Case 4: Discussion

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Epidemiology and Risk Factors

During the 1980s and 1990s, numerous reports emerged describing the development of fluconazole (Diflucan)-resistant oropharyngeal candidiasis in AIDS patients following prolonged exposure to fluconazole [1]. The emergence of fluconazole-resistant candidiasis in HIV-infected persons correlated with the widespread use of fluconazole for oropharyngeal candidiasis duirng this time period. 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. During the 1980s and 1990s, the percentage of fluconazole-resistant Candida species ranged from approximately 5% to 33% [1,2]. 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 that persist for longer than 7-14 days after appropriate therapy [3]. Investigators identified low CD4 cell count, advanced immune suppression, greater number of fluconazole-treated episodes, and longer median duration of fluconazole therapy as the most important risk factors [3-6]. 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 highly effective antiretroviral therapy [7]. Nevertheless, treatment refractory oropharyngeal candidiasis still occurs in approximately 5% of HIV-infected persons [3].

Mechanisms for Fluconazole Resistance

Fluconazole exerts its action on the fungal membrane by inhibiting the synthesis of ergosterol, the predominant sterol in the fungal cell membrane [6]. Specifically, fluconazole blocks a step in the conversion of squalene to ergosterol by inhibiting the fungal cytochrome P-450 enzyme 14 alpha-demethylase (Figure 1) [6]. This inhibitory action prevents fungal cell replication and causes a build-up of lanosterol and other ergosterol precursors in the fungal cell membrane. The abnormalities in the fungal cell membrane eventually lead to 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. Resistance to fluconazole can develop as a result of an alteration in the target enzyme 14 alpha-demethylase (change in binding site or overexpression of the enzyme) or from enhanced drug efflux caused by plasma membrane transporters (Figure 2) [6-10]; many of the strains of fluconazole-resistant Candida species display multiple mechanisms of resistance [7].

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 µg/ml are classified as sensitive (S), those with 16-32 µg/ml as dose-dependent sensitive (S-DD), and those with greater than or equal to 64 µg/ml are resistant (Figure 3) [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 [6]. 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 [14].

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 in the setting of recurrent episodes of oropharyngeal candidiasis [15]. Patients with cryptococcal meningitis or recurrent esophageal candidiasis clearly require continuous fluconazole therapy, but systemic antifungal therapy can usually be avoided at earlier stages of HIV infection 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 a number of recommended treatment options for fluconazole-refractory oropharygeal candidiasis (Figure 3) [3]. These guidelines give the highest rating for itraconazole (Sporanox) oral solution and posaconazole (Noxafil) oral solution. A specific duration of therapy is not listed in the guidelines, but most experts would recommend 10-days of therapy, with continuation of a more extended course if the response is not complete. In addition, a number of effective intravenous options are available, including conventional deoxycholate amphotericin B, amphotercin B lipid complex (Abelcet), liposomal amphotericin B (AmBisome), micafungin (Mycamine), caspofungin (Cancidas), anidulafungin (Eraxis), and voriconazole (Vfend); voriconazole is also available in an oral form. The echinocandins have a mechanism of action distinct from the azoles: these agents inhibit the synthesis of fungal cell wall synthesis by blocking the synthesis of 1,3-beta-D-gulcan. For patients who have esophageal involvement, the treatment recommendations are not the same as for oropharyngeal candidiasis [3].

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 who had diffuse oral candidiasis after 14 days of treatment with fluconazole (200 mg PO qd) received amphotericin B oral suspension (100 mg/ml) 5 ml swish and swallow qid and 23 (43%) 54 subjects responded by day 28 [17]. 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 fluconazole-resistant candidiasis with high-dose fluconazole [18]. Typically, though, resistance eventually emerges. Several reports have shown good efficacy with itraconazole (Sporanox) oral solution given at a dose of 100-200 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 qd) 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 [20]. Voriconazole (Vfend) is a new antifungal agent available in oral and intravenous preparations, and studies have shown good in vitro activity against fluconazole-susceptible and fluconazole-resistant strains of Candida [21]. 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 [22]. Clinicians have used low dose (0.3 mg/kg/d) intravenous amphotericin B (Amphocin, Fungizone) for fluconazole-refractory oropharyngeal candidiasis with good success rates [13], but intravenous amphotericin B has significant adverse effects. Although intravenous liposomal amphotericin B preparations would likely provide good responses, they are significantly more expensive than amphotericin B. Caspofungin (Cancidas) is a novel antifungal agent that exerts its action by inhibiting cell wall synthesis. In vitro studies have shown excellent activity against fluconazole-resistant isolates [23], and clinical studies have shown good responses in patients with esophageal candidiasis [24], including fluconazole-refractory cases [25]. Although this drug is generally better tolerated than amphotericin B [24], it is very expensive.

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