Clinical Outcomes of the Oral Suspension vs Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections

Abstract Background Posaconazole is effective prophylaxis for invasive fungal infections (IFIs). We compared incidence of breakthrough IFI (bIFI) and early posaconazole discontinuation between patients receiving delayed-release tablet and oral suspension formulations. Methods This was a retrospective cohort study of patients receiving posaconazole at Oregon Health & Science University Hospital between 1/1/2010 and 6/30/2016. Oral suspension was the preferred formulation until 2/2014; afterwards the tablet was preferred. We included all courses of primary prophylaxis for each patient during the study period. Data were extracted from an electronic health record repository and via chart review. Three independent reviewers identified bIFI using European Organization for Research and Treatment of Cancer criteria. We assessed rationale for early discontinuation of posaconazole for patients that were still indicated for antifungal prophylaxis based on National Comprehensive Cancer Network (NCCN) criteria. Results 547 patients received 859 courses of posaconazole (53% oral suspension and 48% tablet). Prophylaxis was indicated according to NCCN criteria in 91% of courses. The primary indications for prophylaxis were acute myelogenous leukemia (68%), graft-vs-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indication between patients receiving the different formulations. The overall incidence rate of bIFI was 4.15/10,000 posaconazole-days (16 total bIFI events). Incidence of bIFI was not significantly different between patients receiving the different formulations (P = 0.92). Posaconazole was discontinued early in 147 (17%) courses; frequency of discontinuation was not significantly different between the tablet (20%) and oral suspension (15%) formulations (P = 0.10). The primary reasons for early discontinuation were elevated liver function tests or QT prolongation (25%), inability to take an oral formulation (17%), and drug cost (17%). Conclusion Among patients receiving posaconazole prophylaxis, incidence of bIFI was low and not significantly different between those receiving the tablet vs oral suspension formulations. Disclosures J. P. Furuno, Merck & Co.: Consultant and Grant Investigator, Consulting fee, Research grant and Speaker honorarium. J. S. Lewis II, Merck & Co.: Consultant, Consulting fee. J. C. McGregor, Merck & Co.: Grant Investigator, Research grant

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Clinical Outcomes of Oral Suspension versus Delayed-Release Tablet Formulations of Posaconazole for Prophylaxis of Invasive Fungal Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00893-18 ◽

2018 ◽

Vol 62 (10) ◽

Cited By ~ 9

Author(s):

Jon P. Furuno ◽

Gregory B. Tallman ◽

Brie N. Noble ◽

Joseph S. Bubalo ◽

Graeme N. Forrest ◽

...

Keyword(s):

Fungal Infections ◽

Hematologic Malignancies ◽

Invasive Fungal Infections ◽

Oral Suspension ◽

European Organization ◽

Delayed Release ◽

Suspension Formulation ◽

Eortc Criteria ◽

Significant Difference ◽

Release Tablet

ABSTRACT Posaconazole is used for prophylaxis for invasive fungal infections (IFIs) among patients with hematologic malignancies. We compared the incidence of breakthrough IFIs and early discontinuation between patients receiving delayed-release tablet and oral suspension formulations of posaconazole. This was a retrospective cohort study of patients receiving posaconazole between 1 January 2010 and 30 June 2016. We defined probable or proven breakthrough IFIs using the European Organization for Research and Treatment of Cancer (EORTC) criteria. Overall, 547 patients received 860 courses of posaconazole (53% received the oral suspension and 48% received the tablet); primary indications for prophylaxis were acute myeloid leukemia (69%), graft-versus-host disease (18%), and myelodysplastic syndrome (3%). There were no significant differences in demographics or indications between patients receiving the different formulations. The incidence and incidence rate of probable or proven IFIs were 1.6% and 3.2 per 10,000 posaconazole days, respectively. There was no significant difference in the rate of IFIs between suspension courses (2.8 per 10,000 posaconazole days) and tablet courses (3.7 per 10,000 posaconazole days) (rate ratio = 0.8, 95% confidence interval [CI] = 0.3 to 2.3). Of the 14 proven or probable cases of IFI, 8/14 had posaconazole serum concentrations measured, and the concentrations in 7/8 were above 0.7 μg/ml. Posaconazole was discontinued early in 15.5% of courses; however, the frequency of discontinuation was also not significantly different between the tablet (16.5%) and oral suspension (14.6%) formulations (95% CI for difference = −0.13 to 0.06). In conclusion, the incidence of breakthrough IFIs was low among patients receiving posaconazole prophylaxis and not significantly different between patients receiving the tablet formulation and those receiving the oral suspension formulation.

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Invasive Fungal Infections in Adults with Newly Diagnosed AML Undergoing Intensive Chemotherapy: Characterization, Risk Factors, and Outcomes in a Single Institution

Blood ◽

10.1182/blood.v118.21.4254.4254 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4254-4254

Author(s):

Kit Lu ◽

Dionissios Neofytos ◽

Amanda Blackford ◽

Amy Seung ◽

Judith E. Karp

Keyword(s):

Risk Factors ◽

Overall Survival ◽

Bacterial Infections ◽

Conflicts Of Interest ◽

Fungal Infections ◽

Significant Risk ◽

Invasive Fungal Infections ◽

Myelogenous Leukemia ◽

Newly Diagnosed ◽

European Organization

Abstract Abstract 4254 Background: Invasive fungal infections (IFI) are a significant cause of morbidity and mortality in patients with acute myelogenous leukemia (AML) undergoing chemotherapy treatment. However, the epidemiology, risk factors, and outcomes of IFI in these patients have been poorly described. Methods: A single-center retrospective analysis was performed to study the epidemiology, risk factors, clinical outcomes, and mortality predictors of IFIs in AML patients undergoing intensive, multi-agent induction timed sequential therapy (TST) between January 2005 and June 2010. Newly diagnosed AML patients, with exception of acute promyelocytic leukemia, were studied. IFIs were defined using the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria. Results: 254 consecutive patients (57% male; median age 54, range 20–78) were analyzed. 123 (48%) of patients had an IFI; of which, 15 patients (12%) had a proven candidal infection, and 108 patients (88%) had a mould infection (5 proven/probable (5%) and 103 (95%) possible mould infections). 237 (93%) patients received antifungal therapy during their treatment course (median day 8, range day -15 to 30). Of those, 63 (27%) received monotherapy (46% liposomal amphotericin, 44% voriconazole) and the rest received multiple antifungal agents. Significant risk factors and trends for developing +IFI shown from univariate analyses are listed in Table 1. Prolonged neutropenia, duration of mucositis, and concurrent bacterial infections did not significantly affect the development of +IFI. Using multivariate analyses, mortality was impacted by patients’ baseline organ function (p=0.002 [1.3,3.1]), specifically, by bilirubin < 2 mg/dL (p=0.003 [1.38,4.57]) and creatinine < 1.5 mg/dL (p=0.01 [1.23,5.4]). Patients with +IFI did not significantly impact overall survival. However, patients with candidal IFIs had a significantly lower overall survival compared to patients with mould IFIs and no IFI (HR 2.01 [1.06, 3.8]) (Figure 1). Candida colonization prior to or during the first week of chemotherapy, and development of mucositis were associated with the development of candidal IFIs (p=0.07). Conclusion: IFIs, particularly mould infections, remain a significant problem in patients with AML. Although overall survival did not appear to be significantly affected by mould infections, patients with candidal infections were more likely to die. Identification of risk factors for each type of IFIs may help to develop effective targeted preventive antifungal strategies. Disclosures: No relevant conflicts of interest to declare.

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Filamentous Fungal Infections in a Tertiary Care Setting: Epidemiology and Clinical Outcome

Journal of Fungi ◽

10.3390/jof7010040 ◽

2021 ◽

Vol 7 (1) ◽

pp. 40

Author(s):

Miriam Van den Nest ◽

Gernot Wagner ◽

Martin Riesenhuber ◽

Constantin Dolle ◽

Elisabeth Presterl ◽

...

Keyword(s):

Clinical Outcome ◽

Fungal Pathogens ◽

Fungal Infections ◽

Tertiary Care ◽

Invasive Fungal Infections ◽

University Hospital ◽

European Organization ◽

Invasive Infections ◽

Life Threatening ◽

Frequent Site

Information on the distribution of filamentous fungal pathogens, which cause potential life-threatening invasive infections mostly in immunocompromised persons, is of great importance. The aim of this study was to evaluate the epidemiology and clinical outcome in patients with infections due to filamentous fungi at the University Hospital of Vienna, Austria. We conducted a retrospective observational study and consecutively included patients of any age with filamentous fungal infections between 2009 and 2017. The classification for probable and proven invasive filamentous fungal infections was based on the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) criteria or the expert opinion of an experienced clinical mycologist. We included 129 patients (median age: 52 years; 47.3% female) with episodes of 101 proven and probable invasive and 35 localized filamentous fungal infections (16 sinus, 14 eye, one ear, and four deep cutaneous). Aspergillus fumigatus alone accounted for 50.3% of the fungi, which was followed by the Mucorales group (13.7%) and Fusarium spp. (8.5%). Diagnosis was mainly based on culture findings. The lung was the most frequent site of infection. The 30-day and 90-day overall mortality of invasive fungal infections was 30.2% and 42.7%, respectively. We observed a high all-cause mortality among patients with invasive filamentous fungal infections. Prospective data collection in a nationwide registry would be necessary to provide important information on surveillance to clinicians and other decision-makers.

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The tablet formulation of posaconazole: clinical pharmacology and the use in patients with hematologic malignancies

Clinical Microbiology and Antimicrobial Chemotherapy ◽

10.36488/cmac.2020.2.96-117 ◽

2020 ◽

Vol 22 (2) ◽

pp. 96-117

Author(s):

Alexander V. Veselov

Keyword(s):

Clinical Studies ◽

Fungal Infections ◽

Plasma Concentrations ◽

Pharmacokinetic Profile ◽

Hematologic Malignancies ◽

Tablet Formulation ◽

Oral Suspension ◽

Tolerability Profile ◽

Hematopoietic Stem ◽

Release Tablet

Posaconazole is a broad-spectrum triazole antifungal agent with potent activity against various fungi, including yeast and molds, including Mucorales, what makes a key difference with itraconazole and voriconazole. Clinical studies have demonstrated his efficacy for prophylaxis against invasive fungal infections in hematological patients at high risk (with acute myeloid leukemia, myelodysplastic syndrome, aplastic anemia, and in patients after hematopoietic stem cell transplantation, especially with graft versus host disease). Posaconazole also use as salvage therapy against invasive aspergillosis, mucormycosis and some other systemic mycoses. For today there are 3 posaconazole formulations – oral suspension, modify release tablet and intravenous solution (not registered in Russia at the time of writing this paper). As far as bioavailability of posaconazole following administration by oral suspension is highly variable with low unstable plasma concentrations and there are number of factors with negatively influence to the pharmacokinetic profile of suspension a delayed-release tablet was developed using hot-melt extrusion technology with a pH-sensitive polymer. The tablet formulation releases the drug in the intestine, and this leads to the enhanced bioavailability and increased posaconazole exposure parameters and, as a result, to a higher efficacy. This was demonstrated in pre-clinical, early phase clinical studies and confirmed with data from real practice. The tablet formulation has well tolerability profile with a low incidence of clinically significant adverse events. For today posaconazole included in all relevant clinical recommendations with high levels of evidence, including prophylaxis of invasive mycoses and therapy of their refractory forms, while the authors agree that for the oral therapy a preference should be given to the tablet formulation of posaconazole.

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Prevention of Invasive Aspergillus Fungal Infections with the Suspension and Delayed-Release Tablet Formulations of Posaconazole in Patients with Haematologic Malignancies

Scientific Reports ◽

10.1038/s41598-018-20136-3 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 7

Author(s):

Elisabeth Leclerc ◽

David Combarel ◽

Madalina Uzunov ◽

Véronique Leblond ◽

Christian Funck-Brentano ◽

...

Keyword(s):

Fungal Infections ◽

Delayed Release ◽

Tablet Formulations ◽

Haematologic Malignancies ◽

Release Tablet

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Primary or Secondary Prophylaxis with Voriconazole Compared with Posaconazole for Prevention of Invasive Fungal Infections After Hematopoietic Stem Cell Transplantation

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.010 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S75-S75

Author(s):

Jeffrey W Jansen ◽

Anupam Pande ◽

Rizwan Romee ◽

Steven J Lawrence ◽

William Powderly

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Fungal Infections ◽

Antifungal Prophylaxis ◽

Invasive Fungal Infections ◽

Hematopoietic Stem ◽

Research Grant

Abstract Background Invasive fungal infections (IFI) remain a serious complication in hematopoietic stem cell transplantation (HSCT) patients and are associated with increased costs, morbidity, and mortality. Posaconazole (PCZ) and voriconazole (VCZ) are frequently utilized as antifungal prophylaxis in this population. To date, no direct comparison between PCZ and VCZ exists for the prevention of IFI in adult HSCT patients. Methods A retrospective cohort analysis of HSCT patients aged ≥18 years who received ≥28 continuous days of primary (PPPx) or secondary (SPPx) antifungal prophylaxis with either VCZ or PCZ between February 26, 2003 and September 30, 2015 at Barnes-Jewish Hospital was conducted. Patients who received PPPx or SPPx with both VCZ and PCZ were analyzed following intention to treat of the initial agent received. Patients who received both PPPx and SPPx were included once for both PPPx and SPPx. The primary outcome of interest was development of possible, probable, or proven IFI as defined by EORTC/MSG guidelines. In the SPPx patients, development of IFI was confirmed as a distinct event from primary IFI based on manual chart review and radiographic evidence. Results Overall, there were 472 patients included; 402 in the VCZ group and 70 in the PCZ group. At baseline, patients in the PCZ group had more graft vs. host disease (GVHD) prior to prophylaxis (27.1% vs. 16.7%, P = 0.04) and were more likely to be on SPPx (60% vs. 41%, P < 0.01). There were 22 and 1 IFI events in the VCZ and PCZ groups, respectively, which corresponded to a crude incidence rate of 0.345 and 0.077 per 1000 person-days of prophylaxis. Figure 1 displays the Cox proportional hazard model which was completed in the backwards stepwise method accounting for gender, transplant type, GVHD prior to prophylaxis, disease remission, and PPPx or SPPX. The hazard ratio for development of IFI while on prophylaxis between VCZ and PCZ was 5.22 (95% CI: 0.69–39.4; P = 0.11) after controlling for PPPx or SPPx. Conclusion There was not a significant difference between rates of IFI in HSCT patients who received antifungal prophylaxis with VCZ compared with PCZ. Our data trends towards favoring PCZ but is limited by low rates of IFI. Larger, prospective analyses are necessary to confirm our findings. Disclosures W. Powderly, Merck: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Astellas: Grant Investigator, Research grant

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Epidemiology and Antifungal Susceptibility Patterns of Invasive Fungal Infections (IFIs) in India: A Prospective Observational Study

Journal of Fungi ◽

10.3390/jof8010033 ◽

2021 ◽

Vol 8 (1) ◽

pp. 33

Author(s):

Yubhisha Dabas ◽

Immaculata Xess ◽

Mragnayani Pandey ◽

Jaweed Ahmed ◽

Janya Sachdev ◽

...

Keyword(s):

Diabetes Mellitus ◽

Observational Study ◽

Odds Ratio ◽

Prospective Observational Study ◽

Fungal Infections ◽

Antifungal Susceptibility ◽

Invasive Fungal Infections ◽

European Organization ◽

Icu Admission ◽

Coronary Arterial Disease

The epidemiology of invasive fungal infections (IFI) is ever evolving. The aim of the present study was to analyze the clinical, microbiological, susceptibility, and outcome data of IFI in Indian patients to identify determinants of infection and 30-day mortality. Proven and probable/putative IFI (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group and AspICU criteria) from April 2017 to December 2018 were evaluated in a prospective observational study. All recruited patients were antifungal naïve (n = 3300). There were 253 episodes of IFI (7.6%) with 134 (52.9%) proven and 119 (47%) probable/putative infections. There were four major clusters of infection: invasive candidiasis (IC) (n = 53, 20.9%), cryptococcosis (n = 34, 13.4%), invasive aspergillosis (IA) (n = 103, 40.7%), and mucormycosis (n = 62, 24.5%). The significant risk factors were high particulate efficiency air (HEPA) room admission, ICU admission, prolonged exposure to corticosteroids, diabetes mellitus, chronic liver disease (CLD), acquired immunodeficiency syndrome (AIDS), coronary arterial disease (CAD), trauma, and multiorgan involvement (p < 0.5; odds ratio: >1). The all-cause 30-day mortality was 43.4% (n = 110). It varied by fungal group: 52.8% (28/53) in IC, 58.8% (20/34) in cryptococcosis, 39.8% (41/103) in IA, and 33.9% (21/62) in mucormycosis. HEPA room, ICU admission for IC; HEPA rooms, diabetes mellitus for cryptococcosis; hematological malignancies, chronic kidney disease (CKD), sepsis, galactomannan antigen index value ≥1 for IA and nodules; and ground glass opacities on radiology for mucormycosis were significant predictors of death (odds ratio >1). High minimum inhibitory concentration (MIC) values for azoles were observed in C. albicans, C. parapsilosis, C. glabrata, A. fumigatus, A. flavus, R. arrhizus, R. microsporus, and M. circinelloides. For echinocandin, high MIC values were seen in C. tropicalis, C. guillermondii, C. glabrata, and A. fumigatus. This study highlights the shift in epidemiology and also raises concern of high MICs to azoles among our isolates. It warrants regular surveillance, which can provide the local clinically correlated microbiological data to clinicians and which might aid in guiding patient treatment.

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