Itraconazole Prevents Invasive Fungal Infections in Neutropenic Patients Treated for Hematologic Malignancies: Evidence From a Meta-Analysis of 3,597 Patients

2003 ◽  
Vol 21 (24) ◽  
pp. 4615-4626 ◽  
Author(s):  
Axel Glasmacher ◽  
Archibald Prentice ◽  
Marcus Gorschlüter ◽  
Steffen Engelhart ◽  
Corinna Hahn ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Meta Analysis ◽  
Hematologic Malignancies ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Drug Discontinuation ◽  
Randomized Controlled Studies ◽  
Neutropenic Patients ◽  
First Time ◽  
New Evidence

Purpose: Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. Patients and Methods: Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. Results: Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% ± 13%; P = .002), the incidence of invasive yeast infections (mean, 53% ± 19%; P = .004) and the mortality from invasive fungal infections (mean, 35% ± 17%; P = .04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% ± 21%; P = .02) and not itraconazole capsules (mean, 75% ± 73% increase; P = .3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. Conclusion: Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and—shown for the first time for antifungal prophylaxis—reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or IV formulations (200 mg/d) of itraconazole are necessary for these effects.

Itraconazole for Antifungal Prophylaxis in Neutropenic Patients: An Update of a Meta-Analysis with Now 3846 Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3224-3224
Author(s):  
Axel Glasmacher ◽  
Corinna Hahn ◽  
Marie von Lilienfeld-Toal ◽  
Katjana Orlopp ◽  
Ingo Schmidt-Wolf ◽  
...  
Keyword(s):  
Relative Risk ◽  
Randomized Clinical Trials ◽  
Fungal Infections ◽  
Meta Analysis ◽  
Cochrane Review ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Significant Difference ◽  
Neutropenic Patients ◽  
Related Mortality

Abstract Invasive fungal infections, esp. from Aspergillus spp., still are a major cause of mortality and morbidity in neutropenic patients with haematological malignancies. We have published a meta-analysis on the use of itraconazole for antifungal prophylaxis (Glasmacher et al., JCO2003; 21: 4615) and now present updated results. Methods: In a continuous search of electronic databases and abstracts we identified randomized clinical trials in neutropenic patients that compared itraconazole with either nothing, oral polyenes or fluconazole. Again, analysis was restricted to proven invasive fungal infections according to EORTC/MSG criteria. Statistical analyses were performed with the Cochrane Review Manager (Version 2.4.8), relative risk ratios (RR) with their 95% confidence intervals (95%CI) and appropriate P values were reported. Subgroups were defined by itraconazole preparation and the comparator. A RR below 1 indicates better results for itraconazole. Results - New Trials: Two new trials with 54 and 195 evaluable patients (pts) were identified and the data of one unpublished trials was updated. Both studies used itraconazole solution (400 mg/d) and compared it to 400 mg/d fluconazole. One study applied intravenous solutions of both drugs if necessary. No study was powered to detect a significant difference in proven invasive fungal infections between the two drugs. One study reported a reduction of fungal-related mortality in the itraconazole arm (fluconazole 9/12, 75%, vs. itraconazole 5/11, 45%; P=0.154). Results - Meta-Analysis: The incidence of proven invasive fungal infection from all studies and arms was 4.1% and 8.3% if suspected infections were included. The reduction in the incidence of proven breakthrough invasive mycosis was significant (Table 1). As in the original analysis, the relative risk is reduced only in the group provided with itraconazole solution and with a relative risk reduction of 46%. Results - Itraconazole vs. Fluconazole: Table 2 reports a comparison of itraconazole solution vs. fluconazole for different relevant outcomes. There is a significant superiority of itraconazole for the reduction of all proven invasive fungal infections and for invasive Aspergillus infections and reductions are in the same range but not significant for the other outcomes. Conclusions: Itraconazole is still and significantly superior to its comparators, including fluconazole, in reducing the rate of breakthrough invasive fungal infections. This effect is only seen with the itraconazole oral or intravenous solution (at least 400 mg/d) which also reduce the rate of proven invasive Aspergillus infections. Table 1: Incidence of proven invasive fungal infections Subgroup No. Pts (Trials) Relative Risk 95%CI P All studies 3846 (15) 0.62 0.45–0.77 0.003 Itraconazole capsules 735 (5) 0.93 0.51–1.69 0.81 Itraconazole solution 3111 (10) 0.54 0.37–0.77 0.0008 Table 2: Comparison of itraconazole solution vs fluconazole (proven only) Outcome No. of trials Itraconazole (n/N) Fluconazole (n/N) Relative Risk 95%CI P Abbrev.: n= pts. with event; N=total pts. Invasive fungal infections 6 23/883 43/874 0.52 0.32–0.84 0.008 Invasive yeast infections 6 9/851 16//854 0.56 0.25–1.24 0.15 Invasive Aspergillus infections 5 12/850 24/853 0.50 0.26–0.98 0.04 Fungal-related Mortality 4 20/754 31/754 0.64 0.38–1.09 0.10

Invasive Fungal Infection in Febrile Patients with Hematologic Malignancies Undergoing Chemotherapy in Iran

2019 ◽  
Vol 19 (3) ◽  
pp. 302-307 ◽  
Author(s):  
Saba Sheikhbahaei ◽  
Alireza Mohammadi ◽  
Roya Sherkat ◽  
Alireza Emami Naeini ◽  
Majid Yaran ◽  
...  
Keyword(s):  
Blood Culture ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Hematologic Malignancy ◽  
Hematologic Malignancies ◽  
Fungal Species ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Severe Neutropenia ◽  
Candida Spp

Background: Patients with hematological malignancies undergoing cytotoxic chemotherapy are susceptible to develop invasive fungal infections particularly Aspergillus and Candida spp. Early detection of these infections is required to start immediate antifungal therapy and increase the survival of these patients. Method: Our study included consecutive patients of any age with hematologic malignancies who were hospitalized to receive chemotherapy and suffer from persistent fever (rectal temperature >38.5°C) for more than 5 days despite receiving broad-spectrum antibiotics. A whole blood sample was taken and sent for blood culture. PCR was also conducted for Aspergillus and Candida species. Results: One hundred and two patients were investigated according to the inclusion criteria. The most common hematologic malignancy was AML affecting 38 patients (37.2%). Six patients were diagnosed with invasive fungal infections (A. fumigatus n=3, C. albicans n=2, A. flavus n=1) by PCR (5.8%) while blood culture showed fungus only in 1 patient. Three more cases were known as probable IFI since they responded to antifungal therapy but the PCR result was negative for them. AML was the most prevalent malignancy in IFI patients (83.3%) and odds ratio for severing neutropenia was 21.5. Odds for each of the baseline characteristics of patients including gender, age>60, diabetes mellitus, previous IFI, history of using more than 3 antibiotics, antifungal prophylaxis, episodes of chemotherapy> 8 and chemotherapy regimen of daunarubicin+cytarabine were calculated. Conclusion: We found that multiplex real-time PCR assay is more accurate than blood culture in detecting fungal species and the results are prepared sooner. Among all factors, the only type of cancer (AML) and severe neutropenia, were found to be risk factors for the development of fungal infections in all hematologic cancer patients and previous IFI was a risk factor only AML patients.

A Strategy For Early Diagnosis Of Invasive Mold Infections In Children With Hematologic Malignancies

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2959-2959
Author(s):  
Shannon Mitchell Cohn ◽  
Hanumantha R. Pokala ◽  
David Leonard ◽  
Tamra Slone ◽  
Martha M. Stegner ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Hematologic Malignancies ◽  
Invasive Fungal Infections ◽  
Nasal Endoscopy ◽  
Recurrent Fever ◽  
Fungal Sinusitis ◽  
Protocol Group ◽  
Screening Protocol ◽  
Neutropenic Patients ◽  
Invasive Mold Infections

Abstract Infections with invasive molds are an important cause of morbidity and mortality with published mortality rates of 21-48% among pediatric cancer patients infected by these organisms. Diagnosing invasive fungal infections is difficult because signs and symptoms are non-specific, and delays in diagnosis limit successful debridement of infected tissues. Despite this, there are no uniform guidelines for the diagnosis of invasive fungal infections. The deaths of three teens, at our institution, with leukemia and widespread mold, lead to the creation of a screening protocol for invasive fungal infection in November 2006. Neutropenic patients with persistent fever at 5 days or recurrent fever after defervescing were evaluated with a non-contrast computed tomography (CT) of the chest, abdominal ultrasound, and nasal endoscopy, performed at the bedside, by an otorhinolaryngologist. Initially the screen included CT of the abdomen, but the proclivity of mold for solid organ involvement supported the use of ultrasound as a screening tool. Additional studies were obtained as clinically indicated. To determine the impact of this screening protocol on mortality associated with invasive mold, we performed a retrospective chart review of patients receiving intensive therapy for hematologic malignancies from 2004-2011 who were diagnosed as having proven, probable, or possible invasive mold (candida excluded) infections (N=52) using the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. Of the 20 mold infections in the pre-protocol group, 14 were classified as proven, 6 as possible. Among the 32 infections in the post-protocol group, 22 were proven, 4 probable, and 6 possible. Organisms included Aspergillus, Bipolaris, Curvalaria, Exserohilum, Fusarium, Rhizopus, and Scedosporium. Clinically indicated evaluations among the 20 patients in the pre-protocol group included, 16 chest CTs, 20 abdominal CTs or ultrasounds, and 7 underwent evaluation of their sinuses by direct nasal endoscopy. The lungs were the most common site of infection, with involvement detected in 15/20 patients (75%). Five patients (25%) had sinus involvement; in 1 patient this was the only site of disease. All 5 were symptomatic with rhinorrhea, congestion, facial pain, or facial numbness. Of the 32 patients in the post-protocol group, 30 had chest CTs, 32 had abdominal imaging (5 CT, 27 ultrasound), and 31 had direct nasal endoscopy. One patient did not have an ENT evaluation or chest CT because fungal disease was only detected post-mortem, and in 1 patient, cardiovascular instability precluded CT imaging. The lungs were again the most common site affected, with fungal pneumonia seen in 23/32 patients (72%). Fourteen patients (44%) had sinus involvement; in 4 patients this was the only site of disease. Nine patients with sinus involvement had no nasal symptoms or findings on routine physical exam. Mortality specifically associated with invasive mold infection decreased significantly after initiation of the screening protocol. Before implementing the screening protocol, 8/20 patients (40%) who developed invasive mold infections died from the infection; afterward 4/32 (12.5%), (Fisher's exact p=0.04). Prior to routine evaluation of the sinuses by direct nasal endoscopy, 5/20 patients with mold infections had demonstrable disease in the sinuses and all had symptoms referable to sinus disease prior to evaluation. Once direct nasal endoscopy was implemented as part of the screening protocol, 14/32 patients with invasive mold infection were found to have sinus disease; 9 had no symptoms other than fever. Age, gender, race and length of hospital stay did not differ significantly before and after implementing the screening protocol. Before implementation, 8/20 patients (40%) died from all causes; afterward 6/32 (19%), (Fisher's exact p=0.12). A screening protocol for the evaluation of neutropenic patients with persistent or recurrent fever led to early detection of invasive fungal infections in patients with hematologic malignancies and a significant decrease in infection associated mortality. Non-invasive, direct nasal endoscopy, performed at the bedside, is an effective tool for diagnosis of invasive fungal sinusitis and often detects fungal sinusitis before specific symptoms develop. Disclosures: No relevant conflicts of interest to declare.

Cost-Effectiveness of Itraconazole for the Prophylaxis of Invasive Fungal Infections for Neutropenic Patients; a Study for 3 European Countries.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3133-3133
Author(s):  
Maarten J. Postma ◽  
Robin de Vries ◽  
Harriet Christopherson ◽  
Sarah Howells ◽  
Keith Tolley ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Length Of Stay ◽  
The Netherlands ◽  
Cost Saving ◽  
Fungal Infections ◽  
Hematologic Malignancies ◽  
Invasive Fungal Infections ◽  
Invasive Infection ◽  
Economic Point ◽  
Neutropenic Patients

Abstract Background: Invasive fungal infections present a leading cause of mortality and morbidity in neutropenic patients treated for hematologic malignancies. As the diagnosis and management of invasive fungal infections is difficult, effective antifungal prophylaxis is desirable. Itraconazole is a broad spectrum antifungal agent with activity against Candida species as well as Aspergillus species, whereas fluconazole primarily targets Candida. There is no published data comparing cost-effectiveness of both antifungal agents. Objective: To asses the cost-effectiveness of itraconazole compared with (i) prophylactic fluconazole and with (ii) no prophylaxis in the prevention of invasive fungal infections in Germany, the Netherlands and the UK. Methods: A probabilistic decision model was designed to evaluate the incremental cost-effectiveness of itraconazole versus fluconazole and versus no prophylaxis (see Figure). Baseline risks for invasive fungal infections and risk reductions for itraconazole (>200mg/day) and fluconazole (400mg/day PO or 200mg/day IV) were taken from studies recently published in two meta-analyses. Costs were evaluated from the health care perspective. Drug acquisition costs for the two prophylactic regimens were calculated using 2003 prices. We estimated the increase in the length of stay as a result of an invasive infection using local or national databases and costed this using reference prices. Results: The meta-analysis revealed that itraconazole is effective in averting invasive fungal disease, in particular aspergillosis. The mean increase in the length of stay for invasive fungal infections was estimated at 9.3 days (rather similar for all 3 countries). As an illustration for our findings: in the Netherlands, itraconazole prophylaxis was expected to be cost-saving compared to fluconazole and provided limited extra costs compared to no prophylaxis at all. Cost-effectiveness was €470 per invasive infection averted for the itraconazole compared to no prophylaxis (95%-CI ranging from cost-saving to €5926 per infection averted). Other country-specific results will be presented at the conference. Discussion & Conclusions: Our study shows that itraconazole prophylaxis is effective and is clinically likely to result in cost-savings or provide an acceptable cost-effectiveness. Itraconazole should be the first choice in the prophylaxis of invasive fungal infections in neutropenic patients with hematologic malignancies, from the clinical and economic point of view. Figure Figure

scholarly journals Cost Analysis of the Use of Voriconazole, Posaconazole and Micafungin in the Primary Prophylaxis of Invasive Fungal Infections in Recipients of Allogeneic Hematopoietic Stem Cell Transplants

10.36469/9832 ◽  
2015 ◽  
Vol 3 (2) ◽  
pp. 153-161
Author(s):  
Santiago Grau ◽  
Carlos Solano ◽  
Carol García-Vidal ◽  
Isidro Jarque ◽  
Jon A. Barrueta ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cost Analysis ◽  
Hematopoietic Stem Cell ◽  
Fungal Infections ◽  
Primary Prophylaxis ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Efficacy Rate ◽  
Hematopoietic Stem ◽  
The Cost

Objectives: Compare the cost of the primary prophylaxis of invasive fungal infections (IFI) with voriconazole, posaconazole, and micafungin in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) in hospitals of the National Health System (NHS) in Spain. Methods: A cost analysis was made for 100 days and 180 days of prophylaxis and a decision tree model was developed. The efficacy rate of IFI prophylaxis and survival rate with liposomal amphotericin B treatment of prophylaxis failures were obtained from randomized trials and a meta-analysis of mixed treatment comparisons. The model simulation was interrupted with IFI treatment (prophylaxis failures). The costs of medication and its intravenous administration in the hospital (in the case of micafungin) were considered. Results: In the non-modeled analysis, the savings per patient of prophylaxis with voriconazole ranged from €1,709 to €9,655 compared with posaconazole oral solution, from €1,811 to €9,767 compared with posaconazole gastro-resistant tablets and from €3,376 to €7,713 compared with micafungin. In the modeled analysis, the mean cost per patient of the prophylaxis and treatment of IFIs was €6,987 to €7,619 with voriconazole, €7,749 with posaconazole, and €22,424 with micafungin. Therefore, the savings per patient of prophylaxis with voriconazole was €130 to €3,664 and €11,132 to €30,374 compared with posaconazole and micafungin, respectively. The result remained stable after modification of the number of days of antifungal prophylaxis and the cost of antifungal treatment of failures. Conclusion: Taking into account this model, antifungal prophylaxis with voriconazole in recipients of hematopoietic progenitor transplants, compared with posaconazole or micafungin, may represent savings for hospitals in Spain.

scholarly journals Clinical Experience of Antifungal Combination Therapy for Invasive Fungal Infections in Pediatric Hematological Malignancy Patients

2021 ◽  
Author(s):  
Saliha Kanık Yüksek ◽  
Aslınur Özkaya Parlakay ◽  
Belgin Gülhan ◽  
Neşe Yaralı ◽  
Namık Yaşar Özbek ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Total Mortality ◽  
Complete Response ◽  
Hematologic Malignancies ◽  
Invasive Fungal Infections ◽  
Attributable Mortality ◽  
Combination Regimen ◽  
Pediatric Leukemia

Background: The role of combination regimens in the treatment of invasive fungal infections (IFI) in patients with hematologic malignancies remains unclear. This study was aimed to demonstrate experience data about combined antifungal therapy (CAT) in pediatric IFI patients with haematological malignancies. Methods: Between January 2014 and December 2017, a total of 33 IFI episodes in 28 patients with hematological malignancies were analyzed retrospectively. Results: Of the patients (19 with acute lymphoblastic leukemia, and 9 with acute myeloblastic leukemia), 21 (75%) had leukemia relapse and 7 (25%) had remission. IFI was classified as possible in 26 (78.8%) episodes, probable in 5 (15.1%) episodes, and proven in 2 (6.1%) episodes. LamB (%50) was the most preferred agent in monotherapy. Mean duration of monotherapy was 12.84 ± 4.28 (5-24) days. LamB plus voriconazole (54.5%) were the most common combination preference in CAT. Mean duration of CAT was 42.36 ± 36.4 days, and unchanged according to combination regimen type (p = 0.571). Total mortality rate and IFI attributable mortality rate were 60.7% vs 76.5%. Mortality rate was significantly higher in patients with relapse (p = 0.006). Complete response was obtained in 81.8% of surviving patients. Duration of neutropenia and CAT, and recovery time were not found statistically different in the episodes with/without death and according to relapse or remission status. Side effects due to CAT use were observed quite low level. Conclusion: CAT has been found to be safe in IFI episodes of pediatric leukemia. The result will contribute to the data about combined antifungal use in daily clinical practice in pediatric haematological patients with IFI.

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