Received Posaconazole Prophylaxis Research Articles

Evaluation of Posaconazole for Primary Prophylaxis of IFI in Acute Myeloid Leukemia under Intensive Induction Chemotherapy. Comparative Real Life Study with Fluconazole in two Hematological Centers in Algeri

Introduction: Acute myeloid leukemia (AML) is a hematological malignancy with a poor prognosis. The early consequences of induction chemotherapy are represented by pancytopenia with severe immunosuppression, which favors the emergence of so-called “opportunistic” infections and in particular invasive fungal infections (IFI) such as invasive aspergillosis (IA). This justifies the implementation of early, empirical, pre-emptive or prophylactic antifungal treatment. The objective of this study is the evaluation of a comparative study before and after the use of primary prevention with posaconazole versus fluconazole, in terms of incidence and mortality of invasive fungal infections (IFIs) during AML inductions, in real life in Algeria. Patients and methods: This study was performed in two periods in the 2 centers concerning the same AML patients receiving the same induction chemotherapy (daunorubicin 60 mg/m2 for 3 days and cytarabine 100 mg/m2 for 7 days) but with a different type of hospitalization with common rooms for Tlemcen and protected single rooms for Oran. Period 1: The retrospective study was performed from 2014 to 2016 and involved 188 patients. 70 patients were hospitalized in a common room (Tlemcen) and 118 patients in a protected single room (Oran). All patients received as primary IFI prophylaxis fluconazole 400 mg/day. Period 2: The prospective study was conducted from April 2017 to September 2018 and involved 55 patients. Fourteen patients were hospitalized in Tlemcen and 41 patients in an Oran. These patients received posaconazole prophylaxis at a dose of 200 mgx3/day. The evaluation and comparison of descriptive and incidence data was performed using Chi2 statistical tests using SPSS version 19 software. Overall survival (OS) were calculated using the Kaplan-Meier estimate and were compared using the log-rank test with a significance level α of 0.05. Results: Period 1: The incidence rate of IFI: 34% at the Oran hospital versus 49% at the Tlemcen hospital (p=0.049). Among the 74 patients who presented with IFI, 39 (53%) died from IFI as the main cause of death, among these deaths, 16 (40%) were recorded at Oran and 23 (68%) at Tlemcen (p=0.011). Period 2: The IFI rate with fluconazole was 39% and that observed with posaconazole 22% (p=0.001) and the cumulative incidence was 39% at 21 days versus 10% at 15 days (p=0.046) with a highly significant decrease in IFI-related deaths: 53% versus 25% (p=0.004). Conclusion: This work has demonstrated the interest in terms of IFI incidence (17% versus 33%, p=0.04) and IFI-related mortality of posaconazole prophylaxis (25% versus 53%, p=0.004) used during AML in the context of hospitalization in common rooms. Furthermore, this work highlights that the combination of posaconazole prophylaxis and hospitalization in a protected single room allows an optimization of the management of this type of patients.
 
 

Posaconazole and fluconazole prophylaxis during induction therapy for pediatric acute lymphoblastic leukemia

To assess and compare the efficacy and safety of posaconazole with fluconazole for the prevention of invasive fungal infections in children who were undergoing induction therapy for acute lymphoblastic leukemia (ALL). To develop an approach to predict invasive fungal infections in ALL patients who accepted posaconazole prophylaxis. This was a single-center, retrospective cohort study of patients with newly diagnosed ALL, comparing invasive fungal infections in patients who received no prophylaxis, posaconazole prophylaxis, or fluconazole prophylaxis during induction therapy. A propensity score-weighted logistic regression model was used to adjust for confounders. Hepatotoxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Out of the 155 ALL patients, 60 received no prophylaxis, 70 received posaconazole prophylaxis, and 25 received fluconazole prophylaxis. Posaconazole prophylaxis reduced the odds of invasive fungal infections by > 60%, prolonged infection-free survival significantly, and did not increase the risk of hepatotoxicity. Additionally, we found that the combination of age at diagnosis, clinically documented bacterial infection in the first 15 days of induction therapy, and absolute neutrophil count (ANC) curve enabled significant prediction of the susceptibility to infections after receiving posaconazole prophylaxis. Our findings supported using targeted prophylaxis with posaconazole in ALL children undergoing induction chemotherapy. Age, clinically documented bacterial infection and ANC are important predictors of invasive fungal infections in patients with posaconazole prophylaxis.

Antifungal prophylaxis with posaconazole tablet and oral suspension in patients with haematologic malignancy: Therapeutic drug monitoring, efficacy and risk factors for the suboptimal level.

Posaconazole is used to prevent invasive fungal infections (IFIs) in patients with haematologic malignancy. In this study, we compared plasma posaconazole concentrations (PPCs) and the incidence of breakthrough IFIs between patients with haematologic malignancy receiving posaconazole oral suspension vs tablet. We retrospectively collected data on adult patients with haematologic malignancies who received posaconazole prophylaxis during chemotherapy from April 2014 through May 2018. A total of 242 cases with PPCs, 88 in the oral suspension group and 154 in the tablet group, were included in this study. Patients receiving tablets achieved a significantly higher mean PPC than did those on oral suspension (1.631±0.878μg/mL in the tablet group vs. 0.879±0.585μg/mL in the oral suspension group). One hundred and thirty-seven of 154 patients (89.0%) receiving tablets had PPCs of 0.7μg/mL or more, while only 41 of 88 patients (46.6%) receiving oral suspension attained an optimal level (P<.001). The incidence of breakthrough IFIs was significantly higher in the oral suspension group compared with in the tablet group (14.8% of oral suspension vs. 4.5% of tablet; P=.005). In the analysis including patients receiving posaconazole tablets, hypoalbuminemia (< 3.5g/dL) was found to be a risk factor associated with suboptimal levels (odds ratio: 8.872; 95% confidence interval: 3.011 - 26.141; P<.001). Suboptimal PPCs in the tablet group were less common than those in the oral suspension group. Therapeutic drug monitoring may be still necessary even in patients receiving posaconazole tablets, especially in those with hypoalbuminemia.

Breakthrough invasive aspergillosis and diagnostic accuracy of serum galactomannan enzyme immune assay during acute myeloid leukemia induction chemotherapy with posaconazole prophylaxis.

Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment.We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed. Diagnostic accuracy of serum galactomannan assay according to posaconazole plasma concentrations has been performed.A total of 288 patients with acute myeloid leukemia, treated by induction chemotherapy, who received posaconazole prophylaxis for more than five days were included in the present study. The incidence of invasive aspergillosis was 8% with 12 (4.2%), 8 (2.8%) and 3 (1%), possible, probable and proven invasive aspergillosis, respectively. Posaconazole plasma concentration was available for 258 patients. Median duration of posaconazole treatment was 17 days, and median posaconazole plasma concentration was 0.5 mg/L. None of patients with invasive aspergillosis and posaconazole concentration ≥ 0.5 mg/L had a serum galactomannan positive test. Sensitivity of serum galactomannan assay to detect probable and proven invasive aspergillosis was 81.8%. Decreasing the cut-off value for serum galactomannan optical density index from 0.5 to 0.3 increased sensitivity to 90.9%.In a homogenous cohort of acute myeloid leukemia patients during induction chemotherapy, increasing the posaconazole concentration decreases the sensitivity of serum galactomannan assay.

Efficacy of Posaconazole Prophylaxis in Patients with Acute Myeloid Leukemia Undergoing Induction Chemotherapy: An Observational Study in Resource Limited Settings.

Large randomized controlled trials have shown significant decrease in incidence of invasive fungal infection in acute myeloid leukemia patients with Posaconazole prophylaxis. However, very less is known about value of Posaconazole prophylaxis in resource limited settings. This observational cohort study evaluated the incidence of fungal infection in patients with hematological malignancies undergoing induction chemotherapy with Posaconazole as antifungal prophylaxis and was compared with historical controls who received Fluconazole as fungal prophylaxis. The study was conducted from Oct 2013 to July 2015 in Department of Hematology of a tertiary care center. Fifty-three patients of acute myeloid leukemia on Posaconazole as fungal prophylaxis and 53 historical controls on Fluconazole as fungal prophylaxis were included for final analysis. Baseline characteristics were well matched between groups. Patients on Fluconazole were more likely to experience breakthrough IFDs (28.3 and 11.3%; p=0.028) than in patients receiving Posaconazole prophylaxis. No significant difference was observed in overall, attributable mortality or in shift to first line antifungal. Both Posaconazole and Fluconazole were well tolerated with no major adverse effects requiring discontinuation of the drug. Minor side effects were seen in 39 and 47% patients in study and control group respectively. Vomiting and nausea were the commonest side effects seen in both study and control group (26 vs. 34% and 38 vs. 40% of patients, respectively). The results of our study in patients with acute myeloid leukemia provide evidence that Posaconazole prophylaxis significantly decreases the incidence of fungal infection and is well tolerated.

Antifungal prophylaxis in newly diagnosed AML patients-Adherence to guidelines and feasibility in a real life setting.

Antifungal posaconazole prophylaxis for AML patients receiving induction chemotherapy has been routine at our centre since 2009. This retrospective study examined the feasibility and practicability of our prophylaxis guidelines in clinical practice. Data sets of 90 patients undergoing induction-chemotherapy for AML between 2011 and 2014 were evaluated regarding adherence to local guidelines for the administration of antifungal prophylaxis with posaconazole. 75.5% of the 90 patients received posaconazole prophylaxis. All but eight patients received the recommended dosage. A total of 77.95% on prophylaxis had serum galactomannan measured twice weekly. Contradicting our guidelines, 89.70% of patients received concomitant therapy with PPI. Overall, 16.17% of patients had prophylaxis discontinued and started empirical antifungal treatment in the absence of diagnostic criteria for IFI. The breakthrough IFI rate was 36.76% (proven, probable and possible) with 7.35% of infections being classified as proven or probable. Although limited by a small sample size, our study demonstrates the feasibility of local guidelines in a real life setting and outlines areas for improvement in both guidelines and clinical practice. We also highlight the importance of ensuring awareness of guidelines and raise questions about a uniform approach to antifungal prophylaxis in AML patients.

Therapeutic Drug Monitoring of Posaconazole in Adult Acute Myeloid Leukemia (Aml) Patients Receiving Posaconazole Prophylaxis during Induction: Experience from a Center with High Invasive Fungal Infection (IFI)Burden

▪Background: Posaconazole has been recommended as an antifungal of choice for IFI prophylaxis in AML during induction therapy. Very high incidence of possible and probable IFI (70%) during induction at our centre led to adoption of posaconazole prophylaxis. However, approximately 50% of patients still require change of antifungal due to suspected breakthrough IFI raising the possibility of inadequate plasma levels due to various factors (variable absorption, metabolism and drug interactions). To address this concern, we evaluated the role of therapeutic drug monitoring (TDM) in AML patients receiving posaconazole prophylaxis to identify whether suboptimal plasma levels (<700 ng/mL) are associated with breakthrough IFI.Method: This prospective observational study included all patients, 18 years or more, undergoing induction chemotherapy for de novo AML with no evidence of IFI (normal CT chest, and galactomannan assay) and on posaconazole prophylaxis between May2015 to February 2016 at our centre. Posaconazole oral suspension 200 mg three times daily was given for antifungal prophylaxis from day 1 of induction until neutrophil recovery to more than 500 cells/μL, occurrence of a confirmed or suspected IFI or development of drug related toxicity or intolerance. The details regarding demography, weight, BMI at diagnosis were recorded. During therapy all adverse events including vomiting and diarrhea were recorded as per CTCAE version 4.03. Concomitant drug history and use of proton pump inhibitors, antacids, metoclopramide and domperidone during treatment period were noted. Blood samples (7 am) for detecting posaconazole trough levels were collected daily from day 4 till day 12 of induction. If patient developed symptoms and signs suggestive of IFI during induction after day 12, then blood sample was drawn for posaconazole trough levels. Plasma posaconazole levels were estimated at by HPLC method. The diagnosis of IFI was in accordance with the revised European Organization for Research and Treatment of Cancer /Mycoses Study Group definitions published in 2008. Breakthrough invasive fungal infection was also diagnosed if there was failure to respond to intravenous antibiotics along with negative cultures and fever defervescence with change in antifungal therapy. The primary objective of the study was to assess the percentage of patients achieving target posaconazole plasma levels. The secondary objectives included i) impact of achieving target drug concentration in preventing breakthrough fungal infections. ii) identification of factors associated with subtoptimal posaconazole levels. iii) Time to achieve steady state concentration or target trough concentrations of posaconazole.Results: A total of 366 samples were collected from 45 patients with median number of 8 samples (range 1-9) per patient. Median age of patients was 36 years (range 18-45 years). Thirty two were males. Thirty-nine patients received 3+7 regimen and 6 were treated with cladribine along with daunomycin and cytarabine. Eleven patients (24%) did not achieve target plasma levels (≥700 ng/mL) even once till day 12. Median time to achieve steady state concentration was 5 days (range 4-10). At steady state 20 (44% ) patients had suboptimal plasma levels. On serial monitoring, a declining trend in plasma levels was observed after day 8 in 31 patients. Twenty three patients (51%) developed possible/ probable IFI on posaconazole prophylaxis. The median time to develop IFI was 13 days (range 4-24 days). Twenty out of 23 patients (87%) who developed IFI had suboptimal plasma levels as compared to 13 out of 22 patients (60%) who did not develop IFI (p-0.04). In all but 3 patients, the plasma levels declined before breakthrough IFI. On logistic regression analysis, both the steady state concentration and plasma posaconazole levels before breakthrough were strong predictors of occurrence of breakthrough IFI. Presence of mucositis, vomiting, diarrhea, use of antacid was associated with low plasma levels on univariate analysis. On multivariate analysis presence of mucositis and antacids remained significantly associated with low plasma levels.Conclusion: TDM has a role in patients receiving posaconazole prophylaxis, however it still needs to be seen if dose adjustments based on plasma levels can reduce the risk of breakthrough IFI. DisclosuresNo relevant conflicts of interest to declare.

(848) - Fungal Colonization and Infection in Lung Transplant Recipients Receiving Posaconazole Prophylaxis

(848) - Fungal Colonization and Infection in Lung Transplant Recipients Receiving Posaconazole Prophylaxis

Decreased invasive fungal disease but no impact on overall survival by posaconazole compared to fluconazole prophylaxis: a retrospective cohort study in patients receiving induction therapy for acute myeloid leukaemia/myelodysplastic syndromes.

ObjectivePosaconazole prophylaxis during induction chemotherapy for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has been shown to significantly decrease the incidence of invasive fungal disease (IFD) and increase overall survival in a trial setting, but only small real‐life studies have been published.MethodsThis was a retrospective cohort study including consecutive patients with AML/MDS treated with intensive induction chemotherapy; 176 patients received fluconazole prophylaxis 2008–2011 and 107 patients received posaconazole prophylaxis 2011–2013. Only proven and probable IFD according to the revised EORTC/MSG criteria were included in the analysis.ResultsThe two cohorts were well matched without significant differences in patient characteristics. At day 100, patients receiving posaconazole had a significantly lower incidence of total IFD (0.9% vs. 10.8%, P < 0.01), invasive aspergillosis (0% vs. 5.7%, P = 0.02) and invasive candidiasis (0% vs. 4.0%, P < 0.05). There was no significant difference in overall survival, neither at day 100 (87% in the posaconazole group vs. 85% in the fluconazole group) nor at end of follow‐up (78% vs. 77%).ConclusionsPosaconazole prophylaxis decreased the incidence of IFD but did not improve short‐term overall survival. Improved treatment efficacy of manifest IFD is likely to explain the lack of survival benefit.

Systemic antifungal treatment after posaconazole prophylaxis: results from the SEIFEM 2010-C survey

To investigate the incidence, treatment and outcome of breakthrough invasive fungal infections (IFIs) in adult acute myeloid leukaemia (AML) patients after posaconazole prophylaxis. From January 2010 to April 2012, all consecutive patients with newly diagnosed AML were prospectively registered at 33 participating Italian centres. All cases of IFIs occurring within 30 days after the end of the first induction chemotherapy were recorded. The strategy of antifungal treatment (empirical, pre-emptive or targeted) and the drugs used were analysed. ClinicalTrials.gov code: NCT01315925. In total, 1192 patients with newly diagnosed AML were enrolled in the study, of whom 510 received posaconazole prophylaxis and were included in the present analysis. Of these patients, 140 (27%) needed systemic antifungal treatment. Among the 127 evaluable cases, an empirical approach was utilized in 102 patients (80%), a pre-emptive approach in 19 patients (15%) and targeted therapy in 6 patients (5%). Only five patients died of IFIs (three in the empirical group and two in the targeted group; 4%). A critical review of IFI diagnoses at 30 days demonstrated that among the patients treated empirically, ∼30% were not affected by IFIs but rather only by fever of unidentified origin. A comparison between the empirical and the pre-emptive groups showed no significant differences regarding the attributable and overall mortalities. This study confirms that posaconazole prophylaxis reduces the incidence of breakthrough IFIs and does not modify the efficacy of subsequent systemic antifungal treatment, regardless of the approach (empirical or pre-emptive) or the antifungal drug used.

Posaconazole concentrations in human tissues after allogeneic stem cell transplantation.

Few data have been published regarding posaconazole tissue concentrations in humans. We analyzed tissue concentrations in biopsy specimens taken at autopsy from seven patients who received posaconazole prophylaxis because of graft-versus-host disease. The results were compared to plasma concentrations collected before death. Tissue concentrations suggestive of an accumulation of posaconazole were found in the heart, lung, liver, and kidney but not in the brain.

Posaconazole Therapeutic Drug Monitoring in the Real‐life Setting: A Single‐Center Experience and Review of the Literature

To evaluate the incidence of posaconazole serum levels below 700μg/L, the rate of breakthrough infections during posaconazole prophylaxis, and factors influencing posaconazole exposure in daily clinical practice. Prospective observational study and review of the literature. Hematology and oncology department in a tertiary care academic medical center. A total of 31 patients with hematologic diseases: 27 received posaconazole prophylaxis and 4 received posaconazole therapy. We analyzed 187 posaconazole serum levels from 31 patients (median of five posaconazole levels per patient; range 1-16). The analyses revealed that 80 of 187 levels (43%) were below 700μg/L, and 68% of patients were found to have at least one measured level below this threshold. Breakthrough invasive fungal infections categorized as probable or possible infections occurred in 4 of 27 patients (15%) receiving the drug as prophylaxis. A multivariate analysis, accounting for repeated measurements per patient, revealed that age (p=0.02) and mucositis (p=0.04) were associated with significantly reduced posaconazole serum levels. A review of the current literature on posaconazole therapeutic drug monitoring data from real-world studies is presented as an overview table, highlighting the frequency of patients with inadequate posaconazole exposure and heterogeneity of factors influencing posaconazole levels. Therapeutic drug monitoring of posaconazole is an important tool of therapy optimization because oral posaconazole suspension shows unreliable absorption rates and exposure.

Fungal pathogens and primary antifungal prophylaxis in patients with hematological malignancies: one year experience.

Febrile neutropenia (FN) is generally a complication of cancer chemotherapy in patients with hematological malignancies. To evaluate the febrile neutropenia episodes of hematological patients and their outcomes with respect to fungal pathogens, primary antifungal prophylaxis antifungal therapy. All consecutive patients older than 14 years of age and who developed febrile neutropenia episodes from September 2010 to November 2011 were incorporated into this study. In total, we retrospectively evaluated 86 consecutive patients and their 148 neutropenic episodes. Of the 86 patients, 45 were male and the mean age was 47,65±15,06 years (range: 17-82 years). The mean MASCC score was 18,72 ± 9,43. Systemic antifungal drug was initiated to 17 patients with probable fungal infection and 12 patients with possible fungal infection. Of seven patients who received posaconazole prophylaxis, five were treated with systemic fungal infection due to possible fungal infection. It is obvious that more studies focused on primary prophylaxis are needed and primary or secondary antifungal prophylaxis should be evaluated in terms of provided benefits and disadvantages. Timely and appropriately initiated antifungal treatment is one of the most important factors for a good prognosis for recovery from a neutropenic phase.