non-Aspergillus Molds Research Articles

Invasive mould infection in immunocompromised children: Pulmonary computed tomography findings from two multicentre paediatric cohorts

BackgroundInvasive fungal disease (IFD) can cause significant morbidity in immunocompromised children. The lung is the most common site for IFD caused by moulds. Timely diagnosis is key to facilitate initiation of appropriate treatment. As clinical manifestations are non-specific, initial diagnosis relies on computed tomography (CT) imaging, yet there are limited recent data documenting imaging changes in paediatric pulmonary IFD. In this study, CT images of children with proven/probable pulmonary IFD from two multi-centre cohorts were assessed to document typical changes, including a comparison between causative pathogens, and to measure reliability of radiological reporting in this context. MethodsPulmonary IFD cases diagnosed between 2003–2013 and 2017–2020 were identified from two respective Australian multi-centre cohort studies of immunocompromised children. Proven/probable IFD was defined according to the EORTC/MSG definitions. Initial CT images at the time of IFD diagnosis were independently reviewed by two board-certified paediatric radiologists. Presence of EORTC/MSG-defined and other changes was documented. Inter-rater reliability was assessed. Impact of specific imaging features on outcome at 6 months was assessed using multivariate regression. ResultsA total of 99 cases were included (65 aspergillosis, 19 non-aspergillus moulds (NAM) and 15 histopathological-mould cases). Median age was 9.6 years (IQR 5.1–13.6); 89.9 % had an underlying haematological malignancy. Nodules (85.4 %), the halo sign (49.5 %) and wedge shaped/segmental consolidation (35.9 %) were the most frequent EORTC/MSG-defined features. Cavitation and air-crescent sign were uncommon. Agreement between radiologists was fair to moderate for most common imaging features. No specific radiological finding differentiated aspergillosis from NAM infection. The presence of mass on initial CT and NAM infection were independently associated with poor outcome. ConclusionsIn proven/probable pulmonary IFD in immunocompromised children, nodules with or without halo sign are the most frequent finding. Agreement between radiologists was variable for common imaging features, and specific findings did not correlate with the causative pathogen. Microbiological confirmation remains vital in children with suspected pulmonary IFD.

In vitro activity of olorofim against 507 filamentous fungi including antifungal drug-resistant strains at a tertiary laboratory in Australia: 2020-2023.

New antifungal agents are required to mitigate against azole-resistant Aspergillus and drug-resistant non-Aspergillus moulds. The novel orotomide, olorofim (F2G, Manchester, UK), has potent fungicidal activity against Aspergillus including azole-resistant Aspergillus fumigatus, Lomentospora prolificans and Scedosporium spp. Development of olorofim-specific clinical breakpoints/epidemiological cut-off values requires reliable MIC data. Determine the in vitro activity of olorofim compared with standard antifungals against mould pathogens at an Australian hospital. Olorofim MICs were determined for 507 clinical mould isolates using the CLSI M38-A3 standard. MICs of amphotericin B, anidulafungin, posaconazole, voriconazole and isavuconazole were obtained using Sensititre™ YeastOne YO10 and AUSNMRCI panels (Thermo-Fisher Scientific). A. fumigatus sensu stricto was the commonest species (33.3%) followed by L. prolificans (18.3%), Scedosporium (11.4%) and Fusarium (6%) species. Olorofim modal MICs were ≤0.25 mg/L (MIC90 0.25 mg/L) for all Aspergillus except Aspergillus Section Usti (1 mg/L); MICs for nine azole-resistant/non-wild-type A. fumigatus ranged from 0.008 to 0.125 mg/L. The MIC90 of olorofim for L. prolificans was 0.5 mg/L, 0.25-0.5 mg/L for Scedosporium spp. and 8 mg/L for the F. solani complex but with modal MICs of 0.25 and 0.008 mg/L for F. oxysporum and F. proliferatum complexes, respectively. For Verruconis gallopava (n = 10), the olorofim MIC90 was 0.06 mg/L (voriconazole MIC90 2 mg/L, isavuconazole MICs of 4->8 mg/L). Olorofim had little activity against other dematiaceous moulds including Exophiala species. Olorofim was highly active against Aspergillus spp. including azole-resistant A. fumigatus, L. prolificans, Scedosporium spp. and some Fusarium species with the new finding of potent activity against V. gallopava.

Investigations of an increased incidence of non-Aspergillus invasive mould infections in an onco-haematology unit.

Invasive mould infections are life-threatening complications in patients with haematologic cancer and chemotherapy-induced neutropenia. While invasive aspergillosis represents the main cause of invasive mould infections, non-Aspergillusmould infections, such as mucormycosis, are increasingly reported. Consequently, their local epidemiology should be closely monitored. The aim of this study was to investigate the causes of an increased incidence of non-Aspergillusmould infections in the onco-haematology unit of a Swiss tertiary care hospital. All cases of proven and probable invasive mould infections were retrospectively identified via a local registry for the period 2007-2021 and their incidence was calculated per 10,000 patient-days per year. The relative proportion of invasive aspergillosis and non-Aspergillusmould infections was assessed. Factors that may affect invasive mould infections' incidence, such as antifungal drug consumption, environmental contamination and changes in diagnostic approaches, were investigated. A significant increase of the incidence of non-Aspergillusmould infections (mainly mucormycosis) was observed from 2017 onwards (Mann and Kendall test p = 0.0053), peaking in 2020 (8.62 episodes per 10,000 patient-days). The incidence of invasive aspergillosis remained stable across the period of observation. The proportion of non-Aspergillusmould infections increased significantly from 2017 (33% vs 16.8% for the periods 2017-2021 and 2007-2016, respectively, p = 0.02). Building projects on the hospital site were identified as possible contributors of this increase in non-Aspergillusmould infections. However, novel diagnostic procedures may have improved their detection. We report a significant increase in non-Aspergillusmould infections, and mainly in mucormycosis infections, since 2017. There seems to be a multifactorial origin to this increase. Epidemiological trends of invasive mould infections should be carefully monitored in onco-haematology units in order to implement potential corrective measures.

High-Risk Neutropenic Fever and Invasive Fungal Diseases in Patients with Hematological Malignancies.

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug-drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs' risk stratification), and new antifungals and their features (rezafungin and olorofim).

IFISTRATEGY: Spanish National Survey of Invasive Fungal Infection in Hemato-Oncologic Patients.

Recent advances in the treatment of hematologic malignancies have improved the overall survival rate, but the number of patients at risk of developing an invasive fungal infection (IFI) has increased. Invasive infections caused by non-Candida albicans species, non-Aspergillus molds, and azole-resistant Aspergillus fumigatus have been increasingly reported in recent years. We developed a cross-sectional multicenter survey which involved a total of 55 hematologists and infectious disease specialists from a total of 31 Spanish hospitals, to determine the most frequent strategies used for the management of IFIs. Data collection was undertaken through an online survey which took place in 2022. Regarding key strategies, experts usually prefer early treatment for persistent febrile neutropenia, switching to another broad-spectrum antifungal family if azole-resistant Aspergillus is suspected, broad-spectrum azoles and echinocandins as prophylactic treatment in patients receiving midostaurin or venetoclax, and liposomal amphotericin B for breakthrough IFIs after prophylaxis with echinocandins in patients receiving new targeted therapies. For antifungals failing to reach adequate levels during the first days and suspected invasive aspergillosis, the most appropriate strategy would be to associate an antifungal from another family.

Non-Aspergillus Hyaline Molds: A Host-Based Perspective of Emerging Pathogenic Fungi Causing Sinopulmonary Diseases.

The incidence of invasive sino-pulmonary diseases due to non-Aspergillus hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well as improvements in the capabilities of molecular-based diagnostics. Herein, we review the following opportunistic pathogens known to cause sinopulmonary disease, the most common manifestation of hyalohyphomycosis: Fusarium spp., Scedosporium spp., Lomentospora prolificans, Scopulariopsis spp., Trichoderma spp., Acremonium spp., Paecilomyces variotii, Purpureocillium lilacinum, Rasamsonia argillacea species complex, Arthrographis kalrae, and Penicillium species. To facilitate an understanding of the epidemiology and clinical features of sino-pulmonary hyalohyphomycoses in the context of host immune impairment, we utilized a host-based approach encompassing the following underlying conditions: neutropenia, hematologic malignancy, hematopoietic and solid organ transplantation, chronic granulomatous disease, acquired immunodeficiency syndrome, cystic fibrosis, and healthy individuals who sustain burns, trauma, or iatrogenic exposures. We further summarize the pre-clinical and clinical data informing antifungal management for each pathogen and consider the role of adjunctive surgery and/or immunomodulatory treatments to optimize patient outcome.

Systemic Antifungal Therapy for Invasive Pulmonary Infections.

Antifungal therapy for pulmonary fungal diseases is in a state of flux. Amphotericin B, the time-honored standard of care for many years, has been replaced by agents demonstrating superior efficacy and safety, including extended-spectrum triazoles and liposomal amphotericin B. Voriconazole, which became the treatment of choice for most pulmonary mold diseases, has been compared with posaconazole and itraconazole, both of which have shown clinical efficacy similar to that of voriconazole, with fewer adverse events. With the worldwide expansion of azole-resistant Aspergillus fumigatus and infections with intrinsically resistant non-Aspergillus molds, the need for newer antifungals with novel mechanisms of action becomes ever more pressing.

Osteoarticular Mycoses.

Osteoarticular mycoses are chronic debilitating infections that require extended courses of antifungal therapy and may warrant expert surgical intervention. As there has been no comprehensive review of these diseases, the International Consortium for Osteoarticular Mycoses prepared a definitive treatise for this important class of infections. Among the etiologies of osteoarticular mycoses are Candida spp., Aspergillus spp., Mucorales, dematiaceous fungi, non-Aspergillus hyaline molds, and endemic mycoses, including those caused by Histoplasma capsulatum, Blastomyces dermatitidis, and Coccidioides species. This review analyzes the history, epidemiology, pathogenesis, clinical manifestations, diagnostic approaches, inflammatory biomarkers, diagnostic imaging modalities, treatments, and outcomes of osteomyelitis and septic arthritis caused by these organisms. Candida osteomyelitis and Candida arthritis are associated with greater events of hematogenous dissemination than those of most other osteoarticular mycoses. Traumatic inoculation is more commonly associated with osteoarticular mycoses caused by Aspergillus and non-Aspergillus molds. Synovial fluid cultures are highly sensitive in the detection of Candida and Aspergillus arthritis. Relapsed infection, particularly in Candida arthritis, may develop in relation to an inadequate duration of therapy. Overall mortality reflects survival from disseminated infection and underlying host factors.

Non-Aspergillus mould lung infections.

Non-Aspergillus filamentous fungi causing invasive mould infections have increased over the last years due to the widespread use of anti-Aspergillus prophylaxis and increased complexity and survival of immunosuppressed patients. In the few studies that have reported on invasive mould infection epidemiology, Mucorales are the most frequently isolated group, followed by either Fusarium spp. or Scedosporium spp. The overall incidence is low, but related mortality is exceedingly high. Patients with haematological malignancies and haematopoietic stem cell transplant recipients comprise the classical groups at risk of infection for non-Aspergillus moulds due to profound immunosuppression and the vast use of anti-Aspergillus prophylaxis. Solid organ transplant recipients also face a high risk, especially those receiving lung transplants, due to direct exposure of the graft to mould spores with altered mechanical and immunological elimination, and intense, associated immunosuppression. Diagnosing non-Aspergillus moulds is challenging due to unspecific symptoms and radiological findings, lack of specific biomarkers, and low sensitivity of cultures. However, the advent of molecular techniques may prove helpful. Mucormycosis, fusariosis and scedosporiosis hold some differences regarding clinical paradigmatic presentations and preferred antifungal therapy. Surgery might be an option, especially in mucormycosis. Finally, various promising strategies to restore or enhance the host immune response are under current evaluation.

P276 Molecular epidemiology of clinical filamentous fungi in Qatar beyond Aspergillus and Fusarium

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM ObjectivesDue to an increasing number of patients at risk, (ie, with a highly compromised immune system and/or receiving aggressive chemotherapy treatment), invasive fungal infections (IFI) are increasingly being reported. They are associated with significantly high mortality rates. Aspergillus spp., particularly A. fumigatus, is the major cause of mold-related IFI around the world followed by Fusarium spp., however, other molds are emerging as human pathogens. The aim of this study was to explore the epidemiology and prevalence of the non-Aspergillus and non-Fusarium molds in human clinical samples over 11 years period in Qatar based tertiary hospital using molecular techniques.MethodsA total of 91 clinical specimens positive for molds belonging to 90 patients were recorded in about 11 years (September 2003 to November 2014). The isolates were identified based on morphological characteristics and by sequencing the internal transcribed spacer (ITS) gene. To confirm the identifications, a phylogenetic tree based on ITS sequences was constructed.ResultsMost patients were males (72%), 6% were immunocompromised, 12% had IFI, and 7% died within 30 days of diagnosis. The fungal isolates were recovered from a variety of clinical samples, including nails, skin, hair, scalp, nasal cavity, wounds, respiratory samples, body fluids, eye, ear, tissue, abscess, and blood specimens. Dematiaceous fungi were overall the most isolated (33/91, 36%), followed by dermatophytes (25/91, 27%), Mucorales (16/91, 18%), and other hyaline molds (17/91, 19%) (Fig. 1). Curvularia was the most isolated genus (22/91, 24%) and Mucorales were the major cause of IF (5/11, 45.5%) (Table 1). Superficial mycoses were caused by dermatophytes (66%) and non-dermatophytes (34%). Furthermore, rare fungi that are not commonly known to cause human disease were recovered such as Rhytidhysteron rufulum, Subramaniula asteroids, Dothichiza pimprina, and Quambalaria cyanescens.ConclusionThe current study highlights the epidemiology and spectrum of mold genera, other than Aspergillus and Fusarium, recovered from human clinical samples in Qatar, which can aid in surveillance of uncommon and emerging mycoses other than aspergillosis and fusuriosis.

Overview of COVID-19-Associated Invasive Fungal Infection.

Purpose of ReviewInvasive fungal infections are a complication of COVID-19 disease. This article reviews literature characterizing invasive fungal infections associated with COVID-19.Recent FindingsMultiple invasive fungal infections including aspergillosis, candidiasis, pneumocystosis, other non-Aspergillus molds, and endemic fungi have been reported in patients with COVID-19. Risk factors for COVID-19-associated fungal disease include underlying lung disease, diabetes, steroid or immunomodulator use, leukopenia, and malignancy. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) are the most common fungal infections described. However, there is variability in the reported incidences related to use of differing diagnostic algorithms.SummaryFungal pathogens are important cause of infection in patients with COVID-19, and the diagnostic strategies continue to evolve. Mortality in these patients is increased, and providers should operate with a high index of suspicion. Further studies will be required to elucidate the associations and pathogenesis of these diseases and best management and prevention strategies.

Fungi in skin and soft tissue infections - a three-year study

Introduction: Exposure of subcutaneous tissue following a loss of skin integrity provides a suitable environment for microbial colonization and proliferation, which contributes to delayed healing and infection of the wound. The aim of this study was to retrospectively investigate the spectrum of fungi responsible for skin and soft tissue infections over a 3-year period, and to compare the results with those from other parts of the world. Material and methods: The study was performed during a 3-year period (2017-2019) and included analysis of 11,863 wound samples, which were obtained from patients hospital­lized at the University Clinics of the “Mother Theresa” campus, City hospital ”8th September” and University Clinic for Surgical Diseases “St. Naum Ohridski” in Skopje. All specimens were analyzed by standard mycological methods at the Institute of Microbiology and Parasitology. Results: Growth of fungi was confirmed in 5.5%, 5% and 6.2% of the positive speci­mens, during a 3-year period, respectively. C. albicans was a predominant yeast (67.6%, 63%, 63.2% in 2017, 2018 and 2019, respectively). Molds were represented by Aspergillus confirmed in 3, 4 and 5 specimens, and Fusarium was confirmed in 2, 3 and 3 specimens during the 3-year period, respectively. Mucor was detected in 3 patients, in 2019 only. Conclusion: Species identification of fungal microbes in wound specimens revealed that Candida species was the most predominant species, followed by Aspergillus and non-Aspergillus molds. It is crucial for every institution that treats patients with wounds to be aware of fungi as possible etiological agents of wound infections.

Elderly versus nonelderly patients with invasive fungal infections: species distribution and antifungal resistance, SENTRY antifungal surveillance program 2017-2019

We utilized the SENTRY surveillance database from 2017 through 2019 to address pathogen frequency and antifungal resistance among 4,497 clinical isolates of fungi from patients who were either ≥ 65 years (2,170 isolates) or between 18 and 64 years of age (2,327 isolates). The younger population was more frequently infected with non-Candida yeasts and non-Aspergillus moulds. Candida glabrata was more common in the older age group (P value = 0.02). Resistance to the triazole and echinocandin classes was less common in the elderly population (4.3% and 2.7%, respectively) compared to the younger age group (11.4% and 4.4%, respectively). Resistance to fluconazole in C. parapsilosis (11.4%) was elevated in the older patient group. Decreased susceptibility to the mould-active triazoles among A. fumigatus isolates was greater in the younger age group (7.8%) than the older age group (4.4%). These data emphasize the importance of species identification and antifungal susceptibility testing to guide the treatment of individual patients.

Consensus guidelines for the diagnosis and management of invasive fungal disease due to moulds other than Aspergillus in the haematology/oncology setting, 2021.

Invasive fungal disease (IFD) due to moulds other than Aspergillus is a significant cause of mortality in patients with malignancies or post haemopoietic stem cell transplantation. The current guidelines focus on the diagnosis and management of the common non-Aspergillus moulds (NAM), such as Mucorales, Scedosporium species (spp.), Lomentospora prolificans and Fusarium spp. Rare but emerging NAM including Paecilomyces variotii, Purpureocillium lilacinum and Scopulariopsis spp. are also reviewed. Culture and histological examination of tissue biopsy specimens remain the mainstay of diagnosis, but molecular methods are increasingly being used. As NAM frequently disseminate, blood cultures and skin examination with biopsy of any suspicious lesions are critically important. Treatment requires a multidisciplinary approach with surgical debridement as a central component. Other management strategies include control of the underlying disease/predisposing factors, augmentation of the host response and the reduction of immunosuppression. Carefully selected antifungal therapy, guided by susceptibility testing, is critical to cure. We also outline novel antifungal agents still in clinical trial which offer substantial potential for improved outcomes in the future. Paediatric recommendations follow those of adults. Ongoing epidemiological research, improvement in diagnostics and the development of new antifungal agents will continue to improve the poor outcomes that have been traditionally associated with IFD due to NAM.

Fungal infections in lung transplantation.

Lung transplant is a potential life-saving procedure for chronic lung diseases. Lung transplant recipients (LTRs) are at the greatest risk for invasive fungal infections (IFIs) among solid organ transplant (SOT) recipients because the allograft is directly exposed to fungi in the environment, airway and lung host defenses are impaired, and immunosuppressive regimens are particularly intense. IFIs occur within a year of transplant in 3–19% of LTRs, and they are associated with high mortality, prolonged hospital stays, and excess healthcare costs. The most common causes of post-LT IFIs are Aspergillus and Candida spp.; less common pathogens are Mucorales, other non-Aspergillus moulds, Cryptococcus neoformans, Pneumocystis jirovecii, and endemic mycoses. The majority of IFIs occur in the first year following transplant, although later onset is observed with prolonged antifungal prophylaxis. The most common manifestations of invasive mould infections (IMIs) include tracheobronchial (particularly at anastomotic sites), pulmonary and disseminated infections. The mortality rate of tracheobronchitis is typically low, but local complications such as bronchomalacia, stenosis and dehiscence may occur. Mortality rates associated with lung and disseminated infections can exceed 40% and 80%, respectively. IMI risk factors include mould colonization, single lung transplant and augmented immunosuppression. Candidiasis is less common than mould infections, and manifests as bloodstream or other non-pulmonary invasive candidiasis; tracheobronchial infections are encountered uncommonly. Risk factors for and outcomes of candidiasis are similar to those of non lung transplant recipients. There is evidence that IFIs and fungal colonization are risk factors for allograft failure due to chronic rejection. Mould-active azoles are frontline agents for treatment of IMIs, with local debridement as needed for tracheobronchial disease. Echinocandins and azoles are treatments for invasive candidiasis, in keeping with guidelines in other patient populations. Antifungal prophylaxis is commonly administered, but benefits and optimal regimens are not defined. Universal mould-active azole prophylaxis is used most often. Other approaches include targeted prophylaxis of high-risk LTRs or pre-emptive therapy based on culture or galactomannan (GM) (or other biomarker) results. Prophylaxis trials are needed, but difficult to perform due to heterogeneity in local epidemiology of IFIs and standard LT practices. The key to devising rational strategies for preventing IFIs is to understand local epidemiology in context of institutional clinical practices.

The Prediction and Prognosis of Fungal Infection in Lung Transplant Recipients-A Retrospective Cohort Study in South Korea.

(1) Background: Lung transplant recipients (LTRs) are at substantial risk of invasive fungal disease (IFD), although no consensus has been reached on the use of antifungal agents (AFAs) after lung transplantation (LTx). This study aimed to assess the risk factors and prognosis of fungal infection after LTx in a single tertiary center in South Korea. (2) Methods: The study population included all patients who underwent LTx between January 2012 and July 2019 at a tertiary hospital. It was a retrospective cohort study. Culture, bronchoscopy, and laboratory findings were reviewed during episodes of infection. (3) Results: Fungus-positive respiratory samples were predominant in the first 90 days and the overall cumulative incidence of Candida spp. was approximately three times higher than that of Aspergillus spp. In the setting of itraconazole administration for 6 months post-LTx, C. glabrata accounted for 36.5% of all Candida-positive respiratory samples. Underlying connective tissue disease-associated interstitial lung disease, use of AFAs before LTx, a longer length of hospital stay after LTx, and old age were associated with developing a fungal infection after LTx. IFD and fungal infection treatment failure significantly increased overall mortality. Host factors, antifungal drug resistance, and misdiagnosis of non-Aspergillus molds could attribute to the breakthrough fungal infections. (4) Conclusions: Careful bronchoscopy, prompt fungus culture, and appropriate use of antifungal therapies are recommended during the first year after LTx.

In vitro activity of posaconazole and comparators versus opportunistic filamentous fungal pathogens globally collected during 8 years

The epidemiology of invasive filamentous fungal diseases requires monitoring due to changes in susceptibility patterns of new and established antifungal agents that may affect clinical practices. We evaluated the activity of posaconazole against 2,157 invasive moulds collected worldwide from 2010−2017. The isolates included 1,775 Aspergillus spp. and 382 non-Aspergillus moulds, including 81 Fusarium spp., 62 Mucorales group, and 57 Scedosporium spp. Isolates were tested using the CLSI reference broth microdilution method. Posaconazole showed similar activity to itraconazole and voriconazole against A. fumigatus. Applying published ECV, 98.0% of the A. fumigatus and 97.7% to 100.0% of other common Aspergillus species were wildtype to posaconazole. Categorical agreement between posaconazole and the other azoles tested against A. fumigatus was 98.7%. Notably, most of the Aspergillus spp. isolates recovered from this large collection were wildtype to echinocandins and all azoles. Posaconazole non-wildtype rates of A. fumigatus varied across the different geographic regions, with 2.1% in Europe, 2.2% in North America, 1.8% in Latin America, and 0.7% in the Asia-Pacific region. The frequency of azole non-wildtype A. fumigatus isolates from Europe increased steadily from 2010−2017 for all 3 triazoles (0.0%−5.0%). The azole non-wildtype A. fumigatus rates from the other geographic areas were stable over time. Fusarium and/or Scedosporium spp. isolates were highly resistant to azoles and echinocandins. Posaconazole and amphotericin B were the most active agents against the Mucorales. Posaconazole was very active against most species of Aspergillus and was comparable to itraconazole and voriconazole against the less common moulds. Posaconazole should provide a useful addition to the anti-mould grouping of antifungal agents.

Antifungal susceptibilities of opportunistic filamentous fungal pathogens from the Asia and Western Pacific Region: data from the SENTRY Antifungal Surveillance Program (2011\u20132019)

Antifungal surveillance is an important tool to monitor the prevalence of uncommon fungal species and increasing antifungal resistance throughout the world, but data comparing results across several different Asian countries are scarce. In this study, 372 invasive molds collected in the Asia-Western Pacific region in 2011–2019 were susceptibility tested for mold-active triazoles (isavuconazole, posaconazole, voriconazole, and itraconazole). The collection includes 318 Aspergillus spp. isolates and 53 non-Aspergillus molds. The MIC values using CLSI methods for isavuconazole versus Aspergillus fumigatus ranged from 0.25 to 2 mg l−1. Isavuconazole, itraconazole, posaconazole, and voriconazole acted similarly against A. fumigatus. The mold-active triazoles exhibited a wildtype phenotype to most of the Aspergillus spp. isolates tested (>94%), but poor activity against Fusarium solani species complex and Lomentospora prolificans. Voriconazole was most active against the Scedosporium spp. and posaconazole was most active against the Mucorales. In summary, isavuconazole displayed excellent activity against most species of Aspergillus and was comparable to other mold-active triazoles against non-Aspergillus molds.

#35: Rapid, Non-invasive Detection and Serial Monitoring of Invasive Fungal Infections in Immunocompromised Children Using the Karius Test (a Plasma-based Microbial Cell-free DNA Sequencing Test)

Abstract Background A diverse spectrum of invasive molds and fungi cause serious opportunistic infections in immunocompromised (IC) children. Their overlap in clinical presentation can make it challenging to differentiate among etiologies and optimally tailor antifungal therapy. Current methods to identify these pathogens lack sensitivity, are limited by long turnaround times and require an array of individual tests on invasively obtained specimens. The delay or lack of a pathogen diagnosis in combination with the reliance on invasive procedures leads to a dependence on broad empiric therapy, the development of antimicrobial resistance and increases in morbidity and mortality. Rapid, non-invasive diagnosis of invasive fungal infections through next-generation sequencing (NGS) of plasma microbial cell-free DNA (mcfDNA) offers a means to overcome these limitations. Methods Karius® Test (KT) results were reviewed for detections of Aspergillus, non-Aspergillus molds and Pneumocystis jirovecii (PJP) in children. KT, developed and validated in Karius’ CLIA certified/CAP accredited lab, detects microbial cell-free DNA (mcfDNA) can assist with the diagnosis of invasive infections. McfDNA is extracted, NGS is performed, human sequences removed and remaining sequences aligned to a curated pathogen database of >1400 organisms. Organisms present above a statistical threshold are reported and quantified. For > 85% of tests the time to result reporting is 24 hours from sample receipt. Clinical information was included from data submitted with the requisition or obtained at the time of reporting from clinical consultations with the provider. Results KT detected 7 different species of Aspergillus in 61 patients (74% IC, 40% with a pulmonary focus). KT detected 15 different non-Aspergillus molds in 51 patients (80% IC, 36% with a pulmonary focus). KT detected PJP in 37 patients (73% IC, 76% with a pulmonary focus, 54% with a DNA virus co-detection and 32% with a herpesvirus co-detections). There were 31 subjects with serial monitoring (97% IC, 70% with a pulmonary focus) including 48% with Aspergillus, 39% with non-Aspergillus molds and 12% with PJP (Figure 1). 71% of subjects demonstrated a decline in the quantitative mcfDNA signal over time; the duration of a positive mcfDNA signal ranged from 3–92 days (median 16 days, SD 22.4). Conclusions Plasma mcfDNA NGS offers a rapid, non-invasive means of detecting a broad diversity of invasive pathogens that overlap in their clinical presentations and are difficult to identify in immunocompromised children. The rapid turnaround time, non-invasive sampling and 1-sample-1000+test-solution may lead to a faster time to pathogen diagnosis, faster time to targeted therapy and obviate the need for invasive diagnostic procedures. The ability with a single test to concomitantly diagnose co-pathogens including reactivating herpesviruses that modulate the progression of principal infecting fungal pathogens (i.e. cytomegalovirus modulation of PJP) can help optimize care. Additionally, this convenient non-invasive means of serial testing of invasive fungal infections may serve as an indicator of burden of infection, provide insight into treatment efficacy and ultimately help define the length and mode (medical/surgical) of therapy required to improve outcomes. Additional studies correlating the mcfDNA signal with individual patient clinical and radiographic parameters will be important to further define the utility of serial mcfDNA monitoring.

Radiological CT Patterns and Distribution of Invasive Pulmonary Aspergillus, Non-Aspergillus, Cryptococcus and Pneumocystis Jirovecii Mold Infections - A Multicenter Study.

Clinical signs and symptoms related to invasive fungal disease are nonspecific and need to be followed up by appropriate diagnostic procedures. The goal of this study was to analyze CT imaging patterns in invasive fungal infections and their correlation with the immune status and clinical outcome. We performed a retrospective multicenter study including 85 consecutive patients with invasive pulmonary fungal infection (2011-2014). Lung patterns on computed tomography (CT) scans were classified according to the Fleischner Society glossary. The patients were grouped according to immune status (neutropenia, steroid therapy, organ transplant recipient, and other cause) and outcome (positive outcome, progressive disease, and death). The Chi square test or Fisher exact test was used. Bonferroni correction was applied. The total number of patients with invasive Aspergillus and non-Aspergillus infection (IANA), Pneumocystis jirovecii pneumonia (PCP), and Cryptococcus (CRY) was 60, 22, and 3, respectively. Patients with IANA demonstrated significantly more nodules (93 % vs. 59 %, p = 0.001), significantly fewer ground glass opacities (58 % vs. 96 %, p = 0.005), and significantly fewer positive lymph nodes (5 % vs. 41 %, p < 0.001) than patients with PCP. All patients with PCP and CRY had a favorable outcome. Patients with IANA and an adverse outcome demonstrated significantly more nodules with halo sign than patients with IANA and a favorable outcome (42.5 % vs. 15.9 %, p < 0.0001). Interestingly, patients with IANA and a favorable outcome had a higher prevalence of pulmonary infarction than patients with an adverse outcome (8 % vs. 1 %, p = 0.047). Patients with neutropenia showed significantly more consolidations (66 %) than organ transplant recipients (27 %, p = 0.045). Patients with IANA showed a higher prevalence of nodules and a lower prevalence of ground glass opacities than patients with PCP. In patients with IANA, nodules with halo sign were associated with an adverse outcome. Patients with neutropenia showed generally more consolidations, but the consolidations were not associated with an adverse outcome. · Nodules, ground glass opacities, and consolidations are common CT findings in all invasive pulmonary fungal infections.. · There is no pattern that is unique for one specific pathogen, although nodules are more predominant in IANA and Cryptococcus, and ground glass opacities are more predominant in PCP patients.. · Immune status had an impact on CT findings in fungal pneumonia with less consolidation in patients after organ transplantation compared to patients with neutropenia.. · Nodules with a halo sign are associated with a worse outcome.. · Obmann VC, Bickel F, Hosek N et al. Radiological CT Patterns and Distribution of Invasive Pulmonary Aspergillus, Non-Aspergillus, Cryptococcus and Pneumocystis Jirovecii Mold Infections - A Multicenter Study. Fortschr Röntgenstr 2021; 193: 1304 - 1314.