Cost-effectiveness analysis of micafungin versus fluconazole for prophylaxis of invasive fungal infections in patients undergoing hematopoietic stem cell transplantation in Korea

Background: Invasive fungal infections are often fatal complications in patients undergoing hematopoietic stem cell transplantation (HSCT), and prophylactic antifungal treatment has been recommended. Within budget-limited health care environments, choosing a cost-effective drug is very important.Objective: This study was conducted to analyze the cost-effectiveness of micafungin and fluconazole for prophylaxis of invasive fungal infections from the payer's perspective in patients undergoing HSCT in a Korean health care setting.Methods: We constructed a decision-analytic model to evaluate both total costs for each state of health and outcomes (such as the fungal-infection prevention rate and life expectancy) for 2 alternatives in a hypothetical cohort of 100 patients undergoing HSCT. The target population was aged 43 years, weighed >50 kg, and had normal renal function. For prophylaxis against systemic fungal infections, patients were administered either micafungin 50 mg/d or fluconazole 400 mg/d, without dose adjustment, as a 1-hour infusion for a mean of 19 consecutive days. Depending on the clinical outcomes with prophylactic therapy, different treatments were assumed. Patients with proven/ probable fungal infection received acute antifungal therapy, and those with suspected fungal infection received empiric antifungal therapy. All patients received general medical care during the analysis period. Results are expressed as Korean won (KW; US $1 = KW 925 as of December 1, 2007).Results: The base-case analysis found that mica-fungin treatment, compared with fluconazole, saved KW 95,511,000, increased the number of infection-free patients by 0.5, and saved 4.8 life-years per 100 patients. Results with micafungin as the dominant strategy were found to be robust in sensitivity analyses for several parameters, including treatment success and failure rates; mortality risk ratio; and costs for general care, empiric therapy, and acute antifungal therapy.Conclusion: Micafungin was a cost-effective prophylactic antifungal strategy by providing lower medical costs and longer life expectancy than fluconazole from the payer's perspective in a hypothetical cohort of Korean adults undergoing HSCT.     

Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant

In this dose escalation study, 74 adult cancer patients undergoing bone marrow or peripheral blood stem cell transplantation received fluconazole (400 mg/day) and either normal saline (control) (12 subjects) or micafungin (12.5 to 200 mg/day) (62 subjects) for up to 4 weeks. The maximum tolerated dose (MTD) of micafungin was not reached, based on the development of Southwest Oncology Group criteria for grade 3 toxicity; drug-related toxicities were rare. Commonly occurring adverse events considered related to micafungin were headache (6.8%), arthralgia (6.8%), hypophosphatemia (4.1%), insomnia (4.1%), maculopapular rash (4.1%), and rash (4.1%). Pharmacokinetic profiles for micafungin on days 1 and 7 were similar. The mean half-life was approximately 13 h, with little variance after repeated or increasing doses. Mean maximum concentrations of the drug in serum and areas under the concentration-time curve from 0 to 24 h were approximately proportional to dose. There was no clinical or kinetic evidence of interaction between micafungin and fluconazole. Five of 12 patients (42%) in the control group and 14 of 62 (23%) in the micafungin-plus-fluconazole groups had a suspected fungal infection during treatment which resulted in empirical treatment with amphotericin B. The combination of micafungin and fluconazole was found to be safe in this high-risk patient population. The MTD of micafungin was not reached even at doses up to 200 mg/day for 4 weeks. The pharmacokinetic profile of micafungin in adult cancer patients with blood or marrow transplants is consistent with the profile in healthy volunteers, and the area under the curve is proportional to dose.     

急性髓系白血病患者诱导缓解治疗期症状群的纵向研究

目的 探讨急性髓系白血病（acute myeloid leukemia,AML）患者诱导缓解治疗（induction therapy,IT）期症状群的变化情况。方法 2018年1月—2020年6月,便利选取山东省某三级甲等医院血液内科首次确诊为AML并接受IT的130例患者,运用中文版记忆症状评估量表在IT开始前1 d（T1）、IT结束当天（T2）、IT结束后第7天（T3）对其进行评估,运用因子分析确立症状群的组成。 结果 T1存在4个症状群,为心理症状群、营养症状群、神经症状群和疼痛-出汗症状群。T2存在3个症状群,为胃肠道症状群、疲乏症状群和治疗相关症状群。T3存在4个症状群,为心理症状群、胃肠道症状群、疲乏症状群和形象改变症状群。其中心理症状群在T1和T3存在,疲乏症状群和胃肠道症状群在T2和T3持续存在。结论 AML患者在IT期经历的症状群呈动态变化。IT前的心理症状群、IT中的胃肠道症状群、IT结束后的疲乏症状群可作为优先干预的症状群。     

A randomized study to compare oral fluconazole to amphotericin B in the prevention of fungal infections in patients with acute leukaemia

In a prospective randomized study the efficacy of fluconazole (50 mg in one single daily dose) was compared with oral amphotericin B in suspension and tablets (each 200 mg four times daily) for prevention of colonization and subsequent infection by yeasts in 50 patients undergoing remission induction treatment for acute leukaemia. All patients received ciprofloxacin for prevention of bacterial infections. Fluconazole was as effective as amphotericin B in preventing severe local and disseminated fungal disease (one documented and one highly suspected infection in each group of patients). Fluconazole effectively prevented yeast colonization of the oropharynx but was less effective than amphotericin B in preventing colonization of the lower alimentary tract. Fifty-two percent of patients receiving fluconazole had persistent positive stool cultures as compared to 4% in the amphotericin B group (P less than 0.01). Fluconazole was better tolerated than amphotericin B. One patient developed an extended rash leading to the termination of fluconazole.     

Epidemiology,outcomes, and risk factors of invasive fungal infections in adult patients with acute myelogenous leukemia after induction chemotherapy

This is a retrospective, single-center study of adult patients with newly diagnosed acute myelogenous leukemia (AML), who received intensive induction timed sequential chemotherapy from 1/2005 to 6/2010. Among 254 consecutive AML patients, 123 (48.4%) developed an invasive fungal infection (IFI): 14 (5.5%) patients with invasive candidiasis (IC) and 108 (42.5%) patients with invasive mould infections (IMI). Among 108 IMI identified, 4 (3.7%) were proven, 1 (0.9%) probable, and 103 (95.4%) were possible, using current definitions. Overall, 6-month mortality was 23.7% (27/114) and 20.6% (26/126) for patients with and without an IFI, respectively. Older age (≥50 years; hazard ratio [HR]: 2.5, P < 0.001), female gender (HR: 1.7, P = 0.006), and baseline renal and/or liver dysfunction (HR: 2.4, P < 0.001) were the strongest mortality predictors. We report relatively low rates of IC despite lack of routine primary antifungal prophylaxis, albeit associated with poor long-term survival. High rates of IMI, the vast majority with a possible diagnosis, were observed. Host-related variables (demographics and baseline organ dysfunction) were identified as the most significant risk factors for IFI and mortality predictors in this series.     

Polymerase chain reaction screening for fungemia and/or invasive fungal infections in patients with hematologic malignancies

Introduction Invasive fungal infections (IFIs) are a life-threatening complication in patients with hematologic malignancies, mainly in acute leukemia patients, following chemotherapy. IFI incidence is increasing, and associated mortality remains high due to unreliable diagnosis. Antifungal drugs are often limited by inadequate antimicrobial spectrum and side effects. Thus, the detection of circulating fungal DNA has been advocated as a rapid, more sensitive diagnostic tool.Patients and methods Between June 01 and January 03, weekly blood samples (1,311) were screened from 193 patients undergoing intensive myelosuppressive or immunosuppressive therapy. IFI cases were classified according to European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Fungal DNA was extracted from whole blood and amplified using polymerase chain reaction (PCR) published primers that bind to the conserved regions of the fungal 18S rRNA gene sequence. In our study, two or more consecutive positive samples were always associated with fungal disease. Results: PCR screening predicted the development of IFI to be 17 days (median). This test had a specificity of 91.1% and a sensitivity of 75%. IFI incidence was 7.8%. Discussion: Therefore, our results confirm the potential usefulness of PCR serial screening and the clinical applicability in everyday routine. PCR screening offers a noninvasive repeatable aid to the diagnosis of IFI.     

RAS mutation analysis in a large cohort of Chinese patients with acute myeloid leukemia

ObjectiveWe examined RAS mutational status and correlated this with presenting morphology, cytogenetics, clinical outcome and other gene aberrations in a large cohort of Chinese acute myeloid leukemia (AML) patients.Designs and methodsN-RAS and K-RAS were screened for mutations at hot-spot codons 12, 13 and 61 using high resolution melting analysis (HRMA) and direct DNA sequencing in 504 Chinese AML patients and their clinical relevance was analyzed.ResultsThe frequencies of mutations of N-RAS and K-RAS were 9.7% (49/504) and 2.9% (15/504), respectively. c.35 G > A (rs121913237: G > A; p.Gly12Asp and rs121913529: G > A; p.Gly12Asp) and c.38 G > A (rs121434596: G > A; p.Gly13Asp and rs112445441: G > A; p.Gly13Asp) were the most common base substitutions (46% in N-RAS and 60% in K-RAS, respectively). AML patients with RAS mutations presented significantly higher white blood cell count (WBC) at diagnosis than those without mutations (p < 0.001). RAS mutations were underrepresented in patients with t(15;17) (2.9%, p = 0.01), while overrepresented in cases with abn11q23 (50%, p = 0.002) and inv(16) (66.6%, p = 0.04). In the FAB subtypes M4 and M5, RAS mutations were more frequent (21.6% and 20.6%, respectively) than they were in other subtypes (7.5%, p = 0.006 and 0.005, respectively). FLT3-ITD and RAS mutation were rarely coexistent (p = 0.03). RAS mutation didn't influence overall survival (OS) either in the entire cohort or within some defined subgroups.ConclusionsRAS mutations are associated with some biologically specific subtypes of AML but don't impact clinical outcome in Chinese patients.     

An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia

OBJECTIVES: This trial studied the efficacy and safety of itraconazole and fluconazole in the prevention of invasive fungal infections in neutropenic patients with haematological malignancies. PATIENTS AND METHODS: An 8 week, open-label, randomized, parallel-group, multicentre trial comparing itraconazole oral solution (2.5 mg/kg twice daily; N=248) with fluconazole oral solution or capsules (400 mg daily; N=246) in 494 patients with anticipated profound neutropenia (i.e. neutrophil count expected to be <500 cells/mm3 for at least 10 days) from tertiary care centres. RESULTS: Invasive fungal infections were reported for 4 out of 248 patients (1.6%) in the itraconazole group and 5 out of 246 patients (2.0%) in the fluconazole group. Invasive Aspergillus infections were proven for 2 out of 248 patients (0.8%) in the itraconazole group and 3 out of 246 patients (1.2%) in the fluconazole group. For both the ITT and profoundly neutropenic populations, no differences were detected between treatment groups in proven or suspected invasive fungal infections or other endpoints. The mortality rates owing to proven invasive fungal infections were 2 out of 248 patients (0.8%) for the itraconazole group and 3 out of 246 patients (1.2%) for the fluconazole group. There was also no difference between treatment groups in the number of patients who recovered from neutropenia or in the duration of neutropenia. More discontinuation of drug intake owing to nausea and more hypokalaemia occurred in the itraconazole group, other adverse events and the total number of adverse events were similar in both groups. CONCLUSIONS: In this study there were no differences in the efficacy and safety of itraconazole and fluconazole prophylaxis in neutropenic patients with haematological malignancies.     

Invasive fungal infections in pediatric patients: a review focusing on antifungal therapy

Invasive fungal infections in children appear to have increased over the past few decades. Substantial differences compared with adult patients in risk factors, pathogen epidemiology, pathophysiology and, most notably, pharmacokinetics of antifungal agents require age-adapted management and treatment approaches. The present article reviews these aspects for invasive aspergillosis and invasive candidiasis, the two most common life-threatening fungal infections.     

Intensive intravenous amphotericin B for prophylaxis of systemic fungal infections. Results of a prospective controlled pilot study in acute leukemia patients

BACKGROUND: Invasive fungal infections are an increasing cause of morbidity in acute leukemia (AL) patients. METHODS: In a prospective pilot trial, the safety and efficacy of antifungal prophylaxis with intravenous (i.v.) amphotericin B (AMB; 1 mg/kg every 48 h) was studied in 46 consecutive cycles. Prophylaxis with i.v. AMB was carried out in patients treated with intensive chemotherapy for AL and compared with a control of 49 cycles without prophylaxis. RESULTS: Pulmonary infiltrates (5 vs. 23; p < 0.001) and fungal microabscesses in the liver or spleen (0 vs. 6; p = 0.014) occurred significantly less frequently in the prophylaxis group. While there were 3 deaths related to systemic fungal infections in the control group, there were none in the prophylaxis group. Escalation to conventional AMB (1.0 mg/kg/day) was significantly less frequent in the prophylaxis group (9 out of 46 cycles) compared with the control arm (29 out of 49 cycles; p = 0.001). A total of 695 mg of AMB per cycle was administered in the prophylaxis arm, compared with 634 mg/cycle for empirical treatment in the control group (p = 0.6). Infusion-related toxicity was documented in 29% of the cycles of prophylaxis compared with 55% of the cycles of empirical treatment with i.v. AMB in the control group. The nephrotoxicity of AMB prophylaxis was moderate, with >/= WHO degree II reported in 1 out of 46 cycles only. CONCLUSION: Intensive i.v. AMB prophylaxis reduced invasive fungal infections and led to a reduction in fungal microabscesses in the liver or spleen, as well as pulmonary infiltrates, in patients treated for AL. The need for escalation to empirical i.v. AMB treatment was significantly reduced. Intensive AMB prophylaxis was feasible, with moderate adverse effects.     

Genetic testing in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a cost‐effectiveness analysis

Summary. Background: The CYP2C19 genotype is a predictor of adverse cardiovascular events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) treated with clopidogrel. Objectives: We aimed to evaluate the cost‐effectiveness of a CYP2C19*2 genotype‐guided strategy of antiplatelet therapy in ACS patients undergoing PCI, compared with two ‘no testing’ strategies (empiric clopidogrel or prasugrel). Methods: We developed a Markov model to compare three strategies. The model captured adverse cardiovascular events and antiplatelet‐related complications. Costs were expressed in 2010 US dollars and estimated using diagnosis‐related group codes and Medicare reimbursement rates. The net wholesale price for prasugrel was estimated as $5.45 per day. A generic estimate for clopidogrel of $1.00 per day was used and genetic testing was assumed to cost $500. Results: Base case analyses demonstrated little difference between treatment strategies. The genetic testing‐guided strategy yielded the most QALYs and was the least costly. Over 15 months, total costs were $18 lower with a gain of 0.004 QALY in the genotype‐guided strategy compared with empiric clopidogrel, and $899 lower with a gain of 0.0005 QALY compared with empiric prasugrel. The strongest predictor of the preferred strategy was the relative risk of thrombotic events in carriers compared with wild‐type individuals treated with clopidogrel. Above a 47% increased risk, a genotype‐guided strategy was the dominant strategy. Above a clopidogrel cost of $3.96 per day, genetic testing was no longer dominant but remained cost‐effective. Conclusions: Among ACS patients undergoing PCI, a genotype‐guided strategy yields similar outcomes to empiric approaches to treatment, but is marginally less costly and more effective.     

High incidence of infectious gastrointestinal complications observed in patients with acute myeloid leukemia receiving intensive chemotherapy for first induction of remission

An increased incidence of severe infections, in particular gastrointestinal complications, was observed in our institution among 35 consecutive patients with acute myelogenous leukemia submitted to their first intensive pilot protocol for induction of remission containing idarubicin, etoposide and cytosine arabinoside. Ten patients presented fever and severe diarrhea (4 or more loose stools/day for at least 4 consecutive days); 3 of these developed ileothyphlitis, which proved fatal in 2 cases, 7 needed amphotericin B addition to antibacterial treatment and, in 6 cases, a fungal infection was documented. We have compared these 10 patients with the other 25 submitted to the same chemotherapeutic protocol and the incidence of candidemias (5/10 compared to 0/25), the early use of systemic fluconazole from the onset of fever (0/10 compared to 9/25) and the pre-emptive use of total parenteral nutrition (0/10 compared to 8/25) differed in the two groups. We conclude that during this chemotherapeutic protocol the incidence of severe gastrointestinal infectious complications was particularly high (28.5%) and, even though only a small number of patients were studied, our results suggest an important role forCandida spp. in the pathogenesis of this disease.     

Efficacy and safety of intravenous voriconazole and intravenous itraconazole for antifungal prophylaxis in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome

Purpose

To compare the efficacy and safety of voriconazole with itraconazole as prophylaxis in leukemia patients.

Methods

Open-label, randomized study. Patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome undergoing induction chemotherapy or first salvage were eligible. Patients received voriconazole (400?mg intravenous (IV) every 12?h for two doses, followed by 300?mg BID) or itraconazole (200?mg IV twice daily for 2?days, followed by 200?mg IV daily).

Results

A total of 127 patients were enrolled. Four were excluded because they did not receive study drug (n?=?3) or received two antifungal agents during the first week on study (n?=?1), leaving 123 patients for analysis. None of the 71 patients receiving voriconazole developed proven or probable invasive fungal infection, compared to two (4%) of the 52 patients receiving itraconazole (P?=?0.17). Drug discontinuation because of adverse events occurred in 15 patients (21%) receiving voriconazole and six (11%) receiving itraconazole (P?=?0.23).

Conclusions

Voriconazole is a good alternative for prophylaxis in patients with leukemia. Elevated baseline bilirubin levels were associated with a higher risk of side effects in patients receiving IV voriconazole or IV itraconazole. Monitoring of liver function and drug levels should be considered for some patients.