Invasive Fungal Infections In Neutropenic Patients Research Articles

Invasive fungal infections: epidemiology and analysis of antifungal prescriptions in onco-haematology

Invasive fungal infections (IFI) are associated with high rates of morbidity and mortality, particularly in onco-haematology patients. We aimed to study the epidemiology of IFI in neutropenic patients and estimate the economic impact of treatment of those infections. All patients hospitalized in onco-haematology, and treated with antifungal agents, in 2005 were investigated. Four features were studied: the diagnosis for each patient, the antifungal drugs used, the thoracic densitometry reports and the sero-mycological data. Infectious episodes were stratified according to the EORTC 2008 classification criteria (10). Of the 1130 patients surveyed, 192 patients received systemic antifungal agents. Of these 46% had acute leukaemia, 29% bone-marrow allografts, 7% lymphoma and 18% other malignant haemopathies. Using the EORTC 2008 criteria (10), there were 8 proved IFI (3 aspergillosis, 3 candidosis and 2 other IFI), 17 probable IFI (11 aspergillosis, 6 candidosis) and 16 possible aspergillosis. The incidence of IFI was 2·1%. Eighty patients (41·7%) had received prophylaxis: 56 with fluconazole and 24 with voriconazole. Treatment was most often empirical (n = 127, 66·1%). Combination of two antifungals was used in 17 cases. The mean duration of prophylactic, empirical, proved/probable aspergillosis-directed, candidaemia-directed and combination treatment was 19, 19, 46, 32 and 27 days, respectively. The cost of antifungal treatment in 2005 reached almost 2,000,000 €, including 427,000 € for documented infections (proved and probable), 1,246,000 € for empirical treatment and 58,300 € for prophylaxis. The incidence of IFI is low but the pharmacoeconomic impact is extremely high. Improved strategies are required to reduce the frequency and duration of empirical treatment without compromising beneficial outcome.

Antifungal prophylaxis with micafungin in neutropenic patients with hematological malignancies

The aim of the study was to assess the antifungal prophylactic efficacy, safety, and tolerability of micafungin, 150 mg daily, and to evaluate the usefulness of monitoring 1,3-β-d-glucan (BG) in neutropenic patients undergoing chemotherapy for hematological malignancies. This investigation was a retrospective, non-randomized study. A group of patients who did not receive systemic antifungal prophylaxis was compared to another group of patients who received micafungin 150 mg daily. All patients admitted with hematological malignancy and undergoing chemotherapy or stem cell transplant were included. The plasma BG level was measured once weekly. The clinical endpoint was the diagnosis of invasive fungal infection (IFI). Antifungal prophylaxis led to a significant decrease in the occurrence of IFI (from 12.3% to 1.5%, p = 0.001). Few severe adverse effects clearly attributable to micafungin were seen. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of BG values >8.9 pg/mL for diagnosis of IFI were 0.90, 0.99, 0.82, 0.99, and 0.99, respectively. Micafungin, 150 mg daily, is an effective and safe drug for antifungal prophylaxis, and monitoring of BG antigenemia is a useful tool for diagnosis of IFI in neutropenic patients with hematological malignancies.

Economic evaluation of posaconazole vs. standard azole prophylaxis in high risk neutropenic patients in the Netherlands

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of invasive fungal infections (IFI). The present study evaluates the cost effectiveness of posaconazole vs. standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands. A decision-tree model was developed using data from a randomized trial that compared posaconazole and standard azole (fluconazole or itraconazole) prophylaxis in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., N Engl J Med 2007;356:348-359). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI-related death, and death from other causes. Patients surviving the prophylaxis are assumed to have a life expectancy according to the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include cost per life year (LY) gained and cost per quality adjusted life year (QALY) gained. The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to 4412 euros (95% uncertainty interval 3403 euros - 5666 euros), which is -183 euros (-1985 euros to 1564 euros) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.08 (0.02-0.15) QALYs gained in comparison with prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 90% probability that the cost per QALY gained with posaconazole is below 20,000 euros. Additional scenario analyzes with different assumptions confirmed these findings. Given the underlying data and assumptions, the economic evaluation demonstrated that posaconazole prophylaxis is expected to be cost-effective compared with fluconazole/itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.

Economic Evaluation of Posaconazole Versus Standard Azole Prophylaxis in High Risk Neutropenic Patients in The Netherlands.

Background: Acute leukemia and high risk myelodysplastic syndrome patients experience prolonged neutropenia after treatment with intensive chemotherapy, leading to a high risk of acquiring potentially fatal invasive fungal infections (IFI). Pharmacoeconomic analysis is considered a valuable tool to justify the significant costs involved in managing these fungal infections. The present study evaluates the cost-effectiveness of posaconazole versus standard azoles for the prevention of IFIs in neutropenic patients in the Netherlands.Methods: A decision-tree model was developed that starts with the choice of antifungal prophylaxis: posaconazole or standard azole treatment (fluconazole or itraconazole). The decision tree was estimated using data from a recently published prospective, randomized, double blind, multi-center trial that compared both treatments in neutropenic patients receiving remission-induction chemotherapy for AML/MDS (Cornely et al., 2007). Following initiation of prophylaxis, clinical events are modeled with chance nodes reflecting probabilities of IFIs, IFI related death, and death from other causes. It is assumed that patients surviving the prophylactic period will have a life expectancy that reflects that of the underlying condition. This allows translation of the trial outcomes to a lifetime horizon. Data on life expectancy, quality of life, medical resource consumption and costs were obtained from the literature. Model outcomes include incremental cost per IFI avoided, incremental cost per life years saved and incremental cost per QALYs gained.Results: The total cost (treatment of breakthrough IFI + prophylaxis) for posaconazole amounted to €4,566 (95% uncertainty interval €3,574 –€5,769), which is €63 (−€1,552 - €1,903) less than costs with standard azoles. Posaconazole prophylaxis resulted in 0.1 (0.03 – 0.15) QALYs gained in comparison to prophylaxis with standard azoles. Results from a probabilistic sensitivity analysis indicate that there is a 87% probability that the cost per QALY gained with posaconazole is below €20,000, a commonly accepted threshold for cost-effectiveness. Additional scenario analyses with different assumptions confirmed these findings.Conclusion: Given the underlying data and assumptions, our economic evaluation demonstrated that posaconazole prophylaxis is cost and QALY saving compared to fluconazole / itraconazole in neutropenic AML/MDS patients after intensive chemotherapy.

Monitoring of 1,3-Beta-D-Glucan (BGL) Antigenemia in Neutropenic Patients with Acute Leukemia at High Risk for Invasive Fungal Infections (IFI).

Invasive candidiasis (IC) and aspergillosis (IA), the most frequent IFI in leukemic patients, are associated with high morbidity and mortality. As early diagnosis of IFI is difficult, empirical antifungal therapy is recommended in persistently febrile neutropenic patients. This standard of care results in a broad use of antifungals. New non-invasive diagnostic tests such as circulating BGL, a fungal cell wall component, are thus needed to optimize management of patients with IFI. The objective of the current study was to evaluate the utility of monitoring BGL antigenemia in neutropenic patients at high risk for IFI. We conducted a prospective study of 189 episodes of neutropenia (median duration 22 days, range 7–113) following induction (n=107) or consolidation chemotherapy (n=82) in 99 consecutive patients with acute leukemia (85 AML, 14 ALL). Blood was collected 2× weekly before onset of fever and daily thereafter until resolution of fever. BGL was measured by colorimetric assay (Wako, Japan). Two cut-off values (5 or 11 pg/ml) were studied. A positive result was defined by 2 consecutive samples with BGL higher than the cut-off value. A median of 2 (0–4) febrile episodes occurred per neutropenic episode. Among 320 febrile episodes, 31 IFI were diagnosed according to EORTC-MSG criteria: 17 IC (4 proven, 13 probable) and 14 IA (5 proven, 9 probable). A median of 15 samples (4–47) per episode of neutropenia were analyzed over a median period of 34 days (19–121). The diagnostic performance of BGL was evaluated in patients with proven or probable IFI compared with febrile patients without IFI (Table). In patients with IC, the median time between onset of fever as first sign of IFI and BGL positivity (>= 5) was 0 (−3 to 17 days) as compared with 16 (0 to 51 days) until diagnosis of infection using conventional microbiological and imaging techniques (p=0.03). In IA patients, it was 3 (−9 to 14 days) vs. 7 (1 to 21 days) (p=0.07). In IC and IA, median peak BGL (21 [6–111] and 15 [7–51] pg/ml) occurred on day 13 (1 to 41) and on day 7 (3 to 20) after fever onset, respectively. Median time to initiation of antifungal therapy after fever onset was similar in IC (2.5, range: 1 to 10 days) and IA (5, range: 0 to 10 days). BGL antigenemia decreased or cleared in patients responding to therapy (n=19) and continued to increase (peak 111 and 66 pg/ml) in 2 cases of IC, in whom therapy failed. BGL was negative (< 5 pg/ml) in 100/102 episodes of bacteremia. In conclusion, monitoring of 1,3-beta-D-glucan antigenemia provides a new tool for early diagnosis and follow-up of IFI in neutropenic patients with acute leukemia.Diagnostic Performance of BGLBGL Cut-off (pg/ml)2 × 52 × 52 × 52 × 112 × 112 × 11Type of proven/probable IFIICIAAll IFIICIAAll IFISensitivity %659376354338Specificity %898989999999PPV %485265868692NPV %949993919386Positive Likelihood Ratio5.98.56.9354338Negative Likelihood Ratio0.40.10.30.70.60.6