Prevention Of Invasive Fungal Infections In Patients Research Articles

Voriconazole and its clinical potential in the prophylaxis of systemic fungal infection in patients with hematologic malignancies: a perspective review.

Invasive fungal infections (IFIs) have become high prevalence in patients with hematologic malignancies. Drug-based strategies for IFIs include various approaches such as prophylactic, empiric, preemptive, and directed treatment. Prophylaxis is an attractive strategy in high-risk patients, given the lack of reliable diagnostics and the high mortality rate associated with IFIs. Prophylaxis includes the use of antifungal drugs in all patients at risk. An ideal antifungal compound for prophylaxis should have a potent and broad activity, be available both orally and intravenously, and have a low toxicity profile. Voriconazole fulfills all these criteria. The clinical efficacy of voriconazole against the majority of fungal pathogens makes it potentially very useful for the prevention of IFIs in patients with hematologic malignancies. Voriconazole appears to be very effective for the primary and secondary prevention of IFIs in these patients and recipients of allogeneic hematopoietic stem-cell transplantation. Randomized controlled trials evaluating voriconazole as primary antifungal prophylaxis in patients with neutropenia treated for a variety of hematologic malignancies have been performed, confirming its value as a prophylactic agent. Voriconazole is generally safe and well tolerated; however, its use is also associated with a number of concerns. In most patients with hematologic malignancies there is the potential for pharmacokinetic drug-drug interactions given that voriconazole is metabolized through the P450 cytochrome system.

Economic evaluation of posaconazole vs fluconazole in the prevention of invasive fungal infections in patients with GVHD following haematopoietic SCT

Posaconazole has been proven to be as effective as fluconazole in the prevention of invasive fungal infections (IFI) in allogeneic haematopoietic SCT patients with GVHD. We assessed, from the perspective of the Spanish National Health Service, the cost-effectiveness of posaconazole vs fluconazole in preventing IFI. A decision-analytic model was developed to assess the average per patient treatment costs, IFIs avoided, life-years gained (LYG) and incremental cost per LYG for each prophylactic treatment used (in euros at 2007 prices). Patients are assumed to have received either posaconazole or fluconazole. The probabilities of IFI, IFI-related death and death from other causes were obtained from a single clinical trial. Long-term mortality and costs were estimated from secondary sources. Posaconazole was associated with fewer IFIs (5.3 vs 9%), increased LYG (8.01 vs 7.78) and higher IFI-related costs ([euro]11 585 vs [euro]6 959) per patient compared with fluconazole. The incremental cost-effectiveness of posaconazole vs fluconazole was estimated at [euro]20 246 per LYG. There was a 70% probability that posaconazole is cost-effective at a [euro]30 000 per LYG threshold. In conclusion, compared with fluconazole, posaconazole prophylaxis is a cost-effective strategy for the prevention of IFI in patients with GVHD.

Cost-Effectiveness of Posaconazole vs Fluconazole in the Prevention of Invasive Fungal Infections among Patients with Graft-Versus-Host Disease (GVHD) in the US.

Trial data suggest that posaconazole is similar to fluconazole in preventing invasive fungal infections (IFIs) among allogeneic progenitor cell transplant recipients with graft-versus-host disease (GVHD). We estimated the cost-effectiveness of posaconazole versus fluconazole in this population in the US. A decision-analytic model was developed to estimate the average per patient treatment costs, IFIs avoided, life-years gained, and incremental cost per life-year gained of prophylaxis (2006 US$). The model extrapolates the trial results to a lifetime horizon to include long-term mortality due to GVHD. In the model, patients are assumed to receive posaconazole or fluconazole; efficacy data were obtained from the clinical trial. Long-term mortality and prophylaxis drug and IFI treatment costs were estimated from secondary sources. One-way and probabilistic sensitivity analyses were conducted. Posaconazole is associated with fewer IFIs (0.05 vs. 0.09), increased life years (7.87 vs. 7.66), and higher IFI-related costs (prophylaxis and IFI treatment) ($8,750 vs. $5,530) per patient relative to fluconazole. Costs for treatment of IFIs comprised 95% of the total cost for fluconazole and 35% for posaconazole. The incremental cost-effectiveness of posaconazole versus fluconazole is estimated to be $15,700 per life-year saved. Results are most sensitive to changes in the cost of treating an IFI and the efficacy of prophylaxis. Results from the probabilistic analysis indicate that there is an 88% probability that posaconazole is cost-effective at a $50,000 per life year saved threshold. We conclude that posaconazole is a cost-effective strategy for the prevention of IFIs in patients with GVHD.

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