Burden Of Invasive Fungal Infections Research Articles

Characteristics and risk factors for invasive fungal infection in hospitalized patients with acute-on-chronic hepatitis B liver failure: a retrospective cohort study from 2010 to 2023.

The global burden of invasive fungal infections (IFIs) is emerging in immunologic deficiency status from various disease. Patients with acute-on-chronic hepatitis B liver failure (ACHBLF) are prone to IFI and their conditions are commonly exacerbated by IFI. However, little is known about the characteristics and risk factors for IFI in hospitalized ACHBLF patients. A total of 243 hospitalized ACHBLF patients were retrospectively enrolled from January 2010 to July 2023. We performed restricted cubic spline analysis to determine the non-linear associations between independent variables and IFI. The risk factors for IFI were identified using logistic regression and the extreme gradient boosting (XGBoost) algorithm. The effect values of the risk factors were determined by the SHapley Additive exPlanations (SHAP) method. There were 24 ACHBLF patients (9.84%) who developed IFI on average 17.5 (13.50, 23.00) days after admission. The serum creatinine level showed a non-linear association with the possibility of IFI. Multiple logistic regression revealed that length of hospitalization (OR = 1.05, 95% CI: 1.02-1.08, P = 0.002) and neutrophilic granulocyte percentage (OR = 1.04, 95% CI: 1.00-1.09, P = 0.042) were independent risk factors for IFI. The XGBoost algorithm showed that the use of antibiotics (SHAP value = 0.446), length of hospitalization (SHAP value = 0.406) and log (qHBV DNA) (SHAP value = 0.206) were the top three independent risk factors for IFI. Furthermore, interaction analysis revealed no multiplicative effects between the use of antibiotics and the use of glucocorticoids (P = 0.990). IFI is a rare complication that leads to high mortality in hospitalized ACHBLF patients, and a high neutrophilic granulocyte percentage and length of hospitalization are independent risk factors for the occurrence of IFI.

Time to Think Antifungal Resistance Increased Antifungal Resistance Exacerbates the Burden of Fungal Infections Including Resistant Dermatomycoses.

Increased antifungal resistance is exacerbating the burden of invasive fungal infections, as well as potentially contributing to the increase in resistant dermatomycoses. In this commentary, we focus on antifungal drug resistance, in contrast to antibacterial resistance. We provide a brief historical perspective on the emergence of antifungal resistance and propose measures for combating this growing health concern. The increase in the incidence of invasive and cutaneous fungal infections parallels advancements in medical interventions, such as immunosuppressive drugs, to manage cancer and reduce organ rejection following transplant. A disturbing relatively new trend in antifungal resistance is the observation of several fungal species that now exhibit multidrug resistance (eg, Candida auris, Trichophyton indotineae). Increasing awareness of these multidrug-resistant species is paramount. Therefore, increased education regarding potential fungus-associated infections is needed to address awareness in the general healthcare setting, which may result in a more realistic picture of the prevalence of antifungal-resistant infections. In addition to education, increased use of diagnostic tests (eg, micro and macro conventional assays or molecular testing) should be routine for healthcare providers facing an unknown fungal infection. Two critical barriers that affect the low rates for Antifungal Susceptibility Testing (AST) are low (or a lack of) sufficient insurance reimbursement rates and the low number of qualified laboratories with the capacity to perform AST. The ultimate aim is to improve the quality of patient care through fungal identification, diagnosis, and, where appropriate, susceptibility testing. Here we propose an all-encompassing call to action to address this emerging challenge.

The Austrian landscape of diagnostic capacity and access to treatment for invasive fungal infections.

Immunosuppression after chemotherapy, stem cell transplantation or solid organ transplantation are the main risk factors for invasive fungal infections in Austria. Here, we aim to describe the status of laboratory mycology and the access to antifungal treatment in Austria. Between October and November 2021, hospitals were contacted to participate in our online survey: www.clinicalsurveys.net/uc/IFI_management_capacity/. Centres were required to provide information on their institutional profile; self-assessment of burden of invasive fungal infections; access to microscopy, culture, serology, antigen detection and molecular testing; and availability of antifungal agents and therapeutic drug monitoring. Responses were collected from university hospitals and laboratories in Graz, Innsbruck, Linz and Vienna. The four hospitals can provide tertiary care and were highly specialised, including management of patients with severe immunosuppression. All sites consider the incidence of invasive fungal infections to be moderate. Access to microscopy, culture, serology, antigen detection and molecular testing is provided regardless of laboratory. The maximum capacity to identify fungi varies from institution to institution. All currently marketed antifungal agents are available at the four sites. Austria is currently well equipped to deal with the emerging threat of invasive fungal infections. However, hospitals may consider preparing for the potential endemicity of certain infections in the near future.

Availability of Systemic Antifungals in Africa: A Comparative Study between North Africa and West Africa

Introduction. Due to the lack of systemic antifungals (SAs), many invasive fungal infections (IFIs) do not yet benefit from effective treatment in Africa. Yet, fungi are a major threat to human health. This study aimed to assess the availability of SAs and compare this availability between West Africa (WA) and North Africa (NA). Materials and methods. The information processed was obtained during the same period between February and June 2021 in Senegal, Mauritania, and Côte d’Ivoire as well as in Morocco and Tunisia. In WA, data were received from wholesale drug suppliers and private pharmacies while in NA, the data were those available on the websites of the pharmacy and drug directorates. Results. All classes of SAs were available. However, this availability was not uniform depending on location, whether in WA or NA. Fluconazole and itraconazole were the only SA available in WA. In NA, all classes of SAs have been found, particularly in Morocco, while flucytosine was the only molecule absent in Tunisia. Conclusion. NA is ahead of WA as regards the burden of IFIs both diagnostically and in the availability of SAs. Studies on the epidemiology of IFIs in Africa, particularly in WA, are limited. The partial data available highlight that IFIs are not negligible, though these may be underestimated. Thus, a network based on the directory of African pharmacy and drug directorates must be set up and run in collaboration with the national laboratory directorates for the harmonization of procedures in order to reduce morbidity and mortality related to IFIs.

294. Risk factors of COVID-19 associated pulmonary aspergillosis in a high endemic setting and development of a bedside clinical risk prediction score.

Abstract Background India has a high burden of invasive fungal infections. Although invasive aspergillosis was also reported during the COVID-19 pandemic, the real world data on the risk factors and outcome of CAPA are limited. Our aim is to determine risk factors and clinical outcomes of CAPA and develop a prediction model for patient stratification. Methods A retrospective, case-control study was conducted at a 1300-bedded South Indian tertiary care academic centre from June 1st, 2020 to May 31st, 2021. CAPA cases were defined by 2020 ECMM/ISHAM consensus criteria as possible, probable, and proven infection. Age and admission period matched control group with COVID-19 but without aspergillosis was selected in a 1:1 ratio. A risk scoring stratification for CAPA was developed based on the significant CAPA risk factors using logistic regression model. Figure 1:Receiving operating characteristic curve of CAPA incidence score for predicting CAPA in the study cohort Results 95 CAPA cases, of which 75(79%) were probable and 20(21%) possible, were diagnosed during the study period. 84(88.4%) patients had moderate to severe COVID-19, and 75(78.9%) were treated with steroids, most commonly dexamethasone (Table 1). The time from COVID-19 diagnosis to CAPA was 13 days (IQR 12). 40(42.1%) of patients were on mechanical ventilation at CAPA diagnosis. Outcome measures (MV, NIV and hospital/ICU stay) were significantly higher in CAPA patients compared to controls(Table 2). Neutropenia, use of steroids, broad spectrum antibiotic use, fluconazole prophylaxis and absence of co-infecting pathogen were found to be significant factors associated with CAPA(p< 0.05) (Table 3). An optimal risk score of ≥10.00 predicted CAPA with a sensitivity of 84.2% and a specificity of 59% with an area under the curve of 0.77 (PPV=67.23%, NPV=78.87%)(Fig 1). 75(78.9%) patients had positive serum aspergillus galactomannan with an average value of 1.89±1.65. 28-day (41.1% vs 33.7%, p=0.13) and 6-week all cause-mortality (48.4% vs 37.9%, p=0.07) were higher, but not statistically significant, for CAPA. Table 1:Baseline characteristics and risk factorsTable 2:Primary and secondary outcomesTable 3:CAPA incidence scoring table Significant univariate variables were included in the multivariate logistic regression model and predicted probabilities based on the beta co-efficients of the significant variables in the model were transformed to generate CAPA incidence score for patients. Conclusion Risk factors of CAPA in Indian were similar to those reported previously in other countries. CAPA can be seen in severe COVID-19 patients who are not mechanically ventilated. A CAPA risk scoring system, that needs external validation, is a simple and feasible tool that could be useful in stratification of patients suspected of CAPA. Disclosures All Authors: No reported disclosures.

TNP Analogues Inhibit the Virulence Promoting IP3-4 Kinase Arg1 in the Fungal Pathogen Cryptococcus neoformans.

New antifungals with unique modes of action are urgently needed to treat the increasing global burden of invasive fungal infections. The fungal inositol polyphosphate kinase (IPK) pathway, comprised of IPKs that convert IP3 to IP8, provides a promising new target due to its impact on multiple, critical cellular functions and, unlike in mammalian cells, its lack of redundancy. Nearly all IPKs in the fungal pathway are essential for virulence, with IP3-4 kinase (IP3-4K) the most critical. The dibenzylaminopurine compound, N2-(m-trifluorobenzylamino)-N6-(p-nitrobenzylamino)purine (TNP), is a commercially available inhibitor of mammalian IPKs. The ability of TNP to be adapted as an inhibitor of fungal IP3-4K has not been investigated. We purified IP3-4K from the human pathogens, Cryptococcus neoformans and Candida albicans, and optimised enzyme and surface plasmon resonance (SPR) assays to determine the half inhibitory concentration (IC50) and binding affinity (KD), respectively, of TNP and 38 analogues. A novel chemical route was developed to efficiently prepare TNP analogues. TNP and its analogues demonstrated inhibition of recombinant IP3-4K from C. neoformans (CnArg1) at low µM IC50s, but not IP3-4K from C. albicans (CaIpk2) and many analogues exhibited selectivity for CnArg1 over the human equivalent, HsIPMK. Our results provide a foundation for improving potency and selectivity of the TNP series for fungal IP3-4K.

Antifungal Drugs TDM: Trends and Update.

The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure. More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available. TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

The rising burden of invasive fungal infections in COVID-19, can structured CT thorax change the game

BackgroundThe occurrence of invasive fungal infections in COVID-19 patients is on surge in countries like India. Several reports related to rhino-nasal-sinus mucormycosis in COVID patients have been published in recent times; however, very less has been reported about invasive pulmonary fungal infections caused mainly by mucor, aspergillus or invasive candida species. We aimed to present 6 sputum culture proved cases of invasive pulmonary fungal infection (four mucormycosis and two invasive candidiasis) in COVID patients, the clues for the diagnosis of fungal invasion as well as difficulties in diagnosing it due to superimposed COVID imaging features.Case presentationThe HRCT imaging features of the all 6 patients showed signs of fungal invasion in the form of cavities formation in the pre-existing reverse halo lesions or development of new irregular margined soft tissue attenuating growth within the pre-existing or in newly formed cavities. Five out of six patients were diabetics. Cavities in cases 1, 2, 3 and 4 of mucormycosis were aggressive and relatively larger and showed relatively faster progression into cavities in comparison with cases 5 and 6 of invasive candidiasis.ConclusionIn poorly managed diabetics or with other immunosuppressed conditions, invasive fungal infection (mucormycosis, invasive aspergillosis and invasive candidiasis) should be considered in the differential diagnosis of cavitary lung lesions.

Fungal infections in transplant recipients: pros and cons of immunosuppressive and antimicrobial treatment

Fungal infections in transplant recipients: pros and cons of immunosuppressive and antimicrobial treatment

Overview on common fungal infections, recovered in Baghdad teaching hospitals in five years

Objective: To evaluate the burden of invasive fungal infections , recovered in a group of patients who were non responsive to antibiotic therapy and have been referred from some Iraqi hospitals in five years interval in a clinical and microbiological scope.
 Methods: 
 Samples were collected during from the 25th of May 2012 to 5th of November 2017 enrolled 1444 Iraqi adult patients who referred by hematology-oncology unit, medical wards, bone marrow transplant unit and respiratory care unit with some other cases received from other hospitals in the capital Baghdad. samples from any infected sites were sent to the central medical mycology lab to identify the causative fungi using wet mount, direct examination, culture and sensitivity tests, biochemical and some serological examinations as galactomannan testing for invasive aspergillosis and PCR test to detect some pathological properties of a group of Aspergillus species.
 
 Results
 Although (26,6%) 387 samples revealed no fungal isolates most of them were of blood culture. The commonest fungus noticed in all samples was Cryptococcus neoformans in the first place 646 samples (38.63%), the next was Candida albicans and non albicans in 594 samples (35.52%).Aspergillus species in 252 samples (15.07%) ,Penicillium 27 samples (1.61%) ,Gieotrichum candidum15 samples (0.89),Zygomycetes and Rhizopus 20 (1.18% ),Trichosporon and Rhodotorula glutinis yeasts 14 )0.83%(, Sporothrixes schenkii 5(0.29%),2(0.11%) two cases of systemic mycosis one Histoplasma capsulatum and the other is Coccidiomycosis immitus .
 Conclusions: The incidence of fungal infection is greatly increased in Iraq in relation to global and local risk factors with tendency for multiple fungal isolates in one patient. represents a major health problem in a wide variety of disease conditions ranging from hematology oncology to uncontrolled diabetic cases. with high case of fatality among hematological malignancies with neutropenia.

Epidemiology and management burden of invasive fungal infections after autologous hematopoietic stem cell transplantation: 10-year experience at a European Pediatric Cancer Center.

Autologous hematopoietic stem cell transplantation (HSCT) carries risks of infectious morbidity. We analysed epidemiology and management burden associated with invasive fungal diseases (IFDs) in children and adolescents undergoing autologous HSCT. In a retrospective, single-centre observational study, epidemiology and management burden associated with IFDs were analysed in all paediatric cancer patients who underwent autologous HSCT between 2005 and 2014. Clinical, radiographic and microbiological data were assessed up to 100days post-transplant. The primary endpoint was the incidence of proven, probable and possible IFDs. Further endpoints included the use of systemic antifungal agents for prevention and management of IFDs; infectious and non-infectious comorbidities; and survival until day+100. Of 95 patients (median age: 8years; r, 0.75-20) underwent 103 HSCT procedures for solid tumours (92) or lymphoma (11). Primary antifungal prophylaxis was administered in 49 procedures (47.5%). No single case of proven/probable IFD was diagnosed. Nine cases (8.7%) fulfilled criteria of possible pulmonary mould infection and received treatment for a median of 14days (r, 7-35). In an additional 12 procedures, empiric antifungal therapy with mould active agents was given for a median of 8days (r, 3-105). Microbiologically documented non-fungal infections were observed in 17 procedures, and five patients were transferred to the ICU. There was one death from biopsy documented toxic endothelial damage at day 83 post-transplant. Autologous HSCT for solid tumours or lymphoma was associated with low morbidity from IFDs. However, utilisation of systemic antifungal agents for prevention and management of suspected IFDs was considerable.

Epidemiology and burden of invasive fungal infections in the countries of the Arab League

The burden of invasive fungal infections is alarming worldwide. The aim of this paper is to review the published literature and evaluate the knowledge gap pertaining to studies on invasive fungal infections in the countries of the Arab League. Few countries from this region have published reports. The most commonly studied invasive fungal infections is invasive candidiasis. Candida albicans remains overall the most common causative pathogen (33.8–60%), however, non-albicans Candida species are increasing. Antifungal susceptibility testing is non-standardized across the published studies. Data on aspergillosis and other fungal infections is scarce. This sheds light on the need for standardized surveillance in the region encompassing more countries of the Arab League to guide diagnostic approach and empiric therapy.

Treatment of immunocompromised patients with suspected invasive fungal infections: economic analysis of diagnostic-driven versus empirical strategies in Algeria and Egypt

ABSTRACTBackground: Invasive fungal infections (IFIs) in immunocompromised patients are associated with high mortality and treatment costs. Identifying appropriate, cost-effective treatment strategies is crucial to reduce the burden of IFIs. This economic assessment compared strategies for treating immunocompromised patients in Algeria and Egypt.Methods: We developed a decision analytic model incorporating clinical and cost inputs associated with a diagnostic-driven (DD) and standard empirical (SE) strategy. Costs and clinical outcomes were used to calculate incremental cost-effectiveness ratios (ICERs) per death avoided.Results: In both countries, 73.8 (DD) and 125.3 (SE) hypothetical patients per 1,000 received antifungal therapy; 73.8 (DD) and 32.7 (SE) had diagnosed IFIs. Survival at 180 days was similar between DD and SE strategies in Algeria (92.0% vs 91.6%) and Egypt (90.2% vs 90.0%). Total costs per patient were lower with the DD than SE strategy (Algeria: $839 vs $1,591; Egypt: $4,077 vs $4,717). ICERs indicated that the DD compared with SE strategy was associated with better clinical outcomes at a lower overall cost in both countries.Conclusion: Diagnostic-driven compared to empirical therapy may be cost-saving in Algeria and Egypt for the management of immunocompromised patients with persistent neutropenic fever, with no increase in mortality.

Dying with or Because of Invasive Fungal Infection? The Role of Immunity Exhaustion on Patient Outcome.

De Rosa et al. considered clinical scores, biomarkers and their combination as useful aids for an early antifungal treatment and advocated the adoption of de-escalation therapy in an antifungal stewardship approach as a possible key for a better management of these patients. Authors considered the high burden of invasive fungal infections in terms of patient outcomes and costs and focused on current strategies for their optimization.

Underestimating the Real Burden of Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients?

Underestimating the Real Burden of Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients?

Prospective Surveillance for Invasive Fungal Infections in Hematopoietic Stem Cell Transplant Recipients, 2001–2006: Overview of the Transplant‐Associated Infection Surveillance Network (TRANSNET) Database

The incidence and epidemiology of invasive fungal infections (IFIs), a leading cause of death among hematopoeitic stem cell transplant (HSCT) recipients, are derived mainly from single-institution retrospective studies. The Transplant Associated Infections Surveillance Network, a network of 23 US transplant centers, prospectively enrolled HSCT recipients with proven and probable IFIs occurring between March 2001 and March 2006. We collected denominator data on all HSCTs preformed at each site and clinical, diagnostic, and outcome information for each IFI case. To estimate trends in IFI, we calculated the 12-month cumulative incidence among 9 sequential subcohorts. We identified 983 IFIs among 875 HSCT recipients. The median age of the patients was 49 years; 60% were male. Invasive aspergillosis (43%), invasive candidiasis (28%), and zygomycosis (8%) were the most common IFIs. Fifty-nine percent and 61% of IFIs were recognized within 60 days of neutropenia and graft-versus-host disease, respectively. Median onset of candidiasis and aspergillosis after HSCT was 61 days and 99 days, respectively. Within a cohort of 16,200 HSCT recipients who received their first transplants between March 2001 and September 2005 and were followed up through March 2006, we identified 718 IFIs in 639 persons. Twelve-month cumulative incidences, based on the first IFI, were 7.7 cases per 100 transplants for matched unrelated allogeneic, 8.1 cases per 100 transplants for mismatched-related allogeneic, 5.8 cases per 100 transplants for matched-related allogeneic, and 1.2 cases per 100 transplants for autologous HSCT. In this national prospective surveillance study of IFIs in HSCT recipients, the cumulative incidence was highest for aspergillosis, followed by candidiasis. Understanding the epidemiologic trends and burden of IFIs may lead to improved management strategies and study design.

Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents

Invasive candidiasis and invasive mold infections cause significant morbidity and mortality in the hematopoietic stem cell transplant population, in particular in recipients of allografts. The introduction of a variety of new antifungal compounds over the past decade has focused attention on prophylactic strategies as a means to decrease the burden of invasive fungal infections (IFIs). Until recently, fluconazole has been the standard agent for prophylaxis before and after engraftment. In 2005, the echinocandin micafungin received US FDA approval for prophylaxis against IFIs in stem cell transplant recipients during the neutropenic period prior to engraftment. In patients with substantial risk for invasive mold infection, many centers now use a mold-active antifungal agent (e.g., a triazole such as itraconazole, voriconazole or posaconazole, or an echinocandin) as prophylaxis after engraftment. Several recent studies have highlighted the efficacy of these newer agents in preventing IFIs in these highly immunocompromised patients. This review will discuss current issues in IFI and new agents available for prophylaxis in allogeneic hematopoietic stem cell transplant recipients.