Preemptive Antifungal Therapy Research Articles

Systematic review on efficacy and safety of empirical versus pre-emptive antifungal therapy among children with febrile neutropenia reveals paucity of data.

Two approaches are used to manage invasive fungal disease (IFD) in febrile neutropenic patients viz. empirical therapy (without attempting to confirm the diagnosis), or pre-emptive therapy (after screening tests for IFD). This systematic review was undertaken to compare these approaches in children. We searched PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, CINAHL, Clinical Trial Registries and grey literature, for randomized controlled trials (RCT) comparing empirical versus pre-emptive antifungal therapy in children with FN suspected to have IFD. We used the Cochrane Risk of bias 2 tool for quality assessment, and evaluated the certainty of evidence using the GRADE approach. We identified 7989 citations. Stepwise screening identified only one relevant RCT that administered empirical (n = 73) or pre-emptive (n = 76) antifungal therapy. There were no significant differences in all-cause mortality (RR 1.56, 95% CI: 0.46, 5.31), IFD mortality (RR 1.04, 95% CI:0.15, 7.20) and other clinically important outcomes such as duration of fever, duration of hospitalization and proportion requiring ICU admission. There were no safety data reported. The number of days of antifungal therapy was significantly lower in the pre-emptive therapy arm. The certainty of evidence for all outcomes was 'moderate'. This systematic review highlighted the paucity of data, comparing empirical versus pre-emptive antifungal therapy in children with febrile neutropenia having suspected invasive fungal disease. Data from a single included trial suggests that both approaches may be comparable in research settings. Robust trials are warranted to address the gap in existing knowledge about the optimal approach in clinical practice.

Safety and efficacy of pre-emptive antifungal therapy versus empirical therapy in patients with febrile neutropenia – A meta-analysis

Febrile neutropenia is a life-threatening complication usually seen in cancer chemotherapy patients. Bacterial agents are the most common etiology of sepsis in febrile neutropenia and warrants empirical antibiotic treatment. However, the efficacy of pre-emptive therapy over empirical therapy is debatable. The objectives of this study were to evaluate the efficacy (difference in mortality rate) of pre-emptive antifungal therapy in patients with febrile neutropenia compared to empirical antifungal therapy and to evaluate the safety (antifungal exposure, adverse effects, and duration of hospital stay) of pre-emptive antifungal therapy. The data source used for the study is only PubMed. Only full-text articles in English language since the year 2000 were included. Unpublished studies will not be sought. Searches will be re-run before analysis. Data extraction was guided by a predetermined checklist. Using RevMan 5 software, the effect of intervention is null (95% CI 0.66–1.91, P = 0.57)]. An insignificant Q statistic (P > 0.66) indicates the absence of heterogeneity (I2 = 0%) as there is not much difference in the mortality rates between two groups. Data analyses were performed from June 2023 to August 2023. The primary outcome is an insignificant Q statistic (P > 0.66) indicates the absence of heterogeneity (I2 = 0%) as there is not much difference in the mortality rates between two groups. Hence, pre-emptive therapy can be considered in place of empirical therapy to avoid over treatment with antifungal agents in patients with febrile neutropenia. A meta-analysis of five eligible comparative studies involving 588 subjects who had pre-emptive antifungal therapy and 587 subjects who had empirical therapy signifies the effect of intervention is null (95% CI 0.66–1.91, P = 0.57). An insignificant Q statistic (P > 0.66) indicates the absence of heterogeneity (I2 = 0%) as there is not much difference in the mortality rates between two groups. Hence, pre-emptive therapy can be considered in place of empirical therapy to avoid over treatment with antifungal agents in patients with febrile neutropenia. This systematic review and meta-analysis demonstrated that pre-emptive therapy can be considered in place of empirical therapy to avoid over treatment with antifungal agents in patients with febrile neutropenia. Trial Registration: PROSPERO receipt number-443707.

Empirical vs pre-emptive broad-spectrum antifungal therapy for acute myelogenous leukaemia in the era of antimould prophylaxis

This study compared clinical outcomes in patients with acute myelogenous leukaemia (AML) who developed prolonged (≥4 days) febrile neutropenia (FN) and received either empirical or pre-emptive antimould prophylaxis in order to evaluate the need for routine empirical antifungal therapy. This retrospective study reviewed adult patients (aged ≥18 years) with AML who developed prolonged FN and received antimould prophylaxis during induction or re-induction chemotherapy at a single centre between September 2016 and December 2020. Patients were categorized into pre-emptive or empirical groups based on whether or not there was clinical evidence of invasive fungal infection (IFI) at the start of antifungal treatment, respectively. Clinical outcomes were compared between the two groups after propensity score matching (PSM). In total, 229 chemotherapy episodes (36 and 193 in the empirical and pre-emptive groups, respectively) were analysed. In the pre-emptive group, broad-spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 PSM, there were no significant differences between the empirical and pre-emptive groups in terms of the incidence of proven or probable IFI [0/36 (0%) vs 5/97 (5.2%); P=0.323], all-cause mortality [3/36 (8.3%) vs 4/97 (4.1%); P=0.388] and IFI-related mortality [0/36 (0.0%) vs 1/45 (2.2%); P=0.556]. The differences in clinical outcomes between empirical and pre-emptive antifungal therapy in patients with AML who received antimould prophylaxis were not significant. Therefore, broad-spectrum antifungal therapy in patients receiving antimould prophylaxis may be delayed until there is clear evidence of IFI.

Guideline for the Management of Fever and Neutropenia in Pediatric Patients With Cancer and Hematopoietic Cell Transplantation Recipients: 2023 Update.

To update a clinical practice guideline (CPG) for the empiric management of fever and neutropenia (FN) in pediatric patients with cancer and hematopoietic cell transplantation recipients. The International Pediatric Fever and Neutropenia Guideline Panel reconvened to conduct the second update of this CPG. We updated the previous systematic review to identify new randomized controlled trials (RCTs) evaluating any strategy for the management of FN in pediatric patients. Using the Grading of Recommendations Assessment, Development and Evaluation framework, evidence quality was classified as high, moderate, low, or very low. The panel updated recommendations related to initial management, ongoing management, and empiric antifungal therapy. Changes from the 2017 CPG were articulated, and good practice statements were considered. We identified 10 new RCTs in addition to the 69 RCTs identified in previous FN CPGs to inform the 2023 FN CPG. Changes from the 2017 CPG included two conditional recommendations regarding (1) discontinuation of empiric antibacterial therapy in clinically well and afebrile patients with low-risk FN if blood cultures remain negative at 48 hours despite no evidence of marrow recovery and (2) pre-emptive antifungal therapy for invasive fungal disease in high-risk patients not receiving antimold prophylaxis. The panel created a good practice statement to initiate FN CPG-consistent empiric antibacterial therapy as soon as possible in clinically unstable febrile patients. The updated FN CPG incorporates important modifications on the basis of recently published trials. Future work should focus on addressing knowledge gaps, improving CPG implementation, and measuring the impact of CPG-consistent care.

208. Clinical outcomes of empirical versus pre-emptive broad spectrum antifungal therapy in patients with acute myelogenous leukemia receiving antimold prophylaxis

Abstract Background Since antimold prophylaxis has been widely used in induction chemotherapy for acute myelogenous leukemia (AML), it should be re-evaluated whether broad spectrum antifungal therapy should be empirically used in prolonged febrile neutropenia. Therefore, we compared clinical outcomes of empirical versus pre-emptive antifungal therapy in patients with AML receiving antimold prophylaxis. Methods From September 2016 to December 2020, all adult AML patients (≥ 18 years) receiving antimold prophylaxis who had febrile neutropenia for ≥ 4 days during induction or re-induction chemotherapy at Seoul National University Hospital were retrospectively reviewed. They were classified into the empirical group (therapeutic broad spectrum antifungal agents had been used without evidence of invasive fungal infection [IFI]) or the pre-emptive group (antimold prophylaxis had been maintained until the emergence of IFI’s evidence). We compared clinical outcomes between the two groups after propensity score matching. Results A total of 229 chemotherapy episodes, 36 in the empirical group and 193 in the pre-emptive group, were analyzed. In the pre-emptive group, broad spectrum antifungal therapy was administered in 45 (23.3%) episodes. After 1:3 matching with age, gender, induction or re-induction chemotherapy, and worst qSOFA score at febrile neutropenia, incidence of proven or probable IFI (0/36 [0%] in the empirical group vs. 5/97 [5.2%] in the pre-emptive group, P=0.323) and all-cause mortality (3/36 [8.3%] in the empirical group vs. 4/97 [4.1%] in the pre-emptive group, P=0.388) were not different between the two groups. Conclusion Clinical outcomes of empirical versus pre-emptive broad spectrum antifungal therapy were comparable in patients with AML receiving antimold prophylaxis. Broad spectrum antifungal therapy could be delayed until the emergence of evidence of IFI, in the current era of antimold prophylaxis. Disclosures All Authors: No reported disclosures.

Pre-emptive antifungal therapy versus empirical antifungal therapy for febrile neutropenia in people with cancer.

Intensive cytotoxic chemotherapy for people with cancer can cause severe and prolonged cytopenia, especially neutropenia, a critical condition that is potentially life-threatening. When manifested by fever and neutropenia, it is called febrile neutropenia (FN).Invasive fungal disease (IFD) is one of the serious aetiologies of chemotherapy-induced FN. In pre-emptive therapy, physicians only initiate antifungal therapy when an invasive fungal infection is detected by a diagnostic test. Compared to empirical antifungal therapy, pre-emptive therapy may reduce the use of antifungal agents and associated adverse effects, but may increase mortality. The benefits and harms associated with the two treatment strategies have yet to be determined. OBJECTIVES: To assess the relative efficacy, safety, and impact on antifungal agent use of pre-emptive versus empirical antifungal therapy in people with cancer who have febrile neutropenia. We searched CENTRAL, MEDLINE Ovid, Embase Ovid, and ClinicalTrials.gov to October 2021. We included randomised controlled trials (RCTs) that compared pre-emptive antifungal therapy with empirical antifungal therapy for people with cancer. We identified 2257 records from the databases and handsearching. After removing duplicates, screening titles and abstracts, and reviewing full-text reports, we included seven studies in the review. We evaluated the effects on all-cause mortality, mortality ascribed to fungal infection, proportion of antifungal agent use (other than prophylactic use), duration of antifungal use (days), invasive fungal infection detection, and adverse effects for the comparison of pre-emptive versus empirical antifungal therapy. We presented the overall certainty of the evidence for each outcome according to the GRADE approach. This review includes 1480 participants from seven randomised controlled trials. Included studies only enroled participants at high risk of FN (e.g. people with haematological malignancy); none of them included participants at low risk (e.g. people with solid tumours). Low-certainty evidence suggests there may be little to no difference between pre-emptive and empirical antifungal treatment for all-cause mortality (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.72 to 1.30; absolute effect, reduced by 3/1000); and for mortality ascribed to fungal infection (RR 0.92, 95% CI 0.45 to 1.89; absolute effect, reduced by 2/1000). Pre-emptive therapy may decrease the proportion of antifungal agent used more than empirical therapy (other than prophylactic use; RR 0.71, 95% CI 0.47 to 1.05; absolute effect, reduced by 125/1000; very low-certainty evidence). Pre-emptive therapy may reduce the duration of antifungal use more than empirical treatment (mean difference (MD) -3.52 days, 95% CI -6.99 to -0.06, very low-certainty evidence). Pre-emptive therapy may increase invasive fungal infection detection compared to empirical treatment (RR 1.70, 95% CI 0.71 to 4.05; absolute effect, increased by 43/1000; very low-certainty evidence). Although we were unable to pool adverse events in a meta-analysis, there seemed to be no apparent difference in the frequency or severity of adverse events between groups. Due to the nature of the intervention, none of the seven RCTs could blind participants and personnel related to performance bias. We identified considerable clinical and statistical heterogeneity, which reduced the certainty of the evidence for each outcome. However, the two mortality outcomes had less statistical heterogeneity than other outcomes. For people with cancer who are at high-risk of febrile neutropenia, pre-emptive antifungal therapy may reduce the duration and rate of use of antifungal agents compared to empirical therapy, without increasing over-all and IFD-related mortality; but the evidence regarding invasive fungal infection detection and adverse events was inconsistent and uncertain.

P427 The value of nasal and oral clinical examination in febrile neutropenic patients for initiating anti-fungal therapy as a preemptive method

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM BackgroundInvasive fungal infections (IFIs) are complications that lead to mortality and morbidity in hematologic malignancies. The time of starting anti-fungal therapy is vital. Preemptive anti-fungal therapy has appeared recently as a new policy for the management of IFIs based on noninvasive ways in neutropenic patients.MethodsWe enrolled leukemia patients with neutropenia after chemotherapy in Imam Khomeini Hospital Complex, Tehran, Iran. Patients who entered the neutropenic phase were divided into two categories (empirical and preemptive) for receiving anti-fungal agents. The patients were clinically examined in the preemptive group every day to find IFIs. As soon as clinical evidence of IFIs was observed, antifungal was prescribed. The empirical group patients received antifungals based on the ward protocol. Based on the data in each group, the diagnostic and therapeutic results of cases are followed-up for 3 months. To compare percentages between the two groups, the Chi-squared test was used. And to compare two means between the two groups, the independent t-test was used. All the statistical analyses were done in the Statistical Package for the Social Sciences (SPSS) version 24 software (IBM Corporation, Armonk, New York, USA).ResultsWe assessed 132 leukemic patients with inclusion and exclusion criteria. Eventually, 80 patients were enrolled. The mean age was 35.52 years. Demographic data and distribution of leukemia type show no significant differences between the two groups. Despite a higher percentage of IFIs discovered in the preemptive group than the empirical group (25 vs. 18.75%, respectively), but data show no significant differences. The average days of IFIs diagnosis since the beginning of neutropenia in the empirical group were 9.5 days while in the preemptive group, the average days were 5.4 days (P <.05). Totally, there were 15 patients with a proven IFI in each group (40% in the empirical group and 60% in the preemptive group). Results significantly show an increase in surgical sinus debridement in the empirical groups (83.3%) vs. the preemptive groups (55.5%), (P <.05). The mortality rate differed significantly among the two groups; it was 7.5% in the preemptive group and 25% in the empirical group (P <.05).ConclusionDaily oral and nasal cavities examination to find the symptoms of IFIs and then start preemptive antifungal agents may be able to lead to accurate diagnosis, earlier treatment, and decreasing sinus surgery debridement in leukemia patients with neutropenia.

Evaluation of the initial 12\u2009months of a routine cryptococcal antigen screening program in reduction of HIV-associated cryptococcal meningitis in Uganda

BackgroundAsymptomatic Cryptococcal Antigenemia (CrAg) patients develop meningitis within a month of testing positive. Pre-emptive antifungal therapy can prevent progression to Cryptococcal meningitis (CM). In April 2016, a national CrAg screening program was initiated in 206 high-volume health facilities that provide antiretroviral therapy in Uganda. We report the evaluation of the CrAg screening cascade focusing on linkage to care, fluconazole therapy for 10 weeks and 6 months follow up, and ART initiation in a subset of facilities.MethodsWe conducted a retrospective, cross-sectional survey of patients with CD4 < 100 at seven urban and seven rural facilities after 1 year of program implementation. We quantified the number of patients who transitioned through the steps of the CrAg screening cascade over six-months follow-up. We defined cascade completion as a pre-emptive fluconazole prescription for the first 10 weeks. We conducted semi-structured interviews with lab personnel and clinic staff to assess functionality of the CrAg screening program. Data was collected using REDCap.ResultsWe evaluated 359 patient records between April 2016 to March 2017; the majority (358/359, 99.7%) were from government owned health facilities and just over half (193/359, 53.8%) had a median baseline CD4 cell count of < 50 cell/μL. Overall, CrAg screening had been performed in 255/359 (71.0, 95% CI, 66.0–75.7) of patients’ records reviewed, with a higher proportion among urban facilities (170/209 (81.3, 95% CI, 75.4–86.4)) than rural facilities (85/150 (56.7, 95% CI, 48.3–64.7)). Among those who were CrAg screened, 56/255 (22.0, 95% CI, 17.0–27.5%) had cryptococcal antigenemia, of whom 47/56 (83.9, 95% CI, 71.7–92.4%) were initiated on pre-emptive therapy with fluconazole and 8/47 (17.0, 95% CI, 7.6–30.8%) of these were still receiving antifungal therapy at 6 months follow up. At least one CNS symptom was present in 70% (39/56) of those with antigenemia. In patients who had started ART, almost 40% initiated ART prior to CrAg screening. Inadequacy of equipment/supplies was reported by 15/26 (58%) of personnel as a program barrier, while 13/26 (50%) reported a need for training about CM and CrAg screening.ConclusionThere was a critical gap in the follow-up of patients after initiation on fluconazole therapy. ART had been initiated in almost 40% of patients prior to CrAg screening.. Higher antigenemia patients presenting with CNS symptoms could be related to late presentation. There is need to address these gaps after a more thorough evaluation.

The Value of Nasal and Oral Clinical Examination in Febrile Neutropenic Patients for Initiating Antifungal Therapy as a Preemptive Method.

BackgroundInvasive fungal infections (IFIs) are complications that lead to mortality and morbidity in hematologic malignancies. The time of starting antifungal therapy is vital. Preemptive antifungal therapy has appeared recently as a new policy for the management of IFIs based on noninvasive ways in neutropenic patients.MethodsWe enrolled leukemia patients with neutropenia after chemotherapy in Imam Khomeini Hospital Complex, Tehran, Iran. Patients who entered the neutropenic phase were divided into two categories (empirical and preemptive) for receiving antifungal agents. The patients were clinically examined in the preemptive group every day to find IFIs. As soon as clinical evidence of IFIs was observed, antifungal was prescribed. The empirical group patients received antifungals based on the ward protocol. Based on the data in each group, the diagnostic and therapeutic results of cases are followed-up to 3 months. To compare percentages between the two groups, the chi-squared test was used. And to compare two means between the two groups, the independent t-test was used. All the statistical analyses were done in the Statistical Package for the Social Sciences (SPSS) version 24 software (IBM Corporation, Armonk, New York, USA).ResultsWe assessed 132 leukemic patients with inclusion and exclusion criteria. Eventually, 80 patients were enrolled. The mean age was 35.52 years. Demographics data and distribution of leukemia type show no significant differences between the two groups. Despite a higher percentage of IFIs discovered in the preemptive group than the empirical group (25 vs. 18.75%, respectively), but data show no significant differences. The average days of IFIs diagnosis since the beginning of neutropenia in the empirical group were 9.5 days while in the preemptive group, the average days were 5.4 days (p < 0.05). Totally, there were 15 patients with a proven IFI in each group (40% in the empirical group and 60% in the preemptive group). Results significantly show an increase in surgical sinus debridement in the empirical groups (83.3%) vs. the preemptive groups (55.5%), (p < 0.05). The mortality rate differed significantly among the two groups; it was 7.5% in the preemptive group and 25% in the empirical group (p < 0.05).ConclusionDaily oral and nasal cavities examination to find the symptoms of IFIs and then start preemptive antifungal agents may be able to lead to accurate diagnosis, earlier treatment, and decreasing sinus surgery debridement in leukemia patients with neutropenia.

Invasive aspergillosis in coronavirus disease 2019: a practical approach for clinicians.

Purpose of reviewInvasive pulmonary aspergillosis (IPA) can affect patients with severe coronavirus disease 2019 (COVID-19), but many questions remain open about its very variable incidence across the world, the actual link between the viral infection and the fungal superinfection, the significance of Aspergillus recovery in a respiratory sample, and the management of such cases. This review addresses these questions and aims at providing some clues for the practical diagnostic and therapeutic approaches of COVID-19-associated pulmonary aspergillosis (CAPA) in a clinical perspective.Recent findingsDefinitions have been proposed for possible/probable/proven CAPA, but distinction between colonization and invasive fungal infection is difficult and not possible in most cases in the absence of histopathological proof or positive galactomannan in serum. Most importantly, the recovery of an Aspergillus by a direct (culture, PCR) or indirect (galactomannan) test in a respiratory sample is an indicator of worse outcome, which justifies a screening for early detection and initiation of preemptive antifungal therapy in such cases.SummaryThe COVID-19 pandemic has increased our awareness of IPA among ICU patients. Although current recommendations are mainly based on experts’ opinions, prospective studies are needed to get more evidence-based support for the diagnostic approach and management of CAPA.

Utility of serum Galactomannan in diagnosing COVID-19 patients with suspected IPA: an observational study in resource limited settings.

To study the utility of Galactomannan (GM) antigen as a screening marker for diagnosing invasive pulmonary aspergillosis (IPA) in coronavirus disease 2019 (COVID-19) patients. The serum samples from patients with severe COVID-19 diseases admitted to the Critical Care Unit were collected on the 5th day of admission for GM screening. The samples were analysed by enzyme linked immune sorbent assay (ELISA) and GM index of more than 1 was considered as positive. All GM positive patients were serially followed until discharge or death. The GM was raised in serum of 12 out of 38 patients, indicating an incidence of possible COVID-19 associated IPA (CAPA) in 31.57% of patients. The median age of these CAPA patients was 56.5 years, males were significantly more affected than females. The inflammatory marker serum ferritin was raised in all 12 patients (median value of 713.74 ng/ml), while IL-6 was raised in 9 patients (median value of 54.13 ng/ml). None of these patients received antifungals. Their median length of hospital stay was 20 days (IQR: 12, 34 days). All these patients succumbed to the illness. The serum GM appears to be sensitive diagnostic tool to identify early IPA in COVID-19 patients and pre-emptive antifungal therapy could play a role in salvaging these patients.

Risk factors of invasive fungal infections in lung transplant recipients: A systematic review and meta-analysis

Invasive fungal infection (IFI) remains a common complication after lung transplantation, causing significant morbidity and mortality. We have attempted to quantify systematically risk factors of IFI in lung transplant recipients. Studies were retrieved from Ovid MEDLINE, Ovid Embase, Cochrane database of systematic reviews and Cochrane central register of controlled trials. All case-control and cohort studies evaluating the risk factors of IFI in adult lung transplant recipients were screened. Two researchers reviewed and assessed all studies independently. We pooled the estimated effect of each factor associated with IFI by using a random effect model. Eight studies were included in the systematic review and 5 studies were eligible for the meta-analysis. Rates of IFI range from 8% to 33% in lung transplant recipients. Independent risk factors for invasive aspergillosis (IA) in lung transplantation include previous fungal colonization (odds ratio [OR] 2.44; 95% confidence interval [CI] 0.08-0.47), cytomegalovirus infection (OR 1.96; 95% CI 1.08-3.56), and single lung transplantation (OR 1.77; 95% CI 1.08-2.91). Pre-emptive antifungal therapy is a protective factor for IA in lung transplant (OR 0.2; 95% CI 0.08-0.47). Cytomegalovirus infection, previous fungal colonization and single lung transplantation independently increase the risk of IA in lung transplant recipients. Pre-emptive antifungal therapy is a protective factor for IA in the lung transplant population.

Development of a Method of Measuring β-D-Glucan and Its Use in Preemptive Therapy for Invasive Fungal Infections

Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal infections. However, many studies have indicated that antifungals were not necessary for over half of patients, and several detriments of empirical therapy were noted, e.g., antifungals caused adverse reactions, an increase in drug-resistant fungi was a possibility, and medical costs soared. β-D-glucan (BDG) is a component of clinically important fungi such as Aspergillus and Candida. The G-test was developed in Japan as a way to measure BDG in serum using a coagulation factor from the blood of the horseshoe crab. Pre-emptive antifungal therapy based upon serodiagnosis with a BDG or galactomannan assay and CT imaging has been introduced. With pre-emptive antifungal therapy, the prognosis is equivalent to that with empirical therapy, and the dose of the antifungal has been successfully reduced. Measurement of BDG has been adopted widely as a method of diagnosing IFIs and is listed in the key guidelines for fungal infections and febrile neutropenia.

Survival following screening and preemptive antifungal therapy for subclinical cryptococcal disease in advanced HIV infection.

Our study's primary objective was to compare 1-year survival rates between serum cryptococcal antigen (sCrAg)-positive and sCrAg-negative HIV-positive individuals with CD4+ cell counts less than 100 cells/μl without symptoms of meningitis in Zimbabwe. This was a prospective cohort study. Participants were enrolled as either sCrAg-positive or sCrAg-negative and followed up for 52 weeks or less, with death as the outcome. Lumbar punctures were recommended to all sCrAg-positives and inpatient management with intravenous amphotericin B and high-dose fluconazole was recommended to those with disseminated Cryptococcus. Antiretroviral therapy was initiated immediately in sCrAg-negatives and after at least 4 weeks following initiation of antifungals in sCrAg-positives. Multivariable logistic regression models were used to determine risk factors for mortality. We enrolled 1320 participants and 130 (9.8%) were sCrAg positive, with a median sCrAg titre of 1 : 20. Sixty-six (50.8%) sCrAg-positives had lumbar punctures and 16.7% (11/66) had central nervous system (CNS) dissemination. Cryptococcal blood cultures were performed in 129 sCrAg-positives, with 10 (7.8%) being positive. One-year (48-52 weeks) survival rates were 83.9 and 76.1% in sCrAg-negatives and sCrAg-positives, respectively, P = 0.011. Factors associated with increased mortality were a positive sCrAg, CD4+ cell count less than 50 cells/μl and having presumptive tuberculosis (TB) symptoms. Our study reports a high prevalence of subclinical cryptococcal antigenemia and reiterates the importance of TB and a positive sCrAg as risk factors for mortality in advanced HIV disease (AHD). Therefore, TB and sCrAg screening remains a crucial component of AHD package, hence it should always be part of the comprehensive clinical evaluation in AHD patients.

Invasive Aspergillosis (IA) in Lung Transplant Recipients (LTRs) with Isolated Positive Bronchoalveolar Lavage Galactomannan (BAL GM) in the First Month Post-Transplant

<h3>Purpose</h3> BAL GM has higher sensitivity than traditional culture methods. However, smaller studies have documented higher false positivity in the early post-transplant period. This study aimed to evaluate the rate of IA in patients who had a negative fungal culture and positive BAL GM in the first 30 days post lung transplant. <h3>Methods</h3> We retrospectively identified LTRs from January 2010 to January 2017, who had a negative <i>Aspergillus</i> culture and positive BAL GM with an index cutoff value of ≥1.0 in the first 30 days post-transplant. Development of IA within 30 days after the initial positivity was evaluated. ISHLT definitions were used to define IA and colonization. <h3>Results</h3> We reviewed 791 LTRs; 119 patients had negative fungal culture and a positive BAL GM in the first 30 days post-transplant. 59% (70/119) were male, mean age 53 years old, 15% (18/119) had cystic fibrosis. 3% (4/119) of the patients had IA at the time of initial positive BAL GM. Of the other 115 patients, 112 were noted to be positive only once, 3 were positive two or more times. 63% (73/115) received preemptive antifungal therapy. None of them developed IA. 37% (42/115) did not receive preemptive antifungal therapy, and only 7% (3/42) developed IA. <h3>Conclusion</h3> In the absence of antifungal therapy, 7% (3/42) of LTRs subsequently developed IA following positive BAL GM >1.0 in the first 30 days post-transplant. Further characterization of patients with positive BAL GM during the first month may be helpful in devising the pre-emptive antifungal therapy in the early period after lung transplantation.

Pre-emptive antifungal therapy versus empirical antifungal therapy for febrile neutropenia in people with cancer

Pre-emptive antifungal therapy versus empirical antifungal therapy for febrile neutropenia in people with cancer

Late Onset Invasive Pulmonary Aspergillosis in Lung Transplant Recipients in the Setting of a Targeted Prophylaxis/Preemptive Antifungal Therapy Strategy.

Invasive pulmonary aspergillosis (IPA) is a significant cause of morbidity and mortality in lung transplant recipients (LTRs). It is unclear how a targeted prophylaxis/ preemptive antifungal therapy strategy impacts the incidence of IPA beyond the first-year posttransplant. This is a retrospective cohort of LTRs from January 2010 to December 2014. We included all LTRs who survived beyond the first year and followed them until death or 4 years postoperatively. Incidence of probable/proven IPA and Aspergillus colonization were assessed as per International Society for Heart and Lung Transplantation (ISHLT) criteria. Patients with risk factors, positive Aspergillus cultures, or galactomannan (GM) received targeted prophylaxis/preemptive therapy within the first-year posttransplant. During the study period, 350 consecutive LTRs underwent 1078 bronchoscopies. Positive bronchoalveolar lavage for GM or Aspergillus cultures was reported for 15% (52/350) of LTRs between 2 and 4 years after transplantation. Among them, the median time to positive Aspergillus culture or GM positivity was 703 days (interquartile range, 529-754 d). The incidence rate of IPA and Aspergillus colonization was 30 of 1000 patient-y, and 63 of 1000 patient-y, respectively. The mortality rate was significantly higher in patients with IPA than without IPA (107/1000 patient-years versus 18/1000 patient-years; P < 0.0001). Rate of first-year colonization and IPA was 33% and 9%, respectively. Among the 201 patients who had a negative bronchoscopy during the first year posttransplant, only 6 (3%) developed IPA during the follow-up. A targeted prophylaxis/preemptive therapy strategy within the first-year posttransplant resulted in 4% incidence of IPA at 4-years after transplantation. However, IPA was associated with higher mortality.

D-Index-Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial.

Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

Pre-emptive versus empirical antifungal therapy in immunocompromised children

Invasive fungal diseases are frequent causes of treatment-related morbidity and mortality in children with haematological malignancies or allogeneic haematopoietic stem-cell transplantation, and their control is an important goal of infectious-disease supportive care in these populations. Over the past three decades, several antifungal strategies have been developed to meet this goal, including antifungal prophylaxis, empirical antifungal therapy, and pre-emptive antifungal therapy. Although they are not mutually exclusive, each of these strategies is characterised by specific advantages and disadvantages, and the preference of a specific strategy depends on factors such as the local epidemiology, individual patient-related risk profiles, and the paediatric validation and availability of diagnostic options.

Candidemia in critically ill immunocompromised patients: report of a retrospective multicenter cohort study

BackgroundImmunocompromised critically ill patients constitute a population with the high risk of candidemia. This retrospective study aimed to assess the outcome of immunocompromised critically ill patients with candidemia. Secondary objectives were to describe clinical phenotypes of these patients, Candida ecology, and factors associated with mortality.ResultsOverall, 121 patients were included in this study. Median delay from candidemia to first antifungal therapy was 3 days, in line with the observed delay of blood culture positivity. Candia albicans was the main Candida specie identified (54%), and susceptibility of Candida to fluconazole and echinocandins was of, respectively, 70% and 92%. Hospital mortality was of 60%. After adjustment for confounders, severity as assessed by the need for vasopressors (HR 1.8, CI95% 1.1–3.1), need for mechanical ventilation (HR 2.0, CI95% 1.1–3.8) and allogenic stem cell transplantation (HR 2.5, CI95% 1.1–6.0) were independently associated with poor outcome. Candida specie, susceptibility and treatment strategies were not associated with outcome.ConclusionsCandidemia in immunocompromised critically ill patients is associated with a grim outcome. Despite the high prevalence of Candida non-albicans species, neither C. species nor its susceptibility was associated with outcome. Conversely, severity and preexisting allogeneic stem cell transplantation were independently associated with poor outcome. Despite antifungal prophylaxis and use of preemptive antifungal therapy in neutropenic patients, antifungal therapy was initiated three days after symptoms onset suggesting needs for specific strategies aiming to reduce this delay.