Drug-Drug Interactions of Clinical Significance in the Treatment of Patients with Mycobacterium avium Complex Disease

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Abstract
Therapeutic and prophylactic regimens directed specifically against Mycobacterium avium complex (MAC) are increasingly being used in patients infected with the human immunodeficiency virus (HIV). Several of the drugs used in the management of MAC have been associated with significant drug interactions involving the cytochrome P450 (CYP) enzyme system. This enzyme system is also highly influenced by other drugs used in the management of patients with HIV, particularly the protease inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and azole antifungals. This article reviews the published literature on the interactions of drugs used for patients with MAC, focusing on those interactions which would be especially common in patients with HIV. Rifabutin is an inducer of CYP, although its potency is less than that of other available rifamycins. Numerous drug interactions resulting in toxic rifabutin concentrations or subtherapeutic concentrations of other drugs have been described. In particular, concurrent use of rifabutin with clarithromycin or fluconazole has resulted in increased concentrations of rifabutin and an accompanying increase in the incidence of rifabutin toxicities, including uveitis and leucopenia. Similar results have been seen when rifabutin is combined with protease inhibitors or delavirdine. The macrolides, clarithromycin and azithromycin, have also been associated with significant drug interactions. Clarithromycin has a higher affinity for CYP than azithromycin and, thus, is more frequently associated with clinically significant drug interactions. Clarithromycin is an inhibitor of CYP and may result in toxic concentrations of other drugs metabolised by this enzyme system. Such interactions have been described with rifabutin and the statin lipid-lowering agents. In addition, nevirapine and efavirenz have been shown to significantly reduce clarithromycin concentrations, whereas the protease inhibitors and delavirdine may increase clarithromycin concentrations. Other drugs used in the management of patients with MAC are not metabolised by CYP and thus have a lower incidence of interactions, although the absorption of ciprofloxacin may be impaired when it is given with products containing multivalent cations, such as didanosine. However, clinicians must remain vigilant for drug interactions when reviewing a patient’s medication profile, keeping in mind both interactions that have been described in the literature and those that may be predicted based upon known pharmacokinetic profiles.