Opportunistic Fungal Infections, Part 1: Antifungal Treatment and Prophylaxis

Patients with advanced HIV-1 infection, those who are receiving chemotherapy for malignancy, and transplant recipients (both hematopoietic stem cell transplant [HSCT] and solid organ transplant [SOT]) are among the populations of immunosuppressed patients at risk for fungal infections. The fungal infections acquired by these patients are a consequence of immunological deficits associated with the underlying disease or complications of therapy.

Diagnosis of fungal infections remains problematic. It is often based on clinical signs and symptoms in an at-risk person, and invasive procedures are frequently required for confirmation. Treatment options have improved with the introduction of newer antifungal classes and medications; however, the optimal treatment for certain infections, such as invasive aspergillosis and infections caused by other invasive moulds (eg, Fusarium species and Zygomycetes) remains controversial.

Prevention of fungal disease is dependent on minimizing exposure and having a functioning immune system. Because these conditions may not be possible to achieve in at risk patients, antifungal prophylaxis has become an important part of care. Development of fungal vaccines remains inherently challenging, given that most vaccine technology relies on host immunity; however, novel approaches are being investigated and may be available in the future.

PATHOGENESIS

HIV-1-associated fungal disease

HIV-1 infection is characterized by the decline in CD4+ cell counts.

¹

The most common fungal pathogens are

Candida albicans

and

Cryptococcus neoformans

.

²

Active infection with C albicans results from overgrowth of the patient's endogenous flora, whereas other fungal infections are associated with exposure to conidia (probably through inhalation). In addition, HIV-1-infected patients are at risk for endemic mycoses, including those caused by

Histoplasma capsulatum, Coccidioides immitis, Coccidioides posadasii, H capsulatum

var

duboisii,

and

Penicillium marneffei.

Pulmonary aspergillosis was more common before the advent of potent antiretroviral therapy. Affected patients typically had low CD4+ T-cell counts (less than 50/?L) and neutropenia, and a history of corticosteroid use, exposure to broad-spectrum antimicrobial therapy, and previous pneumonia or underlying pulmonary disease.

³

Malignancy and neutropenia
Neutropenia (defined as an absolute neutrophil count [ANC] of less than 500/?L or less than 1000/?L in a patient who is clinically deteriorating) often develops in patients who receive chemotherapy for treatment of a malignant neoplasm.⁴ A nadir neutrophil count and protracted neutropenia (defined as an ANC of less than 500/?L for 10 days or more) are strong determinants of the development of opportunistic infection. ⁵ Fever is often the only clinical sign. Although virtually any fungus with low intrinsic virulence may infect patients with severe neutropenia, Candida and Aspergillus species are the most frequently identified organisms.²

HSCT
HSCT infusion of progenitor cells is typically performed to reestablish bone marrow components after ablative therapy. Allogeneic HSCT recipients have a profound impairment of host immune function during the first 4 to 5 months after engraftment, regardless of the type of graft, the underlying disease, the conditioning regimen, or the presence of acute graft versus host disease (GVHD). Immune reconstitution in most healthy long-term survivors is accomplished 1 to 2 years after engraftment, whereas the same process in patients with GVHD is delayed.

Risk of fungal infection is greatest during periods of neutropenia and GVHD. C albicans poses the greatest risk and is thought to result from unopposed growth at mucosal surfaces, leading to fungemia. SOT Infections in SOT recipients are dependent on exposure to the pathogens and the net state of immunosuppression. ⁶ Colonization with yeasts and moulds occurs frequently both in transplant candidates with end-organ disease and in recipients. Donor-related transmission of fungal infections to the organ recipient is uncommon but often involves an undetectable or quiescent infection in the donor's bloodstream or transplanted organ.⁷

The initial immunosuppressive medications used for antirejection therapy are similar in all forms of organ transplant and typically include cyclosporine or tacrolimus (Table 1). The risk of fungal infection varies depending on the type of organ transplanted, with lung transplant recipients at the highest risk because of airborne exposure and diminished mucociliary clearance.⁷

Table 1

ANTIFUNGAL CLASSES

Antifungal therapy is a mainstay of both prophylaxis against and treatment of fungal infections in immunocompromised persons. The medications differ in their spectrum of activity against major pathogens and in adverse effects. The major classes of antifungal medications are reviewed below and summarized in Table 2. Disease-specific indications for antifungal therapy will be reviewed in parts 2 and 3 of this series of articles.

Table 2

Polyenes
Amphotericin B deoxycholate was introduced in 1959. Because of the severe toxicity associated with this medication (most notably renal toxicity), lipid-based delivery technologies were developed. Currently, there are 3 FDA-approved lipid-based formulations of amphotericin B: amphotericin B complex, liposomal amphotericin B, and amphotericin B cholesteryl sulfate complex.⁸

As a class, polyenes have broadspectrum activity against Candida species, endemic fungi, and moulds. Amphotericin B deoxycholate and the lipid-based formulations are administered intravenously only. They have excellent tissue and body fluid penetration, and high concentrations in the cerebrospinal fluid (CSF) are achieved. Current dosing recommendations are given in Table 2.

Triazoles
Triazole antifungals were introduced almost 30 years ago. They include fluconazole, itraconazole, voriconazole, and posaconazole. Their mechanism of action involves inhibition of a fungal cytochrome-dependent enzyme that converts lanosterol to ergosterol, an essential molecule of the fungal cell membrane. Posaconazole is structurally similar to itraconazole, and voriconazole is structurally similar to fluconazole.⁹ The antifungal spectrum of the agents differs depending on the compound. Drug-drug interactions are common with this class.

Fluconazole has excellent in vitro activity against a wide variety of yeasts, including Candida species, with the exception of Candida krusei, which has intrinsic resistance to fluconazole, and Candida glabrata, which has decreased susceptibility to the drug. Fluconazole has limited activity against moulds.

The antifungal is very well absorbed by the GI tract (bioavailability of over 80%) and is available in oral and intravenous formulations. It has excellent diffusion into body fluids and tissues and achieves concentrations in the CSF that are at least 70% of blood levels even in the absence of inflamed meninges. Hepatic cytochrome P-450 (CYP) 2C9 plays a minor role in its metabolism. Dose adjustments for renal impairment are required.⁹ Ocular penetration of the antifungal is good as well.¹⁰

Fluconazole is metabolized via the liver and CYP isoenzymes; therefore, potential drug interactions must be considered. Dose reduction of tacrolimus, cyclosporine, and warfarin may be necessary when these drugs are coadministered with fluconazole. Levels of these drugs need to be monitored closely when they are used with fluconazole.¹⁰

Itraconazole has excellent in vitro activity against a wide variety of yeasts and moulds. Its absorption is more variable than that of fluconazole. The capsule is best absorbed with food, and the oral solution is better absorbed in a fasting state. It also has an intravenous formulation; however, it is no longer available in the United States.

Itraconazole does not penetrate the CSF. It is a substrate and strong inhibitor of CYP3A4, so drug-drug interactions are common.

Voriconazole is a second-generation azole antifungal that has excellent in vitro activity against a wide variety of yeasts and moulds. This drug is approved for the treatment of invasive aspergillosis and for the treatment of infections attributed to Pseudallescheria boydii, Scedosporium apiospermum, and Fusarium species in patients who are intolerant or refractory to other antifungal therapy.¹¹

Bioavailability of voriconazole following oral administration of either tablet or solution is 96%. Oral absorption is decreased by 22% when taken with food. There is also an intravenous formulation.

Voriconazole penetrates the blood-brain barrier, and CSF concentrations are approximately 46% of serum levels. Dose adjustment should be made in patients with mild to moderate hepatic disease, and the intravenous formulation should be used with caution in patients with a creatinine clearance of less than 50 mL/min/1.73 m2. The potential for drug interactions with voriconazole is high because of its metabolism by CYP isoenzymes. Dose reduction of tacrolimus, cyclosporine, and warfarin is necessary when any of these drugs are coadministered with voriconazole. Levels of these drugs should be monitored closely.^9,11

Posaconazole is a triazole antifungal with a spectrum of activity that includes yeastlike fungi, such as Candida and Cryptococcus species; many moulds, including Zygomycetes; and some endemic fungi. Posaconazole is approved for the treatment of oropharyngeal candidiasis and as prophylaxis for Aspergillus and Candida infections in persons at high risk for development of these infections (HSCT recipients with GVHD or hematological malignant neoplasms with prolonged chemotherapy-associated neutropenia).¹²

Posaconazole is available only as a suspension for oral use. Absorption is increased when taken with food, especially a fatty meal. Optimal absorption of the drug occurs when it is administered 4 times daily.⁹ Dose adjustment is not needed for patients with renal or hepatic dysfunction. Posaconazole inhibits hepatic CYP isoenzymes; therefore, when it is coadministered with tacrolimus or cyclosporine, the doses of the latter should be reduced to approximately three-fourths and one third, respectively, of the original doses, and serum levels should be monitored closely.¹²

Echinocandins
The echinocandins are noncompetitive inhibitors of (1,3)-?-glucan synthase, which results in the selective inhibition of glucan, an essential component of the cell wall of many pathogenic fungi. All currently available echinocandin preparations are intravenous and are poor substrates for CYP enzymes.

The antifungal spectrum of this class is restricted to Candida species and Aspergillus species, with few exceptions. This class is inactive against Zygomycetes, C neoformans, Fusarium species, and Trichosporon species. It may have some activity against C immitis, Blastomyces dermatitidis, H capsulatum, and Scedosporium species, but at this time, there is a lack of clinical data to support the use of echinocandins in diseases caused by these organisms.¹³

In general, this class has limited penetration into the CSF and urine. To date, acquired resistance to echinocandins in susceptible fungal yeastlike species has been extremely rare. Currently, there are 3 FDA-approved drugs in this class: caspofungin, micafungin, and anidulafungin. Subtle differences exist between each of these drugs, although there is no indication that one is clinically superior to the other.

Caspofungin was the first drug in the echinocandin class to receive FDA approval for the treatment of mucosal and invasive candidiasis and invasive aspergillosis. It is also approved for the empirical treatment of febrile neutropenia. No dose modifications are required in patients with renal insufficiency, and the drug is not discontinued during hemodialysis. Dose reduction is recom- mended for patients with moderate to severe hepatic insufficiency (Child-Pugh score, greater than 7).

Serum levels of caspofungin are increased by 35% when the drug is given concurrently with cyclosporine. Coadminstration of caspofungin with tacrolimus decreases tacrolimus levels by approximately 20%. As a result, monitoring of tacrolimus levels is recommended. Caspofungin is classified as pregnancy category C.¹⁴

Micafungin has received FDA approval for the treatment of mucosal and invasive candidiasis. No dose modifications are required in patients who have renal insufficiency or mild to moderate hepatic impairment.

Coadministration of micafungin with cyclosporine mildly inhibits cyclosporine metabolism; thus, monitoring of cyclosporine levels is prudent. Micafungin increases serum concentrations of sirolimus and nifedipine by 21% and 18%, respectively. Monitoring of drug levels is important to prevent toxicity.¹⁵

Anidulafungin is the newest echinocandin antifungal to be approved by the FDA for the treatment of esophageal candidiasis, candidemia, and deep tissue candidiasis. It is unique among the echinocandins because it slowly degrades in human plasma, undergoing a process of biotransformation rather than being metabolized.¹⁶ No dose modifications are required in patients with renal insufficiency or any degree of hepatic impairment.

PROPHYLAXIS AND TREATMENT

Febrile neutropenia

Caspofungin has been shown to be as effective as amphotericin B for empirical antifungal therapy in patients with persistent febrile neutropenia (defined as an ANC of less than 500/?L for at least 96 hours and temperature of greater than 38.0C [100.4F].)

¹⁷

In a randomized doubleblind trial of 1095 patients who were selected to receive either caspofungin or liposomal amphotericin B in a 1:1 ratio, the overall success rates were 33.9% for caspofungin and 33.7% for liposomal amphotericin B.

¹⁷

Among patients with baseline fungal infections, 51.9% who were treated with caspofungin had a successful outcome compared with 25.9% of patients treated with amphotericin B (P = .04). Rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in the 2 groups

Voriconazole has also been evaluated as empirical antifungal therapy in patients with persistent febrile neutropenia.¹⁸ In this large, multicenter, randomized trial, patients were selected to receive voriconazole (n = 415) or liposomal amphotericin B (n = 422). Overall success rates were 26% for the voriconazole arm and 30.6% for the liposomal amphotericin B arm. Fewer documented breakthrough fungal infections were seen in patients treated with voriconazole than in those who received liposomal amphotericin B (1.9% versus 5%; P = .02). However, the voriconazole group did not meet the predefined composite end point for noninferiority, compared with the liposomal amphotericin B group in relation to overall response to therapy. Because of this, the FDA did not approve voriconazole for empirical treatment of fungal infections in febrile neutropenic patients. The results of the trial as well as the FDA decision remain controversial.^11,19-22

Prophylaxis in high-risk
patients Fluconazole prophylaxis has been a mainstay of therapy in allogeneic HSCT recipients. When no prophylaxis is administered, invasive fungal infections, mainly due to C albicans and other Candida species, can be expected to develop in 16% to 18% of patients. Two randomized placebo- controlled trials in allogeneic bone marrow transplant recipients showed that fluconazole, given at a dosage of 400 mg qd, significantly reduced the incidence of superficial fungal infections, invasive fungal infections, and mycosis-related mortality. ^23,24 However, the benefits of fluconazole prophylaxis in high-risk patients with leukemia were less conclusive.²⁵

In SOT, liver transplant recipients should be stratified according to their risk factors for invasive fungal infections. It is recommended that those at high risk receive fluconazole prophylaxis.²⁶

Several studies have evaluated the use of itraconazole as prophylaxis, given its extended spectrum of antifungal activity, which includes Aspergillus. In a study of allogeneic HSCT recipients in which itraconazole was compared with fluconazole, fewer invasive fungal infections were detected in the itraconazole arm (9%) than in the fluconazole arm (25%).²⁷ In addition, itraconazole was compared with fluconazole as prophylaxis in liver transplant recipients. However, unlike the findings seen in HSCT recipients, the rate of proven invasive fungal infections was not statistically different between the 2 arms (9% in the itraconazole arm versus 4% in the fluconazole arm [P = .25]).²⁸ Use of itraconazole for prophylaxis has been limited because of issues regarding absorption and drug-drug interactions.

The only echinocandin that has been studied in the context of prophylaxis to date is micafungin, which proved to be more effective than the study comparator, fluconazole. ²⁹ Micafungin (50 mg qd) was compared with fluconazole (400 mg qd) as prophylaxis in 882 adult and pediatric patients undergoing autologous or allogeneic HSCT in a randomized double-blind trial. Overall success was 80% in the micafungin arm and 73.5% in the fluconazole arm (P = .03). Frequency of invasive fungal infections was similar between the 2 groups, with a trend toward reduced frequency of invasive aspergillosis in allogeneic HCST recipients in the micafungin arm.

Findings from 2 studies examining posaconazole prophylaxis suggest that the drug is safe and effective in patients at high risk for invasive fungal infections.^30,31 In the first trial, HSCT recipients with GVHD were randomly selected to receive either posaconazole (n = 301) at a dosage of 200 mg tid PO or fluconazole (n = 299) at a dosage of 400 mg qd PO.³⁰ There was no significant difference in the incidence of proven or probable fungal infections in the posaconazole arm (5.3%) compared with the fluconazole arm (9%; P = .07) at the end of 112 days; however, fewer invasive fungal infections were observed in the posaconazole arm than in the fluconazole arm (7 cases vs 22 cases; P = .004). No significant differences in mortality were seen between the 2 groups, but the observed rate of mortality attributed to invasive fungal infection was significantly lower in the posaconazole arm than in the fluconazole arm (1% vs 4%, respectively; P = .041).

In the other trial, which was open label, prophylactic posaconazole (200 mg tid PO) was compared with either fluconazole (400 mg qd PO) or itraconazole (200 mg qd PO) in 602 patients who were receiving myelosuppressive chemotherapy for hematological malignant neoplasms. Seven (2%) invasive fungal infections were identified in the posaconazole arm compared with 25 (8%) in the comparator arm (P < .001). Despite the lack of clinical trial data, voriconazole is often used as prophylaxis for HSCT recipients in lieu of fluconazole, given its broader antifungal spectrum.

Findings of a small double-blind trial investigating prophylactic voriconazole versus placebo in patients with acute myelogenous leukemia suggest that the drug is valuable in this setting.³² Ten patients received voriconazole 200 mg bid and 15 received placebo. The primary end point was the detection of lung infiltrates or resolution of neutropenia. The incidence of lung infiltrates up to day 21 was 0 (0%) in the voriconazole group and 5 (33%) in the placebo group. A randomized doubleblind clinical trial that compared the effectiveness of voriconazole with that of fluconazole in HSCT recipients has recently been completed and will provide further data regarding the value of voriconazole as prophylaxis against invasive fungal infections in high-risk patients.

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