A murine model of Cryptococcus gattii meningoencephalitis.

OBJECTIVES: Meningoencephalitis caused by Cryptococcus gattii is associated with significant morbidity and the need for aggressive therapy, and often necessitates neurosurgical intervention. We adapted a previously described murine model of cryptococcal meningoencephalitis due to Cryptococcus neoformans to that caused by C. gattii. METHODS: Mice were inoculated intracranially with either C. gattii (genotype VGIIa) or C. neoformans. In virulence studies, different C. gattii infecting inocula were compared with a fixed inoculum of C. neoformans, and differences were assessed by survival, brain tissue fungal burden, serum antigen titres and histopathological changes within brain tissue. For treatment, fluconazole or posaconazole (10 mg/kg orally twice daily) was initiated 24 h post-inoculation. RESULTS: C. gattii was more virulent than C. neoformans, as evident by shorter median survival, earlier histopathological changes and higher serum antigen titres. However, no differences in fungal burden or dissemination to other organs were observed among the various groups. In treatment studies, both fluconazole and posaconazole improved the median survival of mice infected with either species. However, neither regimen improved the percentage of animals surviving to the predetermined study endpoint. CONCLUSIONS: These results demonstrate the virulence of C. gattii meningoencephalitis and the potential of this model for the assessment of new treatment strategies.

Adiaspiromycosis causing respiratory failure and a review of human infections due to Emmonsia and Chrysosporium spp.

We report a case of a 27-year-old male who presented with respiratory distress that required mechanical ventilation. Transbronchial biopsy revealed adiaspores of the fungus Emmonsia crescens within granulomata, a condition known as adiaspiromycosis. The patient received amphotericin products and corticosteroids, followed by itraconazole, and made a full recovery. Emmonsia crescens is a saprobe with a wide distribution that is primarily a rodent pathogen. The clinical characteristics of the 20 cases of human pulmonary adiaspiromycosis reported since the last comprehensive case review in 1993 are described here, as well as other infections recently reported for the genus Emmonsia. Pulmonary adiaspiromycosis has been reported primarily in persons without underlying host factors and has a mild to severe course. It remains uncertain if the optimal management of severe pulmonary adiaspiromycosis is supportive or if should consist of antifungal treatment, corticosteroids, or a combination of the latter two. The classification of fungi currently in the genus Emmonsia has undergone considerable revision since their original description, including being grouped with the genus Chrysosporium at one time. Molecular genetics has clearly differentiated the genus Emmonsia from the Chrysosporium species. Nevertheless, there has been a persistent confusion in the literature regarding the clinical presentation of infection with fungi of these two genera; to clarify this matter, the reported cases of invasive Chrysosporium infections were reviewed. Invasive Chrysosporium infections typically occur in impaired hosts and can have a fatal course. Based on limited in vitro susceptibility data for Chrysosporium zonatum, amphotericin B is the most active drug, itraconazole susceptibility is strain-dependent, and fluconazole and 5-fluorocytosine are not active.

Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety.

BACKGROUND. It is generally acknowledged that amphotericin B is the most effective treatment for cryptococcal meningitis. However, administration of this drug is accompanied by substantial adverse effects. This double-blind study, performed before the routine availability of highly active antiretroviral therapy, was designed to compare the efficacy and safety of liposomal amphotericin B to conventional amphotericin deoxycholate in patients with acquired immunodeficiency syndrome (AIDS) and acute cryptococcal meningitis. METHODS. Patients were randomized (ratio, 1:1:1) from multiple sites in the United States and Canada to receive either amphotericin B at 0.7 mg/kg/day (n = 87), liposomal amphotericin B at 3 mg/kg/day (n = 86), or liposomal amphotericin B at 6 mg/kg/day (n = 94). RESULTS. Efficacy was similar among all 3 treatment groups. The overall incidence of infusion-related reactions was significantly lower for both the 3 mg/kg/day and 6 mg/kg/day dosages of liposomal amphotericin B, compared with conventional amphotericin B (P < .001). Significantly fewer patients who received the 3 mg/kg/day dosage of liposomal amphotericin B developed nephrotoxicity, indicated by a doubling of the serum creatinine value, compared with recipients of conventional amphotericin B (P = .004). Overall mortality at 10 weeks was 11.6%, with no significant differences among the treatment groups. CONCLUSIONS. Liposomal amphotericin B provides an equally efficacious alternative to conventional amphotericin B deoxycholate in patients with AIDS and acute cryptococcal meningitis. Liposomal amphotericin B at a dosage of 3 mg/kg/day is accompanied by significantly fewer adverse effects.

Efficacy of posaconazole as treatment and prophylaxis against Fusarium solani.

Invasive fusariosis is a highly aggressive fungal infection associated with high mortality in heavily immunocompromised patients. Although posaconazole is efficacious as salvage therapy against infections caused by Fusarium species, concerns remain regarding this agent in the setting of reduced potency. To evaluate the efficacy of posaconazole as treatment or prophylaxis against invasive fusariosis caused by Fusarium solani, we utilized a neutropenic murine model of disseminated disease. ICR mice were administered escalating doses of posaconazole (6.25, 12.5, 25, or 50 mg/kg of body weight twice daily [BID]) by oral gavage beginning 2 days prior to inoculation in the prophylaxis studies or beginning 12 h after inoculation as treatment. Therapy was continued until day 9 postinoculation, and animals were monitored off therapy until day 15 for survival. Fungal burden was assessed as CFU in the kidneys. A clear dose-response relationship was observed, as the highest dose of posaconazole (50 mg/kg) was the most effective in prolonging survival and reducing tissue fungal burden both as prophylaxis and as treatment. This dose response was associated with high posaconazole serum concentrations as measured by bioassay. However, the extent of efficacy was also dependent on the infecting inoculum, as greater increases in survival and reductions in fungal burden were observed with the lower inocula tested. In this model high dosages of posaconazole were effective as treatment and prophylaxis against disseminated fusariosis caused by F. solani.

Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america.

Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients.

Inhaled voriconazole for prevention of invasive pulmonary aspergillosis.

Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing the intravenous formulation of voriconazole as prophylaxis against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled voriconazole significantly improved survival and limited the extent of invasive disease, as assessed by histopathology, compared to control and amphotericin B treatments.

The north and south of candidemia: Issues for Latin America.

Candidemia is a growing problem in tertiary care hospitals all over the world. It is generally difficult to diagnose, leads to prolonged hospitalization, has a mortality rate of around 50% and is a financial burden to healthcare systems. The different distribution profiles of Candida species underlying candidemia seen in Latin America, North America, Canada and Europe, along with the emergence of antifungal drug resistance, make it essential to optimize regional guidelines for treating hematogenous candidiasis. This article reviews the importance of candidemia epidemiology and diagnosis from region to region and highlights the antifungal agents currently available to clinicians, comparing antifungal susceptibility profiles that dominate therapeutic strategies for candidemia in specific high-risk populations.

Posaconazole as salvage therapy in patients with invasive fungal infections after solid organ transplant.

BACKGROUND: The incidence of invasive fungal infections (IFIs) in solid organ transplant (SOT) recipients has increased during the past 20 years and is associated with significant morbidity and mortality. In this post hoc analysis of a large, open-label, multicenter study, we evaluated efficacy and safety of posaconazole, a new extended-spectrum triazole, as salvage therapy for IFIs in SOT recipients. METHODS: Twenty-three SOT recipients with proven or probable IFI and evidence of disease refractory to, or intolerant of, standard antifungal therapies received posaconazole oral suspension (40 mg/mL) 800 mg daily in divided doses. An independent, blinded data-review committee assessed patient diagnosis and outcome. RESULTS: Complete or partial response was documented in 13 of 23 (57%) SOT recipients with proven or probable IFIs, including 1 of 2 (50%) refractory patients, 5 of 8 (63%) intolerant to prior therapy, and 7 of 13 (54%) who were both. Successes by type of IFI included 7 of 12 with invasive aspergillosis, 2 of 2 with invasive fusariosis, 1 of 1 with cryptococcosis, and 1 of 2 with zygomycosis. Treatment-related adverse events (TRAEs) were reported in 12 of 23 patients. Severe TRAEs occurred in 4 of 23 patients including increased levels of cyclosporine or tacrolimus requiring immunosuppressive dose adjustments in three patients and in one, termination of posaconazole. Severe TRAEs associated with renal and liver toxicities were uncommon. CONCLUSION: Posaconazole was well tolerated and effective against IFIs including invasive aspergillosis, zygomycosis, fusariosis, and cryptococcosis in SOT recipients intolerant of or failing other antifungal therapies. Calcineurin inhibitor levels should be closely monitored in patients treated concomitantly with posaconazole to avoid toxicity from drug interaction.

Defining responses to therapy and study outcomes in clinical trials of invasive fungal diseases: Mycoses Study Group and European Organization for Research and Treatment of Cancer consensus criteria.

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

Evaluation of aminocandin and caspofungin against Candida glabrata including isolates with reduced caspofungin susceptibility.

BACKGROUND: Aminocandin is an investigational echinocandin with excellent activity against Candida species, including Candida albicans and Candida tropicalis. However, few data are available for this agent versus Candida glabrata. We compared the in vitro potency and in vivo efficacy of aminocandin and caspofungin against clinical isolates of C. glabrata including those with reduced caspofungin susceptibility (MIC > 2 mg/L). METHODS: In vitro activity was assessed using microdilution broth susceptibility testing. Three isolates, one with a low and two with elevated caspofungin MICs, were chosen and mice were infected with C. glabrata followed by a single dose of aminocandin or caspofungin (0.5-100 mg/kg), or daily doses of caspofungin (0.07-14.3 mg/kg) begun 1 day after inoculation. Reduction in fungal burden, assessed in kidney tissue on day 8 post-inoculation, was the marker of antifungal response. RESULTS: Aminocandin was more potent than caspofungin against each isolate with reduced caspofungin susceptibility. Mice infected with the caspofungin-susceptible isolate had significant decreases in tissue burden with low doses of either drug. Higher single doses of aminocandin (> or = 10 mg/kg) were required to reduce fungal burden against the two isolates with elevated caspofungin MICs. Single dose administration of caspofungin was ineffective against one of these isolates, and higher daily doses were required to reduce fungal burden. CONCLUSIONS: These studies suggest that aminocandin has the potential for extended interval dosing in the treatment of C. glabrata infections caused by susceptible isolates. However, higher doses may be required against isolates with reduced caspofungin susceptibility.

Assessment of Aspergillus fumigatus burden in pulmonary tissue of guinea pigs by quantitative PCR, galactomannan enzyme immunoassay, and quantitative culture.

Early diagnosis of invasive pulmonary aspergillosis is problematic in some patient groups due to the lack of rapid, sensitive, specific, and reliable diagnostic tests. Fungal burden and therapeutic efficacy were assessed by survival, quantitative culture (CFU counts), galactomannan enzyme immunoassay (GM-EIA), and quantitative PCR (qPCR) in a new guinea pig model of invasive pulmonary aspergillosis using an aerosol challenge. At 1 day postinfection, qPCR determined that the pulmonary fungal burden was 2 log(10) higher than that determined by CFU counting and increased significantly (P < 0.03) over time. In contrast, the tissue burden assessed by CFU counting did not rise over the course of the study. Therapy with the antifungal drug voriconazole produced statistically significant decreases in pulmonary fungal burden, as detected by CFU counting (P < 0.02), qPCR, and GM-EIA (both P < 0.0002). Daily assessment of the progression of fungal infection in serum was performed by qPCR and GM-EIA. GM-EIA demonstrated a statistically significant reduction in the fungal load on days 6 and 7 in voriconazole-treated animals compared to time-matched controls (P < 0.02). Confirmation of fungal tissue burden by two or more methods should provide a more precise account of the burden, allowing improved assessment of diagnostic and therapeutic strategies in invasive pulmonary aspergillosis.

Fungicidal versus Fungistatic: what's in a word?

BACKGROUND: Historically clinicians have preferred to use 'cidal' antifungal agents, particularly in critically ill patients. However, data to support the belief that the preferential use of a 'cidal' agent results in better patient outcomes has been lacking. OBJECTIVE: This review examined the in vitro definitions of fungicidal and fungistatic as well as their strengths and limitations. METHODS: A Medline search was performed in order to identify literature that examined the in vitro or in vivo impact of fungicidal and fungistatic activity. The study examined three common invasive fungal infections, namely cryptococcal meningitis, candidemia and invasive aspergillosis, where sufficient comparisons of fungicidal and fungistatic agents have been performed to allow for the evaluation of the clinical importance of these in vitro findings. RESULTS AND CONCLUSION: A clear clinical benefit of fungicidal agents over those with fungistatic activity remains elusive. Patients with cryptococcal meningitis clearly benefit from early fungicidal therapy but require long-term suppression. The data in invasive Candida sp. infections are tantalizing and suggest that fungicidal therapy may be important. However, the data for invasive aspergillosis do not support the hypothesis that fungicidal activity improves outcomes.

Assessment of serum (1->3)-beta-D-glucan concentration as a measure of disease burden in a murine model of invasive pulmonary aspergillosis.

Serum (1-->3)-beta-D-glucan concentrations were serially measured in the presence and absence of antifungal therapy in a murine model of invasive pulmonary aspergillosis. Serum (1-->3)-beta-D-glucan was detected early during the course of infection, and reductions in this biomarker were associated with improved survival in animals treated with antifungal agents.

Antimicrobial resistance prevention initiative--an update: proceedings of an expert panel on resistance.

Antimicrobial resistance is a growing problem that complicates the treatment of important nosocomial and community-acquired infections. It is a worldwide problem that spans the range of human pathogens, including bacteria, fungi, and viruses. This update from the Antimicrobial Resistance Prevention Initiative (ARPI) provides a review of some important trends in antibiotic, antifungal, and antiviral resistance. Areas of focus include multidrug-resistant bacteria in the hospital setting; the growing problem of community-acquired methicillin-resistant Staphylococcus aureus; triazole and polyene resistance in nosocomial infections caused by non-Candida albicans or Aspergillus species, and the utility of in vitro susceptibility testing for these fungal infections; antiviral resistance in alpha- or beta-herpesviruses causing genital herpes or cytomegalovirus infection in immunocompromised hosts; and concerns about a possible pandemic involving avian influenza A and the importance of minimizing emergence of resistant strains of this highly pathogenic virus. The challenges in each area are different, but the general keys to addressing the growing problem of antimicrobial resistance continue to be responsible antimicrobial stewardship and the development of newer antimicrobial agents.

Therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate for coccidioidomycosis in a mouse model.

OBJECTIVES: The therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate was evaluated in treatment of murine coccidioidomycosis. METHODS: Survival and tissue burdens of the spleens and livers were used as antifungal response markers. In a monotherapy study, caspofungin was injected intraperitoneally at 0.1, 0.2, 0.5, 1 and 5 mg/kg per day on days 2 through 15. Amphotericin B deoxycholate was given at 0.1, 0.2 and 0.5 mg/kg intravenously and 1 and 5 mg/kg intraperitoneally three times per week for 2 weeks. In a combination therapy study, amphotericin B deoxycholate at 0.1 mg/kg was administered intravenously three times per week for 2 weeks, respectively, with and without caspofungin intraperitoneally given at 0.1, 0.5 and 5 mg/kg daily on days 2 through 15 post-infection. RESULTS: The study shows that caspofungin and amphotericin B deoxycholate at > or =0.5 and > or =0.1 mg/kg, respectively, were significant in both prolongation of survival and reduction of the tissue fungal burdens of mice compared with controls. No sterilization of either organ was observed with caspofungin doses. In combination therapy, any combination of caspofungin (0.1, 0.5 and 5 mg/kg) with amphotericin B deoxycholate (0.1 mg/kg) improved the period of survival and significantly reduced spleen and liver counts compared with controls. CONCLUSIONS: This study indicates that caspofungin has efficacy against systemic coccidioidomycosis in a murine model given in combination with amphotericin B deoxycholate.

Antimicrobial resistance prevention initiative--an update: proceedings of an expert panel on resistance.

Antimicrobial resistance is a growing problem that complicates the treatment of important nosocomial and community-acquired infections. It is a worldwide problem that spans the range of human pathogens, including bacteria, fungi, and viruses. This update from the Antimicrobial Resistance Prevention Initiative (ARPI) provides a review of some important trends in antibiotic, antifungal, and antiviral resistance. Areas of focus include multidrug-resistant bacteria in the hospital setting; the growing problem of community-acquired methicillin-resistant Staphylococcus aureus; triazole and polyene resistance in nosocomial infections caused by non-Candida albicans or Aspergillus species, and the utility of in vitro susceptibility testing for these fungal infections; antiviral resistance in alpha- or beta-herpesviruses causing genital herpes or cytomegalovirus infection in immunocompromised hosts; and concerns about a possible pandemic involving avian influenza A and the importance of minimizing emergence of resistant strains of this highly pathogenic virus. The challenges in each area are different, but the general keys to addressing the growing problem of antimicrobial resistance continue to be responsible antimicrobial stewardship and the development of newer antimicrobial agents.

New guinea pig model of Cryptococcal meningitis.

We developed a guinea pig model of cryptococcal meningitis to evaluate antifungal agents. Immunosuppressed animals challenged intracranially with Cryptococcus neoformans responded to fluconazole and voriconazole. Disease was monitored by serial cerebrospinal fluid (CSF) cultures and quantitative organ cultures. Our model produces disseminating central nervous system disease and responds to antifungal therapy.

Aerosolized nanostructured itraconazole as prophylaxis against invasive pulmonary aspergillosis.

OBJECTIVE: Prophylactic strategies against invasive pulmonary aspergillosis are often limited by drug interactions and toxicities. Targeted airway delivery of antifungals to the lungs may avoid these pitfalls. We evaluated the effectiveness of an aerosolized nanostructured formulation of itraconazole produced by spray freezing into liquid (SFL) as prophylaxis against invasive pulmonary aspergillosis caused by A. fumigatus. METHODS: Immunocompromised Balb/C mice received either itraconazole by oral gavage (Sporanox Oral Liquid [SOL] 30 mg/kg TID) or by aerosolization (SFL 30 mg/kg via 20 min aerosolizations, or control, BID). Dosing began 2 days prior to pulmonary inoculation with A. fumigatus and continued for 7 days post-inoculation. Changes in lung histopathology were also assessed. In the survival arm, mice were monitored over a 5 day period following discontinuation of therapy and survival was assessed by Kaplan-Meier analysis. RESULTS: SFL survival (35%) was greater compared to control (10%; p=0.03) and SOL (0%; p=0.02). Histopathology demonstrated severe invasive disease involving vessels and small airways in control and SOL animals. SFL animals demonstrated colonization with some invasion predominately of large airways. CONCLUSIONS: Prophylactic aerosolization of nanostructured SFL significantly improved survival and limited invasive disease of small airways due to A. fumigatus.

In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera.

In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.

Posaconazole for the treatment of azole-refractory oropharyngeal and esophageal candidiasis in subjects with HIV infection.

BACKGROUND: We evaluated the efficacy and safety of oral posaconazole for human immunodeficiency virus (HIV)-infected subjects with oropharyngeal candidiasis (OPC) and/or esophageal candidiasis (EC) who were clinically refractory to treatment with oral fluconazole or itraconazole. METHODS: Subjects with confirmed OPC or EC who did not improve after receiving standard courses of fluconazole or itraconazole treatment were eligible for study enrollment. Subjects received either oral posaconazole (400 mg twice daily) for 3 days followed by oral posaconazole (400 mg once daily) for 25 days (regimen A; 103 patients) or oral posaconazole (400 mg twice daily) for 28 days (regimen B; 96 patients). The primary end point was cure or improvement after 28 days. Primary efficacy analyses were performed on the subset of treated subjects with refractory disease (e.g., baseline culture positive for fluconazole- or itraconazole-resistant Candida species or persistent or progressive clinical signs or symptoms consistent with treatment failure). RESULTS: Of the modified intent-to-treat population, 132 (75%) of 176 subjects achieved a clinical response to posaconazole treatment. Clinical response rates were similar between regimen A recipients (75.3%) and regimen B recipients (74.7%). Clinical responses occurred in 67 (73%) of 92 subjects with baseline isolates resistant to fluconazole, 49 (74%) of 66 subjects with baseline isolates resistant to itraconazole, and 42 (74%) of 57 subjects with isolates resistant to both. Clinical response was achieved in 32 (74.4%) of 43 subjects with endoscopically documented EC. The most common treatment-related adverse events were diarrhea (11%), neutropenia (7%), flatulence (6%), and nausea (6%). Eight subjects (4%) discontinued therapy as a result of a treatment-related adverse event. CONCLUSIONS: Posaconazole offers a safe and effective treatment option for HIV-infected subjects with azole-refractory OPC and/or EC.