifabutin levels. If uveitis occurs CSM recommends that rifabutin should be stopped and patient should be referred to an ophthalmologist (See reference number 16). Because of increased risk of uveitis they also say that consideration should be given to reducing dosage of rifabutin to 300mg daily in presence of macrolides (See reference number 16)

Apseloff G,Foulds G, LaBoy-Goral L, Willavize S, Vincent J. Comparison of azithromycinand clarithromycin in their interactions with rifabutin in healthy volunteers. J Clin Pharmacol (1998) 38, 830–5.

Hafner R,Bethel J, Power M, Landry B, Banach M, Mole L, Standiford HC, Follansbee S,Kumar P, Raasch R, Cohn D, Mushatt D, Drusano G. Tolerance and pharmacokinetic interactions of rifabutin and clarithromycin in human immunodeficiency virus-infected volunteers. Antimicrob Agents Chemother (1998) 42, 631–9.

Wallace RJ,Brown BA, Griffith DE, Girard W, Tanaka K. Reduced serum levels of clarithromycin in patients treated with multidrug regimens including rifampin or rifabutin for Mycobacterium avium-M. intracellulare infection. J Infect Dis (1995) 171, 747–50.

Jordan MK,Polis MA, Kelly G, Narang PK, Masur H, Piscitelli SC. Effects of fluconazoleand clarithromycin on rifabutin and 25-O-desacetylrifabutin pharmacokinetics. Antimicrob Agents Chemother (2000) 44, 2170–2.

Shafran SD,Deschênes J, Miller M, Phillips P, Toma E. Uveitis and pseudojaundice duringa regimen of clarithromycin, rifabutin, and ethambutol. N Engl J Med (1994) 330, 438–9.

Becker K,Schimkat M, Jablonowski H, Häussinger D. Anterior uveitis associated with rifabutin medication in AIDS patients. Infection (1996) 24, 34–6.

Kelleher P,Helbert M, Sweeney J, Anderson J, Parkin J, Pinching A. Uveitis associated withrifabutin and macrolide therapy for Mycobacterium avium intracellulare infections in AIDS patients. Genitourin Med (1996) 72, 419–21.

Le Gars L,Collon T, Picard O, Kaplan G, Berenbaum F. Polyarthralgia-arthritis syndromeinduced by low doses of rifabutin. J Rheumatol (1999) 26, 1201–2.

Shafran SD,Singer J, Zarowny DP, Deschênes J, Phillips P, Turgeon F, Aoki FY, Toma E,Miller M, Duperval R, Lemieux C, Schlech WF, for the Canadian HIV Trials Network Protocol 010 Study Group. Determinants of rifabutin-associated uveitis in patients treated withrifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. J Infect Dis (1998) 177, 252–5.

Havlir D,Torriani F, Dubé M. Uveitis associated with rifabutin prophylaxis. Ann Intern Med (1994) 121, 510–12.

Yamamoto F,Harada S, Mitsuyama T, Harada Y, Kitahara Y, Yoshida M, Nakanishi Y. Concentration of clarithromycin and 14-R-hydroxyclarithromycin in plasma of patients with Mycobacterium avium complex infection, before and after the addition of rifampicin. Jpn JAntibiot (2004) 57, 124–33.

Ketek (Telithromycin). Sanofi-Aventis. UK Summary of product characteristics,May 2007.

Piette F,Peyrard P. Ictère bénin médicamenteux lors d’un traitement associant rifampicinetriacétyloléandomycine. Nouv Presse Med (1979) 8, 368–9.

Givaudan JF,Gamby T, Privat Y. Ictère cholestatique après association rifampicine-troléandomycine: une nouvelle observation. Nouv Presse Med (1979) 8, 2357.

Opremcak EM,Cynamon M. Uveitogenic activity of rifabutin and clarithromycin in the Mycobacterium avium-infected beige mice. Am Soc Microbiol 2nd Nat Conf. Human retroviruses and related infections. Washington DC, Jan 29—Feb 2 1995, 74.

Committee on the Safety of Medicines. Rifabutin (Mycobutin) – uveitis. Current Problems (1994) 20,4.

Committee on Safety of Medicines/Medicines Control Agency. Revised indications and druginteractions of rifabutin. Current Problems (1997) 23,14.

Clinical evidence,mechanism, importance and management

A 31-year-old woman was given intravenous rifampicin 300mg every 8 hrs and linezolid 600mg every 12 hrs for an MRSA infection. During rifampicin treatment her linezolid peak and trough levels were 7.29 and 2.04 micrograms/mL,respectively. However, when rifampicin was stopped linezolid peak and trough levels were higher, at

12.46 and 5.03 micrograms/mL,respectively (See reference number 1).

In an earlier study,healthy subjects were given a single 600mg dose of intravenous linezolid either alone or with a single 600mg dose of intravenous rifampicin. This study also found that rifampicin reduced serum levels of linezolid by 10%, 20 % and 35 % at 6, 9 and 12 hours, respectively.

Linezolid is not metabolised by cytochrome P450 enzyme system so reduction in levels is unlikely to be due to increased metabolism associated with rifampicin enzyme induction. The reduction in linezolid serum levels may be attributable to induction of P-glycoprotein by rifampicin, resulting in increased excretion of linezolid (See reference number 1,2).

The clinical significance of this interaction is unclear and concurrent use of rifampicin and linezolid is not established. The available evidence suggests that,where possible, linezolid levels should be monitored if both drugs are given. If this is not possible it would seem prudent to monitor concurrent use closely to ensure that antibacterial treatment is effective.

Gebhart BC,Barker BC, Markewitz BA. Decreased serum linezolid levels in a critically ill patient receiving concomitant linezolid and rifampin. Pharmacotherapy (2007) 27, 476–9.

Egle H,Trittler R, Kümmerer K, Lemmen SW. Linezolid and rifampicin: drug interaction contrary to expectations? Clin Pharmacol Ther (2005) 77,451–3.

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 (continued)

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 (continued) This table is principally intended to show the extent and the variation that can occur

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

1. Sisson TL,Jungbluth GL, Hopkins NK. A pharmacokinetic evaluation of concomitant administration of linezolid and aztreonam. J Clin Pharmacol (1999) 39, 1277–82.

Food reduces maximum plasma levels of loracarbef, but doesnot alter its bioavailability.

Clinical evidence,mechanism, importance and management

Loracarbef 400mg was given to 12 healthy subjects either in a fasting state or following a standard breakfast. Food slowed rate of absorption, but not total bioavailability of loracarbef (See reference number 1). In another study food was found to decrease maximum plasma levels of a single 200mg dose of loracarbef and increase time to achieve maximum levels but AUC of loracarbef was not significantly affected by food (See reference number 2). Loracarbef should be taken 1 hour before or 2 hrs after food (See reference number 3).

Roller S,Lode H, Stelzer I, Deppermann KM, Boeckh M, Koeppe P. Pharmacokinetics of loracarbef and interaction with acetylcysteine. Eur J Clin Microbiol Infect Dis (1992) 11, 851–5.

DeSante KA,Zeckel ML. Pharmacokinetic profile of loracarbef. Am J Med (1992) 92 (Suppl 6A), 16S–19S.

Lorabid (Loracarbef). Monarch Pharmaceuticals,Inc. US Prescribing information, September2002.

In an analysis of phase III studies,changes in vital signs did not differ between patients given linezolid and comparator drugs (i.e. antibiotics) when either were used with drugs known to interact with MAOIs,including unnamed SSRIs (See reference number 1,2). One patient taking fluoxetine had a transient episode of asymptomatic hypertension after one dose of linezolid,but since this patient had no other symptoms of serotonin syndrome, it was not considered an interaction (See reference number 2). However, a 4-year-old girl given fluoxetine 5mg daily developed symptoms of serotonin syndrome 2 days after starting linezolid 140mg every 12 hours, and after a procedure for which she was given fentanyl 200 micrograms. Fentanyl may have been a contributing factor (See reference number 3). Another case report describes an 85-year-old woman taking citalopram who developed tremor,confusion, dysarthria, hyperreflexia, agitation, and restlessness after linezolid was started. Citalopram was stopped and symptoms resolved over 72 hrs (See reference number 4). There are several other case reports of this interaction between linezolid and SSRIs(See reference number 5-8) including citalopram,(See reference number 5,6)sertraline(See reference number 6,7) and paroxetine (See reference number 8,9).

In an analysis of phase III studies,changes in vital signs did not differ between patients given linezolid and comparator drugs (i.e. antibiotics) when either were used with drugs known to interact with MAOIs,including unnamed cyclic antidepressants (See reference number 1,2). A case report describes serotonin syndrome in an elderly patient treated with linezolid 600mg every 12 hours, 21 days after amitriptyline 10mg daily, paroxetine 20mg daily and alprazolam 500 micrograms daily were started (See reference number 9).

Mirtazapine. A patient taking linezolid 600mg twice daily developed delirium,confusion and visual hallucinations 2 weeks after starting to take mirtazapine 15 or 30mg daily and gabapentin 300mg at night. Gabapentin was stopped and delirium resolved. About 4 weeks later delirium recurred and then resolved when patient discontinued mirtazapine. Mirtazapine was restarted without recurrence of delirium. The patient subsequently took mirtazapine 15mg daily with linezolid 600mg twice daily without adverse effects (See reference number 10).

Venlafaxine. An 85-year-old man taking venlafaxine 150mg daily was prescribed ciprofloxacin,rifampicin and linezolid 600mg twice daily for a hip prosthesis infection. After 20 days he was found to be confused and disorientated,and 4 days later he was also drowsy, and suffering myoclonic jerks. Linezolid and venlafaxine were stopped and symptoms resolved over 2 days (See reference number 11). However,another case report describes a 7-year-old boy treated with venlafaxine and methylphenidate who was prescribed linezolid for osteomyelitis. He was given all three drugs (doses not stated) for several days without any alterations in vital signs or evidence of serotonin syndrome (See reference number 12).

Not fully understood. Linezolid has weak MAOI effects, and serotonin syndrome is known to occur when MAOIs are given with SSRIs’, , tricyclics, and venlafaxine, . In case of patient taking linezolid with amitriptyline and paroxetine, it is possible that an interaction between amitriptyline and paroxetine contributed to development of serotonin syndrome. Consider also ‘Tricyclic and related antidepressants + SSRIs.

Information on reaction between linezolid and SSRIs, tricyclics, mirtazapine or venlafaxine appears to be limited, but what is known suggests that interaction is probably rare. The manufacturers of linezolid say that patients taking SSRIs and tricyclic antidepressants should have their blood pressure monitored and be closely observed if given linezolid. They say that if this is not possible,concurrent use should be avoided (See reference number 13). If linezolid is used with a drug with serotonergic actions it would seem prudent to monitor for symptoms of serotonin syndrome, which may take several weeks to manifest. See The serotonin syndrome,, for further details.

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