Warfarin
Azithromycin (Zithromax) Interactions
Antacids containing aluminum salts and/or magnesium salts can decrease the oral absorption of azithromycin, resulting in lower peak plasma concentrations. If antacids must be taken, stagger the administration of the antacid and azithromycin by several hours.
The effect of food on the oral bioavailability of azithromycin is variable depending on the specific azithromycin dosage form. Azithromycin capsules (no longer marketed) have an oral bioavailability of 37%; food reduces the extent of absorption (AUC) by about 43%. Therefore, azithromycin capsules should be administered 1 hour before or 2 hours after meals. In contrast, azithromycin serum concentrations increase by about 23%, while AUC remains unchanged, when tablets are administered with a high-fat meal. Therefore, azithromycin tablets can be taken with or without food. Food increases the rate of absorption (Cmax) of the suspension by about 56%; however, the extent of absorption is unchanged. Because peak azithromycin serum concentrations are increased substantially when the suspension is taken with food, the suspension should be taken on an empty stomach.
The literature reports differences among the macrolides in their abilities to inhibit CYP450 enzymes and, thus, to cause clinically significant drug-drug interactions. Of the macrolides, azithromycin and dirithromycin do not inhibit cytochrome P450 enzymes and are not implicated in clinically significant drug-drug interactions with theophylline or aminophylline. No dosage adjustment of theophylline (or aminophylline) is required when azithromycin is coadministered.
The literature reports differences among the macrolides in their abilities to inhibit CYP450 enzymes and, thus, to cause clinically significant drug-drug interactions. Of the macrolides, azithromycin and dirithromycin do not inhibit cytochrome P450 enzymes and are not implicated in clinically significant drug-drug interactions involving the CYP450 enzyme system. Coadministration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the following drugs: atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, triazolam, sulfamethoxazole; trimethoprim, or zidovudine. No dosage adjustment of the drugs listed is recommended when coadministered with azithromycin. Conversely, no dosage adjustment of azithromycin is recommended when efavirenz, fluconazole, or rifabutin are coadministered with azithromycin. However, coadministration of nelfinavir with azithromycin has been associated with increased azithromycin serum concentrations and the manufacturer of azithromycin recommends monitoring for known side effects of azithromycin, such as hepatic enzyme abnormalities and hearing impairment.
Azithromycin did not affect the prothrombin time response to a single dose of warfarin. Compared to other macrolides, azithromycin has less of an effect on cytochrome P450 isoenzymes. Although more than 40 spontaneous reports of an interaction between azithromycin and warfarin have been made to the manufacturers, at this time, there is not enough evidence to prove causality. However, it would be prudent for clinicians to closely monitor the INR in patients who receive warfarin and azithromycin concurrently as a potential interaction may occur. The concurrent use of other macrolides and warfarin in medical practice has been associated with increased anticoagulant effects.
In approximately 10% of patients, significant gastrointestinal metabolism of digoxin occurs. Elevated digoxin concentrations have been observed when certain macrolide antibiotics have been coadministered with digoxin. Originally, this interaction was thought to be due to inhibition of intestinal flora, which leads to decreased intestinal metabolism of digoxin to inactive digoxin reduction products (DRPs). Only 5% of a digoxin dose is subject to metabolism by gut flora and this proposed mechanism does not account for the large increases in digoxin levels that occur with the co-administration of certain macrolides (e.g., clarithromycin, erythromycin) with digoxin. Inhibition of P-glycoprotein, an energy-dependent drug efflux pump, may play a role; inhibition of this protein in the intestinal cell wall leads to increased oral absorption and decreased renal and non-renal clearance of digoxin. An interaction between azithromycin and digoxin has been reported, however, the effect of azithromycin on P-glycoprotein is not clearly defined. Careful monitoring of the patient is advised if digoxin and azithromycin are used together.
Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin and either ergotamine or dihydroergotamine concurrently. The simultaneous use of certain ergot alkaloids (e.g., dihydroergotamine or ergotamine) with certain macrolides (i.e., clarithromycin, erythromycin or troleandomycin) may produce ergot toxicity (e.g., severe peripheral vasospasm with possible ischemia, cyanosis, and numbness of the extremities or other serious effects). The mechanism is related to inhibition of ergot metabolism via CYP3A4. Of the macrolides, azithromycin does not inhibit cytochrome P450 enzymes and is not likely to be implicated in clinically significant drug-drug interactions involving the CYP450 system. However, specific drug interaction studies have not been performed with the combination of azithromycin and ergot alkaloids.
Of the macrolides, azithromycin does not inhibit cytochrome P450 enzymes and is not likely to be implicated in clinically significant drug-drug interactions involving the CYP450 system. Azithromycin was not implicated in clinical trials with drug interactions with the following drugs: cyclosporine; however, specific drug interaction studies have not been performed with the combination of azithromycin and cyclosporine. One patient had increased cyclosporine concentrations after administration of azithromycin and decreased cyclosporine concentrations after azithromycin discontinuation. The mechanism of the potential interaction is unknown but may be related to competition for biliary excretion. Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin with cyclosporine.
Of the macrolides, azithromycin does not inhibit cytochrome P450 enzymes and is not likely to be implicated in clinically significant drug-drug interactions involving the CYP450 system. Azithromycin was not implicated in clinical trials with drug interactions with the following drugs: cyclosporine, terfenadine, hexobarbital or phenytoin. However, specific drug interaction studies have not been performed with the combination of azithromycin and these drugs. Until more data are available, the manufacturer of azithromycin recommends caution and careful monitoring of patients who receive azithromycin with any of the drugs listed.
QT prolongation was reported in a 68-year old woman receiving azithromycin and amiodarone. The patient had a history of stable congestive heart failure and a posterior communicating artery aneurysm. She was receiving amiodarone (200 mg/day) for over a year for paroxysmal atrial fibrillation. Additional medications included furosemide, enalapril, and aspirin. A regular sinus rhythm with normal P-R, QRST, and QTc intervals was noted prior to initiation of azithromycin therapy. Therapy with azithromycin was started at 500 mg PO on day 1, followed by 250 mg PO qd for 4 days. Sinus bradycardia with marked QT prolongation and increased QT dispersion were noted on day 3 of treatment. Azithromcyin was discontinued; QT and QTc intervals and QT dispersion returned to baseline in 4 days. Hypokalemia or hypomagnesemia were not noted in the patient and the amiodarone dose remained consistent at 200 mg/day.
Lincomycin and macrolide antimicrobials are bactericidal or bacteriostatic via the same or similar mechanisms of action. Antagonism in vitro has been demonstrated when lincomycin was coadministered with erythromycin. The manufacturer of lincomycin does not recommend concurrent use of lincomycin with macrolides.
Many texts discourage concomitant use of bacteriostatic and bactericidal antibiotics. The classic explanation of this antagonism is that the bacteriostatic antimicrobial agent inhibits the growth of the target organism, and interferes with the action of the bactericidal agent, which is dependent on cell growth/replication for proper activity. However, despite reports of pharmacologic antagonism in vitro with such combinations, few clinical data to substantiate in vivo antagonism exist. Combination antimicrobial therapy has been a useful strategy for treating clinical infections. Although the potential for antagonism should be considered when prescribing antibiotics, in general it is safe to administer macrolides in combination with other antibiotics such as penicillins and cephalosporins, refining treatment based on the nature of the clinical infection and individual parameters such as susceptibility data.
Bacteria in the intestine produce enzymes which hydrolyze the soy isoflavones to the active isoflavonoids genistein and daidzein; alterations in gut microflora have been correlated with effects on soy isoflavone bioavailability. Selected antibiotics (e.g., clindamycin, lincomycin, macrolides, neomycin, tetracyclines) significantly reduce the GI microflora and could theoretically prevent the formation of the active components of the soy isoflavones.
[ Last revised: 2/22/2005 10:53:00 AM ]
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