Fungal Endocarditis

Fungi are uncommon but emerging causes of infective endocarditis, most recently accounting for 1-10% of organisms isolated, including ~10% of cases of prosthetic valve endocarditis [338].

Simplistically, fungi are classified as yeasts or moulds. Yeasts are facultatively anaerobic, unicellular, non-filamentous fungi that are typically spherical or oval in shape. The most common yeasts involved in fungal endocarditis (FE) are the Candida spp. [338,339], although FE with the other opportunistic yeasts (e.g., Cryptococcus spp. [340-342], Saccharomyces spp. [343], Trichosporon spp. [344-347], and Rhodotorula spp. [348,349] ) have been sporadically reported. Moulds are aerobic, filamentous fungi. The predominant moulds involved in FE are the Aspergillus spp. [339]. Dimorphic fungi are those organisms that exist as moulds (mycelial form) when incubated at room temperature under laboratory conditions and yeast phase, yeast-like cells, or spherule form when grown in human tissue or incubated at 37°C on synthetic laboratory media. Histoplasma capsu-latum is the most commonly reported dimorphic fungus involved in FE [339,350].

The development of antifungal therapies with diverse mechanisms of action is increasing. Currently, there are five classes of antimycotic agents that may be used for invasive fungal infections. These are the polyenes, the azoles, the allylamines, the fluoropyrimidines, and the echinocandins. To establish the spectrum of activity of these agents requires standardization of an antifungal susceptibility testing procedure. Such a procedure requires two components: a standardized method for in vitro testing, as well as criteria for the interpretation of such results that correlates with clinical outcome. Standardized methodologies for yeast [351,352] and for molds [353] have been adopted, and interpretive breakpoints for susceptibility testing for Candida spp. to azoles has been established [354]. This is an emerging field in diagnostic microbiology.

The main antifungal polyenes are natamycin, nystatin, and amphotericin B. Of these, amptho-tericin B (AmB) remains the drug of choice for the treatment of most invasive fungal infections [355,356]. AmB acts by hydrophobically binding to the ergosterol component of fungal membranes, creating aqueous pores consisting of an annulus of eight AmB molecules [357]. These channels render the fungal cytoplasmic membrane permeable and allow the leakage of vital molecules from the cells, leading to cell death. As such, AmB exerts a fungicidal activity. Unfortunately, cross-reactivity to cholesterol in the mammalian cell membrane accounts for its toxic effects that often limits the dose of medication administered or requires premature termination of treatment.

Based on clinical experience and current interpretive criteria, the antimycotic spectrum of activity of AmB is extensive. It includes most commonly clinically encountered yeasts (e.g., Candida spp., Saccharomyces spp., Trichosporon spp.), molds (e.g., Aspergillus spp.) and dimorphic fungi (e.g., Histoplasma capsulatum, Coccidioides spp., Blastomyces dermatitidis) [356]. It should be remembered, however, that AmB does not reliably cover all fungal pathogens. Resistance to AmB may either be inherent or acquired. C. lusitaniae, for example, has been reported to be inherently resistant to AmB [355,358], although a review by Ellis [356] suggests that the data, in fact, may be contradictory and that most strains appear susceptible by current in vitro criteria. Furthermore, it is important to remember that despite appearing susceptible in vitro, invasive fungal infections may be frequently associated with clinical failure, possibly due to associated patient co-morbidities. Although acquired resistance to AmB has been sporadically reported, it does not appear to be a significant factor in the management of patients [356].

The major issues related to use of AmB are infusion-related adverse events and nephrotoxi-city [359]. Of these, the most serious is the latter. In a study of patients with suspected or proven aspergillosis (non-endocarditis) [360], AmB was administered for a mean of 20 days and a median of 15 days to 239 patients; 53% developed nephrotoxicity (defined as doubling of baseline creatinine). Of these, about 15% required renal dialysis. To circumvent the problems of renal toxicity, various lipid formulations of AmB have been created: AmBisome (Astellas Pharma US, Inc.), a unilamellar liposomal preparation; Abelcet (Enzon, Inc.), a ribbon-form lipid complex; and Amphocil or Amphotec (Intermune, Inc., Burlingame, Calif.), a discoidal complex of cholesteryl sulfate and AMB. These different formulations all contain AmB, but they differ with respect to reticuloendothelial clear-

ance, volume of distribution, peak serum concentration (Cmax), and area under curve (AUC) [359,361]. Although these are major differences from a pharmacological perspective, the clinical significance of this difference is unclear. However, these formulations do represent significant improvement in terms of renal-sparing properties relative to the conventional preparation of AmB (i.e., AmB deoxycholate) [362-364]. In terms of efficacy, numerous trials demonstrated that the lipid formulations were consistently at least as effective as conventional AmB [361,363,365]. This equivalence (and potential superiority) may be related to the higher dosages permitted with these preparations. Certain preparations may also have more advantageous distribution to sites of infection. For example, administration of AmBisome in a rabbit pharmacokinetic model demonstrated sixfold more AmB in brain tissue than administration with other agents [366]. The clinical signficance remains to be established, but in the presence of endocarditis with embolic disease to the central nervous system, such property may favor its selection. Conventional AmB has poor penetration into cardiac vegetations [367,368]. The penetration of the various lipid-based formulations for AmB into cardiac vegetations has not been published.

Nystatin is an established antifungal agent but is restricted to topical use as it is ineffective orally and severely toxic when administered intravenously [369]. Because it has demonstrated broad in vitro antifungal activity against clinically relevant fungi, including those resistant to fluconazole and amphotericin B products, there has been renewed interest in its use via an altered preparation. Liposomal nystatin is one such formulation, and there is some evidence to suggest that it may be effective as salvage therapy for patients with invasive aspergillosis refractory to or intolerant of AmB [370]. Its role in the management of endocarditis remains speculative.

The azoles are divided into the older imida-zoles, such as miconazole and ketoconazole, and the triazoles, which currently include flucona-zole, itraconazole, voriconazole, posaconazole, and ravuconazole. These agents function by inhibiting the lanosterol 14a-demthylase enzyme, leading to decreased synthesis of ergos-terol, the main sterol in the fungal cell membrane [357]. The depletion of ergosterol alters membrane fluidity, thereby reducing the activity of membrane-associated enzymes and leading to increased permeability and inhibition of cell growth and replication [371]. Consequently, azoles exert a fungistatic effect. A major distinction between the imidazoles and the triazoles is the preferential affinity of the latter for fungal, as opposed to human, cytochrome P-450 enzymes, which subsequently accounts for its improved toxicity profile [372].

The spectrum of activity of the azoles expands with newer generations. The imidazoles are not used in the treatment of systemic fungal infections because of poor pharmacokinetics, unpredictable drug interactions, and/or adverse events profile [373]. Fluconazole is a highly water-soluble triazole, developed in both oral and parenteral preparations. The oral formulation has very good absorption, with ~90% bioavailability [374]. The spectrum of activity of fluconazole relative to fungal causes of endocarditis includes the majority of Candida spp., Cryptococcus neoformans, Trichosporon spp., and the dimorphic fungi [373,375]. Of note, fluconazole does not possess activity against all yeasts (e.g., C. glabrata, C. krusei) [376] and has no clinically meaningful activity against filamentous fungi (e.g., Aspergillus spp., Fusarium spp., Scedosporium spp., and the Zygomycetes, such as Mucor spp.) [373,377]. In a rabbit model of endocarditis, the ability of fluconazole to penetrate into cardiac vegetations appeared superior to that of AmB [378]. The distribution of fluconazole is excellent, including CSF penetration, with achieved CSF levels of approximately 80% of corresponding serum levels [379]. As such, it may be the drug of choice for endocarditis caused by susceptible yeasts complicated by septic emboli to the central nervous system. Fluconazole is safe, even at doses up to 1,600 mg daily [380]. In contrast to imidazoles, flucona-zole has significantly less interaction with human cytochrome enzymes, and thus does not interefere with the synthesis of mammalian sterol-based hormones [373].

Itraconazole is a highly lipid soluble triazole with a broader spectrum of activity. In addition to Candida spp., Cryptococcus neoformans, and endemic dimorphic fungi, itraconazole also has activity against Candida non-albicans spp. and Aspergillus spp. [373,377]. As with fluconazole, itraconazole possesses no reliable activity against other filamentous fungi. The major limitation of itraconazole is its formulations. Initially introduced as a capsular form, which demonstrated erratic absorption, the prepara tion was modified to a novel, cyclodextrin-based oral solution, which demonstrated a bioavail-ability 60% greater than that of capsules [381]. Recently, an intravenous formulation has been developed. Clinical studies have demonstrated efficacy in prophylaxis against yeast and mold infections in patients at high-risk for disease (i.e allogeneic stem cell transplant recipients) [382,383]. The literature on the use of itracona-zole in fungal endocarditis is limited. The major shortcomings of itraconazole are its lower rates of tolerability and increased potential for drug interactions, when compared with fluconazole [381].

Voriconazole, a second-generation triazole derivative of fluconazole, has a very wide spectrum of activity, including Candida spp. (albicans and non-albicans), Cryptococcus neoformans, Aspergillus spp., endemic dimorphic fungi, as well as other yeasts (e.g., Trichosporon spp.) and emerging molds (e.g., Fusarium spp., Scedosporium spp.) [384). Voriconazole, however, has no significant clinical activity against the zygomycetes [373,384]. In addition to demonstrating in vitro activity against these fungi, the magnitude of the activity is significantly higher; for example, voriconazole is several-fold more active than the predecessor triazoles against Candida spp. [373]. Furthermore, voriconazole has both an oral and parenteral formulation, with excellent bioavail-ability (98.99%, slightly decreased with concomitant food intake) [385]. As with fluconazole, voriconazole has good penetration into the CSF and brain parenchyma, and it has been used in the treatment of CNS aspergillosis (with improved, albeit unsatisfactory, survival rates) [384,386,387]. The major adverse events associated with voriconzole include the more-common, dose-related transient visual disturbances (up to 10% of patients), as well as the uncommon potential for hepatic dysfunction [384]. Unfortunately, cross-resistance to voriconazole, among isolates resistant to fluconazole and itraconazole, can occur [373]. Such a factor must be borne in mind when selecting empiric antifungal therapy.

Posaconazole is an analogue of itraconazole, and has potent activity against Candida spp. Aspergillus spp., as well as dematiaceous molds and zygomycetes [373]. Ravuconazole, another derivative of fluconazole, also has in vitro activity against a variety of yeasts and molds. These agents are currently undergoing clinical trials.

Their role in the management of endocarditis is undefined.

The allylamine antifungals inhibit squalene epoxidase, an enzyme involved in the synthesis of lanosterol, the precursor of ergosterol [388]. Among this class of agents, terbinafine is the most effective to date. Up to this point, terbinafine has been used principally in the management of dermatophytic infections. However, in vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi, including Candida spp. (albicans and non-albicans), and filamentous fungi [388,389]. Among three patients with bronchopulmonary aspergillosis not responsive to the usual antimy-cotic therapies, systemic terbinafine resulted in eradication of A. fumigatus [390]. There is some evidence, however, that the anti-Aspergillus activity of terbinafine is greater for the non-fumigatus species [391]. Results from in vitro testing in combination with polyenes and azoles against Candida spp. and Aspergillus spp., suggests that the therapeutic potential of terbinafine may extend well beyond its current use and that further investigations are warranted [392,393].

The only fluoropyrimidine antimetabolite antifungal currently available is 5-fluorocyto-sine (5-FC, flucytosine), which exists in both oral and intravenous formulations [377]. 5-FC exerts its effect by being preferentially taken up within fungal cells, where it is converted to 5-fluorouracil (5-FU) [377,388]. 5-FU has two fates: It is converted to 5-fluorouridine triphos-phate [5-FUTP], which is subsequently incorporated into fungal RNA, leading to inhibition of protein synthesis. 5-FU is also converted to flu-orodeoxyuridine monophosphate (5-F-dUMP), which inhibits thymidylate synthetase and intereferes with dNa synthesis. Monotherapy with 5-FC is strongly discouraged because resistance occurs rapidly [377,388]. Combination therapy with amphotericin B and flucy-tosine is considered to be the treatment of choice for cryptococcal infections [394]. One case report describes the use of this combination in the management of a child with repaired congenital heart disease who developed C. albicans endocarditis [395]. The authors suggest that this antifungal combination should be considered an option, although their patient also underwent surgical intervention, and so the clinical benefit of the combination therapy per se is unclear. 5-FC / azole combination therapy has also been proposed, as it appeared more efficacious in an animal model of invasive candidal disease, when compared to azole monotherapy, with significant decrease in tissue fungal burden and prolonged survival [396]. Case reports in humans have also reported on the efficacy of such combinations [397,398]. Currently, there is no clinical data on the efficacy of this combination for fungal endocarditis.

The echinocandins are a novel class of semi-synthetic lipopeptides that inhibit the synthesis of P-(1,3)-D glucan, a polysaccharide in the cell wall of many pathogenic fungi that is responsible for the cell wall's strength and shape [377]. Consequently, these agents render the fungal cell wall osmotically unstable. Caspofungin (Merck &Co., Inc.), the prototypical echinocan-din, has broad-spectrum activity against Candida and Aspergillus spp. and is approved by the Food and Drug Administration (FDA) in the United States for treatment of aspergillosis in patients refractory to or intolerant of other therapies [399]. Caspofungin also has demonstrated potent in vitro and in vivo activity against Candida spp. and has approved indications for treatment of candidemia, intra-abdominal abscesses, peritonitis, pleural space infections, and esophageal candidiasis [399]. Cases in which Caspofungin has been successfully used as lone therapy for candidal endocarditis (i.e., without valvular replacement) have been reported [400-402]. Caspofungin, however, has poor CNS penetration in animal models [403,404], and there is concern that it may be inadequate as therapy for fungal endocarditis that is complicated by unrecognized embolic foci of infection [405].

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