Invasive Fungal Infections in Immunocompromised Patients: A Review of Antifungal Agents

US Pharm. 2006;31(1)(Oncology suppl):3-15.

Fungal infections are a major cause of morbidity and mortality in immunocompromised patients. Filamentous mold and yeast-like fungi are ubiquitous organisms found worldwide in many different media. The Candida species are the most common cause of fungal infections. However, epidemiologic shifts have begun to occur, most likely due to the prophylactic and empiric use of antifungal agents. Emerging fungal pathogens, such as Aspergillus, Fusarium, and Zygomycetes, are changing the clinical spectrum of fungal diagnoses. Pharmacists have more choices than ever before to aid in the treatment of these highly morbid and lethal infections.

Pathogens
Fungi are opportunistic pathogens that take advantage of immune system defects and are capable of causing disease in many sites and settings. Common fungal infections are cutaneous (including nails), disseminated fungemia, pneumonia, peritonitis, osteomyelitis, and endocarditis. Fungal infections may also occur following various types of traumatic injuries.

General risk factors for invasive fungal infections are exposure to pathogens, an impaired immune system, and fungal spores. The presence of a colonized environment, partnered with a disruption in a physiologic barrier, potentiates the risk of an invasive fungal infection in an immunologically impaired host, such as a patient infected with HIV, someone taking chronic systemic steroids, or a transplant recipient. In addition, contaminated implanted devices (e.g., catheters, prostheses), external devices (e.g., contact lenses), and community reservoirs (e.g., hand lotion, pepper shakers) have all been implicated as sources of fungal outbreaks.¹

The Candida species are particularly hard to eradicate from infections that involve implanted foreign bodies because they have been shown to create a protective barrier over colonies as they are established. The exopolymeric nature of these protective biofilms limits the access of antifungal agents to the pathogens, decreasing the possibility of a cure when the foreign body still resides within the patient. The filtering effect of the biofilm, along with the varying fungal colony growth rates and the ability to excrete antifungals from the colony within the film, may be key factors in the persistence of candidal infections, despite adequate antifungal levels and susceptible organisms.² 

Candida albicans continues to be the most frequent cause of invasive fungal infections in most patient populations. However, prophylaxis and the widespread use of antifungal agents as empiric therapy for neutropenic fever have led to a shift in the epidemiology of invasive Candida infections. Infections with species other than C. albicans (Candida glabrata, Candida parapsilosis , Candida tropicalis, Candida krusei, and Candida lusitaniae ) are becoming more prevalent. Fluconazole prophylaxis selects for these emerging species and as a result, they are more likely to be resistant to triazole antifungal agents. Due to susceptibility variations between species, species identification and susceptibility testing have become important tools. ³

The second most common fungal pathogen to cause invasive fungal disease is Aspergillus. Found worldwide, Aspergillus is able to thrive in almost every environment. The organism is found primarily in soil but is also commonly isolated from water, food, and air. The usual route of infection for invasive aspergillosis is via inhalation of conidia (asexual spores). As a result, the lung is the most common location of invasive infection. The sinuses, central nervous system, and skin are also areas that can become infected. Clinically, the most common species to cause infection are Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, and Aspergillus niger . Despite the availability of antifungal agents to treat infections caused by Aspergillus, the morbidity and mortality of invasive aspergillosis remains high.⁴

Although still rare, infections caused by the mold pathogens Fusarium and Zygomycetes are increasingly prominent.^5,6 Fusarium can cause a wide variety of fungal infections. Resistance to antifungal agents is common; therefore, Fusarium infections are highly lethal. However, there have been recent reports of successful treatment with voriconazole.⁷ Zygomycosis (commonly called mucormycosis) is an extremely aggressive fungal infection that causes angioinvasive disease.⁸ It typically involves the sinuses and spreads rapidly to the brain, resulting in a very high mortality rate. Cutaneous disease is less common but is associated with a better outcome. Unfortunately, amphotericin B products are the only antifungal agents currently available on the market with adequate coverage of species within this class.

Antifungal Therapy
Diagnosing invasive fungal infections early, reliably, and definitively continues to be a major challenge to practitioners. As a result, empiric therapy is generally initiated in response to a persistent fever in a vulnerable patient.⁹ Suspicion for a fungal infection is increased when other types of infections, such as viral or bacterial, have been ruled out and the patient is known to have fungal colonization or suspicious radiographic findings. Through the correlation of known host factors, microbiologic knowledge, and clinical input, a probable fungal infection can be imputed. This is considered appropriate criteria for beginning empiric antifungal therapy aimed at the most likely pathogen in that patient population.¹⁰ One example of such a clinical system, validated in cancer and hematopoietic stem cell transplant (HSCT) patients, is found in table 1. Empiric therapy is generally begun with a single agent targeted at the most common pathogen. For Candida , this is usually a triazole antifungal, such as fluconazole. Fluconazole is still considered the agent of choice for C. albicans. However, if another Candida species is suspected, an echinocandin should be selected for its broader spectrum of activity. If a mold is suspected, an amphotericin product is generally chosen empirically. However, depending on the certainty of the diagnosis and each patient's specific clinical situation, an extended-spectrum triazole (e.g., voriconazole) or an echinocandin (e.g., caspofungin), both of which have anti-Aspergillus activity, may be chosen instead. These newer agents are approved for the treatment of Aspergillus but have variable levels of activity against other types of filamentous fungi, such as Fusarium and Zygomycetes.

Combination antifungal therapy has become an area of interest due to the high rates of morbidity and mortality associated with fungal infections. This tactic was recognized as an important tool in the treatment of cryptococcal meningitis when flucytosine was combined with amphotericin B. However, the clinical use of combination therapy for either established fungal infections or drug-resistant species had been slow to develop due to in vitro reports of decreased efficacy and possible antagonism when amphotericin and azoles were used in combination. Antagonism between these two agents is possible because of their mechanisms of action. (Azoles block ergosterol synthesis, whereas amphotericin causes membrane damage by binding to ergosterol.)  Yet, with the advent of echinocandins and extended-spectrum triazoles, combination antifungal therapy is an area where research has developed dramatically. Echinocandins inhibit the synthesis of (1,3)-beta-D-glucan (a component of the fungal cell wall), therefore targeting a different cellular site than azoles or amphotericin. To improve cure rates against various fungal pathogens (primarily Aspergillus ), combinations of an echinocandin and a triazole or amphotericin B are being investigated. Good outcomes with combination therapy involving in vitro studies, animal data, and case reports have been published. In fact, triple therapy has been used in at least one case report.¹¹ An observational study evaluating the use of voriconazole and caspofungin as salvage therapy for invasive aspergillosis against a historical group that received voriconazole alone reported promising effects of combination therapy. ¹² However, comparative clinical data are limited, and the benefit of combination antifungal therapy still remains uncertain.

Polyenes: Polyenes act by binding to ergosterol within the fungal cell wall, creating pores that increase permeability and cause leakage of fungal cell contents. Amphotericin B is the only systemic agent to belong to the polyene class of antifungals. Four amphotericin B formulations are currently available on the market. For more than 40 years, conventional amphotericin B deoxycholate (Fungizone) has been the standard therapy for invasive fungal infections. Three lipid-based formulations are also available: amphotericin B colloidal dispersion (Amphotec), amphotericin B lipid-complex (Abelcet), and liposomal amphotericin B (Ambisome). All four formulations have excellent activity against a wide range of fungal pathogens, and resistance to these agents is rare. The major advantages of the lipid preparations are that they achieve higher concentrations in the reticuloendothelial organs (liver, lung, and spleen), they have fewer infusion-related reactions, and they are less nephrotoxic than conventional amphotericin B. However, superior clinical efficacy over conventional amphotericin B has not been established in clinical trials, and the lipid formulations are significantly more expensive in comparison.

It is well known that amphotericin B is associated with significant adverse events. Acute infusion-related reactions, such as fever, chills, rigors, and hypotension, are most common with the conventional formulation. However, these reactions can also occur with lipid formulations. The reactions are most frequent during the initial infusions of amphotericin B and often diminish with subsequent infusions. Premedication with antipyretics, antihistamines, and corticosteroids will usually lessen these effects. Amphotericin B causes a dose-dependent decrease in the glomerular filtration rate that is dose-limiting. Permanent loss of renal function is thought to be related to the cumulative total dose, rather than the level of temporary azotemia. Sodium loading with 500 to 1,000 mL of normal saline prior to each infusion is believed to lessen the nephrotoxic effects, but its exact effects are uncertain.¹³ Amphotericin B can also cause significant electrolyte abnormalities (hypomagnesemia and hypokalemia). These effects occur in the majority of patients within the first week of therapy. Electrolytes should be monitored daily and replaced as needed.

Doses of amphotericin B deoxycholate for the treatment of invasive fungal infections range from 0.5 to 1.5 mg/kg/day. Higher doses (1 to 1.5 mg/kg/day) are usually utilized for patients with invasive aspergillosis or mucormycoses. Although the incidence of acute hypersensitivity reactions is rare, and many clinicians feel that it is unnecessary, a test dose of 1 mg can be administered. Initial doses of the lipid preparations range from 2.5 to 5 mg/kg/day. Dosage adjustments for renal or hepatic dysfunction are unnecessary for any of the formulations, but renal insufficiency often limits its use. Drug interactions with amphotericin products are minimal. However, concomitant administration with other nephrotoxic drugs (e.g., aminoglycosides and cyclosporine) warrants caution.

Triazoles: Triazole antifungals agents exhibit their effects by blocking the synthesis of ergosterol, a component of the fungal cell wall. As a result, the integrity of the cell wall is compromised, and increased permeability leads to cell lysis and subsequent cell death. Fluconazole, itraconazole, and voriconazole are available in both oral and intravenous formulations. The less toxic effects to the kidneys make triazoles a more desirable choice than amphotericin B. However, due to their effects on the liver enzyme systems, drug interactions are common with these agents. The susceptibility patterns of triazoles vary for different species of yeast and molds.

Fluconazole has excellent activity against most species of Candida. However, the use of this agent for prophylaxis has resulted in increased resistance among non- albicans species. Fluconazole is not active against Aspergillus, Fusarium, or Zygomycetes. The dosage of fluconazole varies greatly depending on the infection site and species of Candida. Normal doses of fluconazole vary from 100 mg daily for oropharyngeal infections to 800 mg daily for serious infections. Oral formulations are highly bioavailable; thus, oral and intravenous dosages are the same. Renal dysfunction requires dosage adjustment. Adverse effects of fluconazole include headache, gastrointestinal disturbances, rash, and hepatic dysfunction. Fluconazole is excreted primarily in the urine as unchanged drug. However, it does inhibit the liver enzyme systems cytochrome P450 (CYP) 2C8/9, CYP2C19, and CYP3A4. Drug interactions are common but are less significant than other agents within this class. See table 2 for drug interactions.

In addition to activity against Candida, itraconazole also has activity against Aspergillus. Oral formulations are poorly bioavailable. Oral capsules should be taken with food, whereas the oral solution should be taken on an empty stomach. Oral itraconazole should not be administered with antacids or other medications that affect gastric pH because coadministration can decrease absorption significantly. The appropriate dosage of intravenous itraconazole for Aspergillus is 200 mg twice daily for four doses, followed by 200 mg daily. Intravenous itraconazole should be avoided in patients with creatinine clearances of less than 30 mL per minute due to reduced clearance of the intravenous vehicle hydroxypropyl-beta-cyclodextrin. Oral itraconazole should be taken as a 200-mg dose three times daily for three days, followed by 200 mg twice daily. The oral solution has an undesirable taste, which is poorly masked despite attempts at flavor enhancement. The most common adverse effect is dose-related gastrointestinal upset. Other adverse effects include headache, rash, and elevated liver function tests. Itraconazole is a substrate and inhibitor of CYP3A4. As a result, there are many significant drug interactions. See table 2.

Exhibiting activity similar to fluconazole against Candida, voriconazole also has added coverage of Aspergillus, Fusarium, and several other yeasts and molds. Voriconazole is generally well tolerated but has significantly more side effects and drug interactions than fluconazole. The most common side effect is visual disturbances, occurring in approximately 30% of patients. Visual disturbances (e.g., color changes, blurry vision, photophobia, decreased visual acuity, rare hallucinations) appear in approximately one third of patients within the first week of therapy. These visual effects are reversible upon discontinuation; however, voriconazole is rarely discontinued secondary to these changes since the disturbances typically diminish or disappear during the course of therapy.¹⁴ Other less typical side effects are rash, elevated liver function tests, headache, and gastrointestinal irritation. Voriconazole is metabolized via CYP2C9, CYP3A4, and CYP2C19 isoenzymes in the liver. It also inhibits each of these enzymes. Consequently, the potential for drug interactions is extremely high (see table 2). Therapy with voriconazole should be initiated with two intravenous loading doses of 6 mg/kg every 12 hours. Maintenance therapy is 4 mg/kg intravenously every 12 hours or 200 mg orally twice daily for patients who weigh more than 40 kg. The dosage for patients who weigh less than 40 kg is 100 mg orally twice daily. Oral bioavailability exceeds 90%, and patients can be easily transitioned to oral therapy. Maintenance doses of voriconazole should be decreased by 50% in patients with mild to moderate hepatic dysfunction (Child-Pugh classes A and B). Voriconazole demonstrates nonlinear pharmacokinetics and considerable interpatient variability with regard to metabolism. As a result, some institutions are monitoring voriconazole drug levels.¹⁵ However, considering the uncertain availability of testing, this practice has not yet become routine, and the clinical significance still remains to be determined. Intravenous voriconazole should be avoided in patients with creatinine clearances of less than 50 mL per minute, secondary to accumulation of the intravenous vehicle sulfobutyl ether beta-cyclodextrin sodium.¹⁴

Echinocandins: The echinocandins caspofungin and micafungin exhibit their antifungal activity by inhibiting the synthesis of (1,3)-beta-D-glucan (a component of the fungal cell wall), resulting in reduced fungal cell wall integrity and subsequent cell death. Both agents are available only as intravenous formulations and have excellent activity against the majority of Candida species, including those resistant to triazoles. Echinocandins also have activity against Aspergillus but are only effective against actively growing and dividing forms. The activity of echinocandins against other fungal pathogens is variable.

Caspofungin is generally well tolerated. Adverse effects are headache, increased liver function tests, infusion site reactions, and other symptoms related to histamine release. Caspofungin undergoes hepatic metabolism via spontaneous peptide hydrolysis and N-acetylation. Metabolites are inactive and excreted primarily via the urine and feces. Caspofungin is not removed by dialysis, and dose adjustments for renal insufficiency are unnecessary. However, plasma concentrations increase with hepatic insufficiency. An initial dose of 70 mg is administered, followed by a 50-mg daily dose in patients with normal hepatic function. Patients with moderate hepatic insufficiency (Child-Pugh score 7–9) should receive the initial 70-mg loading dose, followed by a reduced daily dose of 35 mg. Dosage recommendations are not made for more severe hepatic dysfunction. Although caspofungin does not appear to inhibit P-glycoprotein or hepatic CYP enzymes, several drug interactions do exist (see table 3).

Approved in March 2005, micafungin is currently indicated for the treatment of patients with esophageal candidiasis and as prophylaxis of Candida infections in patients undergoing HSCT.¹⁷ The spectrum of antifungal activity is similar to that of caspofungin. The recommended dose for the prophylaxis of Candida infections in HSCT patients is 50 mg/day. The treatment of esophageal candidiasis requires 150 mg per day. Dose adjustment is not necessary for renal or hepatic impairment. Micafungin has an adverse effect and safety profile similar to that of caspofungin. However, micafungin is metabolized by catechol O-methyltransferase, does not affect P-glycoprotein, and appears to only minimally affect the CYP enzyme systems. As a result, significant drug interactions are minimal.

Pyrimidine: Flucytosine is the only agent in the pyrimidine class of antifungals. The antifungal effects of flucytosine are exerted by its conversion to 5-fluorouracil within the fungal cell and interference with fungal RNA and protein synthesis. It has activity against Candida, Cryptococcus , and several molds. However, resistance develops quickly when flucytosine is used as the sole antifungal agent; therefore, it is used usually only in combination with other agents. Its use is also significantly hampered by frequent and serious adverse effects such as bone marrow suppression, hepatic dysfunction, renal dysfunction, rash, and gastrointestinal disturbances. Flucytosine is given orally at doses of 50 to 150 mg/kg/day divided every six hours and requires dosage adjustment for renal dysfunction. Therapy often requires monitoring serum flucytosine concentrations to avoid the dose-dependent bone marrow suppression. Since this agent is primarily eliminated renally as an unchanged drug, interactions are minimal.

Investigational Agents: Several investigational antifungal agents may soon be available. Posaconazole and ravuconazole are triazole antifungals that are currently in various stages of development. Posaconazole has demonstrated in vitro activity against Zygomycetes.¹⁸ Anidulafungin is an investigational echinocandin that is now being evaluated in clinical trials.

Pharmacist's Role
Despite recent advances in antifungal therapy, fungal infections continue to be a significant threat to immunocompromised patients. It is important for the pharmacist to know the common fungal pathogens that are seen in various patient groups. By assessing patients' risk factors, culture results, radiographic information, organ function parameters, clinical symptoms, and comorbidities, pharmacists can guide both empiric and pathogen-directed therapy. Depending on the pathogen involved, significantly decreased renal function makes amphotericin products less appealing and increases the suitability of a triazole or echinocandin. Diminished hepatic function may require dose adjustments of some antifungals or lead the medication selection toward an agent that is metabolized via another route. Other medical conditions that require a patient to take interacting medications will also rule out or further guide the selection when multiple drugs have the potential to treat a patient's infection. An individual patient's drug of choice is rarely determined by a single therapeutic factor. It is frequently the pharmacist who is best able to sort through the many variables to choose the optimal medication.

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