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Read about the new class of antifungal therapy -- the echinocandins, and more. ...
New Antifungal Therapies for Treatment of Invasive Mycoses CME
http://www.medscape.com/viewarticle/546635
Thomas F. Patterson, MD
Disclosures
Release Date: August 11, 2006; Valid for credit through August 11, 2007
CME Information
Introduction
Systemic fungal infections are significant causes of morbidity and mortality in immunosuppressed patients. These infections are difficult to definitively diagnose, and, until very recently, options for therapy have been extremely limited. In order to effectively manage patients at risk for these infections, clinicians must identify patients at increased risk and recognize the factors associated with invasive mycoses. The etiologic agents of these infections have continued to change; more infections are due to yeasts other than Candida albicans, and unusual moulds have emerged as important causes of infection in severely immunosuppressed patients.
Regardless of these advances, management of these infections is challenging, due to the emergence of resistant organisms, the lack of reliable markers for early invasive infection in high-risk patients, and limited evidence of optimal strategies for utilizing available antifungals.[1]
Assessment for Risk Factors
Assessment of risk factors for these infections is critical in initiating early antifungal therapy. Specific risk factors can be suggestive of yeasts (including Candida species) or moulds, such as Aspergillus.
Candida
Candida is among the leading cause of nosocomial bloodstream infections worldwide.[2-4] Candida species are an important cause of sepsis in the intensive care unit (ICU) and have been shown to have increased by 207% from 1979 to 2000, which was the largest increase observed due to any group of organisms.[5] Risk factors for invasive candidiasis are common in seriously ill hospitalized patients in ICUs,[6] including Candida colonization, abdominal surgery, central vascular lines (often the major portal of entry in ICU patients), multiple or broad-spectrum antibiotics, use of total parenteral nutrition, and hospital length of stay (HLOS). Candida colonization increases when HLOS exceeds 3 days, with peak incidence of infection around day 10.[6] Similar risk factors are present in neonates, who also have increased risk due to prematurity and very low birth weight.[7]
Despite the recognition of risk factors for invasive Candida infection, it is difficult to predict which patients will develop infection because diagnostic tools, such as non-culture-based methods and even blood cultures, have limited utility.[8] Crude mortality rates of candidemia range from 30% to 61%.[3,9] Reasons include Candida's ability to form biofilm on catheters and other surfaces, which provides a difficult-to-eradicate nidus of infection.[10] However, the prevalence of colonization is high compared with that of infection; thus, the predictive value of colonization is poor. Nevertheless, colonization in ICU patients with unexplained fever, leukocytosis, and hypotension may be an important indication of invasive candidiasis.[6]
The epidemiology of Candida (the most virulent species[11]) infection has shifted from C albicans as the predominant species associated with nosocomial candidemia, which now comprises less than half of the isolates of candidemia worldwide,[2, 12-14] to a variety of non-albicans species. This change is due to a number of factors, including antifungal use, particularly fluconazole.
Aspergillus
Risk factors for invasive moulds, such as Aspergillus and other less common moulds, have also changed. The incidence of invasive aspergillosis has increased substantially during the last few decades. Patients at risk for invasive aspergillosis include those with severely compromised immune systems due to chemotherapy (with prolonged and deep neutropenia); solid organ, bone marrow, and hematopoietic stem cell transplant recipients (especially those treated with newer immunosuppressive therapies, such as the tumor necrosis factor-alpha antagonists [eg, infliximab]); those with AIDS; and those on high-dose corticosteroids.[15,16] The changes in epidemiology of invasive aspergillosis may also be the result of a growing awareness of aspergillosis among clinicians, the introduction of noninvasive diagnostic tools, and improved microbiological laboratory techniques. However, invasive aspergillosis remains an important life-threatening complication and is the leading cause of infection-related mortality in many types of immunocompromised patients.[17] Despite advances in diagnosis and therapy, as well as improvements in immunosuppressive therapy, invasive aspergillosis remains a dreaded complication in immunosuppressed patients with mortality rates greater than 60% and even higher in patients with widely disseminated infection.[17-19] Aspergillus fumigatus, the most pathogenic species, has been associated with the majority of infections.[20] However, other species, including Aspergillus flavus, Aspergillus terreus, and Aspergillus niger, have been increasingly reported in invasive infection.[21,22]
Treatment With Antifungal Agents
Several studies have documented the limited efficacy and substantial toxicity of amphotericin B deoxycholate in high-risk patients.[19,20,23,24] Furthermore, costs associated with amphotericin B deoxycholate toxicity actually increase overall healthcare expenses, so that any economic benefit of the low drug acquisition cost may be lost.[23] For these reasons, primary therapy with amphotericin B is no longer recommended for use in many systemic mycoses, including moulds, such as Aspergillus.[25] In recent years, new antifungal therapies with activity against invasive mycoses have been developed, including lipid formulations of amphotericin B, extended-spectrum triazoles, and a new class of antifungal therapy -- the echinocandins.
Lipid formulations of amphotericin B are less toxic, but are as microbiologically active as the parent compound. These agents have pharmacokinetic differences, including tissue distribution, but the clinical impact of these differences remains controversial.[26-28] There are some differences in toxicity, but only limited direct comparisons have been made and the compounds in use now (amphotericin B lipid complex and liposomal amphotericin B) are generally well tolerated.[29,30] These agents have been most extensively evaluated as empiric therapy in febrile neutropenia and salvage therapy for invasive mycoses, for which they are approved for use.[31,32]
Echinocandins
The echinocandins are a new class of antifungal agent with activity against Candida and Aspergillus, but not Cryptococcus or Zygomycetes (at least as a single agent), and probably not very active against other moulds.[33-38] These agents inhibit glucan synthase, which is needed for the production of beta-1,3-glucan in fungal cell walls,[39] and are fungicidal against Candida. Against Aspergillus, however, they disrupt only the growing fungal cell wall.[39] Currently available echinocandins include caspofungin, micafungin, and anidulafungin.
Caspofungin is approved for primary therapy of Candida infections, including candidemia, as well as empiric therapy in fever and neutropenia. A double-blind study comparing caspofungin with amphotericin B for candidemia and serious Candida infections showed similar efficacy with significantly decreased toxicity of caspofungin; caspofungin is now recommended as a first-line treatment option for candidemia.[40,41] Other echinocandins include anidulafungin and micafungin.
Extended-Spectrum Triazoles
The extended-spectrum triazoles, including voriconazole and posaconazole, were developed to specifically target Aspergillus and other moulds. Itraconazole is approved for use as salvage therapy of aspergillosis, but its utility is limited due to erratic bioavailability, toxicity, and drug interactions. Itraconazole is approved for prophylaxis and empiric therapy,[42,43] but potential toxicity with chemotherapeutic agents and intolerance has limited its use.[44] Voriconazole is approved for use as primary therapy of Aspergillus, and salvage therapy of Fusarium species and Scedosporium apiospermum, Candida esophagitis, and candidemia. Voriconazole is the recommended primary therapy for most patients with invasive aspergillosis.[45,46] A major advantage of voriconazole is that it can be given orally for resistant yeasts, which makes it more convenient to administer and less expensive.
Posaconazole, which is only available for oral administration, has been shown to have activity against Aspergillus and other moulds, including Zygomycetes.[47-49] In an open-label trial of salvage therapy for invasive mycoses, posaconazole had good activity in patients with invasive aspergillosis, particularly against potential polyene non-fumigatus species and other opportunistic yeasts and moulds.[50,51] Posaconazole is the only clinically available triazole that has shown favorable results in activity against zygomycosis.[48,52] In addition, posaconazole has been evaluated in 2 large, randomized, prophylaxis studies in high-risk patients. Posaconazole significantly reduced breakthrough fungal infection, including Aspergillus,[53,54] and significantly reduced breakthrough fungal infection and improved survival compared with standard prophylaxis with either fluconazole or itraconazole.[54]
Combination Therapy
Poor outcomes of mould infection, along with the availability of several antifungal drugs and drug classes, have generated increased interest in combination antifungal therapy.[55,56] Potential concerns about the deleterious effects of combination therapy stem from classic studies in vitro and in an animal model by Schaffner and colleagues,[57] who elegantly demonstrated antagonism between ketoconazole and amphotericin B due to depletion of ergosterol in the cell membrane. Although studies of potential negative effects have not been consistently demonstrated with newer compounds, these concerns remain.[58-60]
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References
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