Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody.

Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 µg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.

Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans.

Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.

Low-Avidity CD4+ T Cell Responses to SARS-CoV-2 in Unexposed Individuals and Humans with Severe COVID-19.

CD4+ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4+ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4+ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4+ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4+ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

Treatment Outcomes Among Patients With a Positive Candida Culture Close to Randomization Receiving Rezafungin or Caspofungin in the ReSTORE Study.

BACKGROUND: Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was non-inferior to caspofungin for Day 30 all-cause mortality (ACM) and Day 14 global cure in the Phase 3 ReSTORE trial (NCT03667690). We conducted pre-planned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS: ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization, or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included Day 30 ACM, Day 14 global cure rate, and Day 5 and 14 mycological response. Adverse events were evaluated. RESULTS: This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively: Day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval] 4.6% [-13.7, 23.5]); Day 14 global response was 55.3% and 50.0% (between-group difference 5.3% [-16.1, 26.0]); and Day 5 mycological eradication was 71.1% and 50.0% (between-group difference 21.1% [-0.2, 40.2]). Safety was comparable between treatments. CONCLUSIONS: These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial.

BACKGROUND: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. FINDINGS: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference -1·1% [95% CI -14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI -9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. INTERPRETATION: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. FUNDING: Cidara Therapeutics and Mundipharma.

Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses.

BACKGROUND: The International Society for Human and Animal Mycology (ISHAM) working group proposed recommendations for managing allergic bronchopulmonary aspergillosis (ABPA) a decade ago. There is a need to update these recommendations due to advances in diagnostics and therapeutics. METHODS: An international expert group was convened to develop guidelines for managing ABPA (caused by Aspergillus spp.) and allergic bronchopulmonary mycosis (ABPM; caused by fungi other than Aspergillus spp.) in adults and children using a modified Delphi method (two online rounds and one in-person meeting). We defined consensus as ≥70% agreement or disagreement. The terms "recommend" and "suggest" are used when the consensus was ≥70% and <70%, respectively. RESULTS: We recommend screening for A. fumigatus sensitisation using fungus-specific IgE in all newly diagnosed asthmatic adults at tertiary care but only difficult-to-treat asthmatic children. We recommend diagnosing ABPA in those with predisposing conditions or compatible clinico-radiological presentation, with a mandatory demonstration of fungal sensitisation and serum total IgE ≥500 IU·mL-1 and two of the following: fungal-specific IgG, peripheral blood eosinophilia or suggestive imaging. ABPM is considered in those with an ABPA-like presentation but normal A. fumigatus-IgE. Additionally, diagnosing ABPM requires repeated growth of the causative fungus from sputum. We do not routinely recommend treating asymptomatic ABPA patients. We recommend oral prednisolone or itraconazole monotherapy for treating acute ABPA (newly diagnosed or exacerbation), with prednisolone and itraconazole combination only for treating recurrent ABPA exacerbations. We have devised an objective multidimensional criterion to assess treatment response. CONCLUSION: We have framed consensus guidelines for diagnosing, classifying and treating ABPA/M for patient care and research.

Quantification of midostaurin in plasma and serum by stable isotope dilution liquid chromatography-tandem mass spectrometry: Application to a cohort of patients with acute myeloid leukemia.

OBJECTIVES: Midostaurin is an oral multitargeted tyrosine kinase inhibitor for the treatment of acute myeloid leukemia (AML). Therapeutic drug monitoring of midostaurin may support its safe use when suspecting toxicity or combined with strong CYP3A4 inhibitors. METHODS: A stable isotope dilution liquid chromatography-tandem mass spectrometry method was developed and validated for the determination and quantification of midostaurin in human plasma and serum. Midostaurin serum concentrations were analyzed in 12 patients with FMS-like tyrosine kinase 3 (FLT3)-mutated AML during induction chemotherapy with cytarabine, daunorubicin, and midostaurin. Posaconazole was used as prophylaxis of invasive fungal infections. RESULTS: Linear quantification of midostaurin was demonstrated across a concentration range of 0.01-8.00 mg/L. Inter- and intraday imprecisions of the proposed method were well within ±10%. Venous blood samples were taken in nine and three patients in the first and second cycle of induction chemotherapy. Median (range) midostaurin serum concentration was 7.9 mg/L (1.5-26.1 mg/L) as determined in 37 independent serum specimens. CONCLUSION: In a real-life cohort of AML patients, interindividual variability in midostaurin serum concentrations was high, highlighting issues concerning optimal drug dosing in AML patients. A personalized dosage approach may maximize the safety of midostaurin. Prospective studies and standardization of analytical methods to support such an approach are needed.

Hybrid immunity to SARS-CoV-2 in patients with chronic lymphocytic leukemia.

OBJECTIVE: Preventing severe COVID-19 remains a priority globally, particularly in the immunocompromised population. As shown in healthy individuals, immunity against SARS-CoV-2 can be yielded by previous infection, vaccination, or both (hybrid immunity). The objective of this observation study was to investigate hybrid immunity in patients with chronic lymphocytic leukemia (CLL). METHODS/RESULTS: Blood samples of six patients with CLL were collected 55 days after fourth COVID-19 vaccination. All patients had a SARS-CoV-2 infection within 12 months before the second booster (fourth vaccination). SARS-CoV-2 spike receptor binding domain (RBD)-specific IgG antibodies were detectable in 6/6 (100.0%) CLL patients after four compared to 4/6 (66.7%) after three vaccinations. The median number of SARS-CoV-2 spike-specific T cells after repeated booster vaccination plus infection was 166 spot-forming cells (SFC) per million peripheral blood mononuclear cells. Overall, 5/5 (100%) studied patients showed a detectable increase in T cell activity. CONCLUSION: Our data reveal an increase of cellular and humoral immune response in CLL patients after fourth COVID-19 vaccination combined with SARS-CoV-2 infection, even in those undergoing B cell-depleting treatment. Patients with prior vaccination failure now show a specific IgG response. Future research should explore the duration and effectiveness of hybrid immunity considering various factors like past infection and vaccination rates, types and numbers of doses, and emerging variants.

The Nairobi Declaration 2023: A commitment to address deadly yet neglected fungal diseases in Africa.

On May 30th and 31st, 2023, delegates representing various African subregions, together with global representatives from the International Society of Human and Animal Mycology (ISHAM), the European Confederation of Medical Mycology (ECMM), the United States Centre for Disease Control and Prevention (CDC), and Global Action for Fungal Infections (GAFFI), convened in Nairobi, Kenya under the aegis of the Pan African Mycology Working Group, a working group of ISHAM. The meeting objectives were, amongst others, to deliberate on a continental response to the World Health Organisation Fungal Priority Pathogen List and facilitate interaction between global and regional leaders. Country delegates and international speakers addressed Africa's fungal disease burden; capacity for diagnosis and management; ongoing surveillance; knowledge gaps and trends in invasive fungal diseases such as Candida auris, mucormycosis, aspergillosis, and Acquired Immune Deficiency Syndrome (AIDS)-related mycoses; and current laboratory practice. During the technical sessions, expert panels deliberated on establishing and financing of national/regional surveillance networks for mycoses; establishing and sustaining African-led collaborations; expanding on existing laboratory and point-of-care diagnostic capacity as well as planning a mycology reference laboratory service and network in Africa. The meeting also highlighted successful African-led collaborations, capacity building, and clinical trial initiatives. The meeting conclusions informed the resolutions of the Nairobi Declaration calling for improved awareness; strong collaborations between clinical and laboratory teams across Africa; improved fungal disease surveillance within the continent; access to antifungals and diagnostics; and leveraging qualified human resources for mycology present within and outside Africa to facilitate trainings, collaborations, and exchanges.

This review presents the current state of the art in medical mycology in Africa discussed at the first scientific meeting of the Pan African Mycology Working Group, an affiliate of the International Society for Human and Animal Mycology (ISHAM) held in Nairobi, Kenya on May 30th and 31st, 2023.

Innovative approaches for vaccine trials as a key component of pandemic preparedness - a white paper.

BACKGROUND: WHO postulates the application of adaptive design features in the global clinical trial ecosystem. However, the adaptive platform trial (APT) methodology has not been widely adopted in clinical research on vaccines. METHODS: The VACCELERATE Consortium organized a two-day workshop to discuss the applicability of APT methodology in vaccine trials under non-pandemic as well as pandemic conditions. Core aspects of the discussions are summarized in this article. RESULTS: An "ever-warm" APT appears ideally suited to improve efficiency and speed of vaccine research. Continuous learning based on accumulating APT trial data allows for pre-planned adaptations during its course. Given the relative design complexity, alignment of all stakeholders at all stages of an APT is central. Vaccine trial modelling is crucial, both before and in a pandemic emergency. Various inferential paradigms are possible (frequentist, likelihood, or Bayesian). The focus in the interpandemic interval may be on research gaps left by industry trials. For activation in emergency, template Disease X protocols of syndromal design for pathogens yet unknown need to be stockpiled and updated regularly. Governance of a vaccine APT should be fully integrated into supranational pandemic response mechanisms. DISCUSSION: A broad range of adaptive features can be applied in platform trials on vaccines. Faster knowledge generation comes with increased complexity of trial design. Design complexity should not preclude simple execution at trial sites. Continuously generated evidence represents a return on investment that will garner societal support for sustainable funding. Adaptive design features will naturally find their way into platform trials on vaccines.

Laboratory and clinical management capacity for invasive fungal infections: the Italian landscape.

BACKGROUND: We assessed the laboratory diagnosis and treatment of invasive fungal disease (IFD) in Italy to detect limitations and potential for improvement. METHODS: The survey was available online at www.clinicalsurveys.net/uc/IFI management capacity/, and collected variables such as (a) institution profile, (b) perceptions of IFD in the respective institution, (c) microscopy, (d) culture and fungal identification, (e) serology, (f) antigen detection, (g) molecular tests, (h) susceptibility testing and (i) therapeutic drug monitoring (TDM). RESULTS: The laboratory capacity study received responses from 49 Italian centres, with an equitable geographical distribution of locations. The majority of respondents (n = 36, 73%) assessed the occurrence of IFD as moderate-high, with Aspergillus spp. being the pathogen of highest concern, followed by Candida spp. and Mucorales. Although 46 (94%) of the institutions had access to microscopy, less than half of them performed direct microscopy on clinical specimens always when IFD was suspected. Cultures were available in all assessed laboratories, while molecular testing and serology were available in 41 (83%), each. Antigen detection tests and antifungal drugs were also generally accessible (> 90%) among the participating institutions. Nevertheless, access to TDM was limited (n = 31, 63%), with a significant association established between therapeutic drug monitoring availability and higher gross domestic product per capita. CONCLUSIONS: Apart from TDM, Italy is adequately prepared for the diagnosis and treatment of IFD, with no significant disparities depending on gross domestic product. Future efforts may need to focus on enhancing the availability and application of direct microscopic methods, as well as TDM, to promote optimal treatment and better patient outcomes.

Challenges in assessing the immunization status of adults in Germany-lessons from a population-based VACCELERATE survey on polio vaccination.

PURPOSE: Considering the re-emergence of poliomyelitis (PM) in non-endemic regions, it becomes apparent that vaccine preventable diseases can rapidly develop epi- or even pandemic potential. Evaluation of the current vaccination status is required to inform patients, health care providers and policy makers about vaccination gaps. METHODS: Between October 28 2022 and November 23 2022, 5,989 adults from the VACCELEREATE Volunteer Registry completed an electronic case report form on their previous PM vaccine doses including number, types/-valencies and the time of administration based on their vaccination records. A uni-/multivariable regression analysis was performed to assess associations in participant characteristics and immunization status. RESULTS: Among German volunteers (n = 5,449), complete PM immunization schedule was found in 1,981 (36%) participants. Uncertain immunization, due to unknown previous PM vaccination (n = 313, 6%), number of doses (n = 497, 9%), types/-valencies (n = 1,233, 23%) or incoherent immunization schedule (n = 149, 3%) was found in 40% (n = 2,192). Out of 1,276 (23%) participants who reported an incomplete immunization schedule, 62 (1%) never received any PM vaccine. A total of 5,074 (93%) volunteers reported having been vaccinated at least once and 2,087 (38%) indicated that they received vaccination within the last ten years. Female sex, younger age, as well as availability of first vaccination record were characteristics significantly associated with complete immunization (p < 0.001). CONCLUSION: Full PM immunization schedule was low and status frequently classified as uncertain due to lack of details on administered doses. There is an obviousneed for improved recording to enable long-term access to detailed vaccination history in the absence of a centralized immunization register.

Questioning the 14-day dogma in candidemia treatment duration.

The growing threat of antimicrobial resistance (AMR) is a global concern. With AMR directly causing 1.27 million deaths in 2019 and projections of up to 10 million annual deaths by 2050, optimising infectious disease treatments is imperative. Prudent antimicrobial use, including treatment duration, can mitigate AMR emergence. This is particularly critical in candidemia, a severe condition with a 45% crude mortality rate, as the 14-day minimum treatment period has not been challenged in randomised comparison. A comprehensive literature search was conducted in August 2023, revealing seven original articles and two case series discussing treatment durations of less than 14 days for candidemia. No interventional trials or prospective observational studies assessing shorter durations were found. Historical studies showed varying candidemia treatment durations, questioning the current 14-day minimum recommendation. Recent research observed no significant survival differences between patients receiving shorter or longer treatment, emphasising the need for evidence-based guidance. Treatment duration reduction post-blood culture clearance could decrease exposure to antifungal drugs, limiting selection pressure, especially in the context of emerging multiresistant Candida species. Candidemia's complexity, emerging resistance and potential for shorter in-hospital stays underscore the urgency of refining treatment strategies. Evidence-driven candidemia treatment durations are imperative to balance efficacy with resistance prevention and ensure the longevity of antifungal therapies. Further research and clinical trials are needed to establish evidence-based guidelines for candidemia treatment duration.

Multicentric Study on the Clinical Mycology Capacity and Access to Antifungal Treatment in Portugal.

The success of the clinical management of invasive fungal diseases (IFD) is highly dependent on suitable tools for timely and accurate diagnosis for effective treatment. An in-depth analysis of the ability of European institutions to promptly and accurately diagnose IFD was previously conducted to identify limitations and aspects to improve. Here, we evaluated and discussed the specific case of Portugal, for which, to our knowledge, there are no reports describing the national mycological diagnostic capacity and access to antifungal treatment. Data from 16 Portuguese medical institutions were collected via an online electronic case report form covering different parameters, including institution profile, self-perceived IFD incidence, target patients, diagnostic methods and reagents, and available antifungals. The majority of participating institutions (69%) reported a low-very low incidence of IFD, with Candida spp. indicated as the most relevant fungal pathogen, followed by Aspergillus spp. and Cryptococcus spp. All institutions had access to culture and microscopy, whereas 94 and 88% were able to run antigen-detection assays and molecular tests, respectively. All of the institutions capable of providing antifungal therapy declared to have access to at least one antifungal. However, echinocandins were only available at 85% of the sites. Therapeutic drug monitoring (TDM) was reported to remain a very restricted practice in Portugal, being available in 19% of the institutions, with the TDM of itraconazole and posaconazole performed in only 6% of them. Importantly, several of these resources are outsourced to external entities. Except for TDM, Portugal appears to be well-prepared concerning the overall capacity to diagnose and treat IFD. Future efforts should focus on promoting the widespread availability of TDM and improved access to multiple classes of antifungals, to further improve patient outcomes.

The Cologne ECMM Excellence Center: A Two-Year Analysis of External Consultation Service for Invasive Fungal Infections.

The European Confederation of Medical Mycology (ECMM), formed due to the surge in invasive fungal infections (IFI), initiated the Excellence Centers program in 2016 to guide stakeholders to leading medical mycology sites. This report focuses on the Cologne ECMM Excellence Center, recognized with Diamond status for active global involvement in 2017. The center offers free consultation via email and phone, responding within 24 h for life-threatening IFI, collecting data on origin, pathogens, infection details, and more. Over two years, 189 requests were received globally, predominantly from Germany (85%), mainly involving Aspergillus spp., Mucorales, and Candida spp. Fungal mixed infections occurred in 4% of cases. The center's service effectively addresses IFI challenges, advocating for a comprehensive study encompassing all ECMM Excellence Centers to enhance global mycological care. Proactive expansion of consultancy platforms is crucial, with future analyses needed to assess expert advice's impact on patient outcomes.

A Phase 3, Randomized, Double-Blind, Comparator-Controlled Study to Evaluate Safety, Tolerability, and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Allogeneic Hematopoietic Cell Transplant Recipients (PNEU-STEM).

BACKGROUND: Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS: Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS: A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90. CONCLUSIONS: V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11.

A conceptual framework for nomenclatural stability and validity of medically important fungi: a proposed global consensus guideline for fungal name changes supported by ABP, ASM, CLSI, ECMM, ESCMID-EFISG, EUCAST-AFST, FDLC, IDSA, ISHAM, MMSA, and MSGERC.

The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

Phase 1b safety and pharmacokinetics of intravenous and oral fosmanogepix in patients with acute myeloid leukaemia and neutropenia.

OBJECTIVES: Fosmanogepix (APX001), a first-in-class, intravenous (IV) and oral (PO) antifungal prodrug, is being developed to treat invasive fungal diseases (IFDs). Manogepix (APX001A; active moiety) targets fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, inhibiting cell wall synthesis causing loss of viability. This open-label, multicentre, Phase 1b study in patients with AML and neutropenia (absolute neutrophil count <500 cells/µL; >10 days) undergoing chemotherapy aimed to assess tolerability, safety and pharmacokinetics (PK) of IV and PO fosmanogepix. METHODS: Of 21 adult AML patients undergoing remission induction chemotherapy, 10 received IV fosmanogepix (600 mg; q24h) and 11 received oral fosmanogepix (500 mg; q24h) over 14 days, with a 28 day follow-up. Patients also received remission induction chemotherapy [sequential high-dose cytarabine and mitoxantrone (S-HAM) or 7 + 3 regimen] for AML and IFD prophylaxis (posaconazole). A two-compartmental PK model from previous studies in healthy volunteers was fitted to manogepix plasma data. RESULTS: Of 26 fosmanogepix-related adverse events (AEs; IV: 14; PO: 12) in 9 (42.9%) patients [IV: 5 (50%); PO: 4 (36.4%)], none were serious or resulted in fosmanogepix discontinuation. Most frequently occurring fosmanogepix-related AEs were Grade 1/2 nausea [four events in three patients (14.3%)]; vomiting, ALT increase, and delirium [two events; two patients (9.5%) each]. One patient experienced fosmanogepix-related Grade 3 hypertension. Dose-corrected geometric mean ratio of AUC (PO-to-IV) was 95%. Elimination half-lives (∼2 days) were consistent with prior studies in healthy volunteers. CONCLUSIONS: Fosmanogepix was safe and well tolerated in AML patients with neutropenia receiving remission induction chemotherapy. Safety and PK profiles were comparable to healthy volunteers.

Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/µL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.

The Argentinian landscape of mycological diagnostic capacity and treatment accessibility.

Immunosuppressed patients, transplant recipients, and those with acute or chronic respiratory disease are at increased risk for invasive fungal infections in Argentina. Although the national public system guarantees universal access to health care for all citizens, little is known about the quality of available diagnostic and treatment armamentaria for invasive fungal infections in the country. Between June and August 2022, infectious disease clinicians from each of the 23 provinces and the Autonomous City of Buenos Aires were contacted to describe local access to fungal diagnostic tools and antifungal agents. The information collected included different aspects such as hospital characteristics, patients admitted and wards, access to diagnostic tools, estimated infection incidence, and treatment capacity. Thirty responses were collected from facilities throughout Argentina. Most institutions were governmental (77%). A mycology department was available in 83% of them. Histopathology was available in almost 93% of the sites, while automated methods and galactomannan tests were available in 57%, each; 53% of the sites had access to MALDI-TOF-MS through regional reference laboratories, and PCR was present in 20% of the sites. Susceptibility testing was available in 63% of the laboratories. Candida spp. (24%), Cryptococcus spp. (20%), Aspergillus spp. (18%), and Histoplasma spp. (16%) were described as the main pathogens. Fluconazole was the only antifungal agent available in all institutions. This was followed by amphotericin B deoxycholate (83%) and itraconazole (80%). If an antifungal agent was not available onsite, then 60% of the patients could receive adequate antifungal treatment within the first 48 h upon request. Although there are no significant differences in access to diagnostic and clinical management of invasive fungal infections among the Argentinean centres studied, national awareness-raising initiatives led by policymakers could help to improve their general availability.