Frequency Of Invasive Fungal Infections Research Articles

Risk of Invasive Fungal Infections in Patients With Chronic Lymphocytic Leukemia Treated With Bruton Tyrosine Kinase Inhibitors: A Case-Control Propensity Score-Matched Analysis.

Prior reports have suggested a possible increase in the frequency of invasive fungal infections (IFIs) with use of a Bruton tyrosine kinase inhibitor (BTKi) for treatment of chronic lymphoid malignancies such as chronic lymphocytic leukemia (CLL), but precise estimates are lacking. We aim to characterize the prevalence of IFIs among patients with CLL, for whom a BTKi is now the first-line recommended therapy. We queried TriNetX, a global research network database, to identify adult patients with CLL using the International Classification of Diseases, Tenth Revision code (C91.1) and laboratory results. We performed a case-control propensity score-matched analysis to determine IFIs events by BTKi use. We adjusted for age, sex, ethnicity, and clinical risk factors associated with an increased risk of IFIs. Among 5358 matched patients with CLL, we found an incidence of 4.6% of IFIs in patients on a BTKi versus 3.5% among patients not on a BTKi at 5 years. Approximately 1% of patients with CLL developed an IFI while on a BTKi within this period. Our adjusted IFI event analysis found an elevated rate of Pneumocystis jirovecii pneumonia (PJP) (0.5% vs 0.3%, P = .02) and invasive candidiasis (3.5% vs 2.7%, P = .012) with the use of a BTKi. The number needed to harm for patients taking a BTKi was 120 and 358 for invasive candidiasis and PJP, respectively. We found an adjusted elevated rate of PJP and invasive candidiasis with BTKi use. The rates are, however, low with a high number needed to harm. Additional studies stratifying other IFIs with specific BTKis are required to identify at-risk patients and preventive, cost-effective interventions.

Invasive fungal infections in patients with multiple myeloma: a possible growing problem in hematology and infectious diseases.

Multiple myeloma is among the most common hematological malignancies and is characterized by a strong susceptibility to infections primarily bacterial and viral and, to a much lesser extent, fungal. There appears to be a slightly increasing frequency of invasive fungal infections. This is attributed to the use of different combinations of newer drugs and patients' exposure to increasing therapeutic lines, and thus to risk factors for invasive fungal infections, especially severe and long-term neutropenia. Novel immunotherapy modalities including bispecific antibodies and chimeric antigen receptor T-cell therapy are being introduced for the treatment of relapsing-refractory forms of the disease. Consequently, in the near future, it can be expected that myeloma patients will exhibit a significantly increased frequency of invasive fungal infections. Therefore, we must carefully monitor all epidemiological trends related to invasive fungal infections in patients with multiple myeloma, both in clinical studies and in real life. This will help us learn to prevent fungal infections, as well as quickly recognize and treat them to reduce their impact on patients' morbidity and mortality. In this review article, we describe in detail the epidemiological characteristics of invasive fungal infections in myeloma patients, the risk factors for these infections, and the treatment and prevention options.

From Widespread to Tailored Antifungal Prophylaxis in Lymphoma Patients Treated with CD19 CAR T- Cell Therapy: Less Is Better

Introduction: Invasive fungal infections (IFI) are a major threat in patients with hematological malignancies with substantial associated morbidity. Patients who receive CD19 CAR T-cell therapy have multiple immune defects that may predispose them to IFI. However, the role and duration of antifungal prophylaxis in this population is debated. Methods: This retrospective study at Memorial Sloan Kettering Cancer Center (MSK) describes the characteristics of antifungal prophylaxis and the frequency of IFI after CD19 CAR T-cell therapy in patients with R/R B-cell lymphoma. Two groups of patients were analyzed. Group A (2016-2020): patients primarily received fluconazole, as clinically indicated, regardless of clinical risk profile; Group B (2020-2023) standard guidelines were established in 2020 with antifungal prophylaxis recommended only in high-risk patients with prolonged neutropenia (≥ 3 weeks), those on systemic steroids (≥0.5 mg/kg/day of prednisone equivalent) for ≥ 3 days, or in patients with previous IFI; patients were treated based on a more restrictive mold-active and patient-tailored prophylactic strategy. Results: Three hundred thirty-two patients treated with CAR T-cell therapy for R/R lymphoma between 2016 and 2023 were analyzed. Group A was comprised of 144 patients, whereas group B had 188 patients. Patients' characteristics are described in Table 1. Overall antifungal prophylaxis was prescribed in 95 (66.4%) and 58 (30.9%) patients in group A and B, respectively. While fluconazole was most frequently given in both groups, there was 50% less use in group B (Figure 1). Anti-mold azoles were prescribed in 8.4% of group A patients, whereas for group B, it increased to 34.5%. In group A, a switch to another antifungal was observed in 42 (29%) patients, mainly to micafungin because of transaminitis with azoles. In group B, 21 (11.2%) patients switched their first antifungal drug, mainly from fluconazole or micafungin to a mold-active agent following updated guidelines. Median duration of grade IV neutropenia was 9 days (range 1-93) for group A and 12 days (range 1-90) for group B. Grade IV neutropenia was present at the start of prophylaxis in 30 (31.5%) patients in group A and 30 (51.7%) patients in group B. In the subgroup of patients without prophylaxis, only 13% in group A and 4% in group B were neutropenic. Bridging therapy was administered in 70% of patients in group A and 80% in group B. IFI infections after CAR T-cell therapy were rare: one patient had cryptococcal meningoencephalitis in group A (0.7%) and one had invasive aspergillosis in group B (0.5%), both on micafungin prophylaxis, not effective on molds and cryptococcus. These results show better rates for IFI compared to the FDA adverse events reporting system (FAERS) database: which is 3.1% considering the same CAR-T products. All-cause mortality was similar between both groups (A: 29.8% vs B: 35.7%). Conclusion: This large single-center cohort of R/R lymphoma patients after CAR T-cell therapy offers a valuable snapshot of two different antifungal prophylactic approaches with remarkably low rates of IFI in both strategies, even after the 2020 guideline update with more restrictive antifungal use. Given the risk of toxicity, drug-drug interactions, and concerns for emerging antifungal resistance with azoles, a restrictive prophylactic strategy seems the best choice in this setting.

Invasive Fungal Infections in Under-Five Diarrheal Children: Experience from an Urban Diarrheal Disease Hospital

Invasive fungal infections (IFIs) are opportunistic, especially in immunocompromised and hospitalized patients. Children with IFIs are more vulnerable to a fatal outcome. For early diagnosis and treatment, knowledge of the spectrum and frequency of IFIs among children is prerequisite. In this prospective observational study, we enrolled 168 children of 2–59 months old of either sex from March 2018 to December 2019 admitted to the Dhaka hospital, icddr,b. Study participants with suspected IFIs were with or without severe acute malnutrition (SAM) along with sepsis/pneumonia and fulfilled any of the following criteria: (i) failure to respond to injectable antibiotics, (ii) development of a late-onset hospital-acquired infection, (iii) needed ICU care for >7 days, (iv) took steroids/antibiotics for >2 weeks before hospitalization, and (v) developed thrush after taking injectable antibiotics. The comparison group included non-SAM (weight-for-length Z score ≥ −2) children with diarrhea and fever <3 days in the absence of co-morbidity. We performed real-time PCR, ELISA, and blood culture for the detection of fungal pathogen. Study group children with SAM, positive ELISA and PCR considered to have a IFIs. In the study group, 15/138 (10.87%) children had IFIs. Among IFIs, invasive candidiasis, aspergillosis, histoplasmosis detected in 6 (4.53%), 11 (7.97%), and 1 (0.72%) children, respectively, and (3/15 [2.17%]) children had both candidiasis and aspergillosis. Children with IFIs more often encountered septic shock (26.7% vs. 4.9%; p = 0.013) and had a higher death rate (46.7% vs. 8.9%; p < 0.001) than those without IFIs. IFIs were independently associated with female sex (OR = 3.48; 95% CI = 1.05, 11.55; p = 0.042) after adjusting for potential confounders. Our findings thus implicate that, malnourished children with septic shock require targeted screening for the early diagnosis and prompt management of IFIs that may help to reduce IFIs related deaths.

Incidence of Breakthrough Fungal Infections in Acute Myeloid Leukemia Patients Receiving Low Intensity Therapy in the Upfront and Relapsed/Refractory Setting

Introduction: New treatment strategies with low intensity therapy have emerged for acute myeloid leukemia (AML) patients who are not candidates for intensive therapy. To date, there is limited data on the frequency of invasive fungal infections (IFIs) in patients treated with low intensity regimens, and there is no consensus on the most appropriate prophylactic antifungal agent to use in either the newly diagnosed or relapsed/refractory setting. At our institution, fluconazole is the prophylactic antifungal agent of choice for neutropenic patients receiving low intensity therapy, however the appropriateness of fluconazole is being questioned due to the depth and duration of neutropenia observed in these patients. Rates of breakthrough IFIs need to be better characterized to optimize antifungal prophylaxis in this patient population.Methods: This is a retrospective review of AML patients treated with low intensity therapy from January 2017 through May 2020 for both newly diagnosed and relapsed/refractory disease. Patients were included if they received fluconazole as prophylaxis during periods of neutropenia and received at least two cycles of low intensity treatment. Low intensity regimens included hypomethylating agent (HMA) monotherapy or a combination of venetoclax with either a HMA or low dose cytarabine (LDAC). Any patient with a contraindication to fluconazole or those who received prophylaxis with an alternative antifungal agent (i.e. posaconazole, voriconazole, isavuconazole, and micafungin), history of previous IFI, or history of a stem cell transplant were excluded. The primary objective was to determine the incidence of breakthrough IFIs. The secondary objective was to further characterize IFI occurrences as possible, probable or proven using criteria defined by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC). An occurrence of IFI was defined as receipt of any systemic antifungal agent, aside from fluconazole, for four or more days for suspected IFI. Patients were evaluated for antifungal escalation from the time of low intensity treatment initiation through 30 days after treatment discontinuation.Results: Eighty encounters were included for analysis. The median age of the cohort was 73 years (interquartile range [IQR] 67 - 80) and 70% of patients were newly diagnosed (n = 56). HMA/venetoclax was the most commonly utilized regimen (66%, n = 53) followed by HMA monotherapy (29%, n = 23) and LDAC/venetoclax (5%, n = 4). The median number of treatment cycles was 5 (IQR 3 - 9). Nineteen IFI occurrences (24%) were documented, with ten in the newly diagnosed population (18%, n = 10/56) and nine in relapsed/refractory patients (38%, n = 9/24). There were no proven, four probable and fourteen possible IFIs. Of the four probable infections, three were in relapsed/refractory patients. Median times to IFI onset from low intensity treatment initiation were 82 and 80 days for the newly diagnosed and relapsed/refractory populations, respectively. Of the patients with an IFI, 15/19 (79%) were neutropenic at IFI onset.Conclusions: IFIs are a serious complication of AML as these infections are associated with significant morbidity and mortality. With 24% of patients requiring antifungal escalation, our study demonstrates that breakthrough IFIs remain a concern for patients receiving low intensity therapy and fluconazole prophylaxis. Incidence of IFI was higher in the relapsed/refractory setting, which is an expected finding as these patients are typically subjected to multiple lines of therapy, leading to poor hematopoietic reserves and more prolonged periods of profound neutropenia. Additional analysis is needed for determination of risk factors, beyond relapsed/refractory disease, to potentially identify subsets of patients at highest risk of developing IFIs as these patients may benefit from closer monitoring and longer durations of prophylaxis. Given these findings, it is reasonable to consider prophylaxis with an extended spectrum antifungal agent against molds for patients receiving low intensity therapy. [Display omitted] DisclosuresEllis: Rafael Pharmaceuticals: Consultancy. Pardee: Karyopharm Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rafael Pharmaceuticals: Consultancy, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Pharmacyclics: Speakers Bureau.

The Emergence of Echinocandin-Resistant Candida glabrata Exhibiting High MICs and Related FKS Mutations in Turkey.

The frequency of invasive fungal infections shows a rising trend as well as a high morbidity and mortality. Among the causative agents, a shift toward the non-albicans Candida species including Candida glabrata species complex is being observed in several centers. Echinocandin resistance is increasingly published; however, isolates presenting with an in vitro resistance have not yet been reported from Turkey. We, herein, report the first FKS mutant and phenotypically echinocandin-resistant C. glabrata clinical strains from a single center in Turkey. In a 43-year-old female patient, several enterocutaneous fistulae developed after a long term hospitalization period and several complicated surgeries. She eventually required parenteral nutrition via a tunneled central venous catheter (CVC). Following a number of bacteremic and fungemic episodes as well as intensive antimicrobial interventions (including fluconazole, caspofungin and anidulafungin), a CVC-related candidemia caused by C. glabrata was detected. The isolated strain yielded high minimum inhibitory concentration (MIC) values for echinocandins and was categorized as resistant. A resistance-related mutation was detected in FKS2 HS1 (D666V). Blood cultures remained negative after the removal of the CVC and treatment with caspofungin and high-dose fluconazole. Following this first case, two additional C. glabrata strains with high echinocandin MICs were isolated from the urine cultures of two unrelated patients from different wards with different mutations in FKS2 HS1 (S663P and delF659). Our findings indicate that routine antifungal susceptibility testing is crucial and underlines the need for attention for the increasing trend of acquired echinocandin resistance in C. glabrata.

Trichosporon Asahii Infection Mortality in Pediatric Oncology Patients: A Report of Six Cases

The frequency of invasive fungal infections in patients with hematological malignancies has dramatically increased over the last two decades mainly due to increased use of more intensive therapies. Trichosporon spp is an uncommon but frequently fatal invasive yeast infection that occur predominantly in patients with hematological malignancies. Trichosporon Asahii (T. Asahii) is the most common genus isolated and is reported to cause serious invasive infections in adults and infrequently in children. Voriconazole (VCZ) remains the antifungal drug of choice. We report six pediatric patients with acute lymphoblastic leukemia (2), acute myeloblastic leukemia (2), lymphoblastic lymphoma (1) who developed invasive T. Asahii infection during the early phases of CTR. The outcome was poor. Five patients have died as a result of the infection after a stormy clinical course and prolonged stay in the pediatric intensive care unit despite receiving proper antifungal treatment. Only one patient survived the infection without serious sequalae. J Microbiol Infect Dis 2020; 8(3):167-172.

Invasive Fungal Infections in People Living with HIV/AIDS

The increased incidence of invasive and opportunistic mycoses is probably related to the growth of the immunocompromised population, such as people living with HIV. This study is a literature review that aims to analyze the frequency of invasive fungal infections in people living with HIV. In most studies evaluated, Pneumocystis pneumonia was the most frequent invasive fungal infection among people living with HIV, and cryptococcosis was the second most frequent. Invasive fungal infections are associated with greater morbidity and mortality in people living with HIV. The most important highlighted information is that the lack of epidemiological data on fungal infections in the studied populations was reported by most studies. Therefore, there is a need for further studies to assess the frequency of invasive fungal infection in people living with HIV, which may serve as subsidies for the implementation of strategies for the prevention and management, with a consequent increase in the quality of life and reduction of morbidity/mortality in this population.

Fatal Invasive Gastrointestinal Fungal Infection in Three Non-immunocompromised Patients.

The importance and frequency of invasive fungal infections in different organs, including the gastrointestinal tract, has increased due to excessive use of aggressive immunosuppressive and immunomodulatory drugs in malignant diseases and organ transplantations as well as increased infections with the human immunodeficiency virus (HIV). Fungal infections in the small intestine or colon are usually part of a disseminated disease process and reach these organs through the bloodstream. Two of the patients were infants 10 and 15 days of age, while one was 23 years old. Patients presented with abdominal pain, intestinal obstruction, and rectal bleeding. Hirchsprung disease was suspected in the two infants. In the adult patient, the diagnosis was unclear. Mucormycosis was diagnosed in two out of three cases. It is imperative for clinicians to consider invasive mycosis in the differential diagnosis in patients of all ages with treatment-resistant severe abdominal pain, diarrhea and fever.

A Low-Density Protein Microarray Device for Detecting Three Antibodies Associated with Invasive Fungal Infections

The frequency of invasive fungal infections has risen dramatically in recent years, and early and accurate diagnosis of these infections is important for appropriate use of antifungal agents. The value of serological tests is apparent, but they suffer from disadvantages, such as being time-consuming and their inability to produce simultaneous results. Protein microarrays are a convenient technology that can be used to perform high-throughput antibody detection and enable the monitoring of different antibodies simultaneously. We constructed a low-density microarray using purified recombinant enolase (Eno) fructose-bisphosphate aldolase (Fba1) from Candida and thioredoxin reductase (TR) from Aspergillus fumigatus as immobilized antigens. Following optimization of microarray construction and serum testing, we investigated the sensitivity, repeatability, and stability of the assay using sera from patients with invasive Candida and/or Aspergillus infections and control subjects. Sera from patients with invasive candidiasis (IC) were subjected to low-density microarray assay for detection of two antibodies from Candida and one antibody from A. fumigatus. Our results indicated a sensitivity and specificity of 67.6% and 96.5% for anti-Eno and 64.8% and 90.3% for anti- Fba1 antibodies, respectively. The combined detection of anti-Eno and anti- Fba1 returned a sensitivity of 81%, and in invasive aspergillosis (IA) patients, the sensitivity and specificity of detection were 71.4% and 98.2%, respectively, for the anti-TR antibody. The low-density protein microarray assay developed in this study was capable of detecting three antibodies against two fungi simultaneously, demonstrating its potential value in diagnosing IC and IA.

Frequency of Invasive Fungal Infections in Patients Undergoing Allogeneic Stem Cell Transplantation Conditioned with Reduced BUCY2 and Antifungal Prophylaxis with Low Dose Amphotericin B

Introduction: Invasive fungal infection (IFI) is a major cause of morbidity and mortality in patients with allogeneic stem cell transplantation (allo-SCT). One well-known risk factor for fungal infection includes bowel mucosal damage due to conditioning chemotherapy regimens. The use of reduced-intensity conditioning may favorably impact the epidemiology of IFI after allo-SCT. Data for IFI in this population are scarce. On the other hand, despite the low incidence of IFI with the use of the new antifungal drugs, the costs remain to be high and sometimes unaffordable for the patients.Objective: To analyze the frequency of invasive fungal infections in patients who underwent stem cell transplantation conditioned with reduced BUCY2, at INCMNSZ, from November 1998 to December 2014.Material and methods: A retrospective analysis was performed in 58 patients receiving reduced BUCY2 as part of their SCT conditioning regimen. Most of the patients received antifungal prophylaxis with low dose of amphotericin B (˂20 mg/day) during the neutropenia following transplant.Results: Fifty eight patients undergoing allo-SCT with conditioning regimen reduced BUCY2, from November 1998 to December 2014, were included. Patients (male, 57%) had a median age of 39 years (range 17-67). The median follow-up was 90 months. The patients had a following range of underlying diseases: myelodysplastic syndrome (n=14, 24.1%), chronic myeloid leukemia (CML, n=14, 24.1%), acute myeloid leukemia (AML, n=12, 21%), acute lymphoblastic leukemia (LLA, n=10, 17%), lymphomas (n=3, 5.2%), myelofibrosis (n=2, 3.4%), or others (n=3, 5.2%). All patients were conditioned with 12mg/kg of busulfan and 80mg/kg of cyclophosphamide. 22% of patients presented mucositis grade III-IV. 85% (50/59) of patients received fungal prophylaxis with low dose amphotericin B. Four patients (6.8%) presented IFI during the first 100 days post-transplant, and one (1.7%) presented late IFI. The mortality secondary to IFI was 5%. Transplant related mortality (TRM) was 17%.Conclusion: From the beginnings of our transplant program we have had a low incidence of IFI and low TRM, with the prophylactic use of low dose amphotericin B and the modified conditioning regimen reduced BUCY2, compared to the reported literature. The use of reduced BUCY2 and low dose amphotericin B can be cost-effective in medical centers in developing countries. DisclosuresNo relevant conflicts of interest to declare.

Frequency and Therapeutic Outcomes of Culture Positive Invasive Fungal Infections at a Tertiary hospital in Lagos, Nigeria.

Invasive fungal infections (IFIs) are life threatening, with high morbidity and mortality. Diagnosis is challenging in our environment where there is paucity of data. The majority of laboratories in the region employ only conventional diagnostic tests. This report documents the frequency and therapeutic outcomes of invasive fungal infections diagnosed at the Lagos University Hospital over a fourteen month period. From May 2012 to July 2013, all cases from consults sent to the clinical microbiologists for review and patients with positive samples were identified from the mycology laboratory registers. Hospital based frequency of Invasive Fungal Infections was 42.5%. Patients' ages ranged from 5 days to 71 years with a median of 29 years ±20.6 SD. There were 2 cases of cryptococcal meningitis, 7 cases of candidaemia, 1 case of mucormycosis, 3 cases of invasive aspergillosis and 4 cases of fungal keratitis. Causative organisms were Candida albicans , non Candida albicans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Fusarium scolani, Scedosporium apiospermiun, and Cryptococcus neoformans. There was an IFI case fatality rate of 47.06%. Serious fungal infections exist in our environment; however they are under diagnosed due to lack of diagnostic acumen; this impacts negatively on the management of the groups of patients at risk for these infections. Keywords: Invasive fungal infections; mucormycosis; candidaemias; keratitis; aspergillosis; cryptococcal meningitis; Lagos, Nigeria.

Micafungin as antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: results of different dosage levels in clinical practice

Micafungin has been approved for the prophylaxis of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Here, we report a single-center experience of three different dose levels regarding efficacy, toxicity, and colonization with Candida ssp. in clinical practice. In total, 150 consecutive adult patients who underwent allo-HSCT received micafungin at a dosage of 50, 100, or 150mg once daily for primary antifungal prophylaxis. Of those patients receiving more than sixd of micafungin prophylaxis, 12/46 (26%), 6/44 (14%), and 9/46 (20%) were switched to empiric antifungal treatment. The frequency of invasive fungal infections (IFIs) according to EORTC criteria did not differ significantly (7/46; 15% vs. 5/44; 11% vs. 5/46; 11%) across the different dosage groups. In the 50-mg group, there was one case of candidemia with C.parapsilosis after 12d of micafungin prophylaxis. In all three groups, micafungin prophylaxis was well tolerated without any case of toxicity-related treatment discontinuation. Renal function was not significantly altered, while increase of bilirubin was mainly due to concomitant ATG application. The incidence of IFIs is similar irrespective of the micafungin dosage while there was a trend toward more frequent change to empiric antifungal treatment as well as oropharyngeal colonization with candida in the lowest dosage group.

Elucidation of Substrate Specificity in Aspergillus nidulans UDP-Galactose-4-Epimerase

The frequency of invasive fungal infections has rapidly increased in recent years. Current clinical treatments are experiencing decreased potency due to severe host toxicity and the emergence of fungal drug resistance. As such, new targets and their corresponding synthetic pathways need to be explored for drug development purposes. In this context, galactofuranose residues, which are employed in fungal cell wall construction, but are notably absent in animals, represent an appealing target. Herein we present the structural and biochemical characterization of UDP-galactose-4-epimerase from Aspergillus nidulans which produces the precursor UDP-galactopyranose required for galactofuranose synthesis. Examination of the structural model revealed both NAD+ and UDP-glucopyranose were bound within the active site cleft in a near identical fashion to that found in the Human epimerase. Mutational studies on the conserved catalytic motif support a similar mechanism to that established for the Human counterpart is likely operational within the A. nidulans epimerase. While the K m and k cat for the enzyme were determined to be 0.11 mM and 12.8 s-1, respectively, a single point mutation, namely L320C, activated the enzyme towards larger N-acetylated substrates. Docking studies designed to probe active site affinity corroborate the experimentally determined activity profiles and support the kinetic inhibition results.

Fungal infections in stem cell transplantation: epidemiology and therapy

Invasive fungal infections (IFIs) are an increasingly important cause of infection-related mortality in stem cell transplantation (SCT). Mortality from IFIs remains high because of diagnostic limitations and has given rise to the concepts of empiric and pre-emptive, as opposed to targeted, antifungal therapy. Data from the 2010 US TRANSET consortium found that Aspergillus (43%) and Candida (28%) were the two most frequently encountered pathogen groups; Zygomycetes and Pneumocystis comprised 8% and 2%, respectively. The frequency of IFIs varies with SCT type with 12 month cumulative incidences highest for matched unrelated SCT and lowest for autologous SCT. Trends in susceptibility to antifungals have identified increasing azole resistance (with cross-resistance) amongst Candid a spp., ampho-tericin B resistance amongst certain moulds and azole resistance in Aspergillus and other moulds. Recommendations for targeted antifungal therapy of yeasts and mould infections of the Infectious Diseases of Society of American, European, and Australian and New Zealand Mycoses Interest Group are similar. Early intervention strategies include empirical therapy which reduces IFIfrequency but has not been shown to reduce mortality and has high costs and drug toxici-ties. Pre-emptive therapy attempts to harness clinical/radiological features in conjunction with fungal biomarkers to detect early disease but its advantage has not been documented.

The prognostic role of hemochromatosis H63D allele in allogeneic hematopoietic stem cell transplantation

Iron overload is considered as a significant cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. The presence of hemochromatosis gene (HFE) mutations might exacerbate iron toxicity in the post-transplant setting. This prospective study was planned to evaluate the genetic spectrum of HFE mutations in Turkish patients undergoing HSCT and the impact of HFE genotype on transplant morbidity and mortality. HFE genotypes of 102 patients [median age, 27.5 years (16-64 years); male/female, 73:29], who underwent allogeneic HSCT, were analyzed. Twenty-two patients were heterozygous and 1 patient was homozygous for the H63D mutation, while the C282Y mutation was observed in none of our patients. The frequency of invasive fungal infections (IFI) was significantly higher in H63D-mutated patients (p=0.004). H63D mutation was identified as an independent risk factor for the development of IFI (p=0.006, OR=0.554, SE=0.208), without an impact on overall survival and transplant-related mortality. The multifactorial iron-overloaded state in HSCT recipients might affect the phenotypic expression of HFE mutations and alter the severity of clinical presentation. The impact of HFE genotype on iron parameters and transplant-related morbidity and mortality should be validated with further studies.

Itraconazole 800 mg for the prophylaxis of fungal infections in patients with acute leukemia and severe neutropenia

Systemic fungal infections and specifically invasive aspergillosis (IA) are associated with a high morbi-mortality rate in patients with hematologic malignancies. Itraconazole kinetic studies show that plasma levels are not satisfactory, even though there is a reduction of the severity in clinical cases. To evaluate the results of oral prophylaxis with high dose itraconazole, 400 mg bid, among patients with adult acute leukemia. Prospective analysis of 93 high risk febrile episodes (with an absolute neutrophil count of less than 500 x mm3 for more 10 days), that occurred in 76 patients. Seventy five percent of episodes occurred in patients with acute myeloid leukemia and 25% in patients with acute lymphoblastic leukemia. Fifty two percent occurred during the induction of chemotherapy. Median duration of severe neutropenia was 21 days (range 10-48). Median duration of itraconazole prophylaxis was 17 days (range 6-34). A low frequency of invasive fungal infections was observed (17%). According to diagnostic criteria, 5% of episodes corresponded to persistent fever , 1% and 11% of episodes, to probable or possible IA, respectively. No confirmed or proven IA was observed. Mortality of IA was 18%. No serious adverse events due to itraconazole were observed. The use of high dose itraconazole prophylaxis in adult patients with acute leukemia and severe neutropenia was associated to low incidence and mortality of invasive mycoses.

Resultados de profilaxis con itraconazol 800 mg/día vía oral en adultos con leucemia aguda y neutropenia de alto riesgo: Hospital del Salvador 2006-2008

Systemic fungal infections and specifically invasive aspergillosis (IA) are associated with a high morbi-mortality rate in patients with hematologic malignancies. Itraconazole kinetic studies show that plasma levels are not satisfactory, even though there is a reduction of the severity in clinical cases.To evaluate the results of oral prophylaxis with high dose itraconazole, 400 mg bid, among patients with adult acute leukemia.Prospective analysis of 93 high risk febrile episodes (with an absolute neutrophil count of less than 500 x mm3 for more 10 days), that occurred in 76 patients.Seventy five percent of episodes occurred in patients with acute myeloid leukemia and 25% in patients with acute lymphoblastic leukemia. Fifty two percent occurred during the induction of chemotherapy. Median duration of severe neutropenia was 21 days (range 10-48). Median duration of itraconazole prophylaxis was 17 days (range 6-34). A low frequency of invasive fungal infections was observed (17%). According to diagnostic criteria, 5% of episodes corresponded to persistent fever , 1% and 11% of episodes, to probable or possible IA, respectively. No confirmed or proven IA was observed. Mortality of IA was 18%. No serious adverse events due to itraconazole were observed.The use of high dose itraconazole prophylaxis in adult patients with acute leukemia and severe neutropenia was associated to low incidence and mortality of invasive mycoses.

Tratamiento combinado de la aspergilosis invasora. ¿Una oportunidad para micafungina?

The frequency of invasive fungal infections, and specifically invasive aspergillosis, has increased in the last few decades. Despite the development of new antifungal agents, these infections are associated with high mortality, ranging from 40% to 80%, depending on the patient and the localization of the infection. To reduce these figures, several therapeutic strategies have been proposed, including combination therapy. Most of the available data on the efficacy of these combinations are from experimental models, in vitro data and retrospective observational studies or studies with a small number of patients that have included both patients in first-line treatment and those receiving rescue therapy; in addition there are many patients with possible forms of aspergillosis and few with demonstrated or probable forms. To date, there is no evidence that combination therapy has significantly higher efficacy than monotherapy; however, combination therapy could be indicated in severe forms of aspergillosis, or forms with central nervous involvement or extensive pulmonary involvement with respiratory insufficiency, etc. Among the combinations, the association of an echinocandin--the group that includes micafungin--with voriconazole or liposomal amphotericin B seems to show synergy. These combinations are those most extensively studied in clinical trials and therefore, although the grade of evidence is low, are recommended by the various scientific societies.

Acute Myelogenous Leukemia Patients Are at Low Risk for Invasive Fungal Infections after High-Dose Cytarabine Consolidations and Thus Do Not Require Prophylaxis

We evaluated the frequency of invasive fungal infections (IFI), the frequency of empirical antifungal use (EAFU), and the efficacy of fluconazole prophylaxis on IFI and EAFU after high-dose cytarabine (HiDAC) consolidations. Twenty-seven acute myelogenous leukemia patients in their first complete remission received 76 cycles of HiDAC (median cycle: n = 3). Fluconazole prophylaxis was administered following 44 cycles (fluconazole group) and not given in 32 cycles (control group). IFI (2 episodes) + EAFU (11 episodes) was observed in 13 of 76 cycles (17%); there was no difference between the fluconazole group and the control group (p = 0.469). Neutropenia duration was <13 days in 89% of the 76 cycles and was similar in the fluconazole and control groups (p = 0.845). Neutropenic fever was observed in 34 of the 76 cycles (45%) and was similar in the fluconazole group and the control group (p = 0.43). Although HiDAC cycle 1 was associated with a shorter neutropenia duration, there was no association between HiDAC cycle numbers and neutropenic fever or IFI + EAFU. HiDAC consolidations resulted in a high rate of neutropenic fever, the lack of an appreciable benefit from EAFU, and rare IFI. Most likely because of the low incidence of IFI, use of fluconazole or another antifungal is not warranted in this setting.