Theophylline with macrolides

Macrolides are metabolized in the liver via the microsomal (cytochrome P450) enzyme system. The alkylxanthines (e.g. theophylline, amino-phylline) utilize the same enzyme system, so concurrent administration with macrolides leads to a doubling of the alkylxanthine concentration and toxicity. Because of similar mechanisms of action, concurrent administration of other macrolides, lincosamides, chloramphenicol or florfenicol is not recommended. 

Terfenadine (Seldane) or astemizole (Hismanal) given with macrolides might cause toxicity to the heart. The patient is also at risk for hemorrhage if the patient takes both warfarin (Coumadin) and marolides within the same time period. The patient may also experience increased theophylline levels which can lead to toxicity when theophylline is given along with zanthines such as aminophylline and caffeine. 

Use of the macrolides increases serum levels of digoxin and increases the effects of anticoagulants. Use of antacids decreases the absorption of most macrolides. The macrolides should not be administered with clindamycin, lincomycin, or chloramphenicol a decrease in the therapeutic activity of the macrolides can occur. Concurrent administration of the macrolides with theophylline may increase serum theophylline levels. 

Drugs that may interact with rifabutin include the following Anticoagulants, azole antifungal agents, benzodiazepines, beta blockers, buspirone, corticosteroids, cyclosporine, delavirdine, doxycycline, hydantoins, indinavir, rifamycins, losartan, macrolide antibiotics, methadone, morphine, nelfinavir, quinine, quinidine, theophylline, aminophylline, tricyclic antidepressants, and zolpidem. 

The most serious toxicity of erythromycin involves cholestatic hepatitis, which occurs mainly in adults and only when the estolate preparation of erythromycin is used. Mild allergic reactions such as urticaria and other rashes, fever, and eosinophilia have occurred occasionally after erythromycin use. Sensorineural hearing loss, although extremely rare, has been reported after the use of large doses of erythromycin or the use of erythromycin in the presence of renal lailure.The hearing loss usually improves gradually on discontinuation of the drug. Concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. 

Antimicrobials are over prescribed for exacerbations of asthma. Respiratory tract infections do cause increased airflow obstruction and hyperresponsiveness, but viral rather than bacterial pathogens are the commonest culprits. Antimicrobials should be prescribed only if there is high suspicion of a bacterial respiratory tract infection, e.g. purulent sputum. Note that macrolide antibiotics, such as erythromycin and clarithromycin, interfere with theophylline metabolism. 

Macrolide Antibiotics. Erythromycin may significantly increase serum concentrations of medications such as theophylline by inhibiting their hepatic metabolism. Clarithromycin (Biaxin) and troleandomycin appear to interact with other medications in a manner similar to erythromycin, whereas azithromycin (Zithromax) is unlikely to interact with these agents. 

The most frequent effects of macrohdes on theophylline pharmacokinetics are increased half-hfe and serum theophylline concentration and reduced clearance (133). The interaction with theophylline is mainly seen with higher doses of macrolides and can result in theophylhne toxicity (108). 

One of the important limitations to the widespread use of the macrolides has been the propensity to interact with other commonly administered medications. Serious, sometimes life-threatening, consequences have resulted from the administration of macrolides to patients receiving routine medications including theophylline, carbamazepine, terfenadine, and other frequently prescribed medications [4-6]. Most of these interactions involve inhibition of drug metabolism via cytochrome P-450 microsomal enzyme. However, not all macrolides have been associated with such drug interactions. 

Suijus, A., Tremblay, D., Saint-Salvi, B., Granier, J., and Lefebvre, M. A. (1986). Pharmacokinetic interaction of a new macrolide, roxithromycin (RU 28965) with theophyllin. Presented at the Third World Conference on Clinical Pharmacology and Therapeutics (Stockholm). Abstr. No. 1203. 

Concomitant administration of recombinant human a-interferon decreased theophylline clearance by 15%. Most macrolides are potent inhibitors of CYP3A4. Erythromycin and its salts as well as troleandomycin reduce theophylline Cl concentrahon-dependently 20-40% reduction after 5—7 days of therapy" " with erythromycin, 50% after 10 days with troleandomycin." Results for clarithromycin are similar to those for erythromycin." Azithromycin does not seem to influence theophylline metabolism, although reported results are contradictory. " ... 

Troleandomycin can increase serum theophylline levels, causing toxicity if the dosage is not reduced. Azithromycin, clarithromycin, dirithromycin, josamycin, midecamycin, rokitamycin, spiramycin, and telithromycin normally only cause modest changes in theophylline levels or do not interact at all. There are unexplained and isolated case reports of theophylline toxicity with josamycin and clarithromycin. Roxithromycin usually has no relevant interaction but a significant increase in theophylline levels was seen in one study. See also Theophylline + Macrolides Erythromycin , p.ll87. 

The interaction between theophylline and troleandomycin is established and well documented. If troleandomycin is given, monitor the levels of theophylline closely and adjust the dose as necessary. Reductions of 25 to 50% may be needed. The situation with roxithromycin is uncertain since only 1 of 4 studies suggested an interaction, but it would be prudent to be alert for the need to reduce the theophylline dosage. Alternative mac-rolides that usually interact only moderately, or not at all are azithromycin, clarithromycin, dirithromycin, josamycin, midecamycin, rokitamycin and spiramycin. Telithromycin may also he a suitable alternative. However, even with these macrolides it would still be prudent to monitor the outcome because a few patients, especially those with theophylline levels at the high end of the range, may need some small theophylline dosage adjustments. In the case of azithromycin, care should be taken in adjusting the dose based on theophylline levels taken after about 5 days of concurrent use, as they may only he a reflection of a transient drop. In addition, acute infection perse may alter theophylline pharmacokineties. 

Gaffuri-Riva V, Crippa F, Guf nti EE. Theophylline interacticn with new quinolones and macrolides in COPD patients. AmRevRespirDis (1991) 143, A498. 

Carbamazepine levels are increased by CYP3A4 inhibitors (cimetidine, macrolides, diltiazem, fluoxetine, ketoconazole, verapamil, valproate) levels are decreased by CYP3A4 inducers (cisplatin, doxorubicin, felbamate, phenobarbital, phenytoin, primidone, rifampin, theophylline). Carbamazepine may increase levels of clomipramine, phenytoin, and primidone and lithium toxicity may decrease levels of phenytoin, warfarin, oral contraceptives, doxycycline, theophylline, haloperidol, alprazolam, clozapine, ethosuximide, and valproate may interfere with other anticonvulsants. 

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