Effect of Rifampin and Rifabutin on Serum Itraconazole Levels in Patients with Chronic Pulmonary Aspergillosis and Coexisting Nontuberculous Mycobacterial Infection

Abstract

bWe investigated the effects of rifampin and rifabutin on serum itraconazole levels in patients with chronic pulmonary aspergillosis. Serum itraconazole concentrations were significantly lower in patients who received itraconazole with rifampin (median, 0.1 g/ml; P < 0.001) or rifabutin (median, 0.34 g/ml; P < 0.001) than those receiving itraconazole alone (median, 5.92 g/ml). Concomitant use of rifampin or rifabutin and itraconazole should be avoided in patients with chronic pulmonary aspergillosis and coexisting mycobacterial infections. Chronic pulmonary aspergillosis (CPA) is a slowly progressive pulmonary infectious disease secondary to local invasion by a species of Aspergillus, usually Aspergillus fumigatus (1, 2). Although the optimal therapeutic regimen and duration of treatment have not been established, long-term oral itraconazole is currently recommended as the primary treatment for CPA (3-5). CPA usually occurs in middle-aged and elderly patients, for whom the most common underlying disease is pulmonary tuberculosis (6, 7). In addition, there is increasing evidence that nontuberculous mycobacterial (NTM) lung disease is an important underlying condition associated with CPA (7-12), with some patients having CPA and coexisting NTM lung disease (12,13).Mycobacterium avium complex (MAC) is the most common etiology of NTM lung disease (14-16). Rifampin is recommended as part of a multidrug antibiotic regimen for the treatment of MAC lung disease (14-16). Rifampin is a potent inducer of hepatic cytochrome P450 enzymes, which in turn can accelerate the hepatic metabolism of antifungal agents. In this way, rifampin presents a practical challenge for choosing the appropriate antibiotics for treating CPA with coexisting NTM lung disease (17,18). Indeed, previous case reports have demonstrated that concurrent administration of rifampin with itraconazole can greatly reduce serum itraconazole concentrations (19)(20)(21)(22).Rifabutin has less severe drug-drug interactions than does rifampin and is used as a substitute for rifampin in the treatment of tuberculosis and NTM lung disease, especially for patients who are receiving medications that have unacceptable interactions with rifampin, such as antiretroviral agents (14, 23). Nevertheless, there are no published studies that evaluated the interaction between rifabutin and itraconazole. Thus, the objective of the present study was to investigate the effects of rifampin and rifabutin on serum itraconazole levels in patients with CPA and coexisting mycobacterial lung disease.This study was a single-institution retrospective review of 66 patients with CPA who were treated with oral itraconazole (Sporanox, Janssen Pharmaceutica) (200 mg twice daily) and for whom serum itraconazole concentrations were measured between January 2013 and June 2014. Peripheral venous sampling was performed prior to morning itraconazole administration to determine trough concentrations after at least 7 days of treatment.The serum concentrations of itraconazole and hydroxyl-itraconazole we...

Chronic Pulmonary Aspergillosis—Where Are We? and Where Are We Going?

“…With rifampicin or rifabutin forming the backbone of most NTM treatment regimens, hepatic induction of CYP-450 and increased azole metabolism make therapeutic drug levels a virtual impossibility. Persistently sub-therapeutic itraconazole levels have been demonstrated in both the presence of rifampicin and rifabutin and, although not formally studied, the effect is likely to be similar in patients on both voriconazole and posaconazole [ 206 ]. Although therapeutic voriconazole levels have been reported in the context of co-existent Aspergillus and M. xenopi infection, concomitant dosing is fraught will difficulty and risks the development of resistance in the fungus [ 207 ].…”

Risk factors for the development of chronic pulmonary aspergillosis in patients with nontuberculous mycobacterial lung disease

“…The development of CPA in patients with NTM-LD poses significant challenges for clinicians because clinical parameters might not accurately differentiate the development of CPA from the aggravation of existing or recurrent NTM-LD after treatment completion, and a misdiagnosis can delay treatment. Moreover, even when the diagnosis of combined CPA and NTM-LD is confirmed, the treatment priority or strategy remains a concern due to the complexity of treatment regimens and potential drug interactions between commonly used antifungal and certain antimycobacterial agents, such as itraconazole and rifamycin, which can compromise the therapeutic effects of the antifungal agents [ 15 , 16 ].…”

A Case of Oral Histoplasmosis Concomitant with Pulmonary Tuberculosis

“…The physician instituted this medicament after effective response to tuberculosis treatment. This decision was also made due to the drug interaction between rifampicin and itraconazole, where itraconazole levels significantly decrease in the presence of the other, so these two drugs should not be administered concomitantly [15, 16]. Additionally, amphotericin B deoxycholate is another medicament that can be used to treat acute and chronic cavitary pulmonary histoplasmosis [17].…”