Oral suspension of itraconazole effective against refractory candidiasis
A therapeutic alternative for patients who fail fluconazole therapy
Fluconazole has long been the standard first-line therapy against mucosal candidiasis, a ubiquitous infection in patients with advanced HIV disease and a source of particular discomfort, particularly when swallowing. Reinfection is so common as to be anticipated, and secondary prophylaxis with fluconazole, to prevent reinfection, has become the standard of care.
As the chronic use of fluconazole has become widespread -- and as longevity has improved in patients with late-stage disease -- there have been increasing numbers of anecdotal reports of patients with fungal infections that are refractory to fluconazole therapy at standard doses (see "The Problem of Azole-Resistant Candidiasis"). The available data suggest that clinicians should anticipate an annual incidence of azole-resistant candidiasis of roughly 4% in patients with CD4 counts below 50 cells/mm3.
Itraconazole -- which Janssen Pharmaceutica markets as Sporanox® -- has long been available in capsule form. A new formulation (in a hydroxypropyl-ß-cyclodextrin solution) is currently being tested in small clinical studies, and this formulation appears to be at least as effective as fluconazole for the treatment of oropharyngeal and esophageal candidiasis. The results of two of these studies were reported last month at the 4th Conference on Retroviruses and Opportunistic Infections in Washington, D.C. These findings suggest that itraconazole in oral solution may offer a safe and effective therapeutic option in patients who have developed candida infections that are no longer responsive to fluconazole therapy.
These paired studies examined the short- and long-term efficacy of itraconazole oral solution in 74 patients who had developed fluconazole-resistant oropharyngeal candidiasis. Treatment consisted of 100 mg of itraconazole solution twice daily for 14 days. Patients who demonstrated an incomplete response were treated for an additional 14 days, and all responders were offered the option of participating in a separate, six-month maintenance protocol (100 mg twice daily, three days a week). If infection recurred during the maintenance period, the dose could be raised to 100 mg twice daily.
These were patients with very advanced disease (median baseline CD4 count: 9 cells/mm3), yet 59% of the 68 evaluable subjects showed a clinical response to treatment -- defined as complete clearing of all lesions -- and another 15% exhibited some clinical improvement by Day 28 (Figure). In the short-term study, conducted by Fessel et al., the relapse rate was 100% after treatment ceased (mean time to relapse: 13 days), suggesting that some form of maintenance therapy is required in all patients who respond to itraconazole oral solution.
Moskovitz et al., who conducted the six-month maintenance phase of this trial, followed 26 of the original 78 patients for as long as 532 days. Half of those patients required daily dosing with itraconazole oral solution to prevent recurrent infection, and 9 of those 13 subjects responded to the higher dose. Significantly, only 6 of the 26 patients on long-term therapy stopped treatment due to adverse events, and only two of those AEs were thought to be drug-related. Gastrointestinal disorders were the most common cause for complaint. These preliminary data strongly suggest that itraconazole oral solution may be a safe and effective chronic therapy in patients who develop resistance to fluconazole.
Fessel WJ, Merrill KW, Ward DJ, Moskovitz BL, et al. An open-label evaluation of itraconazole oral solution in the treatment of HIV-positive or AIDS patients with fluconazole-refractory oropharyngeal candidiasis. 4th Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January 22-26, 1997. Abstract 693.
Moskovitz BL, Wu J, Baruch A, Benken C, Richards H, Klausner M. Long-term safety and efficacy of itraconazole oral solution (IS) for treatment of fluconazole-refractory oropharyngeal candidiasis (OC) in HIV-positive patients (Pts). 4th Conference on Retroviruses and Opportunistic Infections, Washington, D.C., January, 1997. Abstract 669.
Dr. William G. Powderly, the author of "The Problem of Azole-Resistant Candidiasis" and a member of the editorial advisory board of HIV Newsline, comments:
Mycoses are the most difficult to treat of all microbial infections, and before the advent of safe and effective antifungal agents, candida infections of the mouth, pharynx, and esophagus caused considerable morbidity in severely immunocompromised patients. Fluconazole has been a mainstay in the treatment of candidiasis in AIDS patients, and its usefulness as suppressive therapy is limited only by the development of resistant isolates in 5% to 7% of patients on chronic therapy.
The finding that itraconazole in oral solution is effective against fluconazole-resistant mucosal candidiasis is therefore welcome news, offering clinicians a therapeutic option heretofore unavailable to them. Although mycologic cure was achieved in only 27% of the subjects studied by Fessel et al., fully 73% of these very sick patients responded wholly or partly to treatment with this oral solution. This new formulation has greater bioavailability than itraconazole in capsule form, it is easier to administer, and it appears to have improved topical and systemic effects.
One way to reduce the incidence of azole-resistant candidiasis is to delay the use of azoles, particularly as prophylaxis in patients at risk of recurrent infection. We now have data suggesting that candida infections are more likely to recur in patients who have a history of PCP and are less likely to recur in African-American patients. These recent findings will help clinicians decide when prophylaxis should be initiated and when it can be safely withheld.