INTRODUCTION

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Although the first agent with antifungal activity, griseofulvin, was isolated in 1939 (28) and the first azole and polyene antifungal agents were reported in 1944 and 1949, respectively (85), it was not until 1958 that oral griseofulvin and topical chlormidazole became available for clinical use (Fig. 1) (13, 21, 28, 41, 85, 94, 103, 109, 132, 133, 151, 250, 274). The introduction of griseofulvin was followed in 1960 by that of amphotericin B (109), which is still the "gold standard" for the treatment of severe systemic mycoses (94). Two topical azole antifungal agents, miconazole and clotrimazole, were introduced in 1969; this was followed by the introduction of econazole in 1974 (109) and a parenteral formulation of miconazole in the late 1970s (21, 103). Today, these three agents remain the mainstay of topical therapy for many dermatophytoses.

View larger version (35K): [in this window] [in a new window]   FIG. 1.   Key events in antifungal drug development.

Progress in the development of both topical and systemic antifungal agents lagged, due in part to the intensive research efforts in the area of antibacterial therapy which began in the 1940s following the large-scale production of penicillin and also to the relatively low incidence of serious fungal infections compared with that of bacterial infections. By 1980, members of the four major classes of antifungal agentspolyenes, azoles, morpholines, and allylamineshad been identified, yet the only new drug introduced for the treatment of systemic fungal infections was oral ketoconazole (132). It would be more than 10 years before either fluconazole or itraconazole became available for the treatment of systemic mycoses (13).

During the 1980s and 1990s, the marked increase in the population of immunocompromised or severely ill individuals as the result of the spread of human immunodeficiency virus (HIV) infection, the increased use of immunosuppressive agents in association with organ transplants, chemotherapy, and improved life-saving medical techniques necessitating indwelling catheters led to a substantial increase in the occurrence of serious fungal infections (94, 95). Consequently, although it takes 10 to 12 years to bring a new drug to market and the cost of doing so has risen steadily (to $359 million in 1994) (20), the growing need for antifungal agents, particularly those for the treatment of systemic mycoses, has made this a worthwhile area of pharmaceutical research.

Advances made during the 1990s led to the introduction of a new allylamine, terbinafine, for the treatment of dermatophytoses and new lipid formulations of amphotericin B with improved safety profiles (95, 132). In addition, new classes of antifungal agents such as the candins (pneumocandins and echinocanidins), the nikkomycins, and the pradamicins-benanomicins are being studied (88, 95, 132). However, with 15 different marketed drugs worldwide (85, 132), the azoles are currently the most widely used and studied class of antifungal agents. This article focuses on the clinically important azole antifungal agents currently marketed in the United States and some promising new agents under development.

For a detailed discussion of the mechanism of action of the azoles and other antifungal agents, the reader is referred to the recent review articles by Georgopapadakou and Walsh (94) and White et al. (269). A brief overview is provided here.

Azole antifungal agents prevent the synthesis of ergosterol, a major component of fungal plasma membranes, by inhibiting the cytochrome P-450-dependent enzyme lanosterol demethylase (also referred to as 14-sterol demethylase or P-450_DM) (94, 95, 136, 269). This enzyme also plays an important role in cholesterol synthesis in mammals (136). When azoles are present in therapeutic concentrations, their antifungal efficacy is attributed to their greater affinity for fungal P-450_DM than for the mammalian enzyme (136). Exposure of fungi to an azole causes depletion of ergosterol and accumulation of 14-methylated sterols (94, 95, 136). This interferes with the "bulk" functions of ergosterol in fungal membranes and disrupts both the structure of the membrane and several of its functions such as nutrient transport and chitin synthesis (94). The net effect is to inhibit fungal growth (136). Ergosterol also has a hormone-like ("sparking") function in fungal cells, which stimulates growth and proliferation (94, 269). This function may be disrupted when ergosterol depletion is virtually complete (>99%) (94).

The azole antifungal agents in clinical use contain either two or three nitrogens in the azole ring and are thereby classified as imidazoles (e.g., ketoconazole and miconazole, clotrimazole) or triazoles (e.g., itraconazole and fluconazole), respectively. With the exception of ketoconazole, use of the imidazoles is limited to the treatment of superficial mycoses, whereas the triazoles have a broad range of applications in the treatment of both superficial and systemic fungal infections. Another advantage of the triazoles is their greater affinity for fungal rather than mammalian cytochrome P-450 enzymes, which contributes to an improved safety profile. Table 1 shows the generic and U.S. trade names, chemical structures, U.S. formulations, and general clinical uses of the clinically important azole antifungal agents currently marketed in the United States. Until the recent approval of itraconazole oral solution, only the itraconazole capsule formulation was available. Throughout this review, where studies pertain to the oral solution, it has been identified as such. Otherwise, "itraconazole" is used to refer to studies with the capsule formulation.

Although the polyene amphotericin B remains the agent of choice for the treatment of most life-threatening systemic mycoses (18, 92, 246), ketoconazole, fluconazole, and itraconazole have a variety of uses in the treatment of disseminated infections due to opportunistic and endemic fungal pathogens. Ketoconazole and itraconazole (Table 1) share a number of pharmacokinetic characteristics. Both are available in oral (p.o.) formulations, whose absorption is affected by gastric acidity and food. By contrast, fluconazole is available in both intravenous (i.v.) and p.o. formulations, and absorption is neither dependent on gastric acidity nor affected by food (47). Because of its relatively low lipophilicity and low degree of protein binding (~12%), fluconazole distributes readily into aqueous body fluids such as the cerebrospinal fluid (CSF) (99). On the other hand, although penetration of ketoconazole and itraconazole into aqueous fluids is negligible due to their high lipophilicity and high degree of protein binding (>99%), these azoles achieve concentrations in fatty tissues and exudates such as pus that are severalfold greater than the concomitant concentrations in serum (54, 101, 259). The therapeutic uses of these three azoles, based primarily on the published recommendations of experts in the field rather than the indications approved by the Food and Drug Administration (FDA), are listed in Table 2 and will be expanded upon in subsequent sections.

Aspergillosis, candidemia, and cryptococcosis have become increasingly prevalent as the population of immunocompromised or seriously ill individuals has increased (94, 95). None of these opportunistic fungal infections are responsive to p.o. ketoconazole (15).

Aspergillosis. Amphotericin B remains the agent of choice for the initial therapy of invasive aspergillosis (16, 54, 110, 161, 259), although a 1990 review of the literature by Denning and Stevens showed that the overall response rate was only 55% (54). Moreover, the therapeutic response to amphotericin B in immunocompromised patients is generally poor (16). Itraconazole is the only currently marketed azole that appears to be a useful alternative (53, 144), and it has been approved by the FDA as a second-line agent for the treatment of pulmonary or extrapulmonary aspergillosis in patients who are refractory to or intolerant of amphotericin B (132). Clinically, itraconazole is often used as consolidation therapy in seriously ill patients who have responded to initial therapy with amphotericin B and as initial therapy in those with less severe infections (132).

(i) Fluconazole. The management of serious infections due to Candida spp., which are becoming increasingly prevalent, is problematic because of the increasing incidence of non-albicans species (1, 188) and the emergence of non-albicans isolates resistant to both amphotericin B and the newer azoles (172). Recently, a panel of 22 international experts in the management of Candida infections held a consensus conference to develop general recommendations for the prevention and treatment of these infections (74). The triazoles fluconazole and itraconazole were among the antifungal agents considered by the participants. Fluconazole, but not itraconazole, is approved by the FDA for the treatment of systemic Candida infections. However, itraconazole has been approved elsewhere for use in deep (nonmucosal) Candida infections and was therefore included among the available therapeutic options (74). Infections considered by the experts included candidemia, candiduria, hepatosplenic candidiasis (chronic disseminated candidiasis), candidal endophthalmitis, and candidal peritonitis. Management strategies were based not only on the site of Candida infection but also on other factors such as neutropenia, susceptibility of the Candida isolate, general condition of the patient, and whether the patient had undergone bone marrow or solid organ transplantation.

(ii) Combination therapy. As noted previously, some participants in the consensus conference on the management of severe candidal infections chose a regimen of fluconazole in combination either with amphotericin B or 5-FC in certain situations (Table 3) (74). However, the use of amphotericin B in combination with an azole is controversial because of the potential for antagonism based on their modes of action (95). With regard to fluconazole-amphotericin B, the antagonism demonstrated in some in vitro studies has not been observed in vivo in experimental animal models (95, 229, 246, 247). In a murine model of invasive candidiasis due to a fluconazole-resistant strain, fluconazole-amphotericin B was more effective than fluconazole alone and was equivalent to amphotericin B alone in protecting both immunocompromised and healthy immune-normal mice from infection and in decreasing fungal burden (247). A subsequent study of neutropenic-mouse and infective-endocarditis rabbit models found no antagonism but, rather, indifference with fluconazole-amphotericin B (229). In mice, fluconazole-amphotericin B and amphotericin B alone significantly prolonged survival compared to untreated controls and both were more effective than fluconazole alone in clearing Candida from the kidneys. However, fluconazole-amphotericin B and fluconazole alone both were more effective than amphotericin B alone in decreasing the fungal burden in the brain. In rabbits, both fluconazole-amphotericin B and amphotericin B alone were highly effective in decreasing Candida concentrations in cardiac vegetations.

(iii) Prophylaxis. Prophylactic administration of a systemic antifungal agent, usually fluconazole, is reserved for selected patients considered to be at high risk of candidemia (74). Although prophylaxis is not routinely recommended for nonneutropenic patients, fluconazole might be appropriate for those in whom the risk of candidemia is increased. The example given in the international consensus conference report is " ... a patient has received antibacterial therapy for >14 days, has indwelling intravascular lines in place, is receiving hyperalimentation fluids, has had Candida isolated from two or more sites, and has undergone complicated intraabdominal surgery" (74). For neutropenic patients who have not undergone bone marrow or organ transplants (i.e., those with leukemia or who are hospitalized in surgical intensive care units), participants in the international consensus conference were reluctant to recommend widespread prophylaxis because of limited data on efficacy and concerns about the development of azole resistance (74). For high-risk neutropenic patients with C. albicans colonization at multiple sites, Lortholary and Dupont reported that low-dose fluconazole (50 mg/day) is appropriate (147). However, as discussed in greater detail below in the section dealing with resistance, most reports of fluconazole resistance in non-HIV-infected patients have involved non-albicans species of Candida, mainly C. krusei and C. glabrata, which generally emerged in patients given low-dose (200-mg/day) fluconazole prophylaxis either alone or in combination with amphotericin B (2, 172, 220, 269). A shift in the species of Candida causing bloodstream infections has also been found in cancer patients receiving fluconazole prophylaxis with higher doses, usually 400 mg/day (1). A retrospective review of medical records of 474 cancer patients who experienced 479 episodes of hematogenous candidiasis between 1988 and 1992 showed that fluconazole prophylaxis was associated with a relative decrease in the proportion of bloodstream infections caused by C. albicans and C. tropicalis and an increase in the proportion of infections due to C. krusei and C. glabrata. These findings provide further support for the recommendation to limit fluconazole prophylaxis to high-risk patients, such as those with neutropenia, and to administer the drug only during periods when the patient is at highest risk, in order to minimize selection of these less susceptible species (1).

Cryptococcosis. For cryptococcosis, the therapeutic regimen is based on the site and severity of infection and the patient's immune status. Treatment options for both pulmonary cryptococcosis and disseminated cryptococcal infection in immunocompetent patients include amphotericin B with or without 5-FC, which is the preferred regimen for patients with severe infection, or p.o. fluconazole (92). One study suggests that fluconazole may be as effective as amphotericin B with or without 5-FC in the treatment of both extrameningeal and meningeal cryptococcosis in HIV-negative patients (70). In a retrospective analysis of 83 HIV-negative patients treated in France between January 1985 and December 1992, cure rates at the end of initial therapy with amphotericin B (usually with 5-FC) or fluconazole (400 mg/day) were 74 and 68%, respectively, among patients with meningeal infection and 75 and 93%, respectively, among those with nonmeningeal infection (70). There are no general recommendations at present for the treatment of extraneural cryptococcosis in HIV-infected patients (161).

Although the endemic mycoses are restricted to certain geographical areas, they are evolving into opportunistic infections that may be encountered elsewhere (147). Immunocompromised individuals (e.g., transplant recipients, HIV-infected persons) residing in areas of endemic infection tend to develop primary infections, whereas reactivation of infection occurs among those who have left the regions (121). Immunocompromised individuals are especially susceptible to all but paracoccidioidomycosis, and those with depleted CD4⁺ cell counts are at high risk of disseminated infection and CNS involvement. Disseminated coccidioidomycosis has been considered to be an AIDS-defining event since 1987, and 10% of HIV-infected individuals living in an area of endemic infection will develop active infection each year (243). Likewise, histoplasmosis affects 2 to 5% of AIDS patients living in areas of endemic infection in the United States and up to 25% of those in certain cities (262). Among organ transplant recipients, histoplasmosis is the most common endemic fungal infection; coccidioidomycosis occurs primarily in those who have received kidney, heart, and heart-lung transplants (147). Blastomycosis is rarely found in either patients with AIDS or transplant recipients (27, 147), and paracoccidioidomycosis and sporotrichosis generally occur in individuals with normal immune systems (208, 212).

Coccidioidomycosis. When Coccidioides immitis infection in an individual with an intact immune system is limited to the lungs, antifungal therapy generally is not needed unless the illness is severe; however, disseminated extrapulmonary infection should be treated in most cases (243). When there is no CNS involvement, extrapulmonary infection may be treated i.v. with amphotericin B (total dose, 1 to 2.5 g) or p.o. with either itraconazole (200 mg b.i.d. with food) or fluconazole (400 to 600 mg q.d.). The efficacy of these triazoles in the treatment of nonmeningeal coccidioidomycosis was evaluated by the NIAID-MSG in separate multicenter, open-label trials (35, 106). Itraconazole (100 to 400 mg/day; 400 mg/day in most patients) was administered to 49 patients for up to 39 months, including 3 immunosuppressed (non-HIV-infected) patients and 29 patients who had relapsed or failed to respond to prior therapy either with amphotericin B or ketoconazole (106). Among 44 clinically evaluable patients who completed therapy, the remission rate was 57% (25 patients), based on a 50% reduction in the pretreatment score (i.e., assessments of lesion number and size, symptoms, culture, and serologic titer). Patients improved slowly, with few achieving remission before 10 months; the rate of response was similar for patients with soft tissue, chronic pulmonary, and osteoarticular disease. At the end of the study, 21 of the 25 patients remained in clinical remission. Four relapses occurred at 4, 4.5, 7, and 21 months among 11 patients after therapy for at least 12 months. In the other study, 78 patients with coccidioidomycosis received fluconazole (200 to 400 mg/day) for up to 1 year, including 7 patients with HIV infection and 48 patients who had experienced prior episodes of coccidioidomycosis (35). Among 75 patients evaluated for efficacy, a satisfactory response (defined as any reduction of baseline abnormality by month 4 and at least a 51% reduction by month 8) was achieved in 12 (86%) of 14 patients with skeletal disease, 22 (55%) of 40 patients with chronic pulmonary disease, and 16 (76%) of 21 patients with soft tissue disease. Forty-one patients who received fluconazole (400 mg/day) for at least part of their treatment were monitored posttreatment for a median of 235 days (range, 21 to 595 days), during which time reactivation of infection occurred in 15 patients (37%). The investigators commented that higher doses of fluconazole should be evaluated, particularly for patients with chronic pulmonary disease. Although some patients with extrapulmonary coccidioidomycosis may respond to ketoconazole (400 mg/day), the likelihood of relapse appears to be even greater than that following treatment with either itraconazole or fluconazole (15, 243). A comparison of these two triazoles for the initial therapy of nonmeningeal coccidioidomycosis is ongoing (243). Although the optimal duration of oral azole therapy for nonmeningeal cryptococcal infections remains to be determined, in view of the tendency of coccidioidomycosis to recur after the completion of therapy, Stevens recommends continued administration for 6 months after the disappearance of disease (243).

Histoplasmosis. Asymptomatic or mildly symptomatic acute pulmonary infection due to Histoplasma capsulatum in patients with normal immune status generally does not require antifungal therapy (29). Amphotericin B is the drug of choice for severe or life-threatening infections, for H. capsulatum meningitis, for patients unresponsive to or relapsing after azole therapy (27, 29, 75, 132, 196), and for the initial therapy of moderate to severe infection in HIV-infected patients (161). The azoles are alternatives to amphotericin B for the initial therapy of patients with milder infections. Following primary therapy with amphotericin B or an azole, most patients require lifelong maintenance therapy to prevent relapse.

Blastomycosis. Many patients with mild pulmonary infection due to Blastomyces dermatitidis recover spontaneously without antifungal therapy and require only prolonged follow-up (27). For seriously ill patients, those with CNS involvement, and HIV-infected patients, amphotericin B is the drug of choice (27, 37, 161, 196). A clinical trial by the NIAID-MSG demonstrated that itraconazole (200 to 400 mg/day) was highly effective in the treatment of nonmeningeal, non-life-threatening pulmonary and extrapulmonary blastomycosis in patients without HIV infection (63). Treatment was successful overall in 43 (90%) of 48 patients, and the percentage cured rose to 95% (38 of 40 patients) among those treated for more than 2 months. The median duration of itraconazole therapy in these 38 responders was 6.2 months (range, 3.0 to 24.4 months), and the median interval from the end of therapy to the last posttreatment examination was 11.9 months (range, 0.0 to 25.1 months). Most relapses of blastomycosis occur within a few months after the completion of therapy, but only one patient treated for more than 2 months relapsed. This patient, who had cutaneous blastomycosis, was markedly immunosuppressed due to a splenectomy and prolonged corticosteroid therapy for autoimmune hemolytic anemia. Based on their findings, the investigators concluded that itraconazole (200 mg/day) was highly effective for most patients with nonmeningeal, non-life-threatening forms of blastomycosis and that the itraconazole dosage should be increased to 400 mg/day for those with progressive or persistent infection. Recently, Bradsher (27) commented that itraconazole (200 mg/day for 6 months) should replace amphotericin B for less seriously ill, compliant patients with nonmeningeal infection but cautioned that patients have developed CNS blastomycosis while receiving either itraconazole or ketoconazole.

Paracoccidioidomycosis. Although usually restricted to tropical and subtropical areas, infection due to Paracoccidioides brasiliensis may be encountered elsewhere among former residents of these areas. It is a unique systemic mycosis, because it can be treated with sulfonamides either alone or in combination with trimethoprim (208). These drugs are administered for 3 to 5 years to prevent relapse (208). Both ketoconazole and itraconazole are also effective in the treatment of paracoccidioidomycosis; itraconazole is preferred over ketoconazole because the duration of therapy is shorter (6 months and 12 to 18 months, respectively), the daily dosage is lower (100 and 200 to 400 mg, respectively), there are fewer relapses (3 to 5% and 10%, respectively), and risk of drug interactions or hepatic toxicity is minimal (208). Fluconazole (200 to 400 mg/day) was effective in 27 of 28 immune-normal patients with paracoccidioidomycosis who were treated in a multinational study (59). Most patients (19 of 28) were treated for 6 months or less, and of the 16 responders who had posttreatment follow-up, only 7 were monitored for at least 1 year. The only relapse occurred 24 months posttreatment in a patient with cutaneous and oral infection who was treated for only 2 months. Larger numbers of patients will have to be treated and observed for several years thereafter before the usefulness of fluconazole in treating this deep mycosis can be determined (59, 208).

Sporotrichosis. Like paracoccidioidomycosis, infections caused by Sporothrix schenckii occur mainly in tropical and subtropical regions (212). Because it is more expensive, itraconazole (100 to 200 mg/day) is considered an alternative to treatment with a saturated solution of potassium iodide but is used for the initial treatment of extracutaneous sporotrichosis in a dose of 200 to 400 mg/day (212). The effectiveness of itraconazole in the treatment of lymphocutaneous, articular/osseous, or pulmonary sporotrichosis was demonstrated in a clinical trial by the NIAID-MSG, in which 27 adults received 30 courses of itraconazole therapy (100 to 600 mg/day) lasting 3 to 18 months (234). Eleven patients had failed to respond to prior therapy, which included ketoconazole in six patients and fluconazole in two others. In 25 of the 30 courses of treatment, patients responded to itraconazole (usually 200 or 400 mg/day). Seven patients who responded to itraconazole relapsed 1 to 7 months posttreatment, two of whom were improving with additional itraconazole therapy. One responder was lost to follow-up after 10 months of itraconazole therapy, 3 responders continued to receive itraconazole, and 14 remained disease free during follow-up periods ranging from 6 to 42 months. Experience with fluconazole in the treatment of sporotrichosis is limited. In a multinational study, 13 of 19 patients with cutaneous or lymphocutaneous sporotrichosis responded to fluconazole (200 to 400 mg/day) (59). Of the 13 patients, 10 responded within 6 months and had remained free of infection for at least 8 months (10 of 13 patients) to 1 year (6 of 10 patients). Only one patient who was treated for only 1 month relapsed 2 months posttherapy. These investigators recommended that patients who respond to fluconazole during the first 6 months of therapy be treated for a minimum of 6 to 12 months. For the treatment of extracutaneous sporotrichosis, both fluconazole (200 to 400 mg/day) and ketoconazole (400 to 800 mg/day) appear to be less effective than itraconazole (212). The efficacy of all three drugs in the treatment of advanced pulmonary sporotrichosis has yet to be established; some patients have responded, and others have not (212). No reports of the use of these azoles in meningeal infection due to S. schenckii have been published (212, 234, 272).

Experience with the azoles in other systemic mycoses is limited but suggests that ketoconazole and itraconazole may be useful in the treatment of more indolent cases of infection due to Pseudallescheria boydii or Penicillium marneffei (17). In addition, a child who developed invasive sinonasal infection with Scopulariopsis candida while undergoing treatment for non-Hodgkin's lymphoma responded to prolonged treatment with a combination of am