Posaconazole Therapy Research Articles

Therapeutic Drug Monitoring of Posaconazole: a Monocentric Study with 54 Adults

Posaconazole is a potent broad-spectrum triazole antifungal. Little is known about the prevalence and risk factors for low plasma posaconazole concentrations (PPCs). We retrospectively reviewed all adult patients whose PPCs were measured after at least 5 days of treatment between April 2006 and July 2008 at the Hôpital Necker Enfants Malades. A low PPC was defined as a concentration lower than 500 ng/ml. Fifty-four patients were included: 36 receiving prophylactic (200 mg three times a day) and 18 receiving curative (400 mg twice a day) posaconazole therapy. The prevalence of low PPCs was 44% (16/36) in the prophylaxis group and 22% (4/18) in the curative-treatment group. In the prophylaxis group, low PPCs tended to be more frequent in cases of digestive disease (62.5% versus 30%; P = 0.051) and were significantly more frequent among patients with diarrhea (71.4% versus 27%; P = 0.009) or mucositis (100% versus 33%; P = 0.004). In the curative-treatment group, low PPCs were significantly more frequent in cases of diarrhea (75% versus 7%; P = 0.018). In the prophylaxis group, the only two patients who subsequently developed invasive fungal infections exhibited low PPCs. The only adverse event was hepatotoxicity for 2/54 patients (3.7%), which was not related to high plasma drug concentrations. In conclusion, low PPC is common, significantly more frequent in cases of diarrhea or mucositis, and potentially associated with subsequent invasive fungal infection. Therapeutic drug monitoring of posaconazole is therefore mandatory for immunosuppressed adults, at least for those with gastrointestinal disorders.

Successful treatment of pulmonary zygomycosis in two transplant recipients with liposomal amphotericin B and partial surgical resection followed by posaconazole

Summary Pulmonary zygomycosis is a relatively uncommon complication of solid organ or peripheral blood stem cell transplantation and has a high associated mortality. Optimal therapy consists of complete resection of infected tissue and treatment with amphotericin B (AmB). We describe two patients, one of whom underwent orthotopic heart transplantation and the other who received a peripheral blood stem cell transplant, who were diagnosed with invasive pulmonary zygomycosis. Both patients were treated with a liposomal preparation of AmB and early partial resection of the infected structures followed by prolonged posaconazole maintenance therapy. Despite incomplete resection, this treatment regimen resulted in a favourable outcome in both patients, including survival of more than 17 months in one patient at last follow up. For patients in whom complete resection of pulmonary zygomycosis is not possible, subtotal resection and treatment with liposomal AmB followed by therapy with posaconazole may be an effective treatment option.

Multiple-azole-resistantAspergillus fumigatusosteomyelitis in a patient with chronic granulomatous disease successfully treated with long-term oral posaconazole and surgery

We describe a patient with chronic granulomatous disease and proven Aspergillus fumigatus osteomyelitis of the midfoot, while receiving itraconazole-prophylaxis. The isolate proved resistant to itraconazole as well as voriconazole, and showed reduced susceptibility to posaconazole. Although molecular analysis demonstrated the presence of a 53 base pair tandem repeat in the promoter region for cyp51A, i.e., the gene coding for the target enzyme of the azole antifungals, there were no mutations in the cyp51A gene. Since transformation of the promoter region into wild-type strains did not result in an azole resistant phenotype, a yet unknown mutation was suspected. The patient was treated with extensive surgery and two weeks of caspofungin therapy, followed by one year of posaconazole therapy. He made a complete recovery and did not experience any side effects. Long-term posaconazole proved to be a safe and effective treatment for multi-azole resistant A. fumigatus osteomyelitis in this immunocompromised patient.

Scedosporium prolificans: an emerging pathogen in France?

For the last ten years, non-Aspergillus mold species have been increasingly involved in human invasive infections, probably as a consequence of more intense immunosuppression and prolonged patient survival, and of selective pressure since antifungal agents are currently used for prophylaxis or therapy. Scedosporium prolificans, one of these emerging fungi, has been isolated in a broad spectrum of clinical presentations in humans, including respiratory-tract colonization, superficial or locally invasive infections, and disseminated infections in immunocompromised patients. Here, we report the recent emergence of invasive infections due to S. prolificans in France, and describe four new cases diagnosed during the last six years. Only one disseminated scedosporiosis has been reported before this in France, in 1994. Three out of our four cases were breakthrough infections in immunocompromised patients receiving posaconazole or voriconazole therapy. The aims of the present review were thus to gain a better understanding of scedosporiosis epidemiology and clinical features, and to review recent advances in multimodal management of these infections, including surgery, recovery and/or enhancement of immunity, and antifungal combinations, especially voriconazole plus terbinafine.

Modern management of chronic granulomatous disease

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder of phagocytic cells resulting in failure to kill a characteristic spectrum of bacteria and fungi and in defective degradation of inflammatory mediators with concomitant granuloma formation. Current prophylaxis with trimethoprim-sulfamethoxazole, itraconazole and in selected cases additional interferon gamma is efficient, but imperfect. A significant recent progress towards new antibiotic (e.g. linezolid) and antifungal (e.g. voriconazole and posaconazole) therapy will allow survival of most patients into adulthood. Adolescent and adult CGD is increasingly characterized by inflammatory complications, such as granulomatous lung and inflammatory bowel disease, requiring immunosupressive therapy. Allogeneic haematopoietic stem cell transplantation from a human leucocyte antigen identical donor is currently the only proven curative treatment for CGD and can be offered to the selected patients. Gene-replacement therapy for patients lacking a suitable stem cell donor is still experimental and faces major obstacles and risks. However, it may offer some transitory benefits and has helped in a few cases to overcome life-threatening infections.

Novel antifungal agents as salvage therapy for invasive aspergillosis in patients with hematologic malignancies: posaconazole compared with high-dose lipid formulations of amphotericin B alone or in combination with caspofungin

In patients with hematologic malignancy, invasive aspergillosis continues to be associated with high mortality even when treated with conventional antifungal therapy. To investigate novel antifungal agents, we compared 53 patients who received posaconazole salvage therapy to 52 contemporary control patients who received high-dose lipid formulation of amphotericin B (HD-LPD/AMB at > or = 7.5 mg kg(-1) per day) and 38 other control patients who received caspofungin plus HD-LPD/AMB. Patients in the three groups had similar. The overall response rate to salvage therapy was 40% for posaconazole, 8% for HD-LPD/AMB (P < or = 0.001) and 11% for combination therapy (P < 0.002). Aspergillosis contributed to the death of 40% of posaconazole group, 65% of the HD-LPD/AMB group and 68% of the combination group (P < or = 0.008). By multivariate analysis, posaconazole therapy independently improved response (9.5; 95% confidence interval, 2.8-32.5; P < 0.001). HD-LPD/AMB alone or in combination was associated with a significantly higher rate of nephrotoxicity (P < or = 0.02) and hepatotoxicity (P < 0.03). In conclusion, posaconazole salvage therapy demonstrated greater efficacy and safety than HD-LPD/AMB alone or in combination with caspofungin in the salvage therapy of invasive aspergillosis in hematologic malignancy.

Safety, Tolerance, and Efficacy of Posaconazole Therapy in Patients with Nonmeningeal Disseminated or Chronic Pulmonary Coccidioidomycosis

Coccidioidomycosis can be difficult to treat with available therapies, particularly in patients with progressive or disseminated disease. Posaconazole is a new azole antifungal with potent activity against Coccidioides species, the causative agent of coccidioidomycosis. Twenty patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis were enrolled in a multicenter trial to study the safety and tolerability of posaconazole therapy, with efficacy as a secondary end point. Patients received posaconazole (400 mg/day) in capsule formulation for up to 6 months. Safety was evaluated on the basis of the occurrence of adverse events. A satisfactory efficacy response was defined as a >or=50% reduction in the Mycoses Study Group score from baseline. Seventeen (85%) of 20 patients had a satisfactory response to treatment. The median duration of treatment was 173 days. Paired baseline and end-of-treatment culture results for Coccidioides species were available for 4 patients, all of whom converted from being positive to being negative for Coccidioides species. Relapse was experienced by 3 of 9 patients who did not receive antifungal therapy during the follow-up period. In general, posaconazole therapy was well tolerated, with 12 of 20 patients reporting adverse events that were possibly or probably related to treatment. The most common adverse events were dry mouth (in 5 patients [25%]) and headache (in 3 patients [15%]). Courses of posaconazole therapy that were up to 6 months in duration were well tolerated in patients with coccidioidomycosis. Although this study was limited by the number of patients enrolled, it clearly demonstrates that posaconazole shows promise in the treatment of patients with coccidioidomycosis and warrants additional investigation in a full-scale clinical trial.

Effect of Oral Posaconazole on the Pharmacokinetics of Cyclosporine and Tacrolimus

To analyze the pharmacokinetic properties of the immunosuppressants cyclosporine and tacrolimus when either is coadministered with oral posaconazole. Two single-center, open-label pharmacokinetic studies of cyclosporine in a multiple-dose design and of tacrolimus in a one-sequence, crossover, single- and multiple-dose design. One clinical investigative center in the United States and one in the United Kingdom. Four adult heart transplant recipients in the cyclosporine study and 36 healthy adult volunteers in the tacrolimus study. In the cyclosporine study, patients who took an established cyclosporine dose 3 times/day for 6 weeks or longer were given posaconazole 200 mg/day for 10 days. In the tacrolimus study, subjects received tacrolimus 0.05 mg/kg/day on days 1 and 14 and posaconazole 400 mg twice/day on days 7-14. In the cyclosporine study, blood samples were collected on day 1 to determine cyclosporine pharmacokinetics and on day 10 to measure the pharmacokinetics of cyclosporine and posaconazole. Coadministration of posaconazole increased cyclosporine exposure and necessitated dosage reductions of 14-29% for cyclosporine in three subjects. In the tacrolimus study, blood samples were collected on days 12-14 to assess posaconazole pharmacokinetics and on days 1 and 14 for as long 72 hours after dosing to evaluate tacrolimus pharmacokinetics. Posaconazole increased the maximum blood concentration and the area under the concentration-time curve for tacrolimus by 121% and 358%, respectively, on day 14 compared with day 1 (both p=0.001). In both studies, posaconazole pharmacokinetics were unaffected. These findings suggest that the dosage of cyclosporine or tacrolimus should be reduced when posaconazole therapy is started and that plasma levels of the immunosuppressant should be monitored during and at the discontinuation of posaconazole therapy so that dosages are adjusted accordingly. This recommendation is consistent with current standard of care for patients receiving cyclosporine or tacrolimus with concomitant azole antifungal therapy.

Posaconazole salvage therapy allows successful allogeneic hematopoietic stem cell transplantation in patients with refractory invasive mold infections

We describe the clinical courses of 3 patients with hematologic malignancies (2 with acute myelogenous leukemia and 1 with multiple myeloma) who developed invasive fungal infections due to uncommon molds (Alternaria spp., Paecilomyces lilacinus, and Zygomycetes). Breakthrough invasive fungal infections of the sinus (n=1), lung (n=3), and pericardium (n=1) developed despite fluconazole prophylaxis and failed to respond to treatment with other licensed antifungal therapies, including amphotericin B (n=3), caspofungin (n=2), and voriconazole (n=3), and surgical intervention (n=2). Salvage therapy with posaconazole oral suspension resulted in successful outcomes in all 3 patients, who subsequently underwent allogeneic hematopoietic stem cell transplantation (HSCT) while on continued posaconazole therapy. The median duration of posaconazole treatment before HSCT was 5 months (range: 1.5-6 months). Posaconazole salvage therapy allowed successful allogeneic HSCT in 3 patients with refractory invasive mold infections.

Successful treatment of disseminated fusariosis with posaconazole during neutropenia and subsequent allogeneic hematopoietic stem cell transplantation

We report the case of a 16-year-old girl with acute myelogenous leukemia with disseminated fusariosis, who responded to salvage posaconazole therapy. She subsequently received additional cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation with posaconazole continued as secondary prophylaxis. Despite intensive immunosuppressive therapy for graft-versus-host disease, no recrudescence of infection occurred.

Posaconazole (Noxafil): A New Triazole Antifungal Agent

Posaconazole is the newest triazole antifungal agent. It is structurally related to itraconazole and has activity against Candida species, Aspergillus species, Cryptococcus neoformans, the zygomycetes, and other filamentous fungi. Randomized, double-blind trials have shown posaconazole to be at least as efficacious as fluconazole for the prevention of invasive fungal infections in immunocompromised patients. It has also shown promising results in the treatment of various fungal infections refractory to other antifungal therapy. The dose of posaconazole is 200 mg orally three times daily for the prevention of invasive fungal infections and 800 mg daily in two to four divided doses for the treatment of invasive fungal infections refractory to other antifungal treatment. All posaconazole doses should be given with food or a nutritional supplement to enhance absorption. The most common adverse effects reported with posaconazole therapy were fever, diarrhea, nausea, vomiting, and headache. Instances of elevated liver enzyme levels, hyperbilirubinemia, and hepatocellular damage were also noted in clinical trials, and these laboratory values should be monitored during treatment with posaconazole.

Posaconazole as Salvage Therapy in a Patient with Disseminated Zygomycosis: Case Report and Review of the Literature

Zygomycosis refers to any fungal infection originating from the class Zygomycetes and the order Mucorales. In immunocompromised patients, these fungi produce a relatively rapid, violently destructive, and highly fatal infection. Treatment approaches include both aggressive antifungal pharmacotherapy and surgical intervention. Unfortunately, even with optimal therapy, morbidity and mortality rates remain relatively high. As failure rates are elevated with commercial antifungals, new treatment options are needed. Posaconazole is an orally available, extended-spectrum triazole antifungal being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections, including zygomycosis. We report the case of a 26-year-old Vietnamese man with a medical history of acute lymphocytic leukemia who had undergone consolidation chemotherapy and had neutropenic fever when he came to the emergency department. The patient was admitted to the hospital and treated with broad-spectrum antibiotics and caspofungin. Two weeks into his admission, however, abscesses in the pelvis, prostate, and musculature surrounding the hip were detected radiographically; these abscesses eventually cultured for Mucor sp. Disseminated zygomycosis was diagnosed. Caspofungin was immediately discontinued, and high-dose liposomal amphotericin B 10 mg/kg/day was begun. Over the next month, infection spread to the right lung, left kidney, middle thoracic spine, and epidural space. As a result, oral posaconazole 200 mg 4 times/day was added to the liposomal amphotericin B. Significant clinical, hematologic, mycologic, and radiologic improvements were demonstrated as early as 10 days after start of posaconazole therapy and continued through 41 days of inpatient treatment. Liposomal amphotericin B was discontinued after 3 weeks of posaconazole, and the patient was discharged on hospital day 92 receiving oral posaconazole, with no major adverse events reported. Five months after discharge, the patient had no evidence of fungal disease recurrence or progression. Posaconazole appears to be a well-tolerated and effective salvage treatment for zygomycosis, including disseminated disease.

Cost-Effectiveness of Posaconazole Versus Standard Azole Therapy in the Prevention of Invasive Fungal Infections among High-Risk Neutropenic Patients in the U.S.

In a recent clinical trial, posaconazole was found to be superior to standard azole therapy (i.e., fluconazole or itraconazole) in preventing both invasive fungal infections (IFIs) and in reducing overall mortality among high-risk neutropenic patients. We conducted a cost-effectiveness analysis based on trial results from a U.S. perspective. A decision-analytic model was developed to estimate the cost-effectiveness of antifungal prophylaxis among patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS) at high risk of developing an IFI due to chemotherapy-induced neutropenia. To extrapolate trial results to a lifetime horizon, the model was extended with one-month Markov cycles in which mortality risk is specific to the underlying disease as estimated from SEER data. Patients in the model were assumed to receive prophylaxis with posaconazole or standard azole therapy (fluconazole, 81%; itraconazole, 19%). The probabilities of experiencing an IFI, IFI-related death, and death from other causes over 100 days of follow-up were estimated from the trial data. Long-term mortality, drug costs, and IFI treatment costs were estimated using published sources. The model was used to estimate costs, IFIs avoided, life-years gained, and the incremental cost-effectiveness of posaconazole versus standard azole therapy (using 2006 dollars). Posaconazole is associated with fewer IFIs (0.05 vs. 0.11), increased life years (0.744 vs. 0.728), and (excluding costs of the underlying condition) slightly lower costs ($4,887 vs. $5,070) per patient relative to standard azole therapy over a lifetime horizon. One-way sensitivity analyses indicate that when model parameters are varied across reasonable ranges of their base-case values, the incremental cost-effectiveness ratio for posaconazole ranges from cost saving to $50,000 per life-year saved relative to standard azole therapy. A second-order probabilistic Monte Carlo sensitivity analysis was conducted to assess the effects of parameter uncertainty on the study findings, particularly as relates to treatment efficacy and the costs of an IFI. Results indicate that there is a 75% probability that posaconazole is cost saving versus standard azole therapy and a 90% probability that the incremental cost-effectiveness ratio for posaconazole is at or below the $50,000 per life year saved threshold. Posaconazole has been shown to be more effective than standard azole therapy (i.e., fluconazole or itraconazole) in preventing IFIs and reducing overall mortality in high-risk neutropenic patients.Based on this analysis, we conclude that posaconazole is likely to be cost saving relative to standard azole therapy (i.e., fluconazole or itraconazole) in the prevention of IFIs among high-risk neutropenic patients.

Infection pulmonaire à Cunninghamella bertholletiae chez une jeune patiente leucémique

Cunninghamella bertholletiae, a zygomycete isolated in soil and plants in temperate climates, causes an infection with a very high mortality rate(76%). The pulmonary form is rare and occurs mostly in patients treated for leukemia. Since 1959 five cases have been reported in children (< 18-years-old), 4 with leukemia, 2 with aspergillosis co-infection and 3 deaths. A 17-year-old girl was treated for relapsed acute lymphoid leukemia. Neutropenia induced by chemotherapy was complicated by fever and was treated with a large broad spectrum antibiotic. At day 13, a chest radiograph revealed a left parahilar alveolar condensation. Direct mycological examination of the bronchoalveolar lavage sample showed mycelium very suggestive of mucorales. At the same time, the galactommanan antigen titer increased to 2.95 ng/ml. Treatment with conventional amphotericin B (Fungizone ®) was started; the patient became afebrile at the 48 th hour. After the fungal culture yielded C. bertholletiae, liposomal amphotericin B (Ambisome ®) was started. Because of the closeness of the pulmonary artery and the persistence of haemoptysis, a resection of the left upper pulmonary lobe was performed. An examination of the mycological parenchyma was negative. Microscopic examination and fungal culture of the pulmonary vein fragment were positive. Histological examination revealed mycelial invasion of the vascular and bronchial lumens and walls. Ambisome ® treatment was continued until day 57, then changed to posaconazole (Noxafil ®). On November 17 the patient received an allogenic bone marrow transplant. At the time of writing, 5 months after the transplant, she is well with no evidence of disease recurrence and posaconazole therapy is being continued.

Treatment of Cavitary Pulmonary Zygomycosis With Surgical Resection and Posaconazole

We describe a 57-year-old woman with acute lymphoblastic leukemia who had a cavitary lesion develop in the right upper lobe caused by Cunninghamella bertholletiae, a zygomycete. The infection was resistant to both high-dose liposomal amphotericin B and voriconazole. The current report demonstrates successful treatment, even in the setting of subsequent bone marrow transplantation and immunosuppression, using a combination of surgical resection and posaconazole therapy.

Safety of Long-Term Oral Posaconazole Use in the Treatment of Refractory Invasive Fungal Infections

Invasive fungal infections are found most frequently in immunosuppressed and critically ill hospitalized patients. Antifungal therapy is often required for long periods. Safety data from the clinical development program of the triazole antifungal agent, posaconazole, were analyzed. A total of 428 patients with refractory invasive fungal infections (n = 362) or febrile neutropenia (n = 66) received posaconazole in 2 phase II/III open-label clinical trials. Also, 109 of these patients received posaconazole therapy for > or = 6 months. Incidences of treatment-emergent, treatment-related, and serious adverse events and abnormal laboratory parameters were recorded during these studies. Treatment-emergent, treatment-related adverse events were reported in 38% of the overall patient population. The most common treatment-related adverse events were nausea (8%) and vomiting (6%). Treatment-related serious adverse events occurred in 8% of patients. Low rates of treatment-related corrected QT interval and/or QT interval prolongation (1%) and elevation of hepatic enzymes (2%) were reported as adverse events. Treatment-emergent, treatment-related adverse events occurred at similar rates in patients who received posaconazole therapy for < 6 months and > or = 6 months. Prolonged posaconazole treatment was associated with a generally favorable safety profile in seriously ill patients with refractory invasive fungal infections. Long-term therapy did not increase the risk of any individual adverse event, and no unique adverse event was observed with longer exposure to posaconazole.

Posaconazole as Salvage Treatment for Invasive Fusariosis in Patients with Underlying Hematologic Malignancy and Other Conditions

Conventional amphotericin B-based antifungal therapy for invasive fusariosis in patients with a hematologic malignancy results in a > or = 70% failure rate. Posaconazole is a broad-spectrum antifungal agent with in vitro and in vivo activity against Fusarium species. In this retrospective analysis of patients from 3 open-label clinical trials, we evaluated posaconazole for the treatment of invasive fusariosis. Twenty-one patients with proven or probable invasive fusariosis who had disease refractory to or who were intolerant of standard antifungal therapy received oral posaconazole suspension (800 mg per day in divided doses) as salvage therapy. Successful outcome occurred in 10 (48%) of all 21 patients. Among patients with leukemia who received posaconazole therapy for >3 days, the overall success rate was 50%; for patients who recovered from myelosuppression, the success rate was 67%, compared with 20% for those with persistent neutropenia. These results suggest that posaconazole is useful for the treatment of invasive fusariosis.

Efficacy of posaconazole (POS) vs standard therapy and safety of POS in hematopoietic stem cell transplant (HSCT) recipients vs other patients with aspergillosis

Introduction: Antifungal therapy response is typically low in HSCT recipients with aspergillosis. We compared (1) outcomes in POS-treated HSCT and non-HSCT recipients with aspergillosis with those of external controls receiving other antifungal therapy; (2) safety of POS in HSCT and non-HSCT recipients with aspergillosis. Methods: Patients with invasive fungal infections, including HSCT recipients, who were intolerant of or refractory to other antifungal therapy received oral POS 800 mg/d in divided doses in a prospective, open-label, multicenter study.

Posaconazole treatment of refractory eumycetoma and chromoblastomycosis

Eumycetoma and chromoblastomycosis are chronic, disfiguring fungal infections of the subcutaneous tissue that rarely resolve spontaneously. Most patients do not achieve sustained long-term benefits from available treatments; therefore, new therapeutic options are needed. We evaluated the efficacy of posaconazole, a new extended-spectrum triazole antifungal agent, in 12 patients with eumycetoma or chromoblastomycosis refractory to existing antifungal therapies. Posaconazole 800 mg/d was given in divided doses for a maximum of 34 months. Complete or partial clinical response was considered a success; stable disease or failure was considered a nonsuccess. All 12 patients had proven infections refractory to standard therapy. Clinical success was reported for five of six patients with eumycetoma and five of six patients with chromoblastomycosis. Two patients were reported to have stable disease. As part of a treatment-use extension protocol, two patients with eumycetoma who initially had successful outcome were successfully retreated with posaconazole after a treatment hiatus of > 10 months. Posaconazole was well tolerated during long-term administration (up to 1015 d). Posaconazole therapy resulted in successful outcome in most patients with eumycetoma or chromoblastomycosis refractory to standard therapies, suggesting that posaconazole may be an important treatment option for these diseases.

Posaconazole vs Standard Azole (FLU/ITRA) Therapy for Prophylaxis of Invasive Fungal Infections (IFIs) among High-Risk Neutropenic Patients: Results of a Randomized, Multicenter Trial.

Background: Patients with severe and prolonged neutropenia are at high-risk of developing life-threatening IFIs. Despite current treatment option, IFIs are difficult to treat and frequently associated with high mortality rates. Antifungal prophylaxis has shown benefits in high-risk populations and is a standard practice in many institutions. We compared Posaconazole (POS), a new broad-spectrum triazole, vs Standard Azoles for the prevention of IFIs in patients with a new diagnosis or first relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) being treated with intensive chemotherapy.Methods: Patients in this randomized, evaluator-blinded, active controlled, multi-center study received oral POS (200mg tid) or oral Standard Azoles (either Fluconazole [FLU 400mg qd] or Itraconazole solution [ITRA 200mg bid]) with each cycle of chemotherapy until complete remission or for up to a maximum of 12 weeks. The primary efficacy end point was the comparison of the incidence of IFIs during the treatment phase (7 days after last dose) as adjudicated by the blinded expert panel based on EORTC/MSG criteria. The incidence of IFIs 100 days after randomization and the clinical outcome at the end of the treatment phase were also compared. Treatment failure was defined as presence of proven or probable IFIs, use of >3 days of empirical systemic antifungal treatment, use of >3 consecutive days or a total of 10 or more days of IV study drug (or alternative formulation for POS), discontinuation due to an adverse event related to study drug or lost to follow-up during treatment.Results: 602 patients were enrolled (304 POS, 298 Standard Azole [240 FLU, 58 ITRA]). The incidence of proven/probable IFIs was lower with POS prophylaxis (see table). The overall mortality was 49 (16%) vs 67 (22%) for patients in the POS and Standard Azoles arms respectively. Analysis of time to death (all cause mortality) within 100 days post randomization yielded a P-value of 0.035, indicating a significant survival benefit in favor of POS. Twenty-one (21) deaths due to IFIs occurred during the study (POS 5, Standard Azoles 16, P = 0.012). Treatment failures were fewer in the POS arm vs Standard Azoles arm (36% vs 46%, P = 0.0091). Safety and tolerability were comparable.Conclusions: In this study, POS was superior to the use of a Standard Azoles (FLU or ITRA) in preventing IFIs and in preventing aspergillosis, in high-risk neutropenic patients with AML or MDS undergoing intensive chemotherapy. Patients receiving POS experienced a significant survival benefit.POS N=304FLU/ITRA N=298Proven/Probable IFIsn (%)n (%)P-valueAll IFIs during Treatment Phase7 (2)25 (8)0.0009Aspergillus during Treatment Phase2 (1)20 (7)0.0001All IFIs within 100 days post-randomization14 (5)33 (11)0.0031