Case 4: Discussion
Epidemiology and Risk Factors
During the 1980s and 1990s, numerous reports emerged describing the development of refractory oropharyngeal candidiasis in AIDS patients following prolonged exposure to fluconazole (Diflucan). The emergence of fluconazole-resistant candidiasis in HIV-infected persons correlated with the widespread use of fluconazole for oropharyngeal candidiasis during this time period. During the 1980s and 1990s, the percentage of fluconazole-resistant Candida species ranged from approximately 5 to 33%[1,2]. In addition, following the widespread use of fluconazole, the proportion of C. albicans isolates decreased and other Candida species, including C. krusei, C. dubliniensis, and C. glabrata, increased. Fluconazole-resistant oropharyngeal candidiasis has involved both C. albicans and the non-albicans species. From a clinical standpoint, treatment-refractory candidiasis is defined as signs and symptoms of candidiasis that persist for longer than 7 to 14 days after appropriate therapy. Investigators have identified low CD4 cell count, advanced immunosuppression, greater number of fluconazole-treated episodes, and longer median duration of fluconazole therapy as the most important risk factors[3,4,5,6]. In more recent years, clinicians have observed a major decrease in the frequency of fluconazole-resistant oropharyngeal candidiasis, predominantly as a result of the widespread use of potent combination antiretroviral therapy. Nevertheless, treatment refractory oropharyngeal candidiasis still occurs in approximately 5% of HIV-infected persons.
Mechanisms for Fluconazole Resistance
Ergosterol is the predominant sterol in the fungal membrane and it serves as a bioregulator of fungal membrane fluidity and integrity. The synthesis of ergosterol requires multiple steps and multiple enzymes (Figure 1). Fluconazole exerts its action on the fungal membrane by inhibiting the fungal cytochrome P-450 enzyme 14 alpha-demethylase, thereby blocking the conversion of lanosterol to ergosterol (Figure 2). The inhibitory action of fluconazole causes depletion of ergosterol which in turn alters the fungal membrane structure and function. The inhibition of 14 alpha-demethylase also results in the build-up of lanosterol and other ergosterol precursors. The alterations in the fungal cell membrane eventually lead to fungal cell death. The selective action of fluconazole for fungal cell membranes occurs because human cells use cholesterol, not ergosterol, for the synthesis of cell membranes. The echinocandins have a mechanism of action distinct from the azoles: these agents inhibit fungal cell wall synthesis by blocking the production of 1,3-beta-D-glucan. Resistance to fluconazole can develop as a result of an alteration in the target enzyme 14 alpha-demethylase (change in binding site or over expression of the enzyme) (Figure 3) or from enhanced drug efflux caused by plasma membrane transporters (Figure 4)[6,7,8,9,10]. Many of the strains of fluconazole-resistant Candida species display multiple mechanisms of resistance.
Definition of Fluconazole Resistance
In 2008, the Subcommittee for Antifungal Testing of the Clinical Laboratory Standards Institute (CLSI) defined breakpoints for antifungal agents active against Candida species. Isolates with a fluconazole MIC less than 8 mcg/ml are classified as sensitive (S), those with 16 to 32 mcg/ml as dose-dependent sensitive (S-DD), and those with greater than or equal to 64 mcg/ml are resistant [11,12]. Primary fluconazole resistance is defined as resistance in the absence of prior fluconazole exposure. Secondary resistance occurs as a result of treatment with fluconazole. Clinical failure refers to persistence or progression of oropharyngeal candidiasis despite antifungal therapy. Factors that can affect clinical response include the immune status of the patient, adherence to antifungal therapy, and the potential presence of biofilms formed by Candida organisms. Most patients who experience clinical failure with fluconazole will have Candida species isolates that show in vitro resistance to fluconazole[6,13]. In contrast, patients in whom fluconazole-resistant Candida is isolated will often still respond clinically to fluconazole.
Prevention of Fluconazole-Resistant Candidiasis
Preventing fluconazole-resistant candidiasis is best achieved by avoiding unnecessary use of fluconazole or other systemic antifungal agents and by maximizing the patient's immune status with effective antiretroviral therapy[15,16]. In addition, most experts do not recommend chronic maintenance therapy following an episode of oropharyngeal candidiasis, or with recurrent episodes of oropharyngeal candidiasis. Patients with cryptococcal meningitis or recurrent esophageal candidiasis require continuous fluconazole therapy, but systemic antifungal therapy can usually be avoided in patients with less advanced HIV disease and for less serious fungal infections.
Recommended Therapy for Fluconazole-Resistant Candidiasis
The Guidelines for Prevention and Treatment of Opportunistic Infections in Adults and Adolescents provides recommended preferred and alternative treatment options for fluconazole-refractory oropharyngeal and esophageal candidiasis (Figure 5). These guidelines give the highest rating for itraconazole (Sporanox) oral solution and posaconazole (Noxafil) oral solution. The opportunistic infections guidelines do not provide a specific duration of therapy, but most experts would recommend at least 10 days of therapy for patients with fluconazole-refractory oropharyngeal candidiasis, with extension of the treatment course if the response is not complete at day 10. Patients with esophageal candidiasis should generally receive a minimum of 21 days of therapy. A number of effective intravenous options are effective, including the following intravenous antifungals: deoxycholate amphotericin B (Amphocin, Fungizone), amphotericin B lipid complex (Abelcet), liposomal amphotericin B (AmBisome), micafungin (Mycamine), caspofungin (Cancidas), anidulafungin (Eraxis), and voriconazole (Vfend). In addition, voriconazole is also available in an oral form and it has excellent bioavailability.
Topical Therapy Studies
Available treatment options for fluconazole-refractory oropharyngeal candidiasis include topical therapy, oral systemic agents, and intravenous therapy. Amphotericin B oral suspension is the best-studied topical therapy for fluconazole-resistant candidiasis. In ACTG Study 295, patients with refractory oral candidiasis (after 14 days of treatment with oral fluconazole 200 mg once daily) received amphotericin B oral suspension (100 mg/ml) 5 ml swish and swallow four times daily; 23 (43%) of 54 subjects responded by day 28. Unfortunately, topical amphotericin B is no longer commercially available. Topical therapy with clotrimazole or nystatin has not usually produced good results.
Systemic Therapy Studies
Several reports have described clinical responses to treatment-refractory candidiasis with high-dose fluconazole, but typically resistance will eventually emerge. Several reports have shown good efficacy with itraconazole (Sporanox) oral solution given at a dose of 100 to 200 mg per day in patients with refractory oropharyngeal candidiasis[10,19,20]. The oral solution should be swished in the mouth and then swallowed, as it probably has some topical effect in addition to its systemic effect. In the largest trial involving itraconazole solution, 41 (55%) of 74 patients who failed fluconazole therapy (200 mg once daily) achieved a clinical response by day 28 when treated with itraconazole oral solution (100 mg bid), with 7 days as the median time to response. One study involving 176 HIV-infected patients with fluconazole-refractory oropharyngeal or esophageal candidiasis reported good response rates with oral posaconazole. Studies with voriconazole have shown good in vitro activity against fluconazole-susceptible and fluconazole-resistant strains of Candida. Investigators found voriconazole (200 mg PO bid) to be at least as effective as fluconazole in the treatment of esophageal candidiasis, but this study did not involve fluconazole-refractory candidiasis. Clinicians have used low dose (0.3 mg/kg/day) intravenous amphotericin B for fluconazole-refractory oropharyngeal candidiasis with good success rates, but intravenous amphotericin B has significant adverse effects, even when given at a lower dose. Although intravenous liposomal amphotericin B preparations would likely provide good responses, they are significantly more expensive than amphotericin B. In vitro studies with caspofungin have shown excellent activity against fluconazole-resistant isolates and clinical studies have shown good responses with caspofungin in patients with esophageal candidiasis, including fluconazole-refractory cases. Although caspofungin is generally better tolerated than amphotericin B, it is very expensive.
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