Cost effectiveness of caspofungin vs. voriconazole for empiric therapy in Turkey

Invasive fungal infections from febrile neutropenia are associated with significant cost and mortality. The mainstay of treatment has been liposomal amphotericin B, however, echinocandins and azoles have shown promise as alternative treatments. Data on clinical efficacy exist, however, data incorporating pharmacoeconomic considerations are required in Turkey. The aim of this study was to investigate the cost effectiveness of caspofungin vs. voriconazole in empiric treatment of febrile neutropenia in Turkey. A decision analytic model was utilised, built upon two randomised‐controlled trials and supplemented with expert panel input from clinicians in Turkey. A five‐point composite outcome measure was utilised and sensitivity analyses were performed to demonstrate the robustness of the model. The base case scenario resulted in caspofungin being preferred by TL2,533, TL29,256 and TL2,536 per patient treated, successfully treated patient and patient survival, respectively (approx. USD1414, 16 328 and 1415); sensitivity analyses did not change the outcome. Monte Carlo simulation highlighted a 78.8% chance of favouring caspofungin. The result was moderately sensitive to treatment duration and acquisition cost of the antifungal agents compared. This is the first pharmacoeconomic study comparing caspofungin to voriconazole within Turkey, resulting in an advantage towards caspofungin. The study will aid in formulary decision‐making based on the clinical and economic consequences of each agent in the Turkish health care setting.     

Economic evaluation of micafungin vs. Liposomal Amphotericin B (LAmB) for the treatment of candidaemia and Invasive Candidiasis (IC)

Micafungin was non‐inferior to liposomal amphotericin B (LAmB) for the treatment of candidaemia and invasive candidiasis (IC) in a major clinical trial. The present study investigated the economic impact of micafungin vs. LAmB in treating candidaemia and IC. A decision analytical model was constructed to capture downstream consequences of using micafungin or LAmB as primary definitive therapy. The main outcomes were treatment success and treatment failure due to mycological persistence, or death. Outcome probabilities were derived from key published sources. Resource used was estimated by an expert panel and cost inputs were from the latest Australian resources. The analysis was from an Australian hospital perspective. Sensitivity analyses using Monte Carlo simulation were conducted. Micafungin (AU$61 426) had a lower total cost than LAmB (AU$72 382), with a total net cost‐saving of AU$10 957 per patient. This was primarily due to the lower cost associated with initial antifungal treatment and shorter length of stay for patients in the micafungin arm. Hospitalisation was the main cost driver for both arms. Results were robust over a wide range of variables. The uncertainty analysis demonstrated that micafungin had a 99.9% chance of being cost‐saving compared with LAmB. Micafungin was associated with cost‐saving relative to LAmB in the treatment of candidaemia and IC in Australia.     

Successful treatment of disseminated fusariosis with voriconazole in an acute lymphoblastic leukaemia patient

Fusarium species are actually the second most common pathogenic mould in immunocompromised patients, and it is difficult to treat such fusarial infections with current antifungal agents. We report the case of a 53-year-old woman with Philadelphia-positive acute lymphoblastic leukaemia. During induction chemotherapy with febrile neutropenia, she developed a disseminated fusariosis, with persistent fever refractory to antibacterial agents and caspofungin (as empirical therapy), painful skin lesions and respiratory impairment. Fusarium solani was isolated from skin biopsy. Voriconazole was successfully implemented as antifungal curative therapy. During the second intensive chemotherapy no reactivation of fusariosis was detected.     

Wait and see or rush and switch? New questions for the management of patients with febrile neutropenia receiving antifungal prophylaxis

Infections are a major threat for patients with haematological malignancies after intensive myelosuppressive chemotherapy. The severity and extent of neutropenia are considered a major risk factor for infections in these patients. Antibacterial treatment for patients with febrile neutropenia was standardised in the late 1990s with no further significant improvements within the last decade. Major progress in febrile neutropenia has come from the advent of new antifungals since the late 1990s. Lipid-based amphotericin B, third-generation azoles and the introduction of echinocandins allow a safer and effective treatment of invasive fungal infections. The mortality rate of invasive fungal infection is as high as 30-100% and a definitive diagnosis by culture may take too long. Thus, early diagnosis and early initiation of antifungal therapy remain important for the reduction of mortality rates. In the last two decades, randomised trials on prophylaxis and empirical therapy of invasive fungal infections were undertaken. Both primary prophylaxis and empirical therapy of invasive fungal infection proved effective. However, important questions remain unanswered. This article points out the clinicians view on unmet needs for patients with suspected invasive fungal infections after a decade of well-designed randomised trials for prevention of invasive fungal infections. Should we wait and see what happens in febrile neutropenic patients on antifungal prophylaxis or under empirical treatment or should we rush and switch antifungal treatment?     

Modern antifungal therapy for neutropenic fever

Empirical antifungal therapy has been shown to decrease the number of documented fungal infections in the setting of persistent fever during neutropenia. For decades, amphotericin B deoxycholate has been considered the agent of choice for first-line therapy in this setting. New antifungal agents associated with less toxicity, including the lipid formulations of amphotericin, voriconazole, and caspofungin, are now available and are considered to be suitable alternative first-line agents. In order to ensure appropriate therapy, however, the clinician must consider not only the differences between these antifungals but also patient-specific factors before initiating treatment.     

Granulocyte colony-stimulating factor in the treatment of high-risk febrile neutropenia: a multicenter randomized trial

BACKGROUND: Granulocyte colony-stimulating factors (G-CSFs) have been shown to help prevent febrile neutropenia in certain subgroups of cancer patients undergoing chemotherapy, but their role in treating febrile neutropenia is controversial. The purpose of our study was to evaluate-in a prospective multicenter randomized clinical trial-the efficacy of adding G-CSF to broad-spectrum antibiotic treatment of patients with solid tumors and high-risk febrile neutropenia. METHODS: A total of 210 patients with solid tumors treated with conventional-dose chemotherapy who presented with fever and grade IV neutropenia were considered to be eligible for the trial. They met at least one of the following high-risk criteria: profound neutropenia (absolute neutrophil count <100/mm(3)), short latency from previous chemotherapy cycle (<10 days), sepsis or clinically documented infection at presentation, severe comorbidity, performance status of 3-4 (Eastern Cooperative Oncology Group scale), or prior inpatient status. Eligible patients were randomly assigned to receive the antibiotics ceftazidime and amikacin, with or without G-CSF (5 microg/kg per day). The primary study end point was the duration of hospitalization. All P values were two-sided. RESULTS: Patients randomly assigned to receive G-CSF had a significantly shorter duration of grade IV neutropenia (median, 2 days versus 3 days; P = 0.0004), antibiotic therapy (median, 5 days versus 6 days; P = 0.013), and hospital stay (median, 5 days versus 7 days; P = 0.015) than patients in the control arm. The incidence of serious medical complications not present at the initial clinical evaluation was 10% in the G-CSF group and 17% in the control group (P = 0.12), including five deaths in each study arm. The median cost of hospital stay and the median overall cost per patient admission were reduced by 17% (P = 0.01) and by 11% (P = 0.07), respectively, in the G-CSF arm compared with the control arm. CONCLUSIONS: Adding G-CSF to antibiotic therapy shortens the duration of neutropenia, reduces the duration of antibiotic therapy and hospitalization, and decreases hospital costs in patients with high-risk febrile neutropenia.     

Time to clinical response: an outcome of antibiotic therapy of febrile neutropenia with implications for quality and cost of care.

PURPOSE: To determine whether antibiotic regimens with similar rates of response differ significantly in the speed of response and to estimate the impact of this difference on the cost of febrile neutropenia. METHODS: The time point of clinical response was defined by comparing the sensitivity, specificity, and predictive values of alternative objective and subjective definitions. Data from 488 episodes of febrile neutropenia, treated with either of two commonly used antibiotics (coded A or B) during six clinical trials, were pooled to compare the median time to clinical response, days of antibiotic therapy and hospitalization, and estimated costs. RESULTS: Response rates were similar; however, the median time to clinical response was significantly shorter with A-based regimens (5 days) compared with B-based regimens (7 days; P =.003). After 72 hours of therapy, 33% of patients who received A but only 18% of those who received B had responded (P =.01). These differences resulted in fewer days of antibiotic therapy and hospitalization with A-based regimens (7 and 9 days) compared with B-based regimens (9 and 12 days, respectively; P <.04) and in significantly lower estimated median costs ($8,491 v $11,133 per episode; P =.03). Early discharge at the time of clinical response should reduce the median cost from $10,752 to $8,162 (P <.001). CONCLUSION: Despite virtually identical rates of response, time to clinical response and estimated cost of care varied significantly among regimens. An early discharge strategy based on our definition of the time point of clinical response may further reduce the cost of treating non-low-risk patients with febrile neutropenia.     

亚胺培南经验性治疗肿瘤患者中性粒细胞缺乏伴发热的回顾性分析

目的评价碳青酶烯类抗生素亚胺培南经验性治疗肿瘤患者中性粒细胞缺乏伴发热的疗效和安全性。方法回顾性分析51例肿瘤患者化疗后出现中性粒细胞缺乏伴发热应用亚胺培南进行经验性治疗的临床资料。结果接受亚胺培南/西司他丁进行初始经验性治疗的51例患者中,痊愈29例,显效8例,进步7例,无效7例,有效率72.5%。2例患者出现了可耐受的不良反应。结论亚胺培南作为肿瘤患者中性粒细胞缺乏伴发热的初始经验性抗菌治疗,具有较高的疗效和良好的耐受性。     

A novel approach to maintain planned dose chemotherapy on time: a decision-making tool to improve patient care

Studies of primary prophylaxis of febrile neutropenia with recombinant granulocyte colony-stimulating factor (r-metHuG-CSF, filgrastim), administered to all patients starting with the initial course of chemotherapy, have demonstrated an economic advantage over a wide range of settings. In these analyses, the threshold risk for febrile neutropenia at which a cost saving is realised is inversely related to the direct medical costs of hospitalisation. Clinical practice guidelines for the use of filgrastim have been developed based on these observations. Recent studies incorporating indirect institutional costs have demonstrated that cost savings can be achieved at substantially lower febrile neutropenia risk thresholds than previously estimated. Despite the demonstrated efficacy of filgrastim in primary prophylaxis, its value may be further enhanced through the appropriate selection of patients for such therapy and a better understanding of the importance of sustaining dose intensity in specific malignancies. Clinical prediction models capable of identifying individuals at high risk for neutropenic complications yield further reductions in febrile neutropenia risk thresholds and treatment costs in patients receiving cancer chemotherapy. Prediction models can also be used to evaluate the cost-effectiveness or cost-efficiency of filgrastim use. Such a model has recently been developed and validated and is described here which incorporates both baseline clinical characteristics as well as the results of the first cycle of chemotherapy in patients with early-stage breast cancer. A cost-effectiveness ratio of US$ 34297 (Euro 32002)dagger per year of life saved (YLS) was calculated based on dose-response assumptions derived from a previously reported adjuvant breast cancer trial studying the impact of dose reduction on disease-free survival. This figure is comparable with accepted cost-effectiveness ratios for other interventions, e.g. US$ 45000/LYS (Euro 41989) for renal dialysis for patients with end-stage renal disease. The cost-effectiveness of filgrastim was evident over a wide range of clinical and cost assumptions. Clinical prediction models permit rational and cost-effective selection of patients for filgrastim support. Current guidelines should be re-evaluated in light of new information available on both the total cost of febrile neutropenia, as well as the cost-effectiveness of these agents in specific clinical situations.     

Cefepime versus ticarcillin and clavulanate potassium and aztreonam for febrile neutropenia therapy in high-dose chemotherapy patients

An open labeled randomized trial comparing the efficacy and cost of empirically applied cefepime (C) as monotherapy versus combination therapy consisting of ticarcillin and clavulanate potassium and aztreonam (T/A) was performed in febrile neutropenic patients following high-dose chemotherapy (HDC) +/- radiation, with or without peripheral blood stem cell support. Over a 28-month period, 126 patients were screened and included in the study. Using afebrile status following 3 days of therapy as a primary endpoint, both regimens produced comparable clinical response rates (C = 55% vs. T/A = 61%). Also, the use of vancomycin for resistant gram-positive infections and alteration of gram-negative infection coverage was similar in both groups (C = 40% vs. T/A = 47% and C = 29% vs. T/A = 24%). Both treatment groups had similar needs for empirical antifungal therapy (C = 25% vs. T/A = 22%). There was a postrandomization difference between the two groups in that the "C" group had a significantly higher number of allogeneic transplants and non-stem-cell-supported patients, whereas the "T/A" group had a significantly greater number of autologous peripheral blood stem cell patients (p < 0.0001). Despite this difference, the C group had a significantly lower cost ratio than the T/A group (p = 0.016). In conclusion, we have shown that C treatment of febrile neutropenic patients following HDC results in similar efficacy and lower cost when compared to T/A, despite the inclusion of higher risk patients in the C group.     

Management of infection in cancer patients. studies of the EORTC International Antimicrobial Therapy Group (IATG)

Infection remains an important cause of morbidity and mortality in cancer patients, especially those undergoing chemotherapy for haematological malignancies. The practice of instituting an empirical broad-spectrum antibiotic therapy as soon as possible after the onset of fever has substantially reduced the clinical impact of this complication. In the last 25 years, the International Antimicrobial Therapy Group of the European Organisation for Research and Treatment of Cancer (EORTC-IATG) have published nearly 30 articles and a number of abstracts on several facets of the epidemiology and management of infection in cancer patients. With a progressive methodological refinement, the EORTC-IATG trials have established the standard for the management of febrile neutropenia, both by setting methodologies and definitions and by testing several antibiotic regimens that are active and effective for this indication. With the aim of supporting a more rational use of antibiotics in cancer patients, the most recent trials have dealt with the management of low risk patients, showing the safety and feasibility of oral therapy.     

Clinical Study on Safety and Efficacy of JiSaiXin (Recombinant Human Granulocyte Colony Stimulating Factor Injection Manufactured in China) for Chinese Undergoing Chemotherapy

Objectives: To assess safety and efficacy of JiSaiXin (Recombinant Human Granulocyte Colony StimulatingFactor Injection manufactured in China, G-CSF) 150ug per day for three days and whether this regimen couldreduce the incidence of febrile neutropenia caused by chemotherapy. Method: From July 2014 to December2014 patients treated by chemotherapy in our hospital were randomly divided into two groups: Group A withprophylactic use of G-CSF (JiSaiXin) 24 hours after chemotherapy for consecutive 3 days; and Group B withG-CSF (JiSaiXin) after neutropenia. Routine blood tests were performed 7 days and 14 days after chemotherapy.Results: A total of 100 patients fulfilled study criteria, and the incidence of severe neutropenia (grade III/IV)and the incidence of febrile neutropenia in Group A were lower than those in Group B. Nine patients were foundsevere neutropenia (grade III/IV) in Group B, but one in Group A, three febrile neutropenia in Group B, but 0 inGroup A. Conclusions: This study suggested that prophylactic use of G-CSF (JiSaiXin) 150ug per day 24 hoursafter chemotherapy for consecutive 3 days is safe and could be effective for preventing febrile neutropenia inpatients with chemotherapy.     

Estimating the Cost-Effectiveness of Lung Cancer Screening with Low-Dose Computed Tomography for High-Risk Smokers in Australia

Introduction

Health economic evaluations of lung cancer screening with low-dose computed tomography (LDCT) that are underpinned by clinical outcomes are relatively few.

Pharmacoeconomic assessment of therapy for invasive aspergillosis

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised hosts. Economic expenditures prompted by this invasive fungal infection (IFI) are significant. Although, the duration and associated costs of hospitalization comprise the largest proportion of costs in large surveillance studies, the newer oral antifungal agents may impact significantly on these costs. A review of the pharmacoeconomic (PE) studies is provided focussing on primary therapy, salvage therapy, empiric therapy and prophylaxis for IA. PE evaluations have demonstrated the cost effectiveness and dominance of voriconazole for targeted primary treatment of IA compared with other available agents. Differences in the drug choice and analytic methodology of the PE analyses of empiric antifungal strategy hamper definitive conclusions about the agents employed as empiric antifungal that may be directed at suspected IA although both caspofungin and voriconazole appear to be cost effective and dominant over liposomal amphotericin B (LAmB), whereas LAmB is more costly than conventional amphotericin B. Posaconazole is the most cost‐effective agent for antifungal prophylaxis against IFI and IA.     

Ceftriaxone in febrile neutropenia

Standard management of febrile neutropenia requires prompt administration of empirical, broad-spectrum antibiotic therapy, since febrile neutropenia is associated with a significant risk of infectious complications and mortality. Risk-assessment models have been developed that differentiate febrile patients with neutropenia according to their risk for infectious complications and/or mortality and have prompted a change in the management of these patients. Ceftriaxone is a long-lasting, broad spectrum cephalosporin which has demonstrated efficacy in this indication in many publications. The role of ceftriaxone in febrile neutropenia will be discussed based on literature analysis and on the author's experience.     

Ceftazidime and amikacin as empiric antibiotic therapy of febrile granulocytopenic patients with hematological malignancies. Report of 171 consecutive episodes

One hundred and seventy-one consecutive febrile episodes occurring in 130 neutropenic adult patients with hematological malignancies (mainly acute leukemia) were empirically treated with a combination antibiotic therapy consisting of ceftazidime (100 mg/kg/day) + amikacin (15 mg/kg/day). Of these, 161 were evaluable. In the majority of episodes (75 per cent) documented infections were identified as a cause of fever. There were 73 bacteremias (34 Gram-negative, 29 Gram-positive, 10 polymicrobial). One third of patients had pneumonia. Cure without change of the initial regimen was achieved in 45/73 (62 per cent) bacteremic episodes and in 12/13 episodes of microbiologically documented infections without bacteremia. There were 35 clinically documented infections and 26 (74 per cent) of these were cured. Of the 40 patients presenting with possible infections 26 (65 per cent) were cured. Overall, cure without modification of the initial antibiotic combination was achieved in 109/161 episodes (68 per cent). In spite of the frequent occurrence of persistent neutropenia (82 per cent), the infectious mortality was low (8.6 per cent), and often due to superinfection. The deaths due to primary infections were 6/161 (3.7 per cent). Side effects were mild and rare. In our experience ceftazidime + amikacin was an effective and safe empirical regimen for this population of hematologic patients with persistent neutropenia and severe documented infections.     

Docetaxel

? Docetaxel is an antimicrotubule agent established as a first- and/or second-line intravenous therapy in a variety of cancers, including locally advanced or metastatic breast cancer. It also is approved in the US as adjuvant therapy in early breast cancer, and continues to be investigated in this setting in combination with other agents and in various dosing schedules. ? The efficacy of docetaxel-containing adjuvant therapy has been evaluated in two large (n >1000 per trial), randomized clinical trials. One trial compared intravenous docetaxel plus doxorubicin and cyclophosphamide (TAC) every 3 weeks with standard fluorouracil plus doxorubicin and cyclophosphamide (FAC) chemotherapy. Another trial compared intravenous docetaxel plus cyclophosphamide (TC) every 3 weeks with doxorubicin plus cyclophosphamide (AC). ? Treatment with TAC improved disease-free survival (75% vs 68%; p = 0.001) and overall survival (87% vs 81%; p = 0.008) at 55 months to a greater extent than FAC. ? There were no significant differences in disease-free survival and overall survival between TC and AC. Nevertheless, a nonsignificant trend in disease-free survival favors TC and follow-up data were for a period of only 43 months. ? Tolerability in docetaxel-containing adjuvant chemotherapy regimens was manageable. The most frequently reported severe adverse events with TAC were predominantly hematologic, including neutropenia, febrile neutropenia, and neutropenic infection.      

Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: a meta-analysis of randomized controlled trials.

PURPOSE: To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality. METHODS: We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included. RESULTS: The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P =.01), and a decrease in hospitalization length, with a weighted mean difference of -1.9 days (95% CI, -2.7 to -1.1 days; P <.00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P =.02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0.87; P =.02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, -4.3; 95% CI, -10.6 to 2.0 days; P =.2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P =.97). CONCLUSION: CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality.     

Bone marrow suppression--including guidelines for the appropriate use of G-CSF

For previously untreated patients receiving most chemotherapy regimens, primary prophylactic administration of granulocyte colony-stimulating factor (G-CSF) cannot be recommended. Secondary prophylactic G-CSF administration can lessen incidence of febrile neutropenia (FN) in subsequent cycles of chemotherapy in patients with a prior episode of FN. Physicians should consider chemotherapy dose reduction after neutropenic fever or severe or prolonged neutropenia after the previous cycle of treatment. Intervention with G-CSF in afebrile neutropenic patients is not recommended. For the majority of patients with FN, the available data do not clearly support the routine initiation of G-CSF as an adjunct to antibiotic therapy. However, certain FN patients may have prognostic factors that are predictive of clinical deterioration, such as pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or fungal infection. The therapeutic use of G-CSF together with antibiotics may be reasonable in such high-risk patients. Empirical antifungal therapy is effective, especially for patients with neutropenia who were treated for seven days with empirical antibiotic therapy but remained febrile, or became afebrile but then had recurrent fever. The patient's overall clinical status and laboratory parameters are both considered when deciding to transfuse a patient. Epoetin may be available for use in the future as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dl. Giving prophylactic platelets at a threshold of 10,000/microliter compared with 20,000/microliter can decrease the total utilization of platelets with only a small adverse effect on bleeding, and no statistically significant effect on morbidity.