Risk Of Invasive Fungal Infections Research Articles

Ibrutinib Alone or in Combination with R-CHOP Chemoimmunotherapy in Relapsed or Refractory Primary Central Nervous System Lymphoma (rrPCNSL): A «Real-Life» Study

Background. Patients (pts) with rrPCNSL have poor prognosis, with median survival after relapse (SAR) of 3.5 months. No standard of care exists in this setting and a few drugs showed activity, usually assessed in small prospective series. Ibrutinib (IBR) monotherapy was associated with an overall response rate (ORR) of 47%-77%, with a few cases of complete response (CR), and a median progression-free survival (PFS) shorter than 5 months in two studies on 30 and 13 pts with rrPCNSL [Soussain et al, EJC 2019; Grommes et al, Cancer Disc 2017]. Confirmatory real-life studies are lacking, and the poor efficacy shown by ibrutinib as single drug has prompted physicians to use this drug in combination with chemoimmunotherapy. The choice often fell on RCHOP on the base of phase III PHOENIX trial [Younes et al. JCO 2019], where IBR + RCHOP was associated with a survival benefit in young pts with non-GCB DLBCL, the prevalent phenotype of PCNSL. Moreover, IBR demonstrated a permeabilizing effect on CNS tumor vessels in preclinical models [Meeks et al. NeuroOncol, 2019], posing the rationale for its combination with R-CHOP in rrPCNSL. Herein, we report tolerability and activity of IBR, alone or combined with RCHOP, in pts with rrPCNSL treated in open access program or compassionate use between January 2021 and June 2022 in 15 Italian centres. Methods. HIV-negative pts with rrPCNSL eligible for IBR and previously treated with a prior line of high-dose-methotrexate (HDMTX)-containing chemotherapy were registered in a retrospective multicenter study and analyzed on intention-to-treat (ITT) principle. Diagnosis of DLBCL was histologically confirmed in all cases. Response and toxicity were assessed and graded according to standardized IPCG criteria [Abrey et al, JCO 2005] and CTCAE v5.0, respectively. ORR was the primary endpoint. Since the increased risk of invasive fungal infection (IFI) reported in previous studies, physicians used Isavuconazole as antifungal prophylaxis. IBR dose and schedule were based on physician's preference. Results: Twenty-seven pts (median age 65, range: 42-77; 8 males) were considered (see tables 1 and 2 for pts characteristics and treatment). Twenty-five (93%) pts received IBR, with the addition of RCHOP (I-RCHOP) in 18; two pts died of progressive lymphoma before to start IBR. The median time from relapse to first IBR dose was 30 (range 10-70) days. Sixteen pts completed at least 2 cycles of RCHOP (median 3, range 1-6), while the other two did not because of infectious complications. Grade≥3 hematological and non-hematological toxicities occurred in 13 (52%) and 7 (28%) pts, respectively; all episodes of grade ≥3 toxicity but one occurred in the I-RCHOP group. The first 11 pts were treated without anti-fungal prophylaxis, three of them had IFI, which was lethal in two. Accordingly, the following pts received isavuconazole as prophylaxis, which was associated with a single case of grade-3 fungal infection. The four IFI occurred in the I-RCHOP group. Isavuconazole was well tolerated, with a single case of transient grade-3 toxicity (liver). The best response was CR in 7 pts (26%) and PR in 8 (30%), with an ORR of 56% (95% CI= 37-75), 13 experienced progressive disease (PD). Six pts with responsive disease (all of them treated with I-RCHOP) received consolidation with ASCT (3), WBRT (1), and/or IBR maintenance (3). At a median follow-up of 15 months (range 2 - 23), 5 responders experienced relapse, 7 remained relapse-free and two died of toxicity while relapse free, with a 1-year PFS and SAR of 26% (95% CI 5-56) and 29% (95% CI 6-54), respectively. Nine pts are alive: 5 (28%) after I-RCHOP and 4 (57%) after IBR alone. Overall, 5 pts (19%) are progression-free ≥12 months, all but one treated with I-RCHOP. Conclusions: This is the first real-life experience on the use of ibrutinib in pts with rrPCNSL. Two thirds of pts treated with I-RCHOP achieved an objective response, which encouraged physicians to indicate consolidation/maintenance, with consequent durable remission in 19% of pts. New IBR-based combinations should be addressed in rrPCNSL pts. In this setting, isavuconazole prophylaxis should be added to prevent IFI, an important life-threatening complication. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Survival and Outcomes after Relapse in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients Treated with Venetoclax-Based Chemotherapy

Background Venetoclax (bcl-2 inhibitor) was first approved in 2018 for use in combination with hypomethylating agents (HMA) or low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in older patients, or those who have comorbidities that preclude use of intensive induction chemotherapy. However, AML is also known to evolve and undergo clonal selection when treated with venetoclax, leading to treatment failure. Mechanisms for adaptive resistance include kinase activation (e.g. FLT3-ITD), clones that acquire biallelic silencing of TP53, and monocytic AML cells that upregulate MCL1 to evade BCL2 blockade. Other issues with venetoclax-based regimens include prolonged cytopenias and increased risk of infection. Our aim was to investigate survival after relapse, subsequent responses to second- line agents, and pattern of infections in patients treated with first-line venetoclax-based combination therapies. Methods This was a retrospective study of patients who received venetoclax-based regimens for untreated AML or myelodysplastic syndrome with excess blasts (MDS-EB) at LAC+USC Medical Center and Norris Cancer Center in Los Angeles, CA from January 1, 2018 to June 30, 2022. The electronic medical record was reviewed for demographics, disease characteristics, clinical history, transplant status, and survival. Results 61 patients received frontline venetoclax-based regimens for untreated AML or MDS-EB with a mean age of 65 (range 22-84); 36% were female, 44% non-Hispanic white and 31% were Hispanic/Latino. 41% had AML-MRC (myelodysplasia-related changes), 36% had De Novo AML, 16% had therapy-related AML, and 7% had MDS-EB. The majority (70%) were adverse risk group per ELN 2017 and 46% had complex cytogenetics. 58 patients had available myeloid mutation panel at time of diagnosis. The most common mutations (median allele frequencies) were: TP53=33% (0.45), ASXL1=17% (0.37), NPM1=16% (0.39), IDH2=9% (0.42), IDH1=7% (0.29), FLT3-ITD=5% (0.51). 70% received venetoclax with decitabine, 21% received venetoclax with azacitidine, and 2% received venetoclax with LDAC. Median number of cycles was 3 (1-16). 10 patients underwent allogeneic stem cell transplant. Out of 61 patients, 12 (20%) had primary refractory disease and 23 (38%) relapsed on frontline venetoclax. 49% of these relapsed/refractory patients received salvage chemotherapy. The median time to relapse and number of cycles prior to relapse was 6.3 months (1.6-17.4) and 4 (1-12) respectively. There was no correlation between cytogenetics and genetic variables and risk of relapse. Only 3 (19%) out of 16 patients and 3 (27%) out of 11 patients who received second- and third-line treatment achieved CRi respectively. Myeloid mutation panel was available for 12 patients at time of relapse. Most common mutations were FLT3-ITD/TKD (n=5), TP53 (n=3) and NPM1 (n=3). Six patients acquired new mutations at the time of relapse: FLT3-ITD (n=2), TP53 (n=1), WT1 (n=2) and ETV6 (n=1). Median time from relapse to death was 3 months (1-23). Median overall survival was 10.2 months. Median survival in responder compared to non-responders after cycle 1 and cycle 2 was 16.8 vs. 5.3 months (p <0.001) and 19.4 months vs. 7.4 months (p=0.031) respectively. Median survival in patients with relapse compared to non-relapse was 12.1 vs 6 months (p=0.187). 40 (66%) patients died; major causes of death were disease progression (50%), bleeding (10%) and infection (25%). 28% patients died in intensive care unit. 9 patients had fungal infections; most common were aspergillosis (n=5) and mucormycosis (n=2). Conclusions Venetoclax-based regimens are effective options for untreated AML in elderly patients. Response to first and second cycle of combination treatment predict survival. Although we observed clonal evolution in relapsed patients, it did not affect their survival. FLT3-ITD was a commonly acquired mutation at time of relapse, thus patients received salvage with targeted agents. Also, as patients relapse, the chance of attaining CR/CRi with subsequent lines of treatment is less than 30% and risk of invasive fungal infection was approximately 15%. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

When to Initiate Antifungal Treatment in COVID-19 Patients with Secondary Fungal Co-infection.

Severe-acute respiratory coronavirus 2 (SARS-CoV-2) has been driving the health care delivery system for over 2years. With time, many issues related to co-infections in COVID-19 patients are constantly surfacing. There have been numerous reports about various fungal co-infections in patients with COVID-19. The extent of severity of fungal pathogens has been recognized as a substantial cause of morbidity and mortality in this population. Awareness, understanding, and a systematic approach to managing fungal co-infections in COVID-19 patients are important. No guidelines have enumerated the stepwise approach to managing the fungal infections co-occurring with COVID-19. This review is intended to present an overview of the fungal co-infections in COVID-19 patients and their stepwise screening and management. The most common fungal infections that have been reported to co-exist with COVID-19 are Candidemia, Aspergillosis, and Mucormycosis. Prevalence of co-infections in COVID-19 patients has been reported to be much higher in hospitalized COVID-19 patients, especially those in intensive care units. While clear pathogenetic mechanisms have not been delineated, COVID-19 patients are at a high risk of invasive fungal infections. As secondary fungal infections have been challenging to treat in COVID-19 patients, as they tend to affect the critically ill or immunocompromised patients, a delay in diagnosis and treatment may be fatal. Antifungal drugs should be initiated with caution after carefully assessing the immune status of the patients, drug interactions, and adverse effects. The crucial factors in successfully treating fungal infections in COVID-19 patients are optimal diagnostic approach, routine screening, and timely initiation of antifungal therapy.

Calcineurin Inhibitors Synergize with Manogepix to Kill Diverse Human Fungal Pathogens.

Invasive fungal infections have mortality rates of 30–90%, depending on patient co-morbidities and the causative pathogen. The frequent emergence of drug resistance reduces the efficacy of currently approved treatment options, highlighting an urgent need for antifungals with new modes of action. Addressing this need, fosmanogepix (N-phosphonooxymethylene prodrug of manogepix; MGX) is the first in a new class of gepix drugs, and acts as a broad-spectrum, orally bioavailable inhibitor of the essential fungal glycosylphosphatidylinositol (GPI) acyltransferase Gwt1. MGX inhibits the growth of diverse fungal pathogens and causes accumulation of immature GPI-anchored proteins in the fungal endoplasmic reticulum. Relevant to the ongoing clinical development of fosmanogepix, we report a synergistic, fungicidal interaction between MGX and inhibitors of the protein phosphatase calcineurin against important human fungal pathogens. To investigate this synergy further, we evaluated a library of 124 conditional expression mutants covering 95% of the genes encoding proteins involved in GPI-anchor biosynthesis or proteins predicted to be GPI-anchored. Strong negative chemical-genetic interactions between the calcineurin inhibitor FK506 and eleven GPI-anchor biosynthesis genes were identified, indicating that calcineurin signalling is required for fungal tolerance to not only MGX, but to inhibition of the GPI-anchor biosynthesis pathway more broadly. Depletion of these GPI-anchor biosynthesis genes, like MGX treatment, also exposed fungal cell wall (1→3)-β-D-glucans. Taken together, these findings suggest the increased risk of invasive fungal infections associated with use of calcineurin inhibitors as immunosuppressants may be mitigated by their synergistic fungicidal interaction with (fos)manogepix and its ability to enhance exposure of immunostimulatory glucans.

Incidence and risk factors of bacterial sepsis and invasive fungal infection in neonates and infants requiring major surgery: an Italian multicentre prospective study

Limited data are currently available on the incidence rates and risk factors for bacterial sepsis and invasive fungal infections (IFIs) among neonates and infants undergoing major surgery. To assess the incidence of bacterial sepsis and IFI, fungal colonization, risk factors for sepsis, and mortality in neonates and infants aged <3 months undergoing major surgery. A multicentre prospective study was conducted involving 13 level-3 neonatal intensive care units in Italy, enrolling all infants aged ≤3 months undergoing major surgery. From 2018 to 2021, 541 patients were enrolled. During hospitalization, 248 patients had a bacterial infection, and 23 patients had a fungal infection. Eighty-four patients were colonized by fungal strains. Overall, in-hospital mortality was 2.8%, but this was higher in infected than in uninfected infants (P= 0.034). In multivariate analysis, antibiotic exposure before surgery, ultrasound-guided or surgical placement of vascular catheters, vascular catheterization duration, and gestational age ≤28 weeks were all associated with bacterial sepsis. The risk of IFI was markedly higher in colonized infants (odds ratio (OR): 8.20; P < 0.001) and was linearly associated with the duration of vascular catheterization. Fungal colonization in infants with abdominal surgery increased the probability of IFI 11-fold (OR: 11.1; P < 0.001). Preventive strategies such as early removal of vascular catheters and the fluconazole prophylaxis should be considered to prevent bacterial and fungal sepsis in infants undergoing abdominal surgery, and even more so in those with fungal colonization.

Antifungal stewardship in solid-organ transplantation: What is needed?

Antifungal stewardship (AFS) lags behind antimicrobial stewardship (AMS) in terms of implementation, evidence base, and workforce experience. Solid-organ transplantation (SOT) carries a significant risk of invasive fungal infection, with high associated mortality, and is therefore associated with significant opportunities to optimize antifungal use. A literature search for the terms "antifungal stewardship" and "solid-organ transplant" revealed a small evidence base to support AFS programs in this patient group. There is significant overlap in the methodology used in AMS and AFS programs, with notable differences in diagnostics, which are discussed in detail. The primary AFS interventions tested in SOT recipients are implementation of clinical guidelines and care bundles, digital enablers of AFS, and post-prescription review/audit and feedback. There is an urgent need for further research to support effective AFS strategies in this highly susceptible population.

P023 Evaluation of Beta-D-glucan assay as a tool for antifungal stewardship at a hospital in Mumbai, India

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMObjectivesClinical evidence suggests that the Beta-D glucan (BDG) test is useful as a tool for antifungal stewardship by helping in discontinuing empiric antifungal therapy. This study was hence initiated with the following objectives: (1) to calculate the percentage of echinocandin prescriptions in patients with a subsequent negative BDG test and the compliance to recommendations for stopping echinocandins for the above prescriptions, (2) to study outcomes in patients where echinocandins were stopped, and (3) to study the total cost savings.MethodsThe study was conducted for a 1-year period from January 2021 to December 2021 in a tertiary care hospital in Mumbai. The antimicrobial stewardship committee recommends sending a serum sample for BDG along with paired blood culture for all patients before starting empirical antifungal therapy. The choice of empiric antifungal therapy at our hospital is echinocandins (caspofungin, micafungin, and anidulafungin). The BDG test was performed using Fungitell® assay (Associates of Cape Cod, Massachusetts) that quantitatively measures 1, 3-β-D-glucan levels which is run twice a week on Wednesday and Saturday. The cut-offs for a negative, indeterminate and positive result are 60 pg/ml, 60-79 pg/ml, and >80 pg/ml respectively. The result of the BDG test and blood culture was promptly informed to the consultant in charge and recommendations were made to discontinue the echinocandin if both tests were negative. The compliance with these recommendations was monitored. The patients in whom the echinocandin was stopped were monitored during their hospital stay or on day 28 after stopping the echinocandin whichever was earlier. The total cost savings [in Indian Rupees (INR) and converted into US Dollars (USD)] were calculated based on an average of 10 days extra therapy with echinocandins.ResultsA total of 337 echinocandins were prescribed in 294 patients and reviewed during the study period; anidulafungin (170, 50%) was the most commonly prescribed echinocandin followed by caspofungin (131, 39%), and micafungin (36, 11%). The BDG result as well as blood fungal cultures were negative for 53 prescriptions in 49 patients (15.7%). The compliance to recommendations for stopping echinocandin in these prescriptions was 100% (53/53). None of these 49 patients had a sterile culture positive for Candida during the follow-up period. A total of 17 patients died, 1 was discharged against medical advice, 19 were discharged and 12 were still in hospital at the end of the follow-up period. No deaths could be attributed to invasive fungal infections at 28-day follow-up. Total cost savings were 6794 440 INR, corresponding to 89 000 USD during the study year.ConclusionBDG test-based stewardship strategy helped in reducing the use of echinocandins with cost savings and no increased risk of invasive fungal infections related to adverse outcomes in patients where echinocandins were discontinued. The universal compliance to recommendations to deescalate could be achieved by constant dialogue between the departments of Clinical Microbiology and Clinical Medicine.

SPECTRUM OF OPPORTUNISTIC FUNGAL INFECTIONS IN COVID-19 AFFECTED PATIENTS IN A TERTIARY CARE HOSPITAL

Background and aim: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread around the world. COVID-19 patients particularly those with Diabetes, Critically ill and Immunocompromised patients have higher probability of suffering from opportunistic fungal infections. Treatment of COVID19 with immunosuppressive agents (e.g. corticosteroids and cytokine blockers) remains a complicated challenge, especially among patients with severe disease which may increase the risk of invasive fungal infections. We studied the association of risk factors in COVID-19 affected patients leading to opportunistic fungal infections. A cross-sectional observationa Materials and Methods: l study was conducted on a total number of 500 clinically suspected cases of fungal infection attending ENT outpatient department during May 2021 to August 2021. Samples were processed and identied by direct microscopy and culture. A total number of 500 clinically susp Results: ected cases were screened for microscopy and culture. Of which 324 cases (64.8%) identied with fungal growth. Among these 324 cases, 51.5% were Aspergillosis, 31.4% were Mucormycosis, 12.9% were Candidiasis, 2.4% were mixed infection with Mucormycosis and Aspergillosis and 1.5% were identied with other opportunistic fungi. Out of 324 cases, known diabetics were 50% and non-diabetic with increase blood glucose levels were 22.8% and on steroid therapy were 66.3%. Most of the cases were presented in the recovery phase of COVID-19 (74%) than during the active phase (26%) of the infection. COVID-19 is associated with secondary fungal infections due to im Conclusion: mune dysregulation and the wide spread use of immunomodulatory drugs along with certain risk factors like diabetes mellitus and immunocompromised conditions. Judicious use of steroids and stringent glycemic control can prevent the severity of the disease. Early recognition of this life threatening infection is the key to allow for optimal treatment and improved outcomes.

Real‐world effectiveness of antifungal prophylaxis with posaconazole as the primary agent in patients with haematological malignancies

Patients undergoing induction/reinduction chemotherapy for haematologic malignancies (HM) are at risk for invasive fungal infections (IFIs). In 2015, Duke University Hospital (DUH) implemented a new standardised fungal prophylaxis protocol for adult patients undergoing induction chemotherapy for acute lymphocytic leukaemia, acute myelocytic leukaemia and myelodysplastic syndrome. This study assessed the impact of protocol implementation on (1) use of antifungal prophylaxis, throughout the at-risk period and (2) patient outcomes such as IFI and mortality. Retrospective, observational study of adult HM patients admitted to DUH for induction/reinduction chemotherapy pre- (7/1/2013-12/31/2014) and post- (1/1/2015-10/31/2016) implementation of standardised antifungal prophylaxis protocol (which recommended posaconazole as the first-line agent). Patients were followed for up to 100 days after initiation of induction chemotherapy to evaluate use of antifungal prophylaxis and patient outcomes. 218 patients with haematologic malignancies were included (90 pre, 128 post). Use of antifungal prophylaxis increased from 81.1% (pre) to 97.7% (post) (p < .0001). Overall, 71% received posaconazole as initial antifungal prophylaxis (64.4% pre, 75.7% post). Approximately one-fourth of patients (25.6%, pre vs 26.6%, post) developed an IFI (proven/probable or possible using modified EORTC definitions) (p=.868); 100-day mortality remained stable (18.9% pre vs 18.8% post, respectively, p=.979). Lack of antifungal prophylaxis and older age (≥60 years) were associated with higher risk of IFI. Implementation of a standardised protocol with posaconazole as the primary agent was associated with increased use of antifungal prophylaxis among patients undergoing induction/reinduction chemotherapy for haematologic malignancies in our hospital. Lack of antifungal prophylaxis was an independent predictor of IFIs, underscoring the importance of prophylaxis in this at-risk population.

A Quality Improvement Project Aimed at Standardizing the Prescribing of Fluconazole Prophylaxis in a Level IV Neonatal Intensive Care Unit.

Invasive candidiasis has a high morbidity and mortality among premature neonates. Antifungal prophylaxis with fluconazole significantly lowers the risk of invasive fungal infection in this population. We noted the use of fluconazole prophylaxis in our level IV neonatal intensive care unit (NICU) was variable and sought to standardize prescribing of prophylactic fluconazole. We formed a multidisciplinary team to develop an evidence-based protocol using literature and expert consensus to guide appropriate use of fluconazole prophylaxis in our level IV NICU. After determining baseline fluconazole prophylaxis prescribing before protocol implementation, we used plan-do-study-act (PDSA) cycles to introduce protocolized prescribing and incorporate it into daily practice. A 6-month intervention phase was followed by a 2-year control phase, in which monthly audits were performed to evaluate protocol adherence. Results were displayed in a statistical process control chart. Before protocol implementation, fluconazole prophylaxis prescribing adhered to the protocol in 81% of patients. During the first PDSA cycle, adherence increased significantly to 94.5% (86/91 patients), which further increased to 98.7% (74/75 patients) during the second PDSA cycle and remained at 96% (120/125 patients) during the control phase (P < 0.0001). A multidisciplinary group-designed protocol was successful in standardizing fluconazole prophylaxis prescribing for infants in the level IV NICU. Adherence to protocol was high following implementation and was sustained for the duration of the project. There were no cases of invasive candidiasis noted.

Relationship Between Invasive Fungal Infection and Hypostatic Pneumonia: A Prospective Cohort Study.

BackgroundThe short-term mortality of hypostatic pneumonia (HP) is very high, and the treatment outcome is poor. The clinical diagnosis and treatment are primarily focused on bacterial and viral infection, ignoring the role of fungal infection at present. This study aims to validate the relationship between Invasive Fungal Infections (IFI) and HP.MethodsIn the cross-sectional study, a total of 11,371 participants have been enrolled. In the prospective cohort study, 4,441 individuals have been included at baseline and followed up from 2015 to 2019 with a total person years of 8,484.65. The standard procedures were used to assess questionnaire investigations, laboratory testing, and anthropometric indicators. For data analysis, logistic regression, restricted cubic spline, log-rank regression, Cox regression, and linear mixed effects model were applied to assess the relationship between IFI and HP risk longitudinally.ResultsIn the cross-sectional study, elevated β-D-Glucan (BDG) concentrations are associated with a higher risk of HP prevalence in the total population, men, and women (ORT3 vs.T1 [95% CIs]: 2.12 [1.55, 2.91]; 2.01 [1.35, 2.99]; 2.34 [1.39, 3.94]), which were verified by a dose–effect relationship in the restricted cubic spline model. In the cohort study, Cox and Log-rank regression showed that the elevated BDG concentrations are associated with a significantly higher risk of HP incidence than participants with lower BDG concentrations (HRT3 vs.T1 [95% CIs]: 2.72 [1.36, 5.43], pLog–rank = 0.0086). During 5 years, the globulin (GLB) and C-reactive protein (CRP) were always on the top in the highest category of BDG concentrations. Between low and high BDG concentration, the total trend of GLB concentration was falling and the total trend of CRP concentration was rising with the increase of years (all the p-values < 0.0001).ConclusionIn this study, IFI is associated with a higher risk of HP, with time sequence and related mechanisms requiring further investigation in the future.

Effectiveness and safety of isavuconazole prophylaxis for invasive fungal infections in the haematologic setting

ABSTRACT Objectives Patients with haematologic malignancies are at high risk of developing invasive fungal infections (IFIs). Current guidelines recommend the use of azoles for IFI prophylaxis; however, in many clinical situations, antifungal prophylaxis is used off-label. We conducted a systematic literature review to provide haematologists with the available evidence on the effectiveness and safety of isavuconazole in IFI prophylaxis in interventional and real-world, observational studies. Methods Embase, MEDLINE and Cochrane Library databases, and relevant conference proceedings and clinical trial registries, were searched for studies on the effectiveness and safety of isavuconazole prophylaxis in adults at high risk of IFIs. Studies were assessed for inclusion and risk of bias. Results Nine studies were eligible for inclusion in the review, eight of which were in haematologic populations (patients undergoing haematopoietic stem cell transplantation or with acute myeloid leukaemia or myelodysplastic syndromes; n = 5) or included haematologic populations (n = 3). Evidence from these studies suggests isavuconazole is effective for IFI prophylaxis in the haematologic setting. However, the studies frequently lacked safety data, most were based on small patient populations from single centres and risk of bias could not be assessed for five studies. Discussion These findings provide evidence for isavuconazole as an alternative azole for prophylaxis in high-risk populations. Limitations include lack of applicability of risk of bias assessment tools, level of filtering applied in the search strategy and focus on English-language publications. Conclusion Isavuconazole may be an effective azole for IFI prophylaxis in high-risk haematologic populations, although further studies are needed.

Efficacy and Safety of Prophylactic Antifungal Agents in Preventing Invasive Fungal Infection and Mortality among Infants Weighing Less than 1500 Grams: A Meta-analysis

Background. Preterm infants with very low birth weight are at increased risk of invasive fungal infections. Preventive strategies are needed to improve their clinical course and survival.&#x0D; Objectives. To assess the efficacy and safety of antifungal agents as prophylaxis in controlling invasive fungal infection and mortality in very low birth weight (VLBW) and extremely low birth weight (ELBW) infants in neonatal intensive care units.&#x0D; Methods. We searched MEDLINE (PubMed), Cochrane databases, Google Scholar, Trip database, Herdin, and ClinicalTrials.gov without language restriction and publications from January 1988 to May 2021. We included randomized controlled trials or controlled clinical trials that compared the effect of prophylactic oral or systemic antifungal agents versus placebo in preterm infants &lt; 37 weeks age of gestation and with birth weight lower than 1500 grams. We conducted a meta-analysis using RevMan 5.4.1 and certainty of evidence rating using GRADEpro software.&#x0D; Results. A total of 14 studies (including 3,001 preterm infants with VLBW) were included. We found that prophylactic use of nystatin significantly reduced the incidence of invasive fungal infections (IFI) (pooled RR 0.16; 95% CI 0.11, 0.23; 4 RCTs, N = 1295; P &lt; 0.00001; moderate certainty evidence) in preterm infants compared to placebo but had no significant effect on the mortality (RR 0.87; 95% CI 0.62, 1.23; 4 RCTs, N = 1295; P = 0.43; low certainty evidence). Similarly, fluconazole decreased the incidence of IFI (RR 0.38; 95% CI 0.28, 0.53; P = 0.02) and showed statistically significant reduction in mortality (RR 0.78; 95% CI 0.61, 0.99; RCTs, N = 1484; P = 0.04; high certainty evidence). The comparison of the two antifungals showed a trend favoring fluconazole, however the difference was not statistically significant in decreasing IFI (RR 1.60; 95% CI 0.68, 3.77; P = 0.28) and mortality (RR 1.62; 95% CI 0.76, 3.45; P = 0.21).&#x0D; Conclusion. Administration of antifungal prophylaxis proves to be beneficial and can probably decrease invasive fungal infection and mortality. The evidence showed that Fluconazole is superior as antifungal prophylaxis compared to placebo while there is no significant difference between fluconazole and nystatin in decreasing fungal infection and mortality among preterm neonates.

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.

Advances in prophylaxis and treatment of invasive fungal infections: perspectives on hematologic diseases.

Invasive fungal infections (IFIs) are common causes of mortality and morbidity in patients with hematologic diseases. Delayed initiation of antifungal treatment is related to mortality. Aspergillus sp. is the leading cause of IFI followed by Candida sp. Diagnosis is often challenging owing to variable conditions related to underlying diseases. Clinical suspect and prompt management is important. Imaging, biopsy, and non-culture-based tests must be considered together. New diagnostic procedures have been improved, including antigen-based assays and molecular detection of fungal DNA. Among hematologic diseases, patients with acute myeloid leukemia, myelodysplastic syndrome, recipients of hematopoietic stem cell transplantation are at high risk for IFIs. Antifungal prophylaxis is recommended for these high-risk patients. There are continuous attempts to achieve ideal management of IFIs. Scoring system for quality control has been developed with important recommendations of current guidelines. Higher adherence to guidelines is related to decreased mortality in IFIs.

Fungal Infections in Critically Ill COVID-19 Patients: Inevitabile Malum.

Patients with severe COVID-19 belong to a population at high risk of invasive fungal infections (IFIs), with a reported incidence of IFIs in critically ill COVID-19 patients ranging between 5% and 26.7%. Common factors in these patients, such as multiple organ failure, immunomodulating/immunocompromising treatments, the longer time on mechanical ventilation, renal replacement therapy or extracorporeal membrane oxygenation, make them vulnerable candidates for fungal infections. In addition to that, SARS-CoV2 itself is associated with significant dysfunction in the patient’s immune system involving both innate and acquired immunity, with reduction in both CD4+ T and CD8+ T lymphocyte counts and cytokine storm. The emerging question is whether SARS-CoV-2 inherently predisposes critically ill patients to fungal infections or the immunosuppressive therapy constitutes the igniting factor for invasive mycoses. To approach the dilemma, one must consider the unique pathogenicity of SARS-CoV-2 with the deranged immune response it provokes, review the well-known effects of immunosuppressants and finally refer to current literature to probe possible causal relationships, synergistic effects or independent risk factors. In this review, we aimed to identify the prevalence, risk factors and mortality associated with IFIs in mechanically ventilated patients with COVID-19.

Risk Factors for Invasive Fungal Infections in Heart Transplant Recipients

<h3>Purpose</h3> Heart transplant (HT) recipients are at risk for invasive fungal infection (IFI), a potentially fatal complication. However, data on predictors of IFI in this patient population are sparse. Our goal was to identify pretransplant and posttransplant risk factors for IFI after HT. Additionally, we sought to assess overall survival and one-year mortality among patients with or without IFI. <h3>Methods</h3> We conducted a retrospective, case-control study in consecutive HT recipients at a single center between 2/1/2014-3/31/2020. Electronic medical records were reviewed to collect the following: demographics, peri-operative and operative characteristics, IFI diagnosis, and mortality. We included IFI cases that were classified as probable or proven according to EORTC/MSG criteria. Statistically significant variables in the univariate analysis were introduced into a multivariate logistic regression model using backward stepwise selection to identify predictors of IFI. The impact of IFIs on overall survival and one-year mortality were assessed using Kaplan-Meier estimation. <h3>Results</h3> We identified 25 cases of IFI among 248 HT recipients, occurring at median 79 days (IQR 15-303 days) following HT. Significant risk factors for IFI on multivariate analysis included an increased length of postoperative intensive care unit (ICU) stay (OR 1.07, 95% CI 1.02-1.12), pretransplant hemodialysis (OR 3.83, 95% CI 1.05-12.58), and African American race (OR 3.18, 95% CI 1.08-8.79). The cumulative incidence of IFI was 10.1%. IFI was associated with death (HR 3.28, 95% CI 1.41-7.64, <i>p</i>=.004) and 1-year mortality (HR 7.16, 95% CI 2.48-20.65, p<0.001). <h3>Conclusion</h3> Identification of local risk factors will allow us to develop a targeted antifungal prophylaxis protocol. Hemodialysis and longer ICU stays have been associated with IFI in other studies as well but the association with African American race is new and must be validated. Optimal strategies addressing antifungal prophylaxis and risk reduction for IFI need to be addressed to improve patient outcomes and survival.

Donor and Peri-Transplant Hospitalization Risk Factors for Invasive Fungal Infection in Lung Transplant Recipients

<h3>Purpose</h3> Invasive fungal infections (IFIs) remain a frequent complication in the lung transplant (LTx) population even in the current era of antifungal prophylaxis. The organ donor and peri-transplant period risk factors for IFI remain ill-defined. Our study goal is to identify novel risk factors for IFI, focusing on the organ donor and the recipient's transplant hospitalization. <h3>Methods</h3> We performed a single-center, case-control study. The source cohort included all adults who underwent LTx between 1/1/12-3/31/17. The primary outcome was a Probable or Proven IFI within 6 months of transplantation, as defined by EORTC/MSG criteria. Multivariable logistic regression and Cox proportional hazard regression analyses were used to identify independent risk factors for IFI. <h3>Results</h3> Of 329 LTx recipients, 45 (14%) developed IFI. The median time to IFI was 50 days (IQR: 25-110) after transplantation. Independent risk factors for IFI included: donor steroid pre-conditioning (aOR 2.24, 95%CI: 1.05-4.77, p=0.04); cardiopulmonary bypass (aOR 3.07, 95%CI: 1.06-8.87, p=0.04); ICU length of stay >30 days (aOR 3.34, 95%CI: 1.48-75, p<0.01); and bronchial anastomotic dehiscence (aOR 14.06, 95%CI: 1.99-99.34, p=0.01). Mold isolated on donor respiratory culture increased the hazard of IFI in LTx recipients (Table 1). Peri-transplant hospitalization complications that increased the hazard of IFI included: multiple positive fungal cultures, airway ischemia, and prolonged ICU stay (Table 1). Fungal treatment for ≥90 days after transplant was protective against development of IFI (Table 1). <h3>Conclusion</h3> IFI was common in our LTx cohort. Certain donor characteristics and peri-transplant complications increased the likelihood of IFI. Interventional studies, targeting the modifiable risk factors identified in this study, are needed to reduce IFI risk in LTx recipients.

A High-Risk Profile for Invasive Fungal Infections Is Associated with Altered Nasal Microbiota and Niche Determinants.

It is becoming increasingly clear that the communities of microorganisms that populate the surfaces exposed to the external environment, termed microbiota, are key players in the regulation of pathogen-host cross talk affecting the onset as well as the outcome of infectious diseases. We have performed a multicenter, prospective, observational study in which nasal and oropharyngeal swabs were collected for microbiota predicting the risk of invasive fungal infections (IFIs) in patients with hematological malignancies. Here, we demonstrate that the nasal and oropharyngeal microbiota are different, although similar characteristics differentiate high-risk from low-risk samples at both sites. Indeed, similar to previously published results on the oropharyngeal microbiota, high-risk samples in the nose were characterized by low diversity, a loss of beneficial bacteria, and an expansion of potentially pathogenic taxa, in the presence of reduced levels of tryptophan (Trp). At variance with oropharyngeal samples, however, low Trp levels were associated with defective host-derived kynurenine production, suggesting reduced tolerance mechanisms at the nasal mucosal surface. This was accompanied by reduced levels of the chemokine interleukin-8 (IL-8), likely associated with a reduced recruitment of neutrophils and impaired fungal clearance. Thus, the nasal and pharyngeal microbiomes of hematological patients provide complementary information that could improve predictive tools for the risk of IFI in hematological patients.

Fluconazole-Induced adrenal insufficiency following allogeneic hematopoietic cell transplant

Adrenal insufficiency (AI) is a potentially life-threatening endocrine abnormality rarely associated with azole antifungals. Patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) are at high risk of invasive fungal infection and frequently receive azoles. Signs and symptoms of AI, such as gastrointestinal symptoms, lethargy, and electrolyte disturbances frequently overlap with common alloHCT toxicities, such that azole-induced AI may be under-reported in this population. We report the first published case of azole-induced AI following alloHCT. The patient presented with orthostasis and nonspecific gastrointestinal and failure to thrive symptoms in the setting of roughly 6 weeks of fluconazole prophylaxis. The patient was found to have primary AI diagnosed via low serum cortisol and inadequate response to cosyntropin. AI symptoms resolved with hydrocortisone supplementation and recurred upon rechallenge with fluconazole. The patient had fluconazole permanently discontinued with resolution of symptoms. We rate this case as a probable adverse drug reaction on the Naranjo scale. AI may be underreported and misdiagnosed in the alloHCT population given the presence of multiple toxicities with overlapping features. Clinicians must be diligent in investigating adrenal function in patients undergoing alloHCT on azole antifungals who present with symptoms of AI.