Zidovudine Clarithromycin

With the introduction of RiF in 1967, the duration of combination therapy for the treatment of TB was significantiy reduced (from 18 to 9 months). Rifampin is nearly always used in combination with one or more other antitubercuiin agents. The drug is potentially hepatotoxic and may produce Gl disturbances, rash, and thrombocytopenic purpura. Rifampin is known to induce hepatic microsomai enzymes (cytochrome P450) and may decrease the effectiveness of oral contraceptives, corticosteroids, warfarin, quinidine, methadone, zidovudine, clarithromycin, and the azoie antifungai agents (see Chapter 10) (33). 

Drugs that may affect tipranavir include aluminum- and magnesium-based antacids, azole antifungals, clarithromycin, efavirenz, loperamide, NRTIs (ie, didanosine, zidovudine), rifamycins (rifampin), St. John s wort, tenofovir. 

Drugs that might affect amprenavir include abacavir, aldesleukin, antacids, anticonvulsants, azole antifungals, clarithromycin, cyclosporine, dexamethasone, buffered didanosine, disulfiram, ethanol, indinavir, methadone, metronidazole, nelfinavir, nonnucleoside reverse transcriptase inhibitors, oral contraceptives, rifamycins, ritonavir, saquinavir, St. John s wort, tacrolimus, and zidovudine. 

Drugs that might be affected by amprenavir include antiarrhythmics, anticonvulsants, azole antifungals, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, cyclosporine, ergot alkaloids, fentanyl, HMG-CoA reductase inhibitors, indinavir, methadone, nelfinavir, oral contraceptives, pimozide, rifabutin, ritonavir, saquinavir, sildenafil, tacrolimus, trazodone, tricyclic antidepressants, warfarin, and zidovudine. 

Drugs that may affect zidovudine include acetaminophen, atovaquone, bone marrow suppressive/cytotoxic agents (eg, adriamycin, dapsone), clarithromycin, doxorubicin, fluconazole, ganciclovir, methadone, nelfinavir/ritonavir, phenytoin, probenecid, ribavirin, rifamycins, stavudine, trimethoprim, and valproic acid. 

Drugs that may be affected by nevirapine include rifamycins, clarithromycin, oral contraceptives, efavirenz, ketoconazole, methadone, protease inhibitors, warfarin, zidovudine. 

Fluconazole, probenecid and atovaquone increase the risk of myelotoxicity by zidovudine. This may be attributed to an increased plasma concentration of zidovudine in the presence of these drugs, perhaps through their inhibitory effects on glucuronose transferase. Rifabutin and rifampin decrease plasma concentrations, and clarithromycin decreases the absorption of zidovudine. Zidovudine and stavu-dine should not be used in combination because they compete for intracellular phosphorylation. 

Clarithromycin reduced the peak concentration and AUC of zidovudine at steady state by about 12% (32), possibly as a result of reduced zidovudine absorption (62). However, if the two drugs were taken at least 2 hours apart, the pharmacokinetics of zidovudine were unaffected. 

Polis M, Haneiwich S, Kovacs J, et al. Dose escalation study to determine the safety, maximally tolerated dose and pharmacokinetics of clarithromycin with zidovudine in HIV-infected patients. In Interscience Conference on Antimicrobial Agents and Chemotherapy American Society for Microbiology, 1991. 

Clarithromycin has an unpredictable effect on the absorption of zidovudine blood concentrations may rise or fall (40,41). 

Gustavson LE, Chu SY, Mackenthun A, Gupta MS, Craft JC. Drug interaction between clarithromycin and oral zidovudine in HIV-1 infected patients. Clin Pharmacol Ther 1993 53 163. 

Vance E, Watson-Bitar M, Gustavson L, Kazanjian P. Pharmacokinetics of clarithromycin and zidovudine in patients with AIDS. Antimicrob Agents Chemother 1995 39(6) 1355-60. 

Clinically important, potentially hazardous interactions with abacavir, atorvastatin, bepridil, bupropion, carbamazepine, clarithromycin, cyclosporine, dexamethasone, digoxin, felodipine, fluticasone propionate, fosamprenavir, itraconazole, ketoconazole, lovastatin, methadone, midazolam, nicardipine, nifedipine, phenobarbital, phenytoin, rifabutin, simvastatin, sirolimus, St John s wort, systemic lidocaine, tacrolimus, tenofovir, trazodone, vinblastine, vincristine, voriconazole, warfarin, zidovudine... 

Studies of the concomitant use of azithromycin with carbamazepine, terfenadine, and zidovudine have not reported drug interactions [131-133]. With the potential exception of antacids, no drug interactions have been reported with azithromycin, which does not appear to be metabolized by the cytochrome P-450 system [4, 134], Both azithromycin and clarithromycin have been associated with digoxin toxicity. The postulated mechanism is by eradication of Eubacterium lentum, an anaerobic gram-positive bacteria responsible for the metabolism of digoxin in some patients [43]. 

Items 92-93. A 30-year-old hospitalized AIDS patient has a CD4 cell count of 50/ tL. He is being treated with a highly active antiretroviral therapy (HAART) regimen consisting of zidovudine (ZDV), lamivudine (3TC), and indinavir. Other drugs being administered to this patient include acyclovir, clarithromycin, foscamet, rifabutin, and trimethoprim-sulfamethoxazole. 

Clarithromycin causes some reduction in the bioavailability of zidovudine, but this is minimised if the two drugs are given at least 2 hours apart. Clarithromycin does not appear to interact with didanosine, stavudine or zalcitabine, and azithromycin does not interact with didanosine or zidovudine. 

Fifteen HIV-positive patients were given zidovudine 100 mg every 4 hours 5 times a day and oral clarithromycin 500 mg, 1 g or 2 g every 12 hours, both together and alone. The pharmacokinetics of the clarithromycin were not substantially changed but the zidovudine levels and AUCs were reduced by 23 to 58% and 12 to 36%, respectively. However, these effects were not seen in all patients. - Another study similarly found that clarithromycin caused a moderate reduction in the AUC of oral zidovudine (by up to 27%). No changes were seen when the zidovudine was giv-... 

The overall picture is slightly confusing, but it seems that some reductions in zidovudine levels are likely if clarithromycin is taken at the same time, but no important changes seem to occur if the administration of the drugs is separated. The authors of one study recommend that the clarithromycin is given at least 2 hours before or after the zidovudine. The UK manufacturer of zidovudine includes this recommendation, but the US manufacturer does not include any information on use with clarithromycin."... 

The authors of the report on didanosine conclude that clarithromycin may safely be given with didanosine, and it also seems likely that didanosine or zidovudine and azithromycin stavudine and clarithromycin and zalcitabine and clarithromycin can be used safely together. 

Polis MA, Piscitelli SC, Vogel S, Witebdey FG, Conville PS, Petty B, Kovacs JA, Davey RT, Walker RE, Falloon J, Metcalf JA, Craft C, Lane HC, Misur H Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection Antimicrob Agents Chemodier 99T)A, 1709-14. 

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