Rifabutin with clarithromycin

Uveitis or arthraigias. 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 600 mg daily The presence of fluconazole does not appear to affect the development of uveitis in patients taking clarithromycin with rifabutin, but it has been suggested that this was because only small doses (50 mg) were used. ... 

Mycobacterium avium complex HIV-infected patients with CD4 count < 75/14. Azithromycin, clarithromycin, or rifabutin Excellent... 

The interaction of clarithromycin with the rifamycins is complex. Clarithromycin inhibits CYP3A4, while both rifampicin and rifabutin induce P450 cytochromes,... 

Severe interactions have been observed when rifabutin and clarithromycin were given simultaneously (103). The mean concentrations of rifabutin and 25-O-desacetyl-rifabutin in healthy subjects who took clarithromycin and rifabutin concomitantly were respectively more than 4 times and 37 times greater than the concentrations recorded when rifabutin was administered alone. Neutropenia was detected in 14 of 18 subjects taking rifabutin. Myalgia and high fever were also common. In another study, clarithromycin increased the AUC of rifabutin by 76% (104). Physicians should be aware that recommended prophylactic doses of rifabutin can be associated with severe neutropenia within 2 weeks after the start of therapy, and aU patients taking rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia. 

Clarithromycin has been shown to be an effective prophylactic agent against MAC infection in patients with advanced HIV infection. In a prospective, doubleblind, placebo-controlled trial, clarithromycin prevented 69% of the expected cases of MAC disease [64]. Other studies have demonstrated that clarithromycin alone or in combination with rifabutin prevents MAC infections in AIDS patients and prolongs survival [65, 66]. However, a large prospective study failed to show that the combination of clarithromycin plus rifabutin combination was more effective than clarithromycin alone [67]. Drug-resistant MAC has been reported in 29-58% of patients who developed disseminated infection while taking prophylaxis with clarithromycin [64, 67]. Resistance to clarithromycin and other macrolides is a serious potential problem due to cross-resistance with azithromycin that narrows the therapeutic options available for MAC disease [68]. 

M avium complex (MAC) is a cause of disseminated infections in AIDS patients. Currently, clarithromycin or azithromycin is recommended for prophylaxis in patients with CD4 counts less than 50/ xL. Treatment of MAC infections requires a combination of drugs, one favored regimen consisting of azithromycin or clarithromycin with ethambutol and rifabutin, a congener of rifampin. 

Drugs for M avium complex A combination of azithromycin or clarithromycin with ethambutol, with or without rifabutin, is favored. 

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. 

The eSM in the UK has warned about the need to be aware of the increased risk of uveitis with clarithromycin and rifabutin and of the raised rifabutin levels. If uveitis occurs the CSM recommends that rifabutin should be stopped and the patient should be referred to an ophthalmologist. Because of the increased risk of uveitis they also say that consideration should be given to reducing the dosage of rifabutin to 300 mg daily in the presence of maerolides. Later review and a case-control study suggest that this dose is associated with a redueed risk of uveitis and maintains efficacy. ... 

Apseloff G, Foulds G, LaBoy-Goral L, Willavize S, Vincent J. Comparison of azithrcniycm and clarithromycin in their interactions with rifabutin in healthy volunteers. J Clin Pharmacol... 

Shafian SD, Singer J, Zarowny DP, Deschenes J, Phillips P, Turgeon F, Aoki FY, Toma E, Miller M, IDuperval R, LemieuxC, Schlech WF, for the Canadian HIV Trials Network Protocol 010 Study Group. Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia a multivariate analysis. /7/ c/Dis (1998) 177,252-5. 

A triple therapy regimen with combinations of clarithromycin or azithromycin plus ethambutol plus rifabutin is the current standard of care. However rifabutin may be omitted in HIV-infected patients on protease inhibitors because of significant interactions (Table 19). 

The adverse effects that most frequently result in discontinuation of rifabutin include GI intolerance, rash, and neutropenia. Rifabutin levels will be increased with concurrent administration of fluconazole and clarithromycin, resulting in anterior uveitis, polymyalgia syndrome, and a yellowish-tan discoloration of the skin (pseudojaundice). Other adverse reactions are similar to those of rifampin, such as hepatitis, red-orange discoloration of body fluids, and drug interactions due to effects on the hepatic P450 cytochrome enzyme system. 

M avium complex Pulmonary disease in patients with chronic lung disease disseminated infection in AIDS Amikacin, azithromycin, clarithromycin, ciprofloxacin, ethambutol, rifabutin... 

Delavirdine is extensively metabolized to inactive metabolites by the CYP3A and CYP2D6 enzymes. However, it also inhibits CYP3 A and thus inhibits its own metabolism. In addition to its interactions with other antiretroviral agents (see Table 49 1), delavirdine will result in increased levels of numerous agents (Table 49-3). Dose reduction of indinavir and saquinavir should be considered if they are administered concurrently with delavirdine. Delavirdine plasma concentrations are reduced in the presence of antacids, phenytoin, phenobarbital, carbamazepine, rifabutin, and rifampin concentrations are increased during coadministration with clarithromycin, fluoxetine, dexamethasone, and ketoconazole. 

Clarithromycin 500 mg orally twice daily, plus ethambutol 15 mg/kg/day orally (Al), and For advanced disease, rifabutin 300 mj day (dose may need adjustment with ART) (Mf... 

RIFAMYCINS MACROLIDES 1.1 levels of clarithromycin and telithromycin with rifampicin 2. t rifabutin levels with macrolides 1. Rifampicins induce metabolism of these macrolides 2. Inhibition of CYP3A4-mediated metabolism of rifabutin 1. Watch for poor response to clarithromycin and telithromycin, which may last up to 2 weeks after stopping rifampicin 2. Watch for early features of toxicity of rifabutin in particular, warn patients to report painful eyes... 

In patients with MAC infections taking rifabutin or rifampicin the addition of clarithromycin resulted in rifamycin-related adverse events in 77% of patients... 

The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabu-tin have been studied in ten HIV-infected patients who were given rifabutin 300 mg qds in addition to fluconazole 200 mg qds and clarithromycin 500 mg qds (73). There was a 76% increase in the plasma AUC of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together. The authors concluded that patients should be monitored for adverse effects of rifabutin when it is co-administered with fluconazole or clarithromycin. 

Wallace RJ Jr, 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(3) 747-50. 

Of 26 patients who received rifabutin 600 mg/day in combination with ethambutol, streptomycin, and either clarithromycin (500 mg bd n — 15) or azithromycin (600 mg/day n — 11), there were rifabutin-related... 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Clinically important, potentially hazardous interactions with atazanavir, carbamazepine, clarithromycin, itraconazole, ketoconazole, nefazodone, nelfinavir, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, ritonavir, saquinavir, St John s wort, troleandomycin, voriconazole, warfarin... 

MAC prophylaxis is now strongly recommended for all HIV-infected adults and adolescents with CD4 counts of fewer than 50 cells/mcL. The first-line choices are either azithromycin (1200 mg once weekly) or clarithromycin (500 mg twice daily) rifabutin is an alternative. Persons considered for prophylaxis should be evaluated to be sure that they do not have active disease owing to MAC or M. tuberculosis. 

Benson CA, Williams PL, Currier IS, et al. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. CUn Infect Dis 2003 37 1234-1243. 

Clarithromycin or azithromycin is recommended as first-line therapy for prophylaxis and treatment of disseminated infection caused by M. avium-intracellulare in AIDS patients and for treatment of pulmonary disease in non-HIV-infected patients. Azithromycin (1.2 g once weekly) or clarithromycin (500 mg twice daily) is recommended for primary prevention for AIDS patients with fewer than 50 CD cells per mm. Single-agent therapy should not be used for treatment of active disease or for secondary prevention in AIDS patients. Clarithromycin (500 mg twice daily) plus ethambutol (15 mg/kg once daily) with or without rifabutin is an effective combination regimen. Azithromycin (500 mg once daily) may be used instead of clarithromycin, but clarithromycin appears to be slightly more efficacious. Clarithromycin also has been used with minocychne for the treatment of Mycobacterium leprae in lepromatous leprosy. 

Rifabutin is effective for the prevention of MAC infection in HIV-infected individuals. At a dose of 3(X) mg per day, rifabutin decreased the frequency of MAC bacteremia (2%). However, azithromycin or clarithromycin are more effective and less likely to interact with highly active antiretroviral therapy (HAART) drugs. Rifabutin also is commonly substituted for rifampin in the treatment of tuberculosis in HIV-infected patients, as it has a less profound CYP-dependent interaction with indinavir and nelfinavir. Rifabutin also is used in combination with clarithromycin and ethambutol for the therapy of MAC disease. 

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