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The role of azoles in the treatment of invasive mycoses: review of the Infectious Diseases Society of America guidelines

Pappas, Peter G

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Current Opinion in Infectious Diseases: August 2011 - Volume 24 - Issue - p S1-S13
doi: 10.1097/01.qco.0000399602.83515.ac
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Abstract

Introduction

Invasive mycoses are a major and increasingly common cause of morbidity and mortality in the United States and other countries [1]. The increase in incidence of invasive mycoses is largely due to the burgeoning number of immunocompromised or severely ill patients now being cared for in healthcare institutions, together with the frequent use of invasive medical techniques. These at-risk individuals are particularly susceptible to serious invasive infection caused by opportunistic fungal pathogens, including the traditional pathogens Candida, Aspergillus, and Cryptococcus species, as well as zygomycetes and endemic opportunistic fungi, such as Histoplasma capsulatum, Coccidioides species, and Blastomyces dermatitidis[1,2].

Clinicians managing patients with or at risk for an invasive fungal infection now have a number of antifungal agents with different mechanisms of action to prevent or treat these systemic infections. Amphotericin B deoxycholate (conventional amphotericin B), a member of the polyene antifungal drug class, has been a fundamental part of the treatment of invasive mycoses since the mid 1950s [3]. Flucytosine appeared on the market in the early 1970s, followed by the systemic azoles ketoconazole in 1980 and fluconazole and itraconazole in the early 1990s. Three lipid formulations of amphotericin B also became available on the United States market in the early-to-mid 1990s. More recent additions to the antifungal armamentarium include three drugs in the echinocandin class (caspofungin, micafungin, and anidulafungin) and two newer, second-generation triazoles (voriconazole and posaconazole).

This review explores the current role of standard triazoles (fluconazole and itraconazole) and newer triazoles (voriconazole and posaconazole) in the management of invasive mycoses, primarily through review of recent clinical practice guidelines from the Infectious Diseases Society of America (IDSA) for the management of candidiasis [4], aspergillosis [5], cryptococcosis [6], histoplasmosis [7], coccidioidomycosis [8], blastomycosis [9], and sporotrichosis [10]. In the process, the roles of other antifungal classes in the management of these conditions will also be discussed, although the main focus will be on triazoles.

As illustrated in Table 1, the spectrum of antifungal activity differs for the various triazoles currently on the market, but is generally quite broad [11,12]. The spectrum of activity expanded with each subsequent triazole approved for use in the United States, being broader with itraconazole than fluconazole, and broader still with the second-generation triazoles. The broadest spectrum of activity is observed with posaconazole, the latest triazole to receive Food and Drug Administration approval. Three other triazoles are currently in development: isavuconazole, ravuconazole, and albaconazole [13,14]. Isavuconazole is currently being investigated in phase III trials, whereas the other two drugs are in earlier stages of development [14,15].

T1-2
Table 1:
Spectrum of antifungal activity for key triazoles

Infectious Diseases Society of America treatment guidelines for invasive candidiasis

In 2009, the IDSA provided a new set of clinical practice guidelines for the management of candidiasis [4]. These guidelines represented an update of the prior 2004 guidelines [16], incorporating agents approved after 2004 (micafungin, anidulafungin, and posaconazole) and additional data gathered since that time with respect to triazoles and other antifungal agents used to treat candidiasis [4]. Although the guidelines discuss the treatment of both invasive and mucocutaneous candidiasis, the present paper deals only with management of invasive candidiasis.

The new guidelines are important because there is now a relatively long list of approved options for the management of invasive candidiasis, including traditional and lipid formulations of amphotericin B, fluconazole, amphotericin B and fluconazole, amphotericin B followed by fluconazole, amphotericin and 5-flucytosine, each of the echinocandins (anidulafungin, caspofungin, and micafungin), voriconazole, and posaconazole for prophylaxis in high-risk patients. The guidelines aim to provide some clarity regarding these choices. In general, there is an emphasis in the 2009 guidelines on fluconazole and echinocandins as the preferred choices for proven or suspected invasive candidiasis, and a de-emphasis on traditional and lipid formulations of amphotericin B under most circumstances [4]. In addition, the 2009 guidelines strongly encourage the concept of step-down therapy, with a general recommendation for voriconazole as step-down therapy for selected isolates such as Candida krusei and Candida glabrata. It should be noted that the IDSA endorsement of step-down therapy is not based entirely on published data, but rather on anecdotal experience in general practice patterns.

More specifically, the IDSA guidelines recommend fluconazole [800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily] or an echinocandin for initial treatment of nonneutropenic adults with proven or suspected candidemia [4]. An echinocandin is the preferred option for patients with moderate-to-severe illness or those with recent triazole exposure (which increases risk of infection with fluconazole-resistant Candida species), with transition to fluconazole for clinically stable patients with isolates likely to be susceptible to triazole therapy. Traditional or lipid formulations of amphotericin B are recommended as alternative therapy for nonneutropenic patients with proven or suspected candidemia when there is intolerance or limited availability of other antifungal agents. With respect to documented infection with specific Candida species, an echinocandin is preferred for candidemia due to C. glabrata, and fluconazole for candidemia due to Candida parapsilosis. In general, voriconazole offers little advantage over fluconazole, but voriconazole [400 mg (6 mg/kg) twice daily for 2 doses, then 200 mg (3 mg/kg) twice daily thereafter] is recommended as step-down therapy for selected cases of candidemia due to C. krusei or voriconazole-susceptible C. glabrata.

For neutropenic adults with proven candidemia, the IDSA guidelines recommend initial treatment with an echinocandin or lipid formulation of amphotericin for most patients [4]. Fluconazole [800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily] may be considered a reasonable alternative for less critically ill patients with no recent exposure to triazoles, as may voriconazole when additional mold coverage is desired. Echinocandin treatment is preferred for neutropenic patients with candidemia due to C. glabrata, and fluconazole or a lipid formulation of amphotericin B for neutropenic patients with candidemia due to C. parapsilosis. An echinocandin, lipid formulation of amphotericin B, or voriconazole is recommended as first-line treatment for neutropenic patients with candidemia due to C. krusei.

The IDSA Candida treatment guidelines are somewhat different for empiric treatment of suspected invasive candidiasis in neutropenic patients [4]. In this situation, the guidelines recommend initial therapy with a lipid formulation of amphotericin B, caspofungin, or voriconazole [6 mg/kg intravenous (IV) administered twice daily for 2 doses, then 3 mg/kg twice daily]. Fluconazole [800 mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily] or itraconazole [200 mg (3 mg/kg) twice daily] are identified as alternative empiric therapies, but they should not be used in patients who have received prophylaxis with a triazole.

The IDSA recommendations for the treatment of invasive candidiasis are based on published reports of the activity of triazoles and other antifungals against the different Candida species. As can be seen in Table 2, triazoles exhibit excellent activity against Candida albicans, Candida tropicalis, C. parapsilosis, and Candida lusitaniae[4,11]. Activity becomes a more important consideration when dealing with C. glabrata, and even more so for C. krusei. C. krusei is rarely susceptible to fluconazole and is not reliably susceptible to itraconazole, but it remains susceptible to the newer triazoles voriconazole and posaconazole. A major question for clinicians is fluconazole susceptibility. In particular, has fluconazole susceptibility diminished over time, and has fluconazole use promoted the development of resistance? Based on longitudinal data from Pfaller et al.[17,18], it appears that resistance of some Candida species to fluconazole increased a few years ago, but no subsequent increases have been observed. More specifically, fluconazole resistance among C. albicans and C. parapsilosis continues to be relatively uncommon, whereas resistance of C. glabrata to fluconazole has essentially stabilized since the early 1990s (Table 3) [17]. Similar results were obtained in a more recent publication by Pfaller et al.[18] that examined trends in in-vitro resistance to fluconazole among Candida species from 1997–2007, as determined by Clinical and Laboratory Standards Institute disk diffusion testing: fluconazole resistance for C. albicans for 1997–2000, 2001–2004, and 2005–2007 was 0.9%, 1.4%, and 1.4%, respectively; fluconazole resistance for C. glabrata during the same periods was 19.2%, 15.9%, and 15.4%, respectively.

T2-2
Table 2:
General pattern of susceptibility of Candida species to various antifungal agents
T3-2
Table 3:
Fluconazole susceptibility over 12 years, 1992–2002a

Most experts agree fluconazole is not reliably active against C. glabrata to be used without susceptibility testing. There was hope the newer triazoles voriconazole and posaconazole might provide a solution to this problem, but subsequent data do not support this conclusion. As depicted in Fig. 1, although minimal inhibitory concentrations (MICs) are generally lower for voriconazole and posaconazole compared with fluconazole for all Candida species tested, there is still a strong positive correlation between the MICs of fluconazole and newer triazoles [19], suggesting the newer triazoles are also not reliably active enough against fluconazole-resistant species to be used routinely without susceptibility data. C. krusei appears to be an exception to this conclusion. In the study by Pfaller et al.[19]C. krusei was highly resistant to fluconazole, but generally susceptible to voriconazole and posaconazole (133 of 144 isolates were susceptible to both these agents at ≤1 μg/ml).

F1-2
Figure 1:
Correlation between (a) voriconazole and (b) posaconazole minimum inhibitory concentration and fluconazole minimum inhibitory concentration for 3932 Candida isolates

Infectious Diseases Society of America treatment guidelines for invasive aspergillosis

The latest IDSA treatment guidelines for aspergillosis were released in 2008 [5]. The guidelines highlight voriconazole as the treatment of choice for most forms of invasive aspergillosis, including invasive pulmonary, invasive sinus, tracheobronchial, and chronic necrotizing pulmonary aspergillosis, as well as aspergillosis of the central nervous system (CNS) [5]. In particular, the guidelines recommend initial treatment with voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h or an oral dosage of 200 mg every 12 h), whereas considering liposomal amphotericin (L-AMB), amphotericin B lipid complex, or caspofungin as alternative treatments for patients refractory to or intolerant of primary antifungal therapy with voriconazole. A phase III trial by Herbrecht et al.[20] helped identify voriconazole as the treatment of choice for invasive aspergillosis, demonstrating more successful outcomes, higher response levels, improved survival, and fewer adverse events with voriconazole versus amphotericin B deoxycholate when used as primary treatment of invasive aspergillosis. Therapeutic drug monitoring appears to be important for optimizing voriconazole safety and, possibly, efficacy [5].

Optimal treatment duration for invasive aspergillosis is poorly defined at present, but most clinicians continue treatment until resolution or stabilization of clinical and radiographic symptoms indicative of aspergillosis. The treatment guidelines recommend a minimum of 6–12 weeks of treatment for most patients, and throughout the period of immunosuppression until lesion resolution in patients receiving immunosuppressive therapy [5]. In addition, the guidelines recommend resumption of antifungal therapy after successful treatment of invasive aspergillosis when there is to be a resumption of immunosuppressive therapy. Surgical removal of Aspergillus-infected tissue is generally recommended when critical blood vessels or pericardium are involved, or when the lesions are causing hemoptysis or an invasion of the chest wall [5]. Furthermore, selected patients with neutropenia may benefit from immunotherapy with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor during the neutropenic phase [5]. The 2008 guidelines also identify posaconazole [200 mg oral four times daily (q.i.d.) initially, then 400 mg twice daily (b.i.d.) after disease stabilization], liposomal formulations of amphotericin, itraconazole, caspofungin, and micafungin as salvage therapy options for selected patients [5]. Itraconazole currently plays a limited role in the management of invasive aspergillosis. In general, there is a paucity of data to guide treatment of patients refractory to voriconazole or salvage therapy. Most cases of invasive aspergillosis are caused by Aspergillus fumigatus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus terreus. A. terreus is resistant to polyene (amphotericin B) therapy, and triazole treatment is preferred for all patients with A. terreus infection.

With respect to empiric therapy for suspected invasive aspergillosis, the guidelines recommend primary treatment with voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 3 mg/kg IV every 12 h or an oral dosage of 200 mg every 12 h), L-AMB, caspofungin, or itraconazole [5]. No other alternatives to these agents are listed. Posaconazole (200 mg every 8 h) is the only antifungal with a United States indication for use as prophylaxis against invasive aspergillosis in high-risk patients [21], and it is recommended in the 2008 guidelines for such use [5]. Two randomized controlled studies documented the utility of posaconazole for the prevention of invasive aspergillosis and other invasive fungal infections in patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome [22] or patients with severe graft-versus-host disease who were receiving immunosuppressive therapy [23]. Itraconazole and micafungin are identified in the 2008 treatment guidelines as possible alternatives to posaconazole for prophylaxis against invasive aspergillosis. However, there is currently no consensus regarding prophylactic therapy to prevent invasive aspergillosis.

Primary combination therapy is not routinely recommended for invasive aspergillosis because of insufficient evidence to support this approach at this time, although the guidelines speculate there might be a role for combination therapy in the context of salvage therapy [5]. A number of animal models of invasive aspergillosis have suggested combining an echinocandin with amphotericin B [24–27] or with voriconazole [28–30] may improve treatment outcomes, and two recent case studies pointed to possible benefits of combination treatment with micafungin with voriconazole or amphotericin B [31,32]. In addition, there is some evidence for synergistic activity against Aspergillus species when echinocandins are combined with second-generation triazoles [33,34]. Although a recent retrospective study of 159 patients who received salvage therapy for invasive aspergillosis with L-AMB alone, an echinocandin alone, or an echinocandin/L-AMB combination failed to demonstrate any additional benefit for combination therapy [35], two other clinical studies of invasive aspergillosis suggested patients benefited from voriconazole/caspofungin combination therapy versus monotherapy [36,37]. A large, prospective, double-blind, placebo-controlled study conducted by the Mycoses Study Group is currently comparing voriconazole with placebo versus voriconazole with anidulafungin in hematologic malignancy patients or stem-cell transplant recipients with presumed invasive aspergillosis [2]. Results from this study are expected in the near future and should help to clarify the role, if any, of combination therapy in the management of invasive aspergillosis.

Most cases of invasive aspergillosis occur in significantly immunocompromised or neutropenic patients, especially those with stem cell or, to a lesser degree, solid organ transplants, especially lung transplant recipients. However, a number of relatively recent reports from around the world demonstrate increased incidence of invasive aspergillosis in critically ill, nonneutropenic patients in hospital ICUs [38]. A number of risk factors for invasive aspergillosis have been identified in these patients, including chronic obstructive pulmonary disease (COPD), prolonged steroid use, and advanced liver disease or failure [38–40].

Infectious Diseases Society of America treatment guidelines for cryptococcosis

Cryptococcosis is a potentially fatal fungal infection caused by Cryptococcus neoformans var. grubii (serotype A), C. neoformans var. gattii (serotypes B and C) or C. neoformans var. neoformans (serotype D) [41]. Cryptococcosis is usually associated with immunodeficiency, and came to prominence in the 1980s with the epidemic of HIV-positive patients [42,43]. The expanded use of anticancer drugs and other immunosuppressive agents has also contributed to the growing incidence of cryptococcosis observed over the past 30 years. It is now recognized that cryptococcosis can also occur in some patients with apparently normal immune function. The incidence of cryptococcosis in HIV-positive patients has dramatically decreased in developed countries since the advent of highly active antiretroviral therapy, although cryptococcosis in AIDS patients is still a major cause of morbidity and mortality in underdeveloped or developing countries. Cryptococcosis usually manifests as CNS infection (meningitis, meningoencephalitis, and cerebral, cerebellar, and spinal cryptococcomas) or pulmonary disease [42,43]. Other organs or organ systems are less commonly the site of cryptococcosis.

In 2010, the IDSA provided updated clinical practice guidelines for the management of cryptococcosis [6], replacing the prior 2000 guidelines [44]. Unfortunately, this is a relatively understudied area, and there are either no or very limited new clinical trial data on the use of newer approved triazoles or investigational agents such as isavuconazole, or on the management of cryptococcosis in normal immunocompetent hosts or transplant recipients. Most of the data to date has focused on the treatment of cryptococcal disease in HIV-infected populations. More recent data involving non-HIV-positive patients come from observational cohort studies generated through larger networks or registries, such as the Prospective Antifungal Therapy Alliance [45], the Transplant-Associated Infection Surveillance Network [46], and the Cryptococcal Collaborative Transplant Study Group [47,48]. The focus thus far has been on optimizing the use of existing standard therapies (amphotericin B, fluconazole, and 5-flucytosine), rather than on incorporating newer agents.

Pulmonary cryptococcosis

There has been little change in the management of pulmonary cryptococcosis. For immunosuppressed and immunocompetent patients with mild-to-moderate uncomplicated pulmonary cryptococcosis, the 2010 guidelines recommend initial treatment with fluconazole (400 mg/day) for a duration of 6–12 months [6]. Itraconazole (200 mg oral b.i.d.), voriconazole (200 mg/day oral b.i.d.), or posaconazole (400 mg oral b.i.d.) are identified as suitable alternatives if fluconazole is unavailable or contraindicated. For immunosuppressed and immunocompetent patients with severe pulmonary cryptococcosis or pneumonia associated with CNS dissemination, the guidelines recommend a treatment plan that mirrors that of patients with CNS cryptococcosis. As discussed below, management of CNS cryptococcosis varies slightly depending on whether it occurs in an HIV-infected patient, an organ transplant recipient, or a non-HIV-infected, nontransplant host.

For transplant recipients or other immunosuppressed patients, a lumbar puncture should be used to rule out CNS involvement, independent of symptoms or serum cryptococcal antigen results [6]. In addition, surgery should be considered for immunosuppressed or nonimmunosuppressed patients with persistent chest X-ray abnormalities and symptoms despite antifungal therapy.

Central nervous system cryptococcosis

More controversy surrounds CNS cryptococcosis management, and the 2010 guidelines reflect the best consensus currently available. The guidelines make recommendations for three phases of treatment: induction, consolidation, and maintenance therapy. In general, the recommendations are similar whether the patient with CNS cryptococcosis is an HIV-infected patient, an organ transplant recipient, or a non-HIV-infected, nontransplant host, although there are some differences between the groups in terms of dosages and treatment duration. In all groups, induction therapy involves an amphotericin B regimen and 5-flucytosine for most patients, with removal of the 5-flucytosine component for patients intolerant of that drug. Liposomal formulations of amphotericin B are preferred in patients with renal issues. In all patient groups, induction therapy is followed by a step-down to fluconazole during the consolidation and maintenance phases of treatment.

More specifically, recommended induction therapy for most patients with CNS cryptococcosis is an amphotericin B formulation and 5-flucytosine (2 weeks for HIV-infected or transplant recipients, and ≥4 weeks for non-HIV-infected/nontransplant hosts). For 5-flucytosine-intolerant patients, an amphotericin B formulation alone is recommended for at least 4–6 weeks. Consolidation therapy is the same for all patient subgroups with CNS cryptococcosis (fluconazole 400 mg/day for 8 weeks), although the guidelines suggest the fluconazole dose can be increased to 800 mg/day for transplant recipients or non-HIV-infected/nontransplant hosts. Maintenance therapy is also generally the same for all patient subgroups: fluconazole 200 mg/day (up to 400 mg/day for transplant recipients) for 6–12 months for transplant recipients or non-HIV-infected/nontransplant hosts, and at least 12 months for HIV-infected patients. Among HIV-positive patients with cryptococcosis who experience immune reconstitution with sustained CD4 lymphocyte recovery (>100 cells/mm3) following initiation of antiretroviral therapy, chronic suppressive fluconazole can be safely discontinued.

It should be noted that there are no approved roles for voriconazole or posaconazole in the primary treatment of CNS cryptococcosis because there are no data regarding their use in this setting. However, there is some limited support for the use of voriconazole [49] or posaconazole [50] as salvage therapy in patients with CNS cryptococcosis refractory to other recommended therapies. The 2010 guidelines state that salvage therapy with either fluconazole (800–1200 mg/day oral), voriconazole (200–400 mg oral b.i.d.), or posaconazole (200 mg oral q.i.d. or 400 mg oral b.i.d.) may be considered in relapsed patients after induction therapy and in-vitro susceptibility testing [6]. Echinocandins are inactive against Cryptococcus species, and are therefore not used to treat cryptococcosis.

Optimal outcomes in patients with CNS cryptococcosis also depend on the successful management of elevated cerebrospinal fluid (CSF) pressure, which frequently accompanies the disease. Elevated CSF pressure can be relieved with lumbar puncture and drainage when there is evidence of pressure of at least 25 cm of CSF and symptoms indicative of increased intracranial pressure [6]. Repeat daily lumbar punctures may be required for persistent pressure elevation of at least 25 cm of CSF until the pressure and symptoms stabilize for more than 2 days. Permanent ventriculoperitoneal shunts may be utilized when other options fail to lower intracranial pressure and associated symptoms.

Generally speaking, when treating a patient with cryptococcosis it is important to institute early, aggressive antifungal therapy to appropriately manage elevated CSF pressure when present in a patient with CNS disease and to provide supportive care. When these goals are achieved, most patients respond well. Patients with nonpulmonary, non-CNS cryptococcosis or crytococcemia are managed similarly to those with CNS cryptococcosis [6].

Infectious Diseases Society of America treatment guidelines for histoplasmosis

Histoplasmosis refers to disease caused by the dimorphic fungus Histoplasmosis capsulatum, endemic in the Mississippi and Ohio River valleys of the United States and areas of Central America, South America, southeastern Asia, and Africa, as well as southern Europe, particularly regions constituting the Mediterranean basin [7,51,52]. Infection typically occurs following inhalation of H. capsulatum and release of its conidia into the structure of the lung. However, most individuals infected by H. capsulatum do not develop symptomatic disease or experience only mild pulmonary symptoms. Histoplasmosis commonly develops in infected individuals with very weakened immune systems or, more rarely, immunocompetent individuals exposed to an especially large inoculum [51,52].

The usual clinical presentation of histoplasmosis is pneumonia or acute pulmonary histoplasmosis, which may develop into chronic cavitary pulmonary histoplasmosis [7,52]. Potential complications of pulmonary histoplasmosis include pericarditis, rheumatologic syndromes, mediastinal lymphadenitis, mediastinal granuloma, mediastinal fibrosis, broncholithiasis, histoplasmomas and pulmonary nodules or coin lesions. Some patients with histoplasmosis develop chronic progressive or rapidly acute and often fatal disseminated disease. Focal involvement of particular organ systems, including CNS, cardiovascular, gastrointestinal, adrenal, or ocular, is also possible. Many cases of histoplasmosis do not require specific antifungal or other therapy and resolve on their own, whereas others can be treated with anti-inflammatory therapy. Some cases require antifungal therapy. Therefore, the clinician managing a patient with histoplasmosis must decide whether treatment is required, and if so, what particular treatment, considering that some forms of histoplasmosis are associated with significant morbidity and life-threatening disease, whereas others are essentially asymptomatic or self-limiting.

In 2007, the IDSA provided updated clinical practice guidelines for the management of histoplasmosis [7]. Unfortunately, as is generally the case for other endemic mycoses, there have been few recent major studies of histoplasmosis to better guide treatment recommendations. Many of the recommendations rely on data generated several years ago. However, the 2007 IDSA guidelines have made an attempt to evaluate the latest data involving newer antifungals such as lipid formulations of amphotericin B and the second-generation triazoles voriconazole and posaconazole, and to incorporate these into the treatment guidelines where possible. The cornerstones of contemporary antifungal therapy for histoplasmosis are itraconazole for mild-to-moderate disease and traditional or lipid formulations of amphotericin B for moderately severe to severe disease.

Acute and chronic pulmonary histoplasmosis

The 2007 guidelines state that antifungal agents for the treatment of mild-to-moderate acute pulmonary histoplasmosis are usually unnecessary. The guidelines recommend itraconazole [200 mg four times daily (t.i.d.) for 3 days, then 200 mg daily (q.d.) or b.i.d. for 6–12 weeks] for patients who continue to have symptoms for more than 1 month [7]. For patients with moderately severe or severe acute pulmonary histoplasmosis, the guidelines recommend first-line therapy with a lipid formulation of amphotericin B for 1–2 weeks, followed by itraconazole (200 mg t.i.d. for 3 days, then 200 mg b.i.d. for a total of 12 weeks). Traditional amphotericin B deoxycholate is considered a suitable alternative to a lipid formulation for patients at low risk for nephrotoxicity. Antifungal therapy may be supplemented by methylprednisolone during the first 1–2 weeks of therapy for patients with moderately severe or severe disease who develop respiratory complications. For patients with chronic cavitary pulmonary histoplasmosis, the guidelines recommend itraconazole (200 mg t.i.d. for 3 days, then 200 mg q.d. or b.i.d.) for at least 1 year, although some clinicians may prefer to use itraconazole for 18–24 months to further reduce the likelihood of relapse.

Complications of pulmonary histoplasmosis

Antifungal or other pharmacologic therapy is not recommended for patients with complications of histoplasmomas, broncholithiasis, or mediastinal fibrosis, although itraconazole (200 mg q.d. for 12 weeks) is recommended when clinical findings cannot differentiate mediastinal fibrosis from mediastinal granuloma [7]. Treatment is usually unnecessary for mediastinal lymphadenitis or mediastinal granuloma. Symptomatic cases of mediastinal granuloma are treated with itraconazole (200 mg t.i.d. for 3 days, then 200 mg q.d. or b.i.d. for 6–12 weeks). The guidelines recommend 1–2 weeks of prednisone therapy for patients with a severe case of mediastinal lymphadenitis and obstruction or compression of contiguous structures. Itraconazole is recommended for patients with mediastinal lymphadenitis warranting corticosteroid therapy or when symptoms persist for more than 1 month.

NSAID therapy is recommended for patients with pulmonary histoplasmosis complicated by mild cases of pericarditis or rheumatologic syndromes. When these complications are severe, the guidelines recommend 1–2 weeks of prednisone therapy, together with itraconazole (200 mg t.i.d. for 3 days, then 200 mg q.d. or b.i.d. for 6–12 weeks) [7].

Progressive disseminated histoplasmosis

Two weeks of L-AMB therapy is recommended for patients with moderately severe to severe progressive disseminated histoplasmosis, followed by oral itraconazole (200 mg t.i.d. for 3 days, then 200 mg b.i.d. for a total of at least 12 months) [7]. For mild-to-moderate disease, the 2007 guidelines recommend itraconazole (200 mg t.i.d. for 3 days, then 200 mg b.i.d. for at least 12 months). Lifelong itraconazole therapy (200 mg/day) is recommended for immunocompromised patients for whom immunosuppression cannot be reversed.

Central nervous system histoplasmosis

The recommended therapy for patients with CNS histoplasmosis is 4–6 weeks of L-AMB, followed by itraconazole (200 mg b.i.d. or t.i.d.) for at least 12 months and until resolution of CSF abnormalities [7].

Alternatives to itraconazole for different forms of histoplasmosis

The 2007 guidelines note that several studies involving a small number of patients have demonstrated successful outcomes with the use of voriconazole [53–56] or posaconazole [57,58] for a variety of different forms of histoplasmosis. However, the data from these studies is inadequate to make an evidence-based recommendation for primary therapy. In addition, the guidelines review other studies suggesting fluconazole is a suitable but less effective alternative to itraconazole [59–61], and that ketoconazole is an effective and less expensive (but more toxic) alternative that may be useful in some milder cases of histoplasmosis. After considering the available evidence, the guidelines consider all these triazoles (fluconazole, ketoconazole, voriconazole, and posaconazole) to be suitable second-line alternatives to itraconazole for patients intolerant to or unable to obtain itraconazole treatment [7]. Ketoconazole is rarely used due to its toxicity compared with other triazoles.

Infectious Diseases Society of America treatment guidelines for coccidioidomycosis

Coccidioidomycosis is a dimorphic endemic mycosis caused by inhaling the spores of Coccidioides immitis or Coccidioides posadasii[8,62]. Most cases of coccidioidomycosis in the United States are reported in Arizona or the southern portion of the San Joaquin Valley of central California, and more rarely in portions of the southwestern states Nevada, Texas, Utah, and New Mexico. Most individuals infected with C. immitis or C. posadasii are asymptomatic. For those who do develop symptomatic disease, the most common manifestation is a self-limited acute or subacute pneumonia that is often confused with bacterial community-acquired pneumonia. A smaller percentage of usually severely immunocompromised individuals develop chronic progressive pneumonia or disseminated extrapulmonary disease.

The 2005 clinical practice guidelines from the IDSA highlight the roles of triazoles and standard or lipid formulations of amphotericin B in the management of the various manifestations of coccidioidomycosis [8]. For uncomplicated acute coccidioidal pneumonia, the guidelines note that most patients do not require treatment, only periodic assessment to ensure the condition resolves without antifungal therapy. Initiation of antifungal therapy is usually required when the condition occurs in a patient who is immunosuppressed or has diabetes mellitus or cardiopulmonary disease. In such cases, the patient is commonly given a course of itraconazole (200–400 mg/day) ranging from 3–6 months in duration. Clinicians may also consider fluconazole (400 mg/day) or posaconazole (400 mg b.i.d.) as alternative options. Antifungal therapy or resection is not indicated in patients with an asymptomatic pulmonary nodule or with asymptomatic pulmonary cavities. Triazole therapy may or may not be initiated in patients with symptomatic pulmonary cavities.

For patients with diffuse pneumonia, the guidelines recommend initiation of treatment with an amphotericin B formulation or high-dose fluconazole, noting that an amphotericin B is the more common choice for initial therapy, particularly when significant hypoxia is present or there is rapid deterioration [8]. Resolution with an amphotericin B formulation typically requires several weeks of therapy, after which amphotericin B may be replaced with an oral triazole. The combined length of therapy with amphotericin B and triazole should be at least 1 year. Triazole therapy may be continued indefinitely for prophylaxis in patients with continued severe immunosuppression. For patients with chronic progressive fibrocavitary pneumonia, the guidelines recommend initiating treatment with an oral triazole. Treatment should be continued for at least 1 year if there is sufficient improvement. When the condition does not improve sufficiently with initial therapy, consideration should be given to using an alternative triazole or switching to amphotericin B. The roles of newer triazoles are not well established at this time, although a recent study reported promising activity with posaconazole (400 mg/day for up to 6 months) in patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis [63].

Recommended initial therapy for patients with disseminated extrapulmonary nonmeningeal coccidioidomycosis is an oral triazole, usually fluconazole (400 mg/day or higher doses up to 2000 mg/day, according to some experts) or itraconazole (400 mg/day or higher doses up to 800 mg/day) [8]. A randomized, double-blind, placebo-controlled trial reported similar activity for fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis [64]. Recommended alternative therapy is amphotericin B deoxycholate or a lipid formulation of amphotericin B [8]. For patients with disseminated meningeal coccidioidomycosis, the 2005 guidelines identify fluconazole or itraconazole as usual initial therapy, although some clinicians begin treatment with intrathecal amphotericin B together with triazole administration [8]. Patients who fail to respond to initial treatment with fluconazole or itraconazole alone may be considered for intrathecal amphotericin B, with or without continuation of triazole therapy. Patients who respond to initial triazole treatment alone should be continued on that therapy indefinitely.

As mentioned, the role of newer triazoles in the management of coccidioidomycosis is currently being investigated. Promising activity for posaconazole has been reported when used as initial therapy in patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis [63], and when used as salvage therapy for pulmonary or disseminated meningeal or nonmeningeal coccidioidomycosis refractory to standard treatment [50,65–67]. Similarly, there are a small number of reports of promising activity of voriconazole alone [54,68,69] or in combination with L-AMB [70] as salvage therapy for refractory coccidioidal meningitis. Voriconazole has also exhibited promising activity in two patients with disseminated nonmeningeal coccidioidomycosis, and one with pulmonary coccidioidomycosis refractory to standard therapy [54].

With respect to echinocandins, one case study reported successful treatment of refractory disseminated coccidioidomycosis with caspofungin [71], whereas another reported an apparent failure of caspofungin therapy in a case of refractory disseminated meningeal coccidioidomycosis [72]. A third study reported successful use of combination therapy with fluconazole and caspofungin in a patient with disseminated nonmeningeal coccidioidomycosis refractory to amphotericin B deoxycholate treatment [73].

Infectious Diseases Society of America treatment guidelines for blastomycosis

Blastomycosis is usually caused by inhalation of conidia from the mold form of the dimorphic fungus B. dermatitidis, and very rarely via cutaneous inoculation following a bite from a B. dermatitidis-infected dog [9,51,74]. B. dermatitidis is endemic to specific regions of the United States and Canada, including the southeastern and south central states that border the Mississippi and Ohio Rivers, the upper midwestern states adjacent to the Great Lakes, and the Canadian provinces that border the Great Lakes and Saint Lawrence Seaway, although sporadic cases have been reported in Colorado, Texas, Kansas, and Nebraska. There have also been some cases reported in parts of Africa and the Mediterranean basin. Blastomycosis is associated with a range of disease, most commonly pulmonary manifestations that vary from subclinical infection to acute or chronic pneumonia and, in rare cases, severe diffuse pneumonia linked with acute respiratory distress syndrome and often death. Disseminated extrapulmonary disease is also relatively common, particularly in immunosuppressed patients. It most commonly involves the skin and, more rarely, the genitourinary tract, osteoarticular structures, or CNS.

The 2008 clinical practice guidelines for management of blastomycosis note that many immunocompetent individuals with mild acute pulmonary blastomycosis will spontaneously recover and may not require antifungal therapy [9]. However, the guidelines also state clinicians should consider treating even these patients to prevent extrapulmonary dissemination. Moderately severe to severe pulmonary blastomycosis or disseminated extrapulmonary blastomycosis are clear indications for antifungal therapy. For patients with mild-to-moderate pulmonary blastomycosis, the guidelines recommend oral itraconazole (200 mg t.i.d. for 3 days, then 200 mg b.i.d., for 6–12 months total therapy). For those with moderately severe to severe pulmonary blastomycosis, the guidelines recommend initial treatment with a lipid formulation of amphotericin B or amphotericin B deoxycholate for 1–2 weeks or until improvement, followed by oral itraconazole (200 mg t.i.d. for 3 days, then 200 mg b.i.d.) for 6–12 months total therapy.

Therefore, the treatment recommendations are similar for disseminated extrapulmonary blastomycosis and pulmonary blastomycosis, based on disease severity (itraconazole for mild-to-moderate disease and amphotericin B followed by itraconazole for patients with life-threatening blastomycosis). Amphotericin B followed by itraconazole is also recommended therapy for immunosuppressed patients with any form of blastomycosis for whom lifelong suppressive therapy with oral itraconazole (200 mg/day) may be required if immunosuppression cannot be reversed. Lifetime itraconazole therapy may also be required in immunosuppressed patients who experience relapse despite appropriate therapy.

For the special cases of patients with CNS blastomycosis, the guidelines recommend initial treatment with a lipid formulation of amphotericin B for 4–6 weeks, followed by an oral triazole for at least 12 months and until resolution of CSF abnormalities [9]. Specified options for triazole therapy include itraconazole (200 mg b.i.d. or t.i.d.), fluconazole (800 mg/day), or voriconazole (200–400 mg b.i.d.). Voriconazole exhibits good CNS penetration and is the treatment of choice for invasive aspergillosis, including CNS aspergillosis [5]. A number of case studies and small series have reported successful outcomes when using voriconazole either as salvage therapy or as step-down therapy following initial treatment with amphotericin B for patients with blastomycosis of the CNS [75–79]. Voriconazole has also shown promising activity when used as initial or salvage therapy for a limited number of patients with pulmonary blastomycosis [54]. Despite the lack of a formal study evaluating voriconazole as treatment for CNS blastomycosis, Ta et al.[80] recently concluded after a review of the existing literature that voriconazole should be considered as an option in patients with CNS blastomycosis for either follow-up therapy after L-AMB therapy or as salvage therapy in patients intolerant of or unsuccessfully treated with amphotericin B or other triazoles. Posaconazole has demonstrated in-vitro and preclinical activity against B. dermatitidis[81], but there are no formal reports of posaconazole in patients with blastomycosis. Although ketoconazole has activity against B. dermatitidis, it is seldom used due to toxicity concerns [9,74].

Infectious Diseases Society of America treatment guidelines for sporotrichosis

Sporotrichosis is caused by conidia from the dimorphic fungus Sporothrix schenckii, which is ubiquitous in decaying vegetation, moss, and soil, particularly in tropical or subtropical zones of the world [10,51,82]. Infection usually occurs after exposure of traumatized skin to S. schenckii in the environment, or following bites or scratches from infected cats or armadillos. More rarely, infection follows inhalation of S. schenckii. Sporotrichosis acquired through the skin usually remains localized to the skin (fixed cutaneous sporotrichosis) or to the skin and subcutaneous tissue (lymphocutaneous sporotrichosis). Sporotrichosis acquired through inhalation usually gives rise to localized pulmonary sporotrichosis. However, S. schenckii can disseminate from the initial site of infection, either cutaneous or pulmonary, to other sites including the skin, lungs, meninges, or osteoarticular structures, particularly in immunocompromised individuals or those with underlying conditions such as diabetes mellitus, COPD, or alcoholism. Sporotrichosis rarely resolves spontaneously, and almost all patients with the condition require antifungal therapy of long duration. Chronic suppressive therapy is the rule, because relapsing disease is common. Cutaneous and lymphocutaneous sporotrichosis are the most common forms and are relatively easily treated, whereas other forms of sporotrichosis are more difficult to treat. Recently, the situation has become more complex, as a number of new Sporothrix species have been proposed, including Sporothrix brasiliensis, Sporothrix globosa, and Sporothrix mexicana, among others [83–85].

In 2007, the IDSA provided updated guidelines for the management of the various forms of sporotrichosis with itraconazole and amphotericin B formulations playing prominent roles, as they generally do for the other endemic mycoses [10]. More specifically, for cutaneous and lymphocutaneous sporotrichosis, the guidelines recommend treatment with itraconazole (200 mg/day oral) for 2–4 weeks after resolution of all lesions, which generally results in a total treatment duration of 3–6 months. A larger amount of itraconazole (200 mg b.i.d.), terbinafine, or a saturated solution of potassium iodide should be given to patients unresponsive to initial itraconazole therapy. Fluconazole may be considered an alternative for patients intolerant to these other agents. Voriconazole has limited in-vitro activity against Sporothrix spp and should not be recommended for use in this condition.

For patients with severe or life-threatening pulmonary sporotrichosis, the guidelines recommend initial therapy with a lipid formulation of amphotericin B until favorable improvement, followed by step-down therapy with itraconazole (200 mg b.i.d. oral) for a total of at least 12 months [10]. Amphotericin B deoxycholate is considered a less-preferable alternative to a lipid formulation for initial therapy. For patients with less severe pulmonary sporotrichosis, the guidelines recommend itraconazole (200 mg b.i.d. oral) for at least 12 months.

The recommended treatments for disseminated systemic sporotrichosis and meningeal sporotrichosis are similar to those for severe pulmonary sporotrichosis: initial treatment with a lipid formulation of amphotericin B for 4–6 weeks, followed step-down therapy with itraconazole (200 mg b.i.d.) after response to initial amphotericin B therapy for a complete total treatment duration of at least 12 months [10]. The recommended treatment for osteoarticular sporotrichosis is itraconazole (200 mg b.i.d. oral) for at least 12 months. An acceptable alternative is initial treatment with a lipid formulation of amphotericin B or amphotericin B deoxycholate until favorable response, followed by itraconazole (200 mg b.i.d. oral) to complete a total of at least 12 months of therapy.

Conclusion

Triazoles play an important role in the management of a broad array of invasive mycoses. Voriconazole remains the agent of choice for patients with invasive aspergillosis, including severe disease. For candidiasis—the most common of the invasive mycoses—fluconazole remains the azole of choice for most patients with milder disease. Voriconazole offers no advantage for most patients, but may be used in patients with C. krusei and fluconazole-resistant, voriconazole-susceptible isolates. Fluconazole plays a major role in the management of nonlife-threatening pulmonary forms of cryptococcosis, and as step-down therapy for life-threatening CNS forms of cryptococcosis. Itraconazole remains a key component of antifungal therapy for the endemic mycoses, histoplasmosis, coccidioidomycosis, sporotrichosis, and blastomycosis. For most of these conditions, several months of continuous therapy is advised, and itraconazole, like other triazoles, is associated with little toxicity and high tolerability. Continuing research should help to better define the roles of the newer triazoles voriconazole and posaconazole in management of invasive mycoses.

Acknowledgement

This supplement was supported through an educational grant from Merck & Co., Inc.

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Keywords:

aspergillosis; blastomycosis; candidiasis; coccidioidomycosis; cryptococcosis; histoplasmosis; invasive mycoses; sporotrichosis; treatment guidelines

© 2011 Lippincott Williams & Wilkins, Inc.