Posaconazole: A Broad-Spectrum Triazole Antifungal Agent

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1 REVIEWS OF ANTI-INFECTIVE AGENTS Louis D. Saravolatz, Section Editor INVITED ARTICLE Posaconazole: A Broad-Spectrum Triazole Antifungal Agent Vijayalakshmi Nagappan 1 and Stan Deresinski 2,3 1 Division of Infectious Diseases, St. John Hospital and Medical Center, Detroit, Michigan; and 2 Santa Clara Valley Hospital, San Jose, and 3 Stanford University, Palo Alto, California Posaconazole is a triazole antifungal agent with a spectrum of activity that includes Candida and Cryptococcus species, many molds, and some endemic fungi. Posaconazole has received US Food and Drug Administration approval for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole. It is also approved as prophylaxis for invasive Aspergillus and Candida infections in patients aged 13 years who are at high risk of developing these infections, in adult and adolescent hematopoietic stem cell transplant recipients with graft-versus-host disease, and in persons with hematologic malignancies and prolonged neutropenia due to chemotherapy, who are at high risk of developing these infections. Approval for additional indications is being sought. Limited clinical experience suggests efficacy for the treatment of infections due to Zygomycetes and as salvage therapy for patients with invasive aspergillosis and coccidioidomycosis. Currently available only as an oral suspension, posaconazole, which has been well tolerated, requires administration with food or a nutritional supplement to assure adequate bioavailability. Posaconazole is predominantly eliminated in the feces, where it appears as unchanged drug. Metabolism, mostly glucuronidation, plays only a minor role in its elimination, as does renal clearance; as a consequence, dose adjustment is not required in the presence of renal or hepatic insufficiency. Although not a substrate of hepatic CYP450 3A4, posaconazole inhibits this enzyme and thus has the potential for significant pharmacokinetic interactions with drugs metabolized by this isoform. Its use in combination with CYP450 substrates that prolong the QTc interval is contraindicated, as is its use with ergot alkaloids; administration of posaconazole with other substrates and/or inducers of this enzyme system requires caution. Posaconazole is both a substrate and inhibitor of P-glycoprotein. Currently, the major roles for posaconazole in clinical practice are as prophylaxis for neutropenic patients with significant risk of infection with filamentous fungi and as therapy for zygomycoses. It may also have a role in the treatment of other filamentous fungal and some yeast infections, but assessment of its overall place in antifungal therapy awaits the availability of further clinical experience. The 5 azole antifungal agents currently available for systemic use in the United States are ketoconazole (an imidazole drug) and 4 triazoles (fluconazole, itraconazole, voriconazole, and the newest agent posaconazole). The major overall advantage of the azoles over amphotericin B is their lower toxicity and availability for oral administration. The latter characteristic also provides an advantage over the echinocandin antifungal agents [1 11]. Received 20 June 2007; accepted 18 August 2007; electronically published 12 November Reprints or correspondence: Dr. Vijayalakshmi Nagappan, Div. of Infectious Diseases, St. John Hospital and Medical Center/Wayne State University, Mack Ave., Ste. 340, Gross Pointe Woods, MI (vijinag@aol.com). Clinical Infectious Diseases 2007; 45: by the Infectious Diseases Society of America. All rights reserved /2007/ $15.00 DOI: / Posaconazole, which is currently only available for oral administration, has been approved by the US Food and Drug Administration (FDA) for the treatment of oropharyngeal candidiasis, including infections refractory to itraconazole and/or fluconazole, as well as for prophylaxis of invasive Aspergillus and Candida infections in patients aged 13 years who are at high risk of developing these infections as a result of severe immunocompromise, such as hematopoietic stem cell transplant recipients with graft-versus-host disease or those with hematologic malignancies with prolonged neutropenia resulting from chemotherapy [12]. In addition, posaconazole shows promise as a therapeutic agent for infections due to some filamentous fungi, including the Zygomycetes, as well as for some endemic mycoses [13 15]. In addition to the FDA indications noted above, it has received European Commission approval for the treatment of invasive aspergillosis, fusariosis, chromo CID 2007:45 (15 December) REVIEWS OF ANTI-INFECTIVE AGENTS

2 blastomycosis, mycetoma, and coccidioidomycosis in adult patients who have refractory disease or who are intolerant of commonly used antifungal agents. MECHANISM OF ACTION Posaconazole differs in structure from the compact triazoles fluconazole and voriconazole in part by virtue of its extended side chain, a feature held in common with itraconazole (figure 1). Posaconazole differs from the latter by the presence of a furan ring and substitution of chlorine with fluorine. The extended side chains of posaconazole and itraconazole provide additional points of contact with the azole target, CYP51 [16]. CYP51 is an integral membrane protein that functions as a 14- a-demethylase in the synthesis pathway of the key sterol of the fungal cell membrane, ergosterol. Inhibition of this enzyme results in decreased membrane ergosterol content and accumulation of toxic methylated intermediates, with resultant disruption of fungal cell membrane function, growth inhibition, and, in some cases, cell death. The multiple hydrophobic contacts resulting from the interaction of the extended side chain within a channel of CYP51 may result in enhanced binding affinities and may account for the preservation of activity of posaconazole against fungi with resistance to fluconazole and voriconazole resulting from mutations at the active site in proximity to the heme moiety of the demethylase [16 18]. PHARMACOLOGY Posaconazole (MW 700.8) is insoluble in water and is administered as a cherry-flavored 40- suspension that contains polysorbate 80 as an emulsifying agent. Posaconazole bioavailability is improved when it is taken with either a nonfat or high-fat meal (2.6-fold and 4.0-fold, respectively) or with a nutritional supplement (Boost Plus; Novartis Medical Nutrition) [19 21]. Unlike itraconazole, the absorption of posaconazole is not affected by changes in gastric acidity [19]. Exposure increases in a dose-dependent fashion up to a total daily dose of 800 mg, with greater exposure when the drug is administered in split doses rather than as a single daily dose. Thus, one study demonstrated that administration of the 400-mg oral suspension twice per day resulted in greater posaconazole exposure than did dosages of 600 mg twice per day or 800 mg once per day [16]. This lipophilic drug has a large volume of distribution despite its high protein binding of 198%. Steady state concentrations are achieved after 7 10 days, at which point the mean terminal elimination half-life is 35 h [19, 21]. This long half-life at steady state is reflected in limited differences between peak and trough serum concentrations. There is considerable interpatient variability in peak serum concentrations. The mean steady-state maximum concentration ( SD) after administration of 200 Figure 1. Structure of itraconazole, posaconazole, voriconazole, and fluconazole. mg 4 times per day or 400 mg twice per day in 194 adults with invasive fungal infection was ng/ml (range, ng/ml) [22]; differences in renal or hepatic function, sex, or body mass or surface area do not account for this variation [21, 22]. Posaconazole is both a substrate and inhibitor of P- glycoprotein, but despite genetic polymorphisms resulting in significant variability in P-glycoprotein expression among racial groups, neither race nor ethnicity significantly affect the pharmacokinetics of posaconazole [23]. Single-nucleotide polymorphisms in UGT that encode uridine diphosphate-glucuronotransferase may play a role [24], but this has not been confirmed. Thus, the reasons for the intersubject bioavailability of posaconazole a problem also observed with both itraconazole and voriconazole remain poorly defined. This unpredictable variability, however, provides a rationale for monitoring of blood concentrations of posaconazole in individual patients. Because metabolism (mostly glucuronidation) and renal clearance play only minor roles in posaconazole s elimination, dose adjustment is not required in the presence of renal or hepatic insufficiency. The pharmacokinetic properties of posaconazole are compared with those of voriconazole in table 1 [7, 11, 12, 16, 19, 20, 25 34]. Data on adverse effects and drug-drug interactions are summarized in table 2. The tolerability of posaconazole is similar to that of fluconazole, with the most frequently reported adverse effects being gastrointestinal symptoms and headache [30, 31, 33]. Elevated transaminase levels are reported, but severe REVIEWS OF ANTI-INFECTIVE AGENTS CID 2007:45 (15 December) 1611

3 Table 1. Comparison of pharmacokinetic properties of posaconazole and voriconazole. Pharmacokinetic property Posaconazole Voriconazole Available forms Oral only Oral and intravenous Absorption Increased by fatty meals Decreased by fatty meals Protein binding, % Pharmacokinetics Linear Linear in children; nonlinear in adults Steady state Achieved after 7 10 days Achieved after 5 6 days Half-life, h Metabolism Only by CYP3A4 enzyme Various hepatic enzymes Dose adjustment Not needed for both renal and hepatic dysfunction Need to adjust dose in hepatic dysfunction; also, intravenous formulation is contraindicated in patients with creatinine clearance rates!50 ml/min NOTE. Data are from [7, 11, 12 16, 19, 20, 25 32]. hepatic dysfunction has been rarely encountered. Although a case of torsades des pointes was observed in a patient who received posaconazole, studies of healthy volunteers have failed to identify evidence of prolongation of the QTc interval [25]. Investigators have also not identified an association between the plasma concentration of posaconazole and common adverse events [35]. Because posaconazole inhibits hepatic cytochrome P 450 3A4, it can cause significant drug interactions with other medications that are metabolized by this enzyme. Therefore, when posaconazole is added to a treatment regimen that contains cyclosporine or tacrolimus, the doses of each of the latter should be reduced to approximately three-fourths and one-third, respectively, of the original doses, and the whole-blood concentrations of these agents should be carefully monitored. Inhibition of CYP3A4 also results in increased exposure to concomitantly administered rifabutin, midazolam, and phenytoin. Coadministration of posaconazole with the CYP3A4 substrates terfenadine, astemizole, cisparide, pimozide, halofantrine, and quinidine, which have the potential to cause QTc prolongation, is contraindicated [12, 25, 26]. Because it is a substrate of P-glycoprotein, coadministration of inducers of this enzyme, such as rifabuitn and phenytoin, results in significantly reduced exposure to posaconazole [25]. Cimetidine reduces posaconazole exposure [25]. Vincristine levels are increased by concurrent use of posaconazole; this may result in an increase in the risk of vincristine-related neuropathy [36]. No clinically significant interaction has been detected when posaconazole is administered with ritonavir. In addition, no pharmacokinetic interaction with either amphotericin B or caspofungin has been identified. The pharmacodynamics of posaconazole in the treatment of experimental Candida albicans infection in the neutropenic mouse model appear to be similar to those of other azole antifungal agents, with the ratio of the 24-h area under the concentration-time curve to the MIC being the critical parameter associated with treatment efficacy [37] IN VITRO STUDIES In vitro activity of posaconazole against Candida species is described in table 3 [38 41]. Pfaller et al. [42] reported that 82.5% of isolates of Candida glabrata were susceptible to posaconazole, whereas 90.3% were susceptible to voriconazole. Posaconazole is fungicidal against Candida krusei and Candida lusitaniae, whereas only fungistatic activity was observed for many other Candida species [43]. The in vitro activity of posaconazole against Cryptococcus species is similar to that of itraconazole and voriconazole [41]. Posaconazole also has activity against Rhodotorula species [44]. With regard to the endemic mycoses, the MIC 90 was for Blastomyces dermatitidis and 0.25 for Histoplasma capsulatum and Coccidioides species [41]. Posaconazole remained active in vitro against H. capsulatum isolates with reduced susceptibility to both fluconazole and voriconazole; these isolates had been recovered from patients with AIDS for whom therapy with fluconazole had failed [45]. Results of susceptibility tests of 448 filamentous fungi are presented in table 4 [46]. Posaconazole was less active than voriconazole against Scedosporium isolates in 2 studies [47, 48]. In vitro data on posaconazole against Zygomycetes are summarized in table 5 [49, 50]. Barchiesi et al. [51] demonstrated fungicidal activity of posaconazole (minimum fungicidal concentration 90, 1 ) against dermatophytes. ANIMAL MODELS Groll and Walsh [52] have reviewed the efficacy and pharmacodynamics of posaconazole in experimental models of a wide variety of invasive fungal infections. Posaconazole was as effective as fluconazole in the treatment of experimental cryptococcal meningitis in a rabbit model [53]. Posaconazole was effective in murine models of invasive aspergillosis [54], zygomycosis [55], fusariosis [56], cerebral phaeohyphomycosis [57, 58], histoplasmosis [59], blastomycosis [60], and coccid CID 2007:45 (15 December) REVIEWS OF ANTI-INFECTIVE AGENTS

4 Table 2. Data on adverse effects, drug interactions, contraindications, and pregnancy categories for posaconazole. Event or consideration Data Adverse effect Gastrointestinal system Skin CNS Cardiovascular system General Kidney Drug interactions Cyclosporine Tacrolimus Rifabutin Phenytoin Midazolam Contraindications Pregnancy NOTE. Data are from [12, 16, 19, 20, 25, 27 34]. Nausea, vomiting, abdominal pain, diarrhea, and/or elevated alanine aminotransferase, aspartate aminotransferase, and/or alkaline phosphatase level Rash Headache, blurred vision, and/or tremors Hypertension ioidomycosis [61, 62]. Posaconazole and amphotericin B, each at 4 different doses, were administered singly and in all possible combinations to mice infected with each of 4 strains of C. albicans with varying susceptibility to fluconazole [63]. No antagonism was identified. A total of 20.3% of the 64 combination regimens tested were more effective than monotherapy with either agent. CASE REPORTS AND SERIES The partial or complete response rate to posaconazole was 60% among 91 patients who experienced treatment failure with or who were intolerant of other licensed antifungal therapies [64]. One-fifth of these patients had developed breakthrough infection with a zygomycete while receiving voriconazole. Sixty-two percent of the patients survived, and only 43% of the deaths, most of which occurred among patients who received!30 days of therapy, were attributed to fungal infection. In comparison, a literature review found survival rates of 61% and 69% among patients treated with amphotericin B deoxycholate and lipidassociated formulations of amphoterticin B, respectively [65]. In addition to the selection bias associated with cases reported in the literature, these patients presumably received amphotericin B as primary therapy rather than as salvage therapy. Both of these factors may lead to an overestimation of the efficacy of polyene therapy in zygomycoses. However, analysis of a postmarketing database found that 72% of 46 patients with zygomycosis responded to treatment with amphotericin B lipid complex, with an 80% response rate among those who received it as primary therapy and a 69% response rate among those who received it because of failure of or intolerance to primary Anorexia, dizziness, fatigue, and/or weakness Increase in creatinine level Reduce dose of cyclosporine to three-fourths of the original dose and monitor Reduce tacrolimus dose to one-third of the original dose Avoid concomitant use; if used, monitor rifabutin levels closely Reduce dose of phenytoin Reduce dose of midazolam Concomitant use of terfenadine, cisapride, pimozide, and quinidine cause prolonged QTc intervals, and drug levels are increased with posaconazole; therefore, concomitant use of these agents is contraindicated Category C therapy [66, 67]. Unfortunately, no mortality data were provided. Posaconazole was successful as treatment of an elderly lung transplant recipient with pneumonia due to Fusarium proliferatum [68], as well as for the treatment of ocular fusariosis [69]. A successful outcome was achieved in 10 of 21 patients who had antifungal-refractory invasive fusariosis or who were intolerant of other antifungal agents [70]. One patient with disseminated phaehyphomycosis had complete response to posaconazole therapy [71]. Posaconazole was successful for the treatment of 6 of 6 patients with histoplasmosis (5 with disseminated infection) for whom prior therapy had failed [72]. An important target of posaconazole therapy is coccidioidomycosis. Success was reported with posaconazole therapy in 5 of 6 patients with coccidioidomycosis refractory to treatment with other antifungals [73]. Separately, 15 patients with proven nonmeningeal coccidioidomycosis refractory to previous antifungal therapy were treated with a total of 800 mg of posaconazole daily given in divided doses as part of a prospective, open-label trial [74]. Of the 14 evaluable patients, 11 (73%) had a partial or complete response. This favorable experience has led to the implementation of a randomized, clinical trial comparing posaconazole with fluconazole therapy for patients with coccidioidomycosis ( /NCT ?orderp2). CONTROLLED CLINICAL TRIALS Ulmann et al. [31] randomized 600 allogeneic hematopoietic stem cell recipients with graft-versus-host disease who had received intensive immunosuppressive therapy to receive pro- REVIEWS OF ANTI-INFECTIVE AGENTS CID 2007:45 (15 December) 1613

5 Table 3. Comparison of MIC 50 and MIC 90 values of posaconazole, voriconazole, fluconazole, and itraconazole against Candida species. Candida species No. of isolates Posaconazole Voriconazole Itraconazole Fluconazole Candida albicans Candida glabrata Candida parapsilosis Candida tropicalis Candida krusei Candida lusitaniae NOTE. Data are from [38 40]. phylaxis with either posaconazole (200 mg 3 times per day) or fluconazole (400 mg once per day). There was no significant difference in the incidence of proven or probable invasive fungal infections in the posaconazole arm (5.3%), compared with the fluconazole arm (9%; P p.07), at the end of 112 days. In a secondary, on-treatment analysis (prophylaxis was actually received for a mean duration of 7 weeks), there were 7 cases of invasive fungal infection noted among posaconazole recipients and 22 among fluconazole recipients, a difference that was statistically significant ( P p.004). There was a significant reduction in the number of cases of invasive aspergillosis, which accounted for the majority of infections, in posaconazole recipients in both analyses. Although there was no significant difference in all-cause mortality, a significant difference was observed in the rate of mortality due to invasive fungal infection (posaconazole arm, 1%; fluconazole arm, 4%; P p.041) [31]. The number needed to treat (NNT) to prevent 1 invasive fungal infection with the use of posaconazole versus fluconazole was 27, whereas the NNT to prevent 1 case of invasive aspergillosis Table 4. Filamentous fungus Aspergillus species Comparison of MIC 50 and MIC 90 values of posaconazole, voriconazole, and itraconazole against filamentous fungi. No. of isolates Posaconazole Voriconazole Itraconazole Aspergillus fumigatus Aspergillus flavus Aspergillus niger Aspergillus versicolor Aspergillus terreus All Penicillium species Fusarium species Paecilomyces species Rhizopus species Mucor species All filamentous fungi was 22. The NNT to prevent 1 death (either in total or attributable to invasive fungal infection) was 33. In the course of the study by Ulmann et al. [31], a 4-fold increase in the MIC of posaconazole was observed in 4 C. glabrata isolates and 2 C. albicans isolates among 21 paired (pre- and posttreatment) oropharyngeal isolates. There were similar findings in fluconazole recipients ( raising concern about the potential for selection of drug-resistant fungal pathogens during prophylaxis. In a separate investigation, Cornely et al. [33] compared prophylactic posaconazole with other azoles in 602 neutropenic patients with acute myelogenous leukemia or myelodysplastic syndrome who were undergoing myelosuppressive chemotherapy. Patients were randomized to receive posaconazole (200 mg 3 times per day) or a comparator triazole (either fluconazole [400 mg once per day] or itraconazole [200 mg twice per day]) in an open-label fashion. Only 19% of patients assigned to receive a comparator were given itraconazole. The mean du- NOTE. Data are from [46] CID 2007:45 (15 December) REVIEWS OF ANTI-INFECTIVE AGENTS

6 Table 5. Comparison of in vitro activity of posaconazole, itraconazole, and voriconazole against Zygomycetes. Species No. of isolates MIC, Posaconazole Itraconazole Voriconazole Mucor species to 164 Rhizopus species to 164 Absidia species to 164 NOTE. Data are from [49, 50]. rations of prophylaxis were 29 days and 25 days in the prophylaxis and comparator arms, respectively. The number of invasive fungal infections identified during this period of drug administration was 7 (2%) in the posaconazole group, compared with 25 (8%) in the comparator group (absolute reduction favoring posaconazole, 6%; 95% CI 9.7% to 2.5%; P!.001). The difference resulted from the more effective prevention of invasive aspergillosis in the posaconazole recipients, among whom there were 2 cases (1%), compared with 20 cases (7%; P!.001) in the comparator arm. This difference was not simply related to fluconazole s lack of activity of against Aspergillus species; the incidence of invasive aspergillosis was 6% among fluconazole recipients and 9% among itraconazole recipients, possibly reflecting the variable gastrointestinal absorption of the latter agent. The NNT to prevent 1 invasive fungal infection, 1 case of aspergillosis, and 1 death was the same for each (i.e., 17), whereas the NNT to prevent 1 death was 33. Prophylaxis failures were not explained by the variability in bioavailability of posaconazole; mean and maximum plasma concentrations of the drug in patients with breakthrough fungal infection were not significantly different from those in the overall patient population. Although the diagnosis of probable aspergillosis in 15 patients (2 posaconazole recipients, 9 fluconazole recipients, and 4 itraconazole recipients) was based only on positive galactomannan assay results (http: // this methodology has recently become widely accepted. Overall, these 2 studies demonstrate that posaconazole is highly effective as prophylaxis for invasive fungal infection in these 2 target groups, consistent with the conclusions of De Pauw and Donnelly [75] that posaconazole is the prophylactic antifungal of choice. However, as these 2 authors note, the value of prophylaxis depends on the background prevalence of invasive fungal infection. Thus, in settings with low prevalence of invasive fungal infection, the NNT would be correspondingly higher, and alternative strategies (e.g., close surveillance combined with early preemptive therapy) may be preferred. Vazquez et al. [76] has compared the efficacy of posaconazole and fluconazole for the treatment of oropharyngeal candidiasis in a multicenter, randomized, evaluator-blinded study. Both posaconazole and fluconazole were administered at a dose of 200 mg (oral suspension) on day 1, followed by 100 mg once per day for the next 13 days. Successful treatment was achieved in 91.7% and 92.5% of the posaconazole- and fluconazoletreated patients, respectively (95% CI, 6.61% to 5.04%), whereas 40.6% and 26.4% of the posaconazole and fluconazole recipients, respectively, achieved mycological success on day 14 ( P p.038). In a noncomparative study, posaconazole treatment was successful in 75% of HIV-infected patients with oropharyngeal and esophageal candidiasis for whom fluconazole or itraconazole therapy had failed [77]. The success rate was 74% in patients whose isolates demonstrated in vitro resistance to fluconazole, itraconazole, or to both. The efficacy of posaconazole as salvage therapy for invasive aspergillosis was evaluated in a multicenter, open-label study of 107 patients with probable or proven infection for whom prior antifungal therapy had failed. Subjects received posaconazole at a total daily dose of 800 mg [78]. Success was achieved in 42% of patients, whereas the response rate was only 26% in an external control group of patients who received other salvage therapies. The rate of successful salvage treatment with posaconazole observed in this study was similar to that previously reported for other antifungals, including caspofungin (45%), amphotericin B lipid complex (42%), and voriconazole (38%). Only 4 (29%) of 14 patients with Aspergillus terreus infection responded to posaconazole salvage therapy, as did only 2 (15%) of 13 patients in the external control group, who received alternative salvage therapies. Success in the posaconazole recipients was associated with higher serum concentrations of posaconazole, ranging from 24% among patients whose concentrations were in the lowest quartile (mean maximum concentration, 142 ng/ml) to 75% among those whose concentration were in the highest quartile (mean maximum concentration, 1489 ng/ml). CONCLUSIONS Posaconazole is a triazole antifungal agent with a spectrum of activity similar to that of voriconazole but with greater promise against infections caused by the zygomycetes. Posaconazole is currently only available as an oral suspension, and it must be taken with food or a nutritional supplement, somewhat limiting its usefulness. The drug is well tolerated, with an overall safety profile comparable to that of fluconazole. Clinical information available to date indicates its efficacy as salvage therapy for oropharyngeal and esophageal candidiasis, as well as for invasive aspergillosis, although data from randomized clinical trials are lacking with regard to invasive aspergillosis. It shows promise as therapy for zygomycosis, for which the available noncomparative data suggest efficacy similar to that reported for lipid formulations of amphotericin B. Posaconazole has also been reported to be effective as salvage therapy in a small number of patients with refractory coccidioidomycosis, and a randomized clinical trial to examine its true efficacy is in progress. It is effective as prophylaxis for invasive fungal infection in particular, aspergillosis in at-risk patients. No results from REVIEWS OF ANTI-INFECTIVE AGENTS CID 2007:45 (15 December) 1615

7 prospective randomized trials to assess the relative efficacy of posaconazole in either invasive candidiasis or aspergillosis are currently in the public domain. Further clinical trial data are necessary to determine the efficacy of this drug versus comparator agents. In the meantime, posaconazole has been demonstrated to be an important addition to the antifungal formulary. Acknowledgments Potential conflicts of interest. S.D. has served as an advisory board member for Schering Plough and Ortho-McNeil and on the speakers bureaus for Merck, Ortho-McNeil, Schering-Plough, Pfizer, Wyeth, and Cubist. V.N.: no conflicts. References 1. Hagen A, Stern H, Porter D, et al. High rate of invasive fungal infections following nonmyeloablative allogenic transplantation. Clin Infect Dis 2003; 36: Marr K, Carter R, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: Baddley J, Stroud T, Salzman D, et al. 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