Prevention Of Invasive Fungal Infections Research Articles

Impact of invasive fungal infections in men from a state in southern Brazil: A geospatial analysis.

To analyse the records of male hospitalisation for fungal infections, including their spatial distribution and the main invasive epidemiological and sociodemographic characteristics in the State of Paraná, Brazil. Spatial analysis based on data from male admission records for invasive fungal infections (IFIs) in the State of Paraná, from 2015 to 2019. Data were taken from the hospital records obtained in the Hospital Information System of the Unified Health System, being collected, georeferenced and analysed to infer the existence of autocorrelation with the hospitalisation rates in the state. From 2015 to 2019, there were 385 cases of IFIs in men, being more prevalent in white individuals aged 61-70 years. We observed that the metropolitan, southeast, central-eastern, north-central, northwestern and western regions formed high-high clusters, with regions with a high number of registered cases. In the regression, there was an association with socioeconomic and demographic factors that showed a correlation with the rates of hospitalisation for IFIs. The study draws attention to Paraná as an endemic region for paracoccidioidomycosis, in addition to presenting high rates of nosocomial fungal infections. We also emphasise the importance of compulsory notification in the state and in the country to gain greater control over the incidence and prevalence of cases and to incentivise the creation of public policies for the prevention of IFIs.

Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia

Invasive fungal infection (IFI) prophylaxis is recommended in patients with acute myeloid leukemia (AML) during induction chemotherapy. Posaconazole (POSA) is the recommended agent of choice; however, this medication can be associated with QTc prolongation, hepatotoxicity, and drug-drug interactions. Furthermore, there is conflicting evidence for the role of isavuconazole (ISAV) in this setting as an alternative to POSA. The primary objective of this study was to evaluate the use of ISAV prophylaxis for primary IFI prevention in patients with AML undergoing induction. Additionally, the study investigated the use of ISAV trough concentration monitoring and compared these results to the efficacy of POSA therapeutic drug monitoring (TDM). Other secondary objectives included assessing the rates of toxicities associated with either prophylactic agent. This study analyzed the impact these toxicities had on patient outcomes by examining the need to hold or discontinue therapy. The final endpoint considered the efficacy associated with multiple dosing strategies employed at the study institution. Specifically, this included the use of loading doses or foregoing these when initiating prophylaxis. This was a retrospective, single-center, cohort study. Patients included in this study were adults with AML admitted to Duke University Hospital between June 30, 2016 and June 30, 2021, who received induction chemotherapy and primary IFI prophylaxis for at least 7 days. Exclusion criteria included patients who received concomitant antifungal agents and patients who received antifungal agents as secondary prophylaxis. 241 patients met inclusion criteria with 12 (4.98%) participants in the ISAV group and 229 (95.02%) participants in the POSA group. The IFI incidence in the POSA group was 14.5%, while the ISAV group did not have any occurrences of IFI. No significant difference was found in the rate of IFI occurrence between the two treatment groups (p = 0.3805). Furthermore, it was demonstrated that the use of a loading dose when initiating prophylaxis could impact rates of IFI for this patient population. Due to no difference in incidence, patient specific factors such as concomitant medications and baseline QTc should influence the choice between prophylactic agent.

Efficacy of anti-fungal agents for invasive fungal infection prophylaxis in liver transplant recipients: A network meta-analysis.

At present, there is still a lack of effective invasive fungal prophylaxis therapy in liver transplant recipients (LTRs). This study aimed to analysis the latest evidence on efficacy of current prophylactic anti-fungal therapy, and systematically compare between anti-fungal agents and placebo by a fixed-effects meta-analysis in all randomised controlled trials. A network meta-analysis was performed for invasive fungal infection (IFI) among different agents in 14 randomised controlled trials, in which 10 anti-fungal approaches were identified. Overall, anti-fungal prophylaxis reduced the rate of IFI (RR 0.30, 95% CI 0.18-0.52) and proven IFI (RR 0.27, 95% CI 0.14-0.53) when compared to placebo. In the network meta-analysis, an equivalent reduction in the rate of IFI was observed in fluconazole (OR 4.70, 95% CI 1.22-18.10), itraconazole (OR 5.82, 95% CI 1.10-30.71) and Liposomal amphotericin B (LAmB, OR 5.74, 95% CI 1.29-25.58) groups when compared with placebo. Anidulafungin might be the most effective agents in IFI prevention; however, this superiority did not meet statistically significance. Our study indicated that fluconazole, echinocandins and LAmB are equivalent in efficacy. Of which, fluconazole is recommended for the prevention of IFI in LTRs due to its efficacy, economics and compliance.

P05 The impact of COVID-19 on antifungal stewardship in a UK tertiary teaching hospital: a review of prescribing practices and therapeutic drug monitoring of posaconazole

BackgroundPosaconazole is a triazole antifungal licensed for the prevention of invasive fungal infections (IFI) in haemato-oncology patients and treatment of IFI where first-line therapy has failed. In January 2020 COVID-19 hit the UK, with many NHS services reduced to meet the unprecedented challenges of the pandemic. We audited prescriptions and therapeutic drug monitoring (TDM) of posaconazole and compared the results with an audit conducted pre-COVID-19 to assess the impact of the pandemic on antifungal stewardship (AFS).MethodsInpatients prescribed posaconazole over two 3 month periods (1 October to 31 December 2019 and 2020) at Addenbrooke's Hospital, Cambridge, were identified using an electronic computer system and their records reviewed for demographic, diagnostic and therapeutic data. Posaconazole levels were performed at the national Mycology Reference Laboratory, Bristol, using guide levels of 0.7–3.75 mg/L (prophylaxis) and 1–3.75 mg/L (treatment). The first pre-dose level for each patient was used in analyses. Audit standards included (i) all inpatients on posaconazole to have an indication in local guidelines; (ii) to have the correct loading dose prescribed; (iii) to have a pre-dose level taken (iv) at the correct time (i.e. between Day 3–8) after commencing therapy or a dose change; (v) to have a turnaround time of ≤5 days; and (vi) to stop posaconazole appropriately.ResultsForty-two 42 inpatients received posaconazole in 2020 (49, 2019). In total, 39/42 (93%) patients had an appropriate indication [46/49, (94%), 2019]: 38/40 (95%) for prophylaxis [45/45, (100%) 2019]; 1/2 (50%) for treatment [1/1, (100%) 2019]. In 2020, 34/42 (81%) of patients received the correct loading dose [41/46 (89%), 2019). TDM was performed on 33/42 (79%) patients [46/46 (100%), 2019], 18/42 (43%) 3–8 days after starting [25/46 (54%), 2019] and 3/13 (23%) after a dose change [9/10 (90%), 2019]; 32/33 (97%) of TDM results were reported in ≤5 days [32/46 (70%), 2019]. Posaconazole was stopped in 24/26 (92%) patients who were no longer receiving immunosuppression and/or neutropenia had resolved [23/23 (100%), 2019].ConclusionsDespite the pressures of COVID-19, there were good standards of care with only slight reductions in compliance, with the exception of TDM. This may have reflected the change from face-to-face to virtual meetings with haemato-oncology, as well as representing issues of staff shortages and changes in hospital priorities. Such data have highlighted the usefulness of technology to facilitate AFS, e.g. electronic prescribing order sets, which would provide us with quality assurance in a system that will be facing ongoing pressures from the pandemic for years to come.

Voriconazole in Hematopoietic Stem Cell Transplantation and Cellular Therapies: Real-World Usage and Therapeutic Level Attainment at a Major Transplantation Center

Voriconazole (VCZ) was one of the first mold-active triazoles available; however, its current use among high-risk hematology populations is unknown as the uptake of posaconazole (PCZ) and isavuconazole (ISZ) increases. We evaluated the usage and therapeutic level attainment of VCZ in hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell (CAR-T) therapy patients at our cancer center. Electronic medical records for all adult HCT or CAR-T patients with an order for VCZ, PCZ, or ISV between January 1, 2018, and June 30, 2020, were extracted. Clinical characteristics, VCZ indication, trough VCZ levels, and frequency of VCZ initiation from 6 months before to 6 months after HCT/CAR-T infusion in consecutive HCT/CAR-T recipients within the study period (infusion between July 1, 2018, and January 1, 2020) were assessed. The association between relevant clinical characteristics and the attainment of subtherapeutic or supratherapeutic levels was also evaluated. Of 468 patients prescribed mold-active triazoles, 256 (54.7%) were prescribed VCZ, 324 (69.2%) PCZ, and 60 (12.8%) ISZ; 152/468 (32.5%) treatment regimens were sequentially modified to alternate mold-active triazoles. Among consecutive HCT and CAR-T recipients at our center, evaluated 6 months pre- or post- HCT/ CAR-T, VCZ was commonly initiated before or after allogeneic HCT (102/381, 26.8%), with most use in the first 30 days after stem cell infusion (40/381, 10.5%); VCZ use was less common in autologous HCT (13/276, 4.7%) and CAR-T (10/153, 6.5%). Of 223 VCZ orders that met inclusion for analysis, indications included empiric treatment in 108/223 (48.4%), directed therapy in 25/223 (11.2%), primary prophylaxis in 69/223 (30.9%) and secondary prophylaxis in 21/223 (9.4%). Of 223 eligible VCZ patients, 144 (64.6%) had at least 1 VCZ level measured during the study period; 75/144 (52.1%) had a therapeutic VCZ level (1.0-5.5 mg/L) at the first measurement (median 2.8mg/L [range 0.1-13.5]) at a median of 6 days of therapy, with 26.4% subtherapeutic and 21.5% supratherapeutic; 46/88 (52.3%) were therapeutic at the second measurement (2.1mg/L [0.1-9.9]) at a median of 17 days of therapy; and 33/48 (68.8%) at the third (2.3mg/L [0.1-7.7]) at a median of 29 days. In multivariable analysis of factors associated with sub- or supratherapeutic levels (body mass index ≥30, concurrent omeprazole use, concurrent letermovir use, indication for VCZ, history/timeframe of HCT), the only significant association was lower odds of a supratherapeutic VCZ level among those undergoing HCT within the previous 30 days compared to those without a history of HCT. VCZ continues to remain an important option in the treatment and prevention of invasive fungal infections in an era when alternative oral mold-active triazoles are available. In spite of long-standing experience with VCZ prescribing, therapeutic level attainment remains a challenge.

Cost-Effectiveness of Posaconazole vs. First-Generation Triazoles for the Prevention of Invasive Fungal Infections Among High-Risk Patients With Hematological Malignancies in China.

BackgroundPosaconazole is confirmed to be more effective for preventing invasive fungal infections (IFIs) than first-generation triazoles (fluconazole and itraconazole), but its economic value has not been comprehensively evaluated in China. This study compared the cost-effectiveness of these two antifungal prophylaxis regimens in hematological-malignancy patients at high risk for IFIs from the Chinese healthcare perspective.MethodsA hybrid decision tree and Markov model were built using published data to estimate the total costs and quality-adjusted life-years (QALYs) of antifungal prophylaxis with posaconazole oral suspension and first-generation triazoles. Regimens with an incremental cost-effectiveness ratio (ICER) lower than the threshold of willingness to pay (WTP) were considered cost-effective. One-way and probabilistic sensitivity analyses were performed to assess model robustness. The regional imbalance of economic development and the tablet formulation of posaconazole were considered in the scenario analyses.ResultsIn the base-case analysis, posaconazole oral suspension provided an additional 0.109 QALYs at an incremental cost of $954.7, yielding an ICER of $8,784.4/QALY, below the national WTP threshold of $31,315/QALY. One-way and probabilistic sensitivity analyses showed that the results were robust. Scenario analyses showed that the base-case ICER was consistently below the WTP thresholds of all 31 Chinese provinces, with the likelihood of posaconazole being cost-effectiveness ranging from 78.1 to 99.0%. When the posaconazole oral suspension was replaced by the tablet formulation, the ICER increased to $29,214.1/QALY, still below the national WTP threshold and WTP thresholds of 12 provinces.ConclusionsPosaconazole oral suspension is a highly cost-effective regimen for preventing IFI in high-risk hematological-malignancy patients from the Chinese healthcare perspective. Posaconazole tablets may also be considered in some high-income regions of China.

Transfusable neutrophil progenitors as cellular therapy for the prevention of invasive fungal infections.

The use of mature neutrophil (granulocyte) transfusions for the treatment of neutropenic patients with invasive fungal infections (IFIs) has been the focus of multiple clinical trials. Despite these efforts, the transfusion of mature neutrophils has resulted in limited clinical benefit, likely owing to problems of insufficient numbers and the very short lifespan of these donor cells. In this report, we employed a system of conditionally immortalized murine neutrophil progenitors that are capable of continuous expansion, allowing for the generation of unlimited numbers of homogenous granulocyte-macrophage progenitors (GMPs). These GMPs were assayed in vivo to demonstrate their effect on survival in 2 models of IFI: candidemia and pulmonary aspergillosis. Mature neutrophils derived from GMPs executed all cardinal functions of neutrophils. Transfused GMPs homed to the bone marrow and spleen, where they completed normal differentiation to mature neutrophils. These neutrophils were capable of homing and extravasation in response to inflammatory stimuli using a sterile peritoneal challenge model. Furthermore, conditionally immortalized GMP transfusions significantly improved survival in models of candidemia and pulmonary aspergillosis. These data confirm the therapeutic benefit of prophylactic GMP transfusions in the setting of neutropenia and encourage development of progenitor cellular therapies for the management of fungal disease in high-risk patients.

Antifungal Prophylaxis With Posaconazole in Immunocompromised Children Younger Than 13 Years.

Prophylaxis with posaconazole (PP) is effective in the prevention of invasive fungal infections in immunocompromised adult patients. However, evaluation of its effectiveness and safety in children is limited. The aim of the study was to describe the use of posaconazole as antifungal prophylaxis in children. We reviewed the medical records of immunocompromised patients younger than 13 years with hematologic diseases and post hematopoietic stem cell transplant (HSCT) who received antifungal PP at the Instituto Nacional de Salud del Niño San Borja (INSN-SB) in Lima, Peru, from January 2014 to December 2018. Fifty-six courses of PP were identified in 47 patients with a median age of 7.5 years (IQR, 4-10), 51.6% (n = 24) of whom were female. The main underlying medical conditions were aplastic anemia (n = 19, 33.9%), acute lymphoblastic leukemia (n = 18, 32.1%), acute myeloid leukemia (n = 14, 25.0%), and 34.1% had undergone HSCT. The median dose of posaconazole was 13.62 mg/kg/day (IQR, 12.0-16.8), and the median duration of PP was 24 days (IQR, 16-82). Gastrointestinal symptoms included abdominal pain (17.9%), nausea (16.1%), diarrhea (7.1%), and vomiting (3.6%). Elevated alanine aminotransferase and aspartate aminotransferase levels were observed in 9/35 patients (25.7%) and 10/51 (19.6%) patients, respectively. Five cases of breakthrough fungal infection were identified (8.9%). Patients younger than 13 years who received PP showed an increase in transaminase values, and the development of breakthrough fungal infections.

Comparative pharmacoeconomic analysis of posaconazole therapy in tablet form and in suspension for invasive fungal infections prevention

The objective of the study was to conduct a comparative pharmacoeconomic analysis of the treatment with posaconazole in a tablet form for the prevention of invasive fungal infections in patients aged 13 years and older with prolonged neutropenia and hematopoietic stem cell transplant recipients.Study design: pharmacoeconomic study, cost–effectiveness analysis; budget impact analysis; sensitivity analysis to changes in the initial parameters of the model.Results and conclusion. A literature review has shown that the use of the compared drugs for the prevention of invasive fungal infections is effective, with posaconazole being the most effective. Based on pharmacokinetic studies data, we can state the equivalence of the action of various drug forms of posaconazole. A cost analysis of drugs showed that the lowest total costs were for the prevention of invasive fungal infections in patients with acute myeloid leukemia with posaconazole tablets (197,149.37 rub.) and posaconazole suspension (215,911.53 rub.). The lowest cost for the prevention of invasive fungal infections in patients with hematopoietic stem cell transplant was shown by posaconazole in tablets (505,070.37 rub.) and posaconazole in suspension (616,652.01 rub.). Budget impact analysis in acute myeloid leukemia patients showed that with a possible cohort size of 2288 people an increase in the share of posaconazole in tablets from 5 to 15 %, in suspension from 20 to 35 % and with a decrease in the share of voriconazole from 25 to 15 %, and the share of fluconazole from 50 to 35 % in public procurement will reduce budget costs by 30,441,219.72 rub., and in patients with hematopoietic stem cell transplant ‒ by 11,219,243.54 rub. (per 100 patients).

Strategies for the Prevention of Invasive Fungal Infections after Lung Transplant.

Long-term survival after lung transplantation is lower than that associated with other transplanted organs. Infectious complications, most importantly invasive fungal infections, have detrimental effects and are a major cause of morbidity and mortality in this population. Candida infections predominate in the early post-transplant period, whereas invasive mold infections, usually those related to Aspergillus, are most common later on. This review summarizes the epidemiology and risk factors for invasive fungal diseases in lung transplant recipients, as well as the current evidence on preventive measures. These measures include universal prophylaxis, targeted prophylaxis, and preemptive treatment. Although there is consensus that a preventive strategy should be implemented, current data show no superiority of one preventive measure over another. Data are also lacking regarding the optimal antifungal regimen and the duration of treatment. As all current recommendations are based on observational, single-center, single-arm studies, it is necessary that this longstanding debate is settled with a multicenter randomized controlled trial.

Review of Pharmacologic Considerations in the Use of Azole Antifungals in Lung Transplant Recipients.

Mold-active azole antifungals are commonly prescribed for the prevention of invasive fungal infections in lung transplant recipients. Each agent exhibits a unique pharmacologic profile, an understanding of which is crucial for therapy selection and optimization. This article reviews pharmacologic considerations for three frequently-used azole antifungals in lung transplant recipients: voriconazole, posaconazole, and isavuconazole. Focus is drawn to analysis of drug-interactions, adverse drug reactions, pharmacokinetic considerations, and the role of therapeutic drug monitoring with special emphasis on data from the post-lung transplant population.

Establishing essential metrics for antifungal stewardship in hospitals: the results of an international Delphi survey.

Guidance on assessment of the quantity and appropriateness of antifungal prescribing is required to assist hospitals to interpret data effectively and structure quality improvement programmes. To achieve expert consensus on a core set of antifungal stewardship (AFS) metrics and to determine their feasibility for implementation. A literature review was undertaken to develop a list of candidate metrics. International experts were invited to participate in sequential web-based surveys to evaluate the importance and feasibility of metrics in the area of AFS using Delphi methodology. Three surveys were completed. Consensus was predefined as ≥80% agreement on the importance of each metric. Eighty-two experts consented to participate from 17 different countries. Response rate for each survey was >80%. The panel included adult and paediatric physicians, microbiologists and pharmacists with diverse content expertise. Consensus was achieved for 38 metrics considered important to routinely include in AFS programmes, and related to antifungal consumption (n = 5), quality of antifungal prescribing and management of invasive fungal infection (IFI) (n = 24), and clinical outcomes (n = 9). Twenty-one consensus metrics were considered to have moderate to high feasibility for routine collection. The identified core AFS metrics will provide a framework to comprehensively assess the quantity and quality of antifungal prescribing within hospitals to develop quality improvement programmes aimed at improving IFI prevention, management and patient-centred outcomes. A standardized approach will support collaboration and benchmarking to monitor the efficacy of current prophylaxis and treatment guidelines, and will provide important feedback to guideline developers.

Review of the Novel Echinocandin Antifungal Rezafungin: Animal Studies and Clinical Data.

Rezafungin is a novel echinocandin drug being developed as a first-line option for treatment and prevention of invasive fungal infections. As a result of a structural modification in its parent molecule anidulafungin, rezafungin has acquired unique chemical stability conferring prolonged pharmacokinetics, as well as an administration advantage in the clinical setting compared to other drugs in the same class. Rezafungin displays potent in vitro activity against a wide spectrum of fungal pathogens, which is reflected in robust in vivo efficacy and/or pharmacodynamic studies using various animal models as well as in promising clinical trials data. This review describes in vivo characterization of rezafungin using animal models, current status of clinical development and key findings from these studies.

Efficacy and safety of posaconazole for the prevention of invasive fungal infections in immunocompromised patients: a systematic review with meta-analysis and trial sequential analysis

Invasive fungal infections are a potentially life-threatening complication in immunocompromised patients. The aim of this study was to assess the efficacy and safety of posaconazole as compared with other antifungal agents for preventing invasive fungal infections in immunocompromised patients. Embase, CENTRAL, and MEDLINE were searched for randomized conweekmonthtrolled trials (RCTs) up to June 2020. A systematic review with meta-analysis of RCTs was performed using random-effects model. Trial sequential analysis (TSA) was conducted for the primary outcome to assess random errors. A total of five RCTs with 1,617 participants were included. Posaconazole prophylaxis was associated with a significantly lower risk of IFIs (RR, 0.43 [95% CI 0.28 to 0.66, p = 0.0001]) as compared to other antifungal agents. No heterogeneity was identified between studies (I2 = 0%). No significant associations were observed for the secondary outcomes measured, including risk reduction of invasive aspergillosis and candidiasis, clinical failure, all-cause mortality, and treatment-related adverse events, except for infection-related mortality (RR, 0.31 [95% CI 0.15 to 0.64, p = 0.0001]). Subgroup analysis favoured posaconazole over fluconazole for the prevention of IFIs (RR, 0.44 [95% CI 0.28 to 0.70, p = 0.0004]). TSA confirmed the prophylactic benefit of posaconazole against IFIs. Posaconazole is effective in preventing IFIs among immunocompromised patients, particularly those with hematologic malignancies and recipients of allogenic hematopoietic stem cell transplantation.

Evaluation of targeted versus universal prophylaxis for the prevention of invasive fungal infections following lung transplantation.

Antifungal prophylaxis to prevent invasive fungal infections (IFI) is widely used following lung transplantation, but the optimal strategy remains unclear. We compared universal with targeted antifungal prophylaxis for effectiveness in preventing IFI. Adult patients who underwent lung transplantation at the University of Michigan from /1 July 2014-31 December 2017 were studied for 18months post-transplant. Universal prophylaxis consisted of itraconazole with or without inhaled liposomal amphotericin B. Using specific criteria, targeted prophylaxis was given with voriconazole for patients at risk for invasive pulmonary aspergillosis (IPA) and with fluconazole or micafungin for patients at risk for invasive candidiasis. Risk factors, occurrence of proven/probable IFI, and mortality were analyzed for the two prophylaxis cohorts. Of 105 lung transplant recipients, 84 (80%) received a double lung transplant, and 38 (36%) of patients underwent transplant for pulmonary fibrosis. Fifty-nine (56%) patients received universal antifungal prophylaxis, and 46 (44%), targeted antifungal prophylaxis. Among 20 proven/probable IFI, there were 14 IPA, 4 invasive candidiasis, 1 cryptococcosis, and 1 deep sternal mold infection. Six (10%) IFI occurred in the universal prophylaxis cohort and 14 (30%) in the targeted prophylaxis cohort. Five of 6 (83%) IFI in the universal prophylaxis cohort, compared with 9/14 (64%) in the targeted prophylaxis cohort, were IPA Candida infections occurred only in the targeted prophylaxis cohort. The development of IFI was more likely in the targeted prophylaxis cohort than the universal prophylaxis cohort, HR=4.32 (1.51-12.38), P=.0064. Universal antifungal prophylaxis appears to be more effective than targeted antifungal prophylaxis for prevention of IFI after lung transplant.

Posaconazole and fluconazole prophylaxis during induction therapy for pediatric acute lymphoblastic leukemia

To assess and compare the efficacy and safety of posaconazole with fluconazole for the prevention of invasive fungal infections in children who were undergoing induction therapy for acute lymphoblastic leukemia (ALL). To develop an approach to predict invasive fungal infections in ALL patients who accepted posaconazole prophylaxis. This was a single-center, retrospective cohort study of patients with newly diagnosed ALL, comparing invasive fungal infections in patients who received no prophylaxis, posaconazole prophylaxis, or fluconazole prophylaxis during induction therapy. A propensity score-weighted logistic regression model was used to adjust for confounders. Hepatotoxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Out of the 155 ALL patients, 60 received no prophylaxis, 70 received posaconazole prophylaxis, and 25 received fluconazole prophylaxis. Posaconazole prophylaxis reduced the odds of invasive fungal infections by > 60%, prolonged infection-free survival significantly, and did not increase the risk of hepatotoxicity. Additionally, we found that the combination of age at diagnosis, clinically documented bacterial infection in the first 15 days of induction therapy, and absolute neutrophil count (ANC) curve enabled significant prediction of the susceptibility to infections after receiving posaconazole prophylaxis. Our findings supported using targeted prophylaxis with posaconazole in ALL children undergoing induction chemotherapy. Age, clinically documented bacterial infection and ANC are important predictors of invasive fungal infections in patients with posaconazole prophylaxis.

Low Rate of Invasive Fungal Infections During Induction and Consolidation Chemotherapy for Adults with De Novo Acute Myeloid Leukemia Without Anti-mold Prophylaxis: Single-Center 2002-2018 Empirical/Pre-emptive Approach.

Broad-spectrum antifungal prophylaxis is currently considered the standard of care for adults with de novo AML for the prevention of invasive fungal infections (IFIs), especially invasive pulmonary aspergillosis (IPA). Because fluconazole has been used in our center as anti-yeast prophylaxis, we sought to analyze in detail the incidence of IFIs over a 17-year period, as well as their impact on outcome. A standardized protocol of patient management, including serum galactomannan screening and thoracic CT-guided diagnostic-driven antifungal therapy, was used in all patients. A total of 214 consecutive adults with de novo AML who were treated in 3 CETLAM (Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias) protocols from 2002 to 2018 were included. The 90-day incidence of any IFI (including possible cases) was 11% (95% CI 4-15%), most cases occurred during induction chemotherapy (8%, 95% CI 4-12%), and most cases were probable/proven IPA (8%, 95% CI 3-13%). Developing an IFI during induction and consolidation had no impact on 1-year survival. A case-control study with 23 cases of IPA and 69 controls identified induction/re-induction chemotherapy, chronic pulmonary disease and age > 60 years/poor baseline performance status as potential pretreatment risk factors. The current study proves that inpatient induction and consolidation chemotherapy for de novo AML can be given in areas with "a priori" high-burden of airborne molds with fluconazole prophylaxis, while the selective use of anti-mold prophylaxis in patients at very high risk may further reduce the incidence of IFI in this specific clinical scenario.

Effectiveness and Cost-Effectiveness of Prophylactic Voriconazole and Fluconazole Regarding Prevention of Post-hematopoietic Stem Cell Transplantation Invasive Fungal Infection and Its Related Death: A Single Center Experience.

Analyzing effectiveness and cost-effectiveness of voriconazole versus fluconazole prophylaxis in hematopoietic stem cell transplantation (HSCT). The research included 70 patients; 34 undergoing allogeneic HSCT and 36 undergoing autologous stem cell transplantation (ASCT), alternated to receive either voriconazole or fluconazole prophylaxis for 180days on a 1:1 basis. Patients were monitored for occurrence of invasive fungal infections (IFI), IFI-related death (IRD) and total death events. Cost-effectiveness of both agents in both groups was also assessed. Antifungal prophylactic drug had no impact on incidence of IFI and IRD in both allogeneic HSCT and ASCT (P = .452 and P = 1.000; P = .457 and P = .146 respectively). An insignificant difference occurred among patients receiving voriconazole or fluconazole regarding overall survival (OS) and fungal infection-free survival (FFS) in both groups (P = .705 and P = .879; P = .713 and P = .681 respectively). Regarding cost-effectiveness, voriconazole dominated fluconazole regarding prevention of IFI and IRD but was less costly/less effective regarding prevention of total death events and gaining life years in the allogeneic HSCT setting. In the ASCT setting, voriconazole was not cost-effective regarding avoidance of IFI and IRD and was dominated by fluconazole regarding avoidance of total death events and gaining life years. Voriconazole does not differ from fluconazole regarding its efficacy in prevention of IFI and IRD and does not improve OS and FFS in both allogeneic HSCT and ASCT settings. Voriconazole is cost-effective regarding protection from IFI and IRD in allogeneic HSCT but not cost-effective in ASCT.

Risk factors of infection-associated mortality in children with lupus nephritis in under-resourced areas.

Treatment of lupus nephritis class III, IV and V with immunosuppressive therapy increases patient survival but poses a risk of infection-related mortality. This study was conducted to evaluate risk factors for fatal infection in children with lupus nephritis in under-resourced areas. Medical records of patients, who were admitted to a tertiary-care university-based hospital from January 2002 to July 2018 with the diagnosis of systemic lupus erythematosus, were reviewed. Only patients aged less than 18 years with lupus nephritis and documented infection were included in the study. The primary outcome was infection-associated mortality. The logistic regression model was used to identify independent variables associated with fatal infection. Predicted probabilities of infection-related mortality adjusted for factors significant in multivariate analysis were calculated using marginal effects at representative values. Infection-related deaths occurred in 27 of 179 patients (15.1%). Hospital-acquired infections occurred in 72 of 375 episodes of hospital admissions (19.2%) and 13 hospital-acquired infections (18.1%) resulted in fatal infection. Invasive fungal infections were the leading cause of death (44.4%) and pulmonary infections were the predominant site (55.5%). Haemoglobin levels and glomerular filtration rates were significantly lower in deceased versus surviving patients. Percentages of patients with hospital-acquired infections, invasive fungal infections and pulmonary infections were significantly higher in deceased than surviving patients. Urine protein, the neutrophil-to-lymphocyte ratio, cumulative methylprednisolone dose and daily prednisolone dose were significantly higher in deceased than surviving patients. In multivariate analysis, a neutrophil-to-lymphocyte ratio more than 20, invasive fungal infections and high daily prednisolone dose were independently predictive of fatal infection with adjusted odds ratio of 3.02 (95% confidence interval 1.02-8.97, p = 0.04), 15.08 (95% confidence interval 4.72-48.24, p < 0.001) and 1.03 (95% confidence interval 1.01-1.06, p = 0.04), respectively. A high daily prednisolone dose intensified the impact of invasive fungal infections and high neutrophil-to-lymphocyte ratio on predicted probability of infection-associated mortality. Prevention of invasive fungal infections and minimization of daily prednisolone should be emphasized in routine clinical practice of children with lupus nephritis in under-resourced areas to achieve better survival. Children with lupus nephritis and a high neutrophil-to-lymphocyte ratio should be under cautious surveillance for infection.

Cost-effectiveness of antifungal prophylaxis, preemptive therapy, or empiric treatment following allogeneic hematopoietic stem cell transplant.

Invasive fungal infection (IFI) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is also associated with excess healthcare costs. Current approaches include universal antifungal prophylaxis, preemptive therapy based on biomarker surveillance, and empiric treatment initiated in response to clinical signs/symptoms. However, no study has directly compared the cost-effectiveness of these treatment strategies for an allogeneic HSCT patient population. We developed a state transition model to study the impact of treatment strategies on outcomes associated with IFIs in the first 100days following myeloablative allogeneic HSCT. We compared three treatment strategies: empiric voriconazole, preemptive voriconazole (200mg), or prophylactic posaconazole (300mg) for the management of IFIs. Preemptive treatment was guided by scheduled laboratory surveillance with galactomannan (GM) testing. Endpoints were cost and survival at 100days post-HSCT. Empiric treatment was the least costly ($147482) and was equally effective (85.2% survival at 100days) as the preemptive treatment strategies. Preemptive treatments were slightly more costly than empiric treatment (GM cutoff≥1.0 $147910 and GM cutoff≥0.5 $148108). Preemptive therapy with GM cutoff≥1.0 reduced anti-mold therapy by 5% when compared to empiric therapy. Posaconazole prophylaxis was the most effective (86.6% survival at 100days) and costly ($152240) treatment strategy with a cost of $352415 per life saved when compared to empiric therapy. One preemptive treatment strategy reduced overall anti-mold drug exposure but did not reduce overall costs. Prevention of IFI using posaconazole prophylaxis was the most effective treatment strategy and may be cost-effective, depending upon the willingness to pay per life saved.