Economic Evaluation of Posaconazole Versus Fluconazole or Itraconazole in the Prevention of Invasive Fungal Infection in High-Risk Neutropenic Patients in Sweden

2014 ◽  
Vol 34 (7) ◽  
pp. 483-489 ◽  
Author(s):  
Johan Lundberg ◽  
Martin Höglund ◽  
Magnus Björkholm ◽  
Örjan Åkerborg
Keyword(s):  
Economic Evaluation ◽  
High Risk ◽  
Fungal Infection ◽  
Invasive Fungal Infection ◽  
Neutropenic Patients

scholarly journals Classical Empiric Antifungal Therapy Vs. D-Index Guided Early Therapy Using Micafungin for Persistent Febrile Neutropenia (CEDMIC trial): A Randomized Controlled Trial from Japan FN Study Group

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 816-816
Author(s):  
Shun-Ichi Kimura ◽  
Yoshinobu Kanda ◽  
Masaki Iino ◽  
Takahiro Fukuda ◽  
Emiko Sakaida ◽  
...  
Keyword(s):  
High Risk ◽  
Febrile Neutropenia ◽  
Fungal Infection ◽  
Antifungal Therapy ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Controlled Trial ◽  
Pharmaceutical Research ◽  
Randomized Controlled ◽  
Neutropenic Patients

Abstract Introduction: Empiric antifungal therapy (EAT) is recommended for persistent or recurrent febrile neutropenia based on an old randomized controlled trial, but such treatment is apparently overtreatment for the majority of patients. On the other hand, preemptive therapy triggered by positive blood tests for fungal antigens and/or imaging study findings was shown to increase the incidence of invasive fungal infection, and thus, a risk-based approach is important. The D-index, which is defined as the area over the neutrophil curve during neutropenia and hence reflects both the duration and depth of neutropenia (Figure 1A), enables real-time monitoring of the risk of invasive fungal infection. Previous studies showed that the cumulative D-index (c-D-index), which was calculated as cumulative D-index from the onset of neutropenia (Figure 1B), had high negative predictive values for invasive mold infection or pulmonary infection with cutoff values of 5,800 or 5,500 in high-risk neutropenic patients [J Clin Oncol 2009; 27: 3849-54. Biol Blood Marrow Transplant 2010; 16: 1355-61]. Methods: We investigated a novel approach, called D-index-guided early antifungal therapy (DET) and compared it to EAT in high-risk neutropenic patients. In the EAT group, empiric antifungal therapy was started for persistent (>=4 days) or recurrent febrile neutropenia. For patients with persistent or recurrent febrile neutropenia in the DET group, preemptive antifungal therapy was applied until c-D-index reached 5,500, but antifungal agent was initiated after c-D-index exceeded 5,500, even if there was no significant finding in serum fungal makers or imaging studies, to prevent excessive invasive fungal infection. Micafungin at 150 mg/day was administered as EAT or DET in this study. We randomized 423 patients who underwent chemotherapy or hematopoietic stem cell transplantation for hematological malignancies, in which predicted period of neutropenia exceeded 7 days, into the EAT group or the DET group, and 413 were eligible for intent-to-treat analyses (201 patients in the EAT group, 212 patients in the DET group). The prophylactic use of fluconazole or itraconazole was allowed. Primary endpoint was the development of proven/probable invasive fungal infection. Results: Backgrounds of the patients were similar between the 2 groups (Table 1). Invasive fungal infection (proven/probable/possible) was observed in 12 patients (6.0%) of the EAT group and 5 patients (2.4%) of DET group, respectively. Proven/probable invasive fungal infection was identified in 5 patients (2.5%) of the EAT group and 1 patient (0.5%) of DET group, which fulfilled the predetermined criteria of non-inferiority of the DET group. Regarding the pathogens, the EAT group included 1 case of candidemia and 4 cases of invasive pulmonary aspergillosis, and the DET group included one fusariosis. The survival rate of the EAT and DET group was 98.0% vs. 98.6% at day 42 and 96.4% vs. 96.2% at day 84, respectively. During the observation period, 31 patients died due to disease progression (n=19), infection (n=5) or other causes (n=7). Causes of infection related mortality included Pseudomonas aerginosa infection (n=2), fusariosis (n=1), toxoplasmosis (n=1) and septic shock by unknown pathogen (n=1). The frequency of micafungin use was significantly lower in the DET group than the EAT group (32.5% vs. 60.2%, P<0.001). Similar results were obtained in per-protocol set analyses. Conclusions: DET successfully reduced the use of antifungal agents without increasing invasive fungal infection or mortality compared to EAT. This randomized controlled study revealed the feasibility of DET in high-risk neutropenic patients. Disclosures Kimura: Astellas: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Other: Investigator in the institute; Nippon Kayaku: Honoraria; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria; Takeda: Honoraria. Kanda:Chugai: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; CSL Behring: Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Tanabe-Mitsubishi: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Dainippon-Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Taisho-Toyama: Research Funding; Taiho: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Takara-bio: Consultancy, Honoraria. Fujiwara:Shire: Consultancy; Pfizer: Consultancy; Chugai: Consultancy; Kirin: Consultancy; Kyowa-Hakko: Consultancy; Astellas: Consultancy. Suzumiya:Celltrion: Research Funding; Taiho: Research Funding, Speakers Bureau; SymBio: Research Funding; Toyama Chemical: Research Funding; Takeda: Research Funding, Speakers Bureau; Eisai: Research Funding, Speakers Bureau; Chugai-Roche: Research Funding, Speakers Bureau; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Zenyaku Kogyo: Consultancy; Abbvie: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Pfizer: Research Funding; Sumitomo Dainioppon: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Ono: Speakers Bureau; Ohtsuka: Speakers Bureau; Shire Japan: Speakers Bureau. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Tamura:Astellas Phrma: Research Funding; Eisai: Speakers Bureau; Kyowa Hakko Kirin: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau.

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

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3335-3335
Author(s):  
Wiro B. Stam ◽  
Amy K. O’Sullivan ◽  
Bart Rijnders ◽  
Elly Lugtenburg ◽  
Lambert F. Span ◽  
...  
Keyword(s):  
Economic Evaluation ◽  
Cost Effectiveness ◽  
High Risk ◽  
Life Expectancy ◽  
Decision Tree ◽  
Incremental Cost ◽  
Fungal Infections ◽  
Intensive Chemotherapy ◽  
Neutropenic Patients ◽  
The Cost

Abstract 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.

Oral Voriconazole for Empiric Antifungal Treatment in Uncomplicated Febrile Neutropenic Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5494-5494
Author(s):  
Kara Keasler ◽  
Joyce Broyles ◽  
Brian McClune ◽  
Francis Buadi ◽  
Donna Przepiorka
Keyword(s):  
Fungal Infection ◽  
Median Duration ◽  
Invasive Fungal Infection ◽  
Broad Spectrum ◽  
Treatment Success ◽  
Autologous Transplantation ◽  
Total Duration ◽  
Allogeneic Transplantation ◽  
Persistent Fever ◽  
Neutropenic Patients

Abstract The addition of an antifungal agent with activity against molds is considered standard of care for neutropenic patients with persistent fever treated with broad spectrum antibacterial antibiotics. The currently available intravenous agents suffer from high cost or high rates of toxicity. Voriconazole, a triazole with excellent activity against yeast and molds, has an oral bioavailability of 96% and comparable AUCs following IV and PO dosing. In 2003, we changed our standard policy to allow use of oral voriconazole in whole or in part for empiric antifungal coverage for neutropenic patients with uncomplicated persistent fever. Voriconazole was to be loaded at 6 mg/kg IV or PO q 12 hrs for 2 doses and followed by 200 mg PO BID. Over a 32-month period, 27 patients were treated for 31 episodes of persistent neutropenic fever. The cohort included 14 males and 13 females of median age 55 yrs (range, 19–78 yrs). Median weight at the time of first treatment was 84 kg (range, 62–122 kg). Nineteen patients had leukemia, 5 had lymphoma, and 3 had myeloma. Of the 31 episodes, 24 were for induction chemotherapy, 6 for autologous transplantation, and 1 for allogeneic transplantation. Standard prophylactic antibiotics included levofloxacin, fluconazole, valacyclovir and weekly nebulized amphotericin. The patients had been treated with vancomycin and cefepime, or a similar broad spectrum regimen, at the time of fever onset. The median time from fever to start of voriconazole was 4 days. All patients had an ANC<1500. The median WBC prior to voriconazole was 200 (range, 100–1700), and the median duration of ANC<500 prior to voriconazole was 9 days (range, 0–35 days). The median total duration of ANC<500 was 19 days (range, 5–86 days). The chest X-ray was abnormal in 8/30 episodes, CT scan was abnormal in 13/20 episodes, and the galactomannan assay was positive in 1/22 episodes. In 8 (26%) episodes, the patients fulfilled the criteria for possible invasive fungal infection, but none had a probable or definite invasive fungal infection at the start of voriconazole. The loading dose was given PO in 18 episodes and IV in 13 episodes. Median duration of therapy was 11 days (range, 2–54 days). Visual disturbances were reported in 0 (0%) episodes, rash in 2 (6%), creatinine ≥2.0 in 3 (10%), bilirubin ≥2.0 in 5 (16%), AST ≥100 in 2 (6%), and ALT ≥100 in 1 (3%). No patient discontinued drug because of toxicity. Success was described as resolution of fever without the need for a change in antibiotics. The success rate was 55% (95% CI, 36–73%). Fever resolved at a median of 4 days whether or not antibiotics were changed. Changes in the antibiotic regimen after voriconazole varied with the clinical circumstances; these included new antifungal agents in 7/14 and new antibacterial agents in 7/14. Gram positive cocci was the most common organism in this group of patients (10/14 (71%)), and a fungal infection (fusarium) was documented in only one patient. Day-90 survival was 81% (95% CI, 63–93%) for all patients. Neither treatment success nor Day-90 survival differed when compared by whether loading was IV vs PO, or whether the patient had a possible invasive fungal infection at the start of voriconazole. We conclude that oral voriconazole is safe for neutropenic patients with uncomplicated persistent fever, and its efficacy should be evaluated in a randomized trial.

Prognostic Factors of Infections and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA): A Prospective Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1917-1917
Author(s):  
Marie Sebert ◽  
Claire Aguilar ◽  
Sylvie Chevret ◽  
Lionel Ades ◽  
Olivier Lortholary ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Fungal Infection ◽  
Predictive Factors ◽  
Invasive Fungal Infection ◽  
Research Funding ◽  
Pulmonary Infection ◽  
Influenza B ◽  
Fatal Infection

Abstract Background: Hypomethylating agents, especially AZA, have become the reference first line treatment of high-risk MDS. Myelosupression, although less important than with chemotherapy, is however observed, leading to potentially life threatening infections. A retrospective study found unfavorable (unfav) cytogenetics and low platelet counts to be predictive factors of infections in high risk MDS and AML patients (pts) receiving AZA (Merkel and al, Am j Hemat 2012). However, prognostic factors of infections, and whether infection prophylaxis would be useful in this situation, has not been prospectively evaluated. Methods: Between June 2011 and March 2013, 120 high-risk MDS pts were included in a randomized phase II trial seeking the most promising drug association with AZA by comparison with AZA alone in higher risk MDS (including AML with 20 to 30% marrow blasts and CMML with > 10% marrow blasts) (NCT01342692). Pts received AZA (75mg/m²/dx7d every 4 weeks) alone (N=40), with Valproic acid (N=40) or with Lenalidomide (N=40) (10mg/dx14d every 4 weeks). G-CSF was not used. Infectious events (IE) (diagnosed as such by the treating physician), hospitalizations for sepsis and pts receiving antimicrobial prophylaxis were reported at each cycle. Predictive factors of the occurrence of IE were analyzed. Results: 75 (62.5%) pts developed 259 IE, including 61 requiring hospitalization in 46 pts (61.3% of infected patients). The number of IE and of infected patients were similar in the 3 study arms. 39 pts died during the study, 12 of them because of infection, none of whom had responded to AZA (4 progressions, 4 failures and 4 deaths before evaluation). IE were more common during the first two cycles of therapy, with 86 (31.3%), 52 (23.5%) 45 (18.9%), 26 (15%), 15(19.2%) and 24 (19.7%) IE during cycles 1, 2, 3, 4, 5, and 6, respectively. Fever of unknown origin (FUO) (39.6%) and pneumonia (28.8%) were the most common type of infections followed by ENT (9.9%), urinary tract (8.1%), skin (5.4%), dental (4.5%) and intra-abdominal (3.6%). 6,3% were bacteriemia. Among the 26 microbiologically documented IE, 13 were CG+ (4 staph aureus, 4 enteroccus species, 4 coag neg staph and 1 other), 9 were BG- (6 E Coli, 1 pseudomonas and 2 others) and 3 were viral (HSV1, influenza B, Hepatitis E) and only one patient had documented invasive fungal infection (asp fumigatus). Overall, 23 (19%), 22 (18%), 10(8%) pts received bacterial (Levofloxacine), fungal (posaconazole) and viral (Valaciclovir) prophylaxis resp. Predictive factors of IE were unfav karyotype (79.5% infections vs. 50.8% in pts with fav or int karyotype; p=0.005) and platelets (PLT) < 20 G/L (92.3% infections vs. 58.9% for platelets > 20 G/L; p=0.03). In multivariate analysis, only unfav karyotype was predictive of IE (p=0.01). Other baseline parameters (including ANC, IPSS, age, sex, Hb level, and BM blast %) and bacterial, fungal or viral prophylaxis had no significant predictive value on the occurrence of IE. In multivariate analysis, predictive factors of pulmonary infection were anemia at baseline (p=0.04) and unfav karyotype (p<0.001), while prophylaxis had no significant impact. Infected pts had significantly more hospitalizations and deaths than non-infected pts (p<0.0001 and p=0.028 resp.). In multivariate analysis, unfav karyotype (p<0.001) and PLT <20 G/L (p=0.05) were significantly predictive of hospitalization for infection, while baseline Hb <10g/dL (p=0.02), and unfav karyotype (p=0.03) were predictors of fatal infection. Conclusion: 62.5% of the 120 pts developed infections during AZA treatment, mainly during the first 2 cycles, and 10% of the pts died from infection. Only one invasive fungal infection was documented. Unfav karyotype was strongly predictive of IE, hospitalization for infection and fatal infections. Other significant predictive factors were baseline anemia for pulmonary infection and fatal infection, and thrombocytopenia for hospitalization for infection, while ANC was not a significant factor. Moreover, prophylaxis was not associated with a decrease of IE in our study, but the small number of pts who received it precludes any conclusion. Disclosures Ades: celgene: Research Funding; Novartis: Research Funding. Fenaux:Novartis: Research Funding; celgene: Research Funding; Janssen: Research Funding.

Pharmacokinetics and Safety of Posaconazole Tablet Formulation in Chinese Participants at High Risk for Invasive Fungal Infection

2020 ◽  
Vol 37 (5) ◽  
pp. 2493-2506
Author(s):  
Kaiyan Liu ◽  
Depei Wu ◽  
Junmin Li ◽  
Hu Chen ◽  
Hongmei Ning ◽  
...  
Keyword(s):  
High Risk ◽  
Fungal Infection ◽  
Invasive Fungal Infection ◽  
Tablet Formulation

scholarly journals Selective fluconazole prophylaxis in high-risk babies to reduce invasive fungal infection

2007 ◽  
Vol 92 (6) ◽  
pp. F454-F458 ◽  
Author(s):  
B. A McCrossan ◽  
E. McHenry ◽  
F. O'Neill ◽  
G. Ong ◽  
D. G Sweet
Keyword(s):  
High Risk ◽  
Fungal Infection ◽  
Invasive Fungal Infection ◽  
Fluconazole Prophylaxis

A Multicenter, Randomized, Open-Label Study to Evaluate Safety and Efficacy of Posaconazole Vs Fluconazole in the Prophylaxis of Invasive Fungal Infection in a Chinese Population

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4916-4916
Author(s):  
Shen Yang ◽  
Xiaojun Huang ◽  
Jianxiang Wang ◽  
Jie Jin ◽  
Jianda Hu ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Failure Rate ◽  
Invasive Fungal Infection ◽  
Conflicts Of Interest ◽  
Statistical Significance ◽  
Randomized Study ◽  
Treatment Phase ◽  
Clinical Failure ◽  
Open Label ◽  
Neutropenic Patients

Abstract Abstract 4916 Background Invasive fungal infection (IFI) is a common and fatal complication in neutropenic patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods In this multicenter, randomized study, we enrolled patients with persistent neutropenia resulting from chemotherapy for the treatment of AML and MDS. Prophylaxis with either posaconazole or fluconazole was given to the patients to compare the efficacy and safety of the 2 drugs. The treatment was given with each cycle of chemotherapy until the patient recovered from neutropenia and had complete remission, an IFI occurred, or until the patient had received a maximum of 12 weeks of treatment. The primary end point was the incidence of possible, proven, or probable diagnosis of IFI during the treatment phase in *the 2 groups; clinical failure rate, all-cause mortality, and time to first systemic antifungal treatment were secondary end points. Results A total of 252 patients were included in this study, and 7 patients were excluded due to withdrawal of informed consent or deviation of eligible criteria. Finally, 124 patients from the posaconazole group and 121 patients from the fluconazole group were included; and 234 patients (117 in each group) entered into statistical analysis, respectively. The incidence of proven, probable, and possible IFI was 9.4% (11/117) and 22.2% (26/117) in the posaconazole and fluconazole groups, respectively (P = 0.0114). The clinical failure rate was lower in the posaconazole group (31.6% [95% CI: 23.3–40.9], 37/117) than in the fluconazole group (41.88% [95% CI: 32.8–51.4], 49/117); however, statistical significance was not reached (P = 0.168). The patients receiving posaconazole had a later onset of first systematic antifungal therapy than those receiving fluconazole (P = 0.0139). The most common clinical adverse reactions were liver function abnormalities, with 11 cases (9.4%) in the posaconazole group and 6 cases (5.1%) in the fluconazole group (P = 0.221). Conclusions Posaconazole demonstrates efficacy as prophylaxis against IFI in high-risk neutropenic patients with AML and MDS undergoing chemotherapy and is well tolerated during long-term use. (ClinicalTrials.gov number, NCT00811928) Disclosures: No relevant conflicts of interest to declare.

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