Activity of posaconazole in the treatment of central nervous system fungal infections

Punnee Pitisuttithum1,*, Ricardo Negroni2, John R. Graybill3, Beatriz Bustamante4, Peter Pappas5, Stanley Chapman6, Roberta S. Hare7 and Catherine J. Hardalo7

1 Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand; 2 Hospital FJ Muñiz, Buenos Aires, Argentina; 3 University of Texas Health Sciences Center, San Antonio, TX, USA; 4 Hospital Nacional Cayetano Heredia, Lima, Peru; 5 University of Alabama at Birmingham, Birmingham, AL; 6 University of Mississippi Medical Center Division of Infectious Diseases, Jackson, MS; 7 Schering-Plough Research Institute, Kenilworth, NJ, USA


* Corresponding author. Tel: +662-246-1272, ext. 891; Fax: +662-248-6610; E-mail: tmppt{at}mahidol.ac.th or punneep{at}dmc.inet.co.th

Received 8 April 2005; returned 19 May 2005; revised 14 July 2005; accepted 24 July 2005


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives: A multinational, multicentre, open-label clinical trial was conducted to evaluate the safety and efficacy of posaconazole, an extended-spectrum triazole antifungal agent, in subjects with invasive fungal infections who had refractory disease or who were intolerant of standard antifungal therapy. In this subanalysis, we report on those subjects in this trial who had a fungal infection that involved the CNS.

Methods: Subjects received posaconazole oral suspension 800 mg/day in divided doses for up to 1 year; however, subjects could receive additional therapy as part of a treatment-use extension protocol. A blinded, third-party data review committee determined subject eligibility and outcome.

Results: Of the 330 subjects who enrolled in the study, 53 had infections of the CNS, of which 39 were considered evaluable for efficacy. Most had refractory disease (37 of 39) and underlying HIV infection (29 of 39). Twenty-nine subjects had cryptococcal infections, and 10 had infections caused by other fungal pathogens [Aspergillus spp. (four), Pseudallescheria boydii (two), Coccidioides immitis (one), Histoplasma capsulatum (one), Ramichloridium mackenziei (one), and Apophysomyces elegans plus a Basidiomycetes sp. (one)]. Successful outcomes were observed in 14 of 29 (48%) subjects with cryptococcal meningitis and five of 10 (50%) subjects with CNS infections due to other fungal pathogens. Posaconazole was well tolerated.

Conclusions: These data suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients failing existing antifungal agents.

Keywords: salvage treatment , cryptococcal infections , triazoles , invasive


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Morbidity and mortality associated with fungal infections of the CNS remains unacceptably high despite treatment with available antifungal therapy.1,2 Most patients with CNS fungal infections are immunocompromised, adding to the challenge of treating these opportunistic infections.25 Cryptococcus neoformans is the most common fungal infection in patients infected with HIV and often represents the AIDS-defining opportunistic infection.6,7 Other fungal pathogens that can invade the CNS include Aspergillus spp., Coccidioides immitis, Histoplasma capsulatum, Pseudallescheria boydii, Blastomyces dermatitidis, Paracoccidioides brasiliensis and Zygomycetes. Zygomycosis may occur in patients who have significant metabolic abnormalities that affect phagocytic responses (e.g. diabetic ketoacidosis, iron overload states and malnutrition).8 Additionally, these fungal pathogens, especially the endemic mycoses such as histoplasmosis and coccidioidomycosis, may also cause severe disease in immunocompetent persons exposed to a large inoculum of conidia.

The most recent treatment guidelines for cryptococcal meningitis recommend therapy with amphotericin B with or without flucytosine;1 however, clinical response rates in HIV-infected patients are low. After 2 weeks of therapy, negative CSF cultures were observed in eight of 12 patients with AIDS treated with amphotericin B and flucytosine, and two of 14 patients treated with amphotericin B alone.9 Fluconazole was shown to be less effective than amphotericin B for induction therapy, but effective as step-down therapy in patients infected with HIV. Prolonged maintenance therapy with fluconazole is recommended to prevent recurrence in patients with HIV; however, some patients experience relapses during therapy.1 Other patients develop immune reconstitution inflammatory syndrome (IRIS) during HAART. Patients with IRIS may develop an inflammatory meningitis, characterized by increased white blood cell counts in the CSF despite negative CSF cultures and declining C. neoformans CSF titres.10

Infections in the CNS are more difficult to treat than those outside of the CNS owing to the added complexity of drug penetration across the meninges. The standard of care for CNS infections caused by moulds has been amphotericin B; however, low efficacy rates and long-term tolerability issues make it less than optimal. Fluconazole is currently the recommended treatment for coccidioidomycosis involving the CNS.11 Voriconazole has demonstrated promising activity in the CNS,12,13 but reports of adverse events and its lack of activity against Zygomycetes14,15 may limit its usefulness as an alternative to amphotericin B. Thus, there remains interest in newer antifungal therapies that have potent activity against a wide range of fungal pathogens in the CNS, are well tolerated and can be administered to seriously ill patients over long periods of time.

Posaconazole is a new extended-spectrum triazole antifungal agent with in vitro activity against many yeasts and moulds that have a predilection for the CNS. These include Zygomycetes, Aspergillus spp., Cryptococcus spp., P. boydii/Scedosporium apiospermum, C. immitis, H. capsulatum, and B. dermatitidis.14,1622 In experimental animal models of CNS fungal disease, including infections with P. boydii, Cladophialophora bantiana, Wangiella dermatitidis and Aspergillus fumigatus, posaconazole substantially reduced fungal burden in the brain and improved survival.2326 In addition, oral posaconazole therapy resulted in negative CSF titres in a rabbit model of cryptococcal meningitis27 and in successful treatment of a CNS infection in a chimpanzee with disseminated coccidioidomycosis.28 Posaconazole, in combination with amphotericin B, was also shown to significantly reduce fungal burden in brain tissue and improve survival in a murine model of cryptococcosis.29 No significant antagonism between these agents was observed.29 These data provide support for the fact that posaconazole, a lipophilic compound, has therapeutic activity in the CNS after oral administration.

Posaconazole is bioavailable following oral administration and is well tolerated in both healthy volunteers and in patients with invasive fungal disease. In a model-dependent pharmacokinetic analysis of patients with refractory invasive fungal infection or febrile neutropenia, posaconazole bioavailability was greatest when administered in divided doses, with average plasma concentrations of 758 and 259 ng/mL following 400 mg twice-daily and 800 mg once-daily dosing, respectively.30 Posaconazole has a large volume of distribution indicating extensive distribution in body tissues.31 Preliminary clinical studies suggest that posaconazole has a favourable safety and tolerability profile during short- and long-term (6–12 month) treatment.3235 Case reports of patients with invasive fungal infection who required lengthy antifungal therapy to control or cure the disease suggest that posaconazole is well tolerated over long-term administration.36,37

The safety and efficacy of posaconazole were evaluated in a large, multinational (11 countries), multicentre (72 centres), open-label study of patients with invasive fungal infections who were intolerant of or who had disease refractory to available antifungal therapy. Herein, we report on those subjects in this trial who had a fungal infection that involved the CNS.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study population

Subjects, aged 13 years or older, with a proven or probable invasive fungal infection (adapted from the European Organisation for Research and Treatment of Cancer/Mycosis Study Group criteria)38 who were intolerant of or had disease refractory to standard therapies were eligible for study participation. Subjects were considered intolerant of available antifungal therapies if they had: (i) history of serious, severe or life-threatening toxicity while receiving antifungal therapy [i.e. organ toxicity (grade 3 or greater); nephrotoxicity defined as persistent serum creatinine greater than 2x the upper limit of normal (ULN) or recurrent serum creatinine greater than 2x the ULN after resumption of amphotericin B therapy; or idiosyncratic or anaphylactic reaction to other antifungal agents]; (ii) preexisting organ dysfunction precluding the use of standard antifungal therapies, including preexisting renal insufficiency; (iii) high risk for toxicity because of underlying disease or concomitant medications; or (iv) previous major idiosyncratic or hypersensitivity reaction to antifungal agents. Subjects were considered to have disease refractory to standard therapies (amphotericin B, other azoles or flucytosine) if they experienced disease progression or if their conditions did not improve clinically, while receiving antifungal therapy given for an adequate period of time (10–14 days for cryptococcal meningitis, 7 days for infections caused by Aspergillus, 14 days for non-Aspergillus moulds, 30 days for histoplasmosis and 180 days for coccidioidomycosis).

Subjects were excluded from participation if they were pregnant or lactating; had not undergone surgical sterilization and were using inadequate contraception (women only); had concurrent progressive neurological disease (e.g. seizures, demyelinating syndromes, unstable multiple sclerosis, peripheral neuropathy); required artificial ventilation but were unlikely to undergo extubation within 24 h of study entry; had a history of serious or severe hypersensitivity to azole antifungals; received medications known to interact with azoles (i.e. quinidine) within 10 days of study entry or drugs that lower azole serum concentrations (i.e. rifampicin, phenytoin) within 7 days of study entry; had electrocardiography results showing prolonged QTc interval (≥20% above normal) within 7 days of study entry; needed concomitant systemic antifungal agents during the study period; had abnormal hepatic function test results (alanine aminotransferase or aspartate transferase greater than 10x ULN); or were expected to live <72 h.

Each subject or a legal representative provided written, informed consent in accordance with the World Medical Association Declaration of Helsinki before receiving the first dose of study drug. The study protocol was reviewed and approved by an institutional review board or an independent ethics committee in accordance with good clinical practices.

Study design and treatment regimen

Subjects were treated with posaconazole oral suspension (40 mg/mL) (Schering-Plough Research Institute, Kenilworth, NJ, USA) at a daily dose of 800 mg in divided doses (200 mg four times daily or 400 mg twice daily). Doses were to be administered with food or a liquid nutritional supplement whenever possible. Subjects were treated for a minimum of 28 days and for at least 7 days after complete resolution of symptoms. The protocol-defined treatment duration was a maximum of 12 months; however, subjects who required longer therapy could be enrolled in compassionate use programmes to continue maintenance therapy.

An independent, blinded, data review committee (DRC) consisting of 15 experts in the diagnosis and treatment of fungal infection or in the radiography of invasive fungal infections, reviewed each case to ensure that predetermined eligibility criteria were satisfied. Teams consisting of three DRC members determined eligibility and outcomes using protocol-defined criteria (see ‘Efficacy and safety definitions’). They reviewed treatment outcomes until the end of therapy or 12 months of treatment, whichever came first.

Efficacy and safety definitions

The primary efficacy endpoint was global response at the end of treatment as assessed by the DRC according to the following definitions. A successful outcome was defined as the resolution of all attributable symptoms, signs and radiographic abnormalities (complete response) or clinically meaningful improvement in attributable symptoms, signs and radiographic abnormalities (partial response). A non-successful outcome was defined as no improvement in attributable symptoms, signs and radiographic abnormalities (stable disease) or deterioration in attributable clinical or radiographic abnormalities that necessitated alternative antifungal therapy or resulted in death (failure). If for any reason the response could not be assessed, the subject was considered to have a non-successful outcome.

Safety and tolerability were evaluated throughout the study period and are reported herein on all subjects who enrolled in the clinical trial (n = 330). Adverse events were recorded and categorized using the National Institute of Allergy and Infectious Diseases AIDS grading system, when possible. Alternatively, adverse events were scored as mild, moderate, severe or life threatening. Investigators also assessed the relationship of each adverse event to study medication (unlikely, possible or probable) and whether the event necessitated premature discontinuation of therapy or hospitalization. Blood samples were collected at each visit during treatment and at the final post-therapy visit for routine haematological and chemistry evaluations. In addition, a standard 12-lead electrocardiogram was obtained at the baseline visit and at week 4 to determine QTc changes.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Fifty-three subjects with CNS infections were enrolled in the study; 43 subjects had cryptococcal infections and 10 subjects had infections caused by other fungal pathogens. Fourteen of 43 subjects with cryptococcal meningitis were deemed ineligible by the DRC for the efficacy analysis. Of these, 13 subjects with proven or probable cryptococcal meningitis did not meet the protocol-defined criteria for refractory disease or intolerance to antifungal therapies, and one subject did not meet the protocol-defined criteria for a proven or probable CNS infection or the criteria for refractory disease or intolerance to antifungal therapies. Of the remaining 29 subjects with cryptococcal meningitis, 26 had refractory infections (25 had failed to improve after a reasonable trial of standard antifungal therapy and one had progressive disease), two were intolerant of other antifungal therapies and one subject met both criteria. All 10 subjects with other fungal CNS infections were evaluable for efficacy; eight subjects had disease refractory to current therapies, and two subjects met both criteria for intolerance and refractory disease. Overall, 39 subjects treated with oral posaconazole were considered evaluable for efficacy.

In the efficacy population, most subjects were men (87.2%) and ranged in age from 18 to 74 years (Tables 1Go3). The cohort with cryptococcal meningitis was generally younger (mean age 33 years) than the subpopulation with CNS infections caused by other invasive fungal pathogens (mean age 45 years). Most evaluable subjects (29 of 39; 74%) had underlying HIV infection. Twenty-eight of the 29 HIV-infected subjects were in the cryptococcal cohort. The subject with cryptococcal disease without HIV infection (subject 20) had hypogammaglobulinaemia as the only known risk factor for invasive fungal infection. Additional underlying immunodeficiencies in subjects with other fungal CNS infections included acute lymphoblastic leukaemia (n = 2), solid organ transplantation (kidney) with end-stage renal disease (n = 2), non-Hodgkin lymphoma (n = 2), bilateral lung transplantation (n = 1) and diabetes mellitus (n = 1). One subject in this cohort had no identifiable risk factor for fungal disease (subject 30).


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Table 1. Summary of subjects with cryptococcal meningitis who had successful outcomes at the end of posaconazole therapy

 

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Table 2. Summary of subjects with cryptococcal meningitis who had non-successful outcomes at the end of posaconazole therapy

 

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Table 3. Summary of subjects with other fungal CNS infections and outcomes at the end of posaconazole therapy

 
Before posaconazole therapy was initiated, subjects had been treated with amphotericin B and/or azoles for varying durations (Tables 13). Subjects with cryptococcal meningitis received antifungal therapy with amphotericin B therapy (range 2–91 days) or fluconazole therapy (range 1–101 days). Similarly, subjects with other fungal CNS infection received one or more different antifungal agents before enrolment (Table 3). Two of these subjects (subjects 30 and 33) had received antifungal therapy for 2–7 years.

Outcomes in subjects with cryptococcal meningitis

Clinical success occurred in 14 of 29 (48%) subjects with cryptococcal meningitis. Complete responses were reported for four subjects, all of whom had not responded to previous standard antifungal therapy. Partial response occurred in 10 subjects, eight of whom had disease refractory to previous antifungal therapy (Table 1). Of the 15 subjects who had a non-successful outcome, eight were treatment failures and six had stable disease; the status of one subject was undetermined (Table 2). Twelve subjects died; six deaths were due to progression of the fungal infection and six deaths occurred after stopping posaconazole and were considered unrelated to treatment. The mean duration of posaconazole therapy in the 29 eligible subjects with cryptococcal meningitis was 81 days (range 4–195 days).

Outcomes in subjects with CNS infections caused by other invasive fungal pathogens

CNS infections were due to Aspergillus spp. (n = 4), P. boydii (the teleomorph of S. apiospermum) (n = 2), C. immitis (n = 1), H. capsulatum (n = 1), Ramichloridium mackenziei (n = 1) and Apophysomyces elegans plus a Basidiomycetes sp. (n = 1), and all infections were refractory to standard antifungal therapy. The case of infection caused by R. mackenziei is discussed in more detail elsewhere.39 Posaconazole resulted in a successful outcome in five of 10 (50%) subjects after 6–12 months of therapy (Table 3). Two of the five subjects had complete responses and three had partial responses.

Among the five subjects who did not have a successful outcome, four died (two with aspergillosis, one with zygomycosis and one with pseudallescheriasis), each within ~2 weeks of the initiation of salvage therapy with posaconazole. All four subjects had advanced disease and severe underlying medical conditions (kidney or lung transplantation, allogeneic bone marrow transplantation with graft-versus-host disease, or lymphoma) when posaconazole therapy was initiated.

Safety and tolerability

Based on the analysis of the safety population (n = 330) from the open-label trial of posaconazole in subjects with invasive fungal infections, the most common drug-related adverse events included nausea (9%), vomiting (6%), headache (5%), abdominal pain (5%), diarrhoea (3%), increased serum glutamic-pyruvic transaminase (alanine aminotransferase) levels (3%), increased serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) levels (3%) and rash (3%). Mild, transient increases in liver function test values were noted in 2–3% of subjects, but they rarely necessitated that posaconazole therapy be discontinued. Posaconazole did not cause QTc prolongation or negative cardiac inotropic effects. Long-term administration (>6 months) of posaconazole did not produce a safety profile different from that for short-term administration (<6 months).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This analysis of subjects with proven CNS fungal infections receiving oral posaconazole for salvage therapy suggests that the new extended-spectrum antifungal agent may be an alternative for treatment of these serious and difficult to treat infections. In the cohort of subjects in this trial with CNS fungal infections, oral posaconazole therapy resulted in an overall success rate of 49% (19 of 39 subjects). Specifically, 50% of subjects with non-cryptococcal CNS infections and 48% of subjects with cryptococcal meningitis had successful clinical outcomes, with a 52% survival rate at the end of therapy for subjects with cryptococcal meningitis. Importantly, these success rates were obtained in a select group of seriously ill subjects, most with underlying immunodeficiencies, who were refractory to other antifungal therapy. Moreover, these success rates were obtained using an oral therapy. Thus, posaconazole may provide an alternative to parenteral therapy for subjects who are refractory to, or intolerant of, intravenous therapy with amphotericin B.

The cases of cryptococcal meningitis presented here were part of a larger study that included several other fungal infections, and therefore response definitions were adapted for the entire study population and not for each fungal infection type. Although our definitions of success (complete or partial response) were not based on absence or presence of positive cultures and may not be optimal for cryptococcal meningitis, the data presented here are useful in determining the efficacy of posaconazole. Response definitions for cryptococcal meningitis vary amongst the large number of antifungal treatment studies. A recent study of voriconazole for refractory fungal infections including cryptococcosis, and a study of triple combination therapy with amphotericin B, flucytosine and itraconazole for cryptococcal meningitis, had similar success definitions to those in this study,40,41 while a number of studies categorized response into clinical success (resolution of signs and symptoms) or mycological success (negative blood/CSF cultures).4246 Conversely, other studies considered patients as successes only if they displayed both resolution of signs and symptoms, and negative blood or CSF cultures.5,4751 Although the definitions of success in these previous studies are somewhat different from those in the present study, and a large majority of these patients entered the trial as a consequence of failure to improve on prior antifungal therapy, it should be noted that all patients presented here who were considered successes also had negative CSF cultures. In addition, failure of posaconazole therapy also included patients with stable disease and survival of >30 days, indicating that the response criteria in the present study were remarkably stringent.

Cryptococcal antigen testing of CSF has been documented by several researchers to be an effective and reliable diagnostic tool for cryptococcal meningitis.52,53 However, Cryptococcus antigen testing was not performed in all instances in this study, since a large proportion of the cases were seen in geographic areas where antigen testing was not readily available.

For cryptococcal meningitis in patients infected with HIV, clinical success rates with induction therapy of amphotericin B plus flucytosine are 40–60%.5,47 Although fluconazole is effective for maintenance therapy, it is less effective than amphotericin B for initial therapy.1,49 Thus, nearly 50% of patients with cryptococcal meningitis require salvage therapy due to refractory disease. Although evaluated in a small number of patients, salvage therapy with amphotericin B lipid complex for cryptococcal meningitis resulted in a 50% clinical success rate, and with voriconazole, <39% of patients had a complete or partial response.40,54

Causes for failure of primary therapy may be related to predictors of poor response to therapy such as extraneural sites of infection, abnormal mental status, hyponatraemia and low CSF white blood cell counts,47 although it is unlikely that failures are due to the development of resistant C. neoformans strains:55 posaconazole MIC90s for C. neoformans range from 0.25 to 0.5 mg/L, while those for itraconazole and fluconazole are 0.5 and 8–16 mg/L, respectively.16,56,57 Failure of posaconazole therapy may be related to the predictors of poor response and non-compliance with medications, and due to the fact that posaconazole was administered as salvage therapy to extremely sick patients with refractory infections. However, it should be emphasized that the response rate seen for posaconazole is very encouraging in patients in whom other antifungals have failed, and given the underlying conditions and refractory disease status of these patients. In addition, some of these patients were also intolerant to prior antifungal therapy; therefore, posaconazole provides an important antifungal treatment option.

Data from this report also demonstrate that posaconazole has a wide spectrum of clinical activity against clinically significant fungal pathogens other than C. neoformans. Posaconazole therapy resulted in a 50% success rate and 60% survival rate in the treatment of advanced CNS infections caused by rare moulds, supporting its extended spectrum of activity. Posaconazole demonstrated clinical activity against R. mackenziei, a dematiaceous fungus exclusively found in the Middle East that has an a predilection for the CNS and a high mortality rate.58 One of three subjects with cerebral aspergillosis achieved a partial clinical response during posaconazole therapy. More research is needed to determine the role of posaconazole as a first-line therapy for the treatment of these invasive and deadly fungal diseases.

Conclusions

In summary, the success rate of posaconazole as salvage therapy for subjects with CNS fungal infections intolerant of or refractory to standard antifungal therapy approached 50%. The activity of posaconazole salvage therapy against cryptococcal meningitis seems to be comparable to that of amphotericin B lipid complex and voriconazole when examining results reported from uncontrolled trials, although direct comparisons cannot be made. With increasing reports of breakthrough fungal disease during long-term maintenance for cryptococcal meningitis with fluconazole in patients with HIV, alternative therapies are needed. Results of this study suggest that posaconazole, as an oral medication, has clinical activity against fungal infections of the CNS and may provide a valuable alternative to parenteral therapy in patients in whom existing antifungal agents have failed.


    Acknowledgements
 
This work was presented in part at the Forty-third Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 14–17 September 2003, Chicago, IL, USA. Financial support for this study was provided by Schering-Plough Research Institute, Kenilworth, NJ, USA.

The following are lists of principal investigators and data review committee members in this clinical trial.

Principal investigators and centre addresses: Hail Al-Abdely (Infectious Diseases, Dept. of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia), Robin Avery (Cleveland Clinic Foundation, Cleveland, OH), Carlos R. Bachier (Southwest Texas Methodist Hospital, San Antonio, TX), Jeffrey L. Blumer (University Hospitals of Cleveland, Cleveland, OH), Aby Buchbinder (North Shore University Hospital, New York University School of Medicine, Manhasset, NY), Beatriz Bustamante (Cayetano Heredia National Hospital, AV Honorio Delgado S/N, URB Ingenieria, San Martin De Porres, Lima, Peru), Antonino Catanzaro (UCSD Medical Center, San Diego, CA), Daniel G. Connaghan (Northside Hospital, Atlanta, GA), Jennifer S. Daly (University of Massachusetts Memorial Medical Center, Worcester, MA), John Galgiani (Southern Arizona VA Healthcare System, Tuscon, AZ), Herve Gallais (Hopital La Conception, Service des Maladies Infectieuses, Marseille, France), Veronica Gaona-Flores (Hospital de Infectologia, Centro Medico Nacional "La Raza" IMSS, Calzada Vallejo y Jacarandas, Mexico), Morey Gardner (St Mary's Health Center, St Louis, MO), Elaine Gluckman (Hopital Saint Louis, Service d'Hematologie, Paris, France), Hewitt C. Goodpasture (Wesley Medical Center, Wichita, KS), Donald R. Graham (Springfield Clinic, Springfield, IL), John R. Graybill (University of Texas Health Science Center, San Antonio, TX), Michael Green (Children's Hospital of Pittsburgh, Division of Allergy, Immunology and ID, Pittsburgh, PA), Steve Green (Department of Infection & Tropical Medicine, Royal Hallamshire Hospital, Sheffield, UK), Richard Greenberg (University of Kentucky Medical Center, Lexington, KY), Susan Hadley (New England Medical Center, Boston, MA), Raoul Herbrecht (Hopital de Hautepierre, Service Onco-Hematolgie, Strasbourg, France), John Hiemenz (Orlando, FL), Scott R. Homann (St Anthony Medical Center, Rockford, IL), Ricky Hsu (St Vincent's Hopsital and Medical Center, New York, NY), Richard A. Hudson (Hudson Medical Group, Atlanta, GA), Alena Jandourek (Henry Ford Hospital, Detroit, MI), Michael J. Joyce (Nemours Children's Clinic, Jacksonville, FL), Harvey Kantor (Texas Tech Internal Medicine Clinic, Odessa, TX), Alexander L. Kisch (Saint Barnabas Medical Center, Livingston, NJ), Hans-Georg Klingemann (Rush Medical College, Chicago, IL), Amelia A. Langston (Emory University Hospital, Atlanta, GA), Kieren Marr (Fred Hutchinson Cancer Research Center, Program in Infectious Diseases, Seattle, WA), Roberto Martinez (Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, Sao Paulo, Brazil), Noel Milpied (Hotel Dieu CHRU de Nantes-Service d'Hematologie Clinique, France), Marco Montiel (Hospital Militar Central, AV. Faustino Sanchez Carrion S/N, Jesus Maria, Lima, Peru), Thomas A. Moore (Via Christi Regional Medical Center – St Francis Campus, Wichita, KS), Han Myint (Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK), Ricardo Negroni (Hospital Muniz, Buenos Aires, Argentina), Mark A. Netherda (Center for HIV Prevention and Care, Santa Rosa, CA), Nicolás Novitzky (Dept of Haematology, Groote Schuur Hospital, Cape Town, South Africa), Edward Ong (Department of Infection & Tropical Medicine, Newcastle General Hospital, Newcastle upon Tyne, UK), John R. Perfect (Duke University Medical Center, Durham, NC), Finn Bo Peterson (University of Utah Health Sciences Center, Blood and Marrow Transplant Program, Salt Lake City, UT), Punnee Pitisuttithum (Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand), Kenneth Presberg (Froedtert Memorial Lutheran Hospital, Milwaukee, WI), Issam I. Raad (The University of Texas MD Anderson Cancer Center, Houston, TX), Annette C. Reboli (Cooper Hospital/UMC, Camden, NJ), Adrian Rendon (Hospital Universitario Dr J. E. Gonzalez, Madero Pte. y Gonzalitos, Monterrey, NL, Mexico), Angela Restrepo (Corporacion Para Investigaciones Biologicas, Medellin, Colombia), W. Rozenbaum (Hopital Rothschild-Service des Maladies Infectieuses, Paris, France), Rodrigo Sanchez (CIMA Centro de Invs. Medicas Asociadas, Hermosillo, Son, Mexico), Ian Sanne (Department of Medicine, JHB General Hospital, Parktown, JHB, South Africa), Gary J. Schiller (UCLA Center for the Health Sciences, Los Angeles, CA), Marcelo Ribeiro Schirmer (Instituto Nacional do Cancer, Praca Cruz Vermalha, Rio de Janeiro, Brazil), Stefano Tarantolo (NHS Clarkson and University Hospitals, Nebraska Medical Center, Omaha, NE), Peter Tutschka (University of Connecticut Health Center, Farmington, CT), Jo-Anne van Burik (Fairview University Medical Center, University of Minnesota, Department of Medicine/Division of Infectious Diseases, Minneapolis, MN), John Wingard (Shands Teaching Hospital, Gainesville, FL), Michael Wong (Beth Israel Deaconess Medical Center, Boston, MA), Ibrahim Yakoub-Agha (CHR Hopital Claude Huriez, Service des Maladies du Sang, Lille, France), Maria Aparecida Shikanai Yasuda (Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Av. Dr Eneas de Carvalho Aguiar, Sao Paulo, Brazil) and Phillip C. Zakowski (Cedars-Sinai Medical Center, Los Angeles, CA).

Data review committee members: Robert Bradsher (University of Arkansas for Medical Sciences, Little Rock, AK), Pranatharthi H. Chandrasekar (Wayne State University, Detroit, MI), Stanley Chapman (University of Mississippi Medical Center, Jackson, MI), Gerald Donowitz (University of Virginia, Charlottesville, VA), Mitchell Goldman (Indiana University School of Medicine, Indianapolis, IN), Corina Elena Gonzales (Georgetown University Hospital, Washington, DC), Reginald Greene (Massachusetts General Hospital, Boston, MA), Vicki A. Morrison (VA Medical Center, Minneapolis, MN), George A. Pankey (Alton Ochsner Medical Foundation, New Orleans, LA), Peter Pappas (University of Alabama at Birmingham, Birmingham, AL), Thomas F. Patterson (co-chairman) (University of Texas Health Science Center, San Antonio, TX), Sanjay G. Revankar (VA Medical Center, Dallas, TX), Brahm H. Segal (Roswell Park Cancer Institute, Buffalo, NY), Mindy G. Schuster (University of Pennsylvania, Philadelphia, PA), David A. Stevens (Santa Clara Valley Medical Center, San Jose, CA), Thomas J. Walsh (co-chairman) (National Cancer Institute, Bethesda, MD) and Charles S. White (University of Maryland, Baltimore, MD).


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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