For an in-depth discussion of the treatment approaches, including use of azole drugs, for the various Candida syn- dromes, see Chap. 11, Candidiasis.
The advent of the AIDS epidemic in the early 1980s brought new focus to the management of oropharyngeal candidiasis (OPC). Physicians quickly recognized that many patients with OPC failed therapy with topical agents, including nystatin swish and swallow, clotrimazole troches, and oral amphoteri- cin B [228, 229]. Consequently, much attention shifted to evaluation of the efficacy and safety of oral azoles, especially fluconazole and itraconazole, for treatment of OPC.
Numerous treatment trials have investigated the efficacy of fluconazole for treatment of these infections. Fluconazole has been shown to be effective for treatment of mucosal
Table 4 Adverse effects of currently available antifungal azoles
Fluconazole Itraconazole Voriconazole Posaconazole
Gastrointestinal tract
Anorexia, nausea, vomiting Anorexia, nausea, vomiting Anorexia, nausea, vomiting Anorexia, nausea, vomiting
Skin Rash Rash Rash, photosensitivity Rash
Liver Hepatitisa Hepatitisa Hepatitisa ?
Cardiac QT prolongation QT prolongation QT prolongation QT prolongation
Other Alopecia, teratogenicity Hypokalemia, pedal edema, hypertension, heart failure, teratogenicity
Visual disturbances, encephalopathy teratogenicity
aUsually asymptomatic elevations of transaminases, but liver failure can occur
75 Azoles
candidiasis in HIV-infected patients in randomized studies.
A comparative trial involving 334 HIV-positive patients with oral candidiasis observed similar efficacy for fluconazole (100 mg daily for 14 days) and clotrimazole (10 mg 5 times daily). Clinical success rates of >90% were documented for both treatment groups, but fluconazole was more successful in mycologic eradication (65% vs 48%) and provided longer relief of symptoms [229]. Another study compared flucon- azole (3 mg/kg PO daily) to combination therapy with itra- conazole (3 mg/kg PO daily) and flucytosine (100 mg/kg PO daily) for treatment of esophageal candidiasis in 85 HIV- infected patients [230]. This double-blind, placebo-con- trolled trial found fluconazole to be as effective as combination therapy [230].
Additional studies have shown that the clinical responses of OPC are excellent for all of the triazoles [17, 228, 231–
233]. Several multicenter, randomized trials have compared the efficacy of fluconazole and itraconazole oral solution for the treatment of oral and esophageal candidiasis in immuno- suppressed patients [233–235]. For the most part, itracon- azole does not offer significant advantage over fluconazole for uncomplicated disease, but has been shown to be useful in fluconazole-refractory cases [232, 236]. Among itracon- azole trials, higher success rates have been observed for the itraconazole oral solution than itraconazole capsules [233, 234, 237, 238].
In the mid 1990s, concerns developed about the emer- gence of Candida species, particularly C. albicans, that were resistant to the azole drugs, especially fluconazole, in patients with low CD4 cell counts (<100/mL) and those receiving prolonged courses of azoles [191–193]. In such patients with recurrent or fluconazole-resistant OPC, alternative treatment strategies have evolved, including high-dose fluconazole (400–800 mg daily); switching to another azole, e.g., itra- conazole oral solution, [236] voriconazole, [239] or posa- conazole [231]; or switching to another class of drug, e.g., a polyene or an echinocandin. The most commonly recom- mended alternative is itraconazole solution. To date, the inci- dence of fluconazole-resistant Candida species causing OPC appears to have leveled off in the 5% range. Fluconazole is approved by the FDA for treatment of oral and esophageal candidiasis. The current 2009 Infectious Diseases Society of America (IDSA) guidelines recommend fluconazole as first- line therapy for treatment of esophageal candidiasis and moderate-to-severe cases of OPC [15]. For patients with recurrent disease requiring suppressive therapy, fluconazole (200 mg 3×/week) is the regimen of choice. Fluconazole is also recommended for treatment of chronic mucocutaneous candidiasis.
Esophageal candidiasis, regardless of the host, cannot be successfully treated with a topical agent, such as nystatin or clotrimazole. The efficacy of each of the available triazoles has been examined in randomized trials and has demonstrated
equivalent efficacy. The drug of initial choice for esophageal candidiasis remains fluconazole based on the rationale used in OPC drug choice. The recommended doses are flucon- azole tablet or suspension, 100–400 mg/day for 14–21 days [234, 240, 241]. Itraconazole solution, voriconazole, and posaconazole are typically reserved for fluconazole refrac- tory disease [242–244]. For example, in a open-label trial enrolling 100 HIV-infected patients with OPC or esophageal candidiasis refractory to previous azole therapy, posacon- azole (400 mg twice daily for 3 months) was successful in 86% of patients [242]. In those few patients who fail azole therapy, treatment with intravenous amphotericin B or an echinocandin is warranted.
Topical azole drugs, such as clotrimazole or miconazole, or nonazole topical agents, such as nystatin or boric acid, have long been associated with high rates of success as ther- apy for Candida vaginitis, especially in immunocompetent patients with infrequent episodes. However, these topical agents are messy, inconvenient to use, and not always effec- tive. Increasingly, women are utilizing short-course, oral azole therapy for treatment of Candida vaginitis. Oral flu- conazole and itraconazole are both highly effective [245–
247]. The 2009 IDSA guidelines recommend either oral fluconazole or topical agents as first-line agents for treat- ment of uncomplicated vaginal candidiasis in nonpregnant women [15]. Single-dose fluconazole (150 mg) has been shown effective for >80% of patients with uncomplicated vaginal candidiasis. Comparable efficacy has also been demonstrated for itraconazole. A meta-analysis examined comparative trials of the efficacy and safety of itraconazole and fluconazole for the treatment of uncomplicated acute vaginal and vulvovaginal candidiasis. Data from six ran- domized trials, including a total of 1,092 nonpregnant women, found no difference in clinical or mycologic cure or adverse events [248].
For complicated vulvovaginal candidiasis, based on sever- ity of symptoms or in an immunocompromised host, a regi- men of fluconazole, 150 mg every 72 h for three doses, has been shown to be superior to single-dose therapy [249]. A multiple-dose regimen is also recommended for patients infected with C. glabrata. For patients with recurring disease (>4 episodes in 1 year), 10–14 days of induction therapy with a topical or oral azole, followed by fluconazole 150 mg weekly for 6–12 months has been shown to be effective [250]. A placebo-controlled, randomized trial examined the efficacy of fluconazole, 150 mg weekly, for preventing relapse in 387 patients with recurrent vaginal candidiasis.
Significantly more patients receiving weekly fluconazole remained disease-free at 6, 9, and 12 months (91%, 73%, and 43%) compared to placebo-treated patients (36%, 28%, and 22%). Weekly fluconazole therapy was safe and did not appear to promote emergence of less susceptible Candida species.
76 D.R. Andes and W.E. Dismukes
Asymptomatic colonization of the bladder by Candida species in a patient with an indwelling Foley catheter is com- mon but rarely requires treatment [251]. In such a patient, treatment will not typically eradicate Candida from the blad- der as long as the catheter remains in place. Within a few days after stopping therapy, the urine will again become col- onized with Candida [252]. For those occasional patients who have symptomatic Candida cystitis and no indwelling catheter, fluconazole is the azole of choice and an effective therapy, owing to the high concentration of active drug in the urine [253, 254] (Table 1). Most recent guidelines recom- mend treatment of asymptomatic candiduria in patients at high risk for developing invasive infection, including neutro- penic patients, low-birth-weight neonates, and patients undergoing urologic procedures [15].
Candida onychomycosis, a less frequent occurrence than dermatophyte onychomycosis and frequently associated with Candida paronychia, is most effectively treated with an oral azole, either itraconazole or fluconazole. Most patients are treated with itraconazole, utilizing a so-called “pulse regi- men,” 1 week per month for 3 months or a daily regimen for 3 months [56, 255, 256]. Fluconazole is also administered in a variant of the itraconazole pulse regimen [257, 258]. Both drugs are associated with remission rates in the 60% range and both are well tolerated. Griseofulvin, frequently used in the past to treat dermatophyte onychomycosis, is not active in vitro against Candida species.
Among the various forms of systemic or invasive candidi- asis, the syndrome of candidemia is the most common and lends itself to comparative clinical trials for evaluation of management strategies. In several trials, amphotericin B and fluconazole were the two comparators. Three of the trials were randomized multicenter studies in nonneutropenic patients; among these, two were nonblinded [259, 260] and one was blinded [261]. The fourth study was a prospective observational trial in nonneutropenic patients, [262] and the fifth study was a matched cohort trial in cancer patients (including a few patients with neutropenia) [263].
Several important findings emerged from these trials.
First, in all trials fluconazole was associated with less toxic- ity than amphotericin B, irrespective of the different doses of study drugs. Second, the success rates were comparable in the two randomized trials that used similar doses of flucon- azole, 400 mg/day, and amphotericin B, 0.5–0.6 mg/day [259, 260] and in the matched cohort study [263]. Third, sig- nificant differences were observed in two measures of out- come only in the blinded trial, which compared combination amphotericin B and high-dose fluconazole, 800 mg/day, to high-dose fluconazole alone, with success rates of 69% and 56%, respectively, and persistent candidemia rates of 6% and 17%, respectively [261]. The 6% rate of persistent candi- demia for the combination treatment arm was lower than the rates of persistent candidemia for all treatment arms in the
prior studies. Also of note in this study, the baseline APACHE II scores were higher in the fluconazole alone treatment group. While the mortality rates in both treatment groups were similar, the toxicity rate was significantly higher in the combination treatment arm. Fourth, in this same study, the combination of amphotericin B and fluconazole was not microbiologically antagonistic compared to fluconazole alone. Fifth, in all studies, removal of vascular catheters reduced time to clearance of the candidemia [264].
The collective results of these five trials establish that flu- conazole and amphotericin B are equally effective therapies for candidemia, especially in nonneutropenic patients, and fluconazole is better tolerated and less toxic than amphoteri- cin B. Combination fluconazole and amphotericin B may have a role in selected patients with candidemia, e.g., criti- cally ill and neutropenic patients.
Fluconazole has been compared to the echinocandin anid- ulafungin for treatment of invasive candidiasis. Anidulafungin was found to be at least as effective as fluconazole for treat- ment of invasive candidiasis [265]. Success rates after 10 days of therapy were 76% for anidulafungin (200 mg IV on day 1, then 100 mg IV daily) and 60% for fluconazole (800 mg IV on day 1, then 400 mg IV daily). At 6-week fol- low-up, success rates (fluconazole 44%, anidulafungin 56%) and mortality rates (fluconazole 31%, anidulafungin 23%) did not differ significantly between the two groups. The effi- cacy of other FDA-approved echinocandins, caspofungin and micafungin, have also been demonstrated efficacious in treatment of candidemia, but were not compared to a triazole regimen.
Voriconazole has also been studied in the setting of candi- demia [266]. In a randomized, multicenter trial, voriconazole was compared to a regimen of amphotericin B followed by fluconazole for treatment of invasive candidiasis. Twelve weeks after the end of therapy, successful clinical outcome was observed for 41% of patients in each group, and voricon- azole met noninferiority criteria. Median time to blood cul- ture negativity and mortality were also similar between the two study groups.
Fluconazole (400 mg daily oral or IV) is recommended by the 2009 IDSA treatment guidelines as an initial therapy option for invasive candidiasis with the exception of patients who are critically ill, neutropenic, or at risk for fluconazole- resistant isolates due to recent azole exposure [15]. Patients in these high-risk cohorts should receive an echinocandin or an amphotericin B formulation as initial therapy. The basis for these recommendations includes lack of study in neutro- penic patients, theoretical concern about use of an inhibitory compared to a fungicidal drug in severe illness, and reduced activity against Candida species, such as C. glabrata and C. krusei, which has been observed in some cohorts following fluconazole prophylaxis. Fluconazole is also commonly used to transition to oral therapy following initial echinocandin or
77 Azoles
amphotericin therapy if the isolate is susceptible and the patient is clinically stable. The role of voriconazole for can- didemia has not been clearly defined but appears to be lim- ited to step-down therapy for the small subset of C. glabrata that are resistant to fluconazole but susceptible to voricon- azole or for C. krusei. Itraconazole and posaconazole have not been similarly studied and at this time appear to have a limited role for invasive candidiasis.
Fluconazole and voriconazole have been used success- fully for other forms of systemic or invasive candidiasis, including endophthalmitis, peritonitis, bone/joint disease, hepatosplenic disease, renal parenchymal disease, and endocarditis.
Cryptococcosis
Azole drugs have greatly impacted the management of cryp- tococcosis over the past several years. While amphotericin B and flucytosine remain key drugs for this disease, flucon- azole and, to a lesser extent, itraconazole, have a definite role, especially in the management of AIDS-associated cryp- tococcosis. Cryptococcal meningitis is the most common form of fungal meningitis in both normal and immunocom- promised hosts. Moreover, fluconazole is the most attractive of the available azoles for therapy of fungal meningitis because of its excellent penetration into the CSF (Table1).
Although the measurable concentrations in CSF of itracon- azole are low, this drug does show moderate efficacy in treat- ment of cryptococcal meningitis [89, 267].
Fluconazole and itraconazole have been used as treatment approaches for different clinical manifestations of crypto- coccosis; however, most of the experience has been in ther- apy of cryptococcal meningitis. Many authorities agree that optimal primary therapy consists of two parts: an induction regimen for 2–3 weeks with combination amphotericin B and flucytosine, followed by a consolidation regimen for 8–10 weeks with an azole, preferably fluconazole [268]. The definitive study in AIDS patients of this treatment approach showed the following: (1) after 2 weeks of induction therapy, CSF cultures were negative in 60% of patients who received the combination regimen versus 51% of patients who received amphotericin B alone (p = 0.06); (2) at the conclu- sion of the 10-week induction/consolidation treatment regimen, clinical responses were similar – 68% in the flu- conazole-treated patients and 70% in the itraconazole-treated patients; (3) CSF cultures were negative in 72% of patients in the fluconazole group, and 60% of the itraconazole group [269]. Although this important study was performed in AIDS patients, the results have been extrapolated to the management of cryptococcal meningitis in non-AIDS patients.
Fluconazole has also been explored in primary therapy of cryptococcal meningitis in a randomized comparison with amphotericin B [270]. Microbiologic success was not sig- nificantly different for patients receiving fluconazole (34%) and those treated with amphotericin B (40%). However, the mortality rate within the first 2 weeks was higher in the flu- conazole treatment group (15% vs 8%). In addition, the median length of time for CSF clearance was longer in patients receiving fluconazole (64 vs 42 days). Considering the trend of increased risk of early death and increased time for CSF sterilization in fluconazole-treated patients, ampho- tericin B is recommended for most serious infections.
More recently, the combination of fluconazole and ampho- tericin B therapy has been investigated for induction therapy in HIV-associated cryptococcal meningitis [271]. Patients were randomized to amphotericin B (0.7 mg/kg), amphoteri- cin B plus fluconazole (400 mg/day), or amphotericin B and high-dose fluconazole (800 mg/day). The combinations were found to be safe and antagonism was not observed. The high- dose combination was more effective at the early treatment end point (14 days), and a difference in favor of this combi- nation was similarly observed at later study periods (42 and 72 days). The results are encouraging and suggest a possible role for the combination of amphotericin B and high-dose fluconazole. This induction regimen may be particularly use- ful in developing countries where flucytosine and toxicity monitoring availability are limited.
The potential role of voriconazole in the treatment of refractory cryptococcosis has been limited to open-label, salvage trials [272]. Of the 18 patients in one trial with refrac- tory cryptococcosis, 39% responded to voriconazole treatment. Study with posaconazole has been limited to ani- mal model investigation.
Another important indication for fluconazole relates to maintenance therapy in AIDS patients with cryptococcal meningitis. Once primary therapy is completed and success- ful, maintenance therapy is required to prevent relapse, which occurs in approximately 15% of patients [273]. Two large randomized trials demonstrated the efficacy of fluconazole in this setting. An initial trial compared oral fluconazole, 200 mg daily, to intravenous amphotericin B, 1 mg/kg/week. The relapse rate in the fluconazole-treated group was only 2%
versus 18% in the amphotericin B–treated group [274]. A subsequent trial compared two azoles, fluconazole, 200 mg daily, versus itraconazole, 200 mg daily. Again fluconazole was superior, showing a 4% relapse rate compared with a 23% relapse rate in the itraconazole group [275]. Accordingly, fluconazole is the recommended maintenance therapy in AIDS patients who have successfully completed primary therapy for cryptococcal meningitis [268]. Recent evidence supports discontinuation of maintenance therapy in patients who have no symptoms of cryptococcosis and have achieved immune reconstitution with HAART therapy [276].
78 D.R. Andes and W.E. Dismukes
Azole therapy, especially fluconazole, has also been utilized for nonmeningeal forms of cryptococcosis, including pulmonary disease, bone disease, skin disease, and isolated cryptococcemia, in AIDS and non-AIDS patients [89, 277, 278]. For a more detailed discussion about azole therapy of cryptococcosis, the reader is referred to the 2010 IDSA con- sensus guidelines [268]. These guidelines recommend flu- conazole for treatment of mild-to-moderate pulmonary disease (200–400 mg daily for 6–12 months). For HIV- positive patients and other immunocompromised patients, fluconazole may also be administered for life-long suppres- sion or for the duration of immunosuppression at a dose of 200–400 mg daily.
Endemic Mycoses (Blastomycosis, Coccidioidomycosis, Histoplasmosis, Penicilliosis, Paracoccidioidomycosis, and Sporotrichosis)
The endemic mycoses, as a rule, tend to be indolent illnesses.
However, each can cause life-threatening meningitis and dis- seminated disease. In addition, these same endemic mycoses are opportunistic in nature and associated with more serious disease in immunocompromised hosts, such as HIV/AIDS patients, transplant recipients, and those receiving corticos- teroid therapy. Since the introduction of ketoconazole in 1981, the older oral antifungal azoles have played an impor- tant role in the therapy of the endemic mycoses. For those patients with serious life-threatening endemic fungal dis- eases, amphotericin B formulation is usually given as an ini- tial therapy; after the patient is stabilized, an azole drug is usually employed. Here, data on azole treatment of each mycosis are summarized briefly.
Both ketoconazole and itraconazole are highly effective in the majority of patients with blastomycosis. Early on, several studies established the efficacy (70–100%) and relative safety of ketoconazole [279, 280]. Subsequently, a large open-label study demonstrated similar efficacy (90–95% of patients) with itraconazole and fewer adverse events compared with keto- conazole. The dose of itraconazole is lower, 200–400 mg daily, compared to ketoconazole, 400–800 mg daily.
Fluconazole is less active in vitro against Blastomyces derma- titidis. Several open-label trials have investigated the utility of fluconazole for treatment of blastomycosis. While the results demonstrated efficacy, the rate of response was lower than that observed in similar studies with itraconazole and higher daily doses of fluconazole (400–800 mg/day) were required for effi- cacy [281, 282]. Voriconazole, the newest triazole, is active in vitro [156] and in animals, but use of this drug has been limited to case series. However, reported successes from these
observations were encouraging and suggest a potential role for voriconazole in patients intolerant of itraconazole [283].
The 2008 IDSA guidelines recommend amphotericin B and itraconazole as first-line agents for treatment of blastomy- cosis, depending on the severity of the infection [284]. This change was not made as requested on first edit [280, 284].
Over the years, coccidioidomycosis has been considered one of the most difficult to treat systemic mycoses. Formerly, intravenous amphotericin B was the mainstay of therapy.
Nowadays, itraconazole and fluconazole are the principal antifungal drugs for this disease, owing in large part to their efficacy, ease of administration by either the oral or intrave- nous routes, and relatively low toxicity profiles [285–289]
when compared to amphotericin B.
A large, comparative trial of itraconazole and fluconazole in patients with progressive, nonmeningeal coccidioidomy- cosis confirmed the efficacy of these drugs [219]. Cure or improvement was achieved in 63% (61/97) of itraconazole recipients and in 50% (47/94) of fluconazole recipients (absolute difference, 13%, 95% CI, –2 to 28). In addition, itraconazole tended to be more effective in patients with coc- cidioidal skeletal disease. Both drugs were well tolerated.
Serious adverse events occurred in 6% of itraconazole patients and 8% of fluconazole patients. While initial studies with oral ketoconazole demonstrated moderate efficacy, the high daily doses (400–800 mg) to achieve efficacy were poorly tolerated [290, 291]. In addition, ketoconazole, because of its poor penetration into CSF, is not recommended for coccidioidal meningitis [292]. Voriconazole has good in vitro activity against C. immitis [156] and good penetra- tion into CSF, but there is minimal clinical experience with this newer triazole drug in coccidioidomycosis. However, the utility of posaconazole for treatment of chronic coccid- ioidomycosis has been recently explored in two open-label trials [293, 294]. One trial enrolled 20 patients with nonmen- ingeal disseminated or chronic pulmonary coccidioidomyco- sis to receive 400 or 800 mg of posaconazole daily [294]. At 24 weeks, 85% of patients received benefit, and the drug was well tolerated with a median duration of therapy of 173 days.
A similar trial investigated the utility of posaconazole (400 mg BID) in a small group of patients with chronic pul- monary or disseminated coccidioidomycosis refractory to conventional therapy [293]. After 1 month of therapy, 73%
of patients experienced a partial or complete clinical response.
IDSA consensus guidelines emphasize the important role of the antifungal azoles in the management of coccidioidomy- cosis and indicate that both itraconazole and fluconazole pro- vide attractive options as initial therapy for most patients with this disease [295–297]. Fluconazole is the treatment of choice for patients with coccidioidal meningitis and must be continued for life in most patients [288, 296, 297].
Azole drugs have also significantly altered the approach to therapy of histoplasmosis. Formerly, amphotericin B was