Novel antifungal agents in clinical trials

Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics. The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics. This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim. We discuss three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.

Immunity to Invasive Fungal Diseases

Invasive fungal diseases are rare in individuals with intact immunity. This, together with the fact that there are only a few species that account for most mycotic diseases, implies a remarkable natural resistance to pathogenic fungi. Mammalian immunity to fungi rests on two pillars, powerful immune mechanisms and elevated temperatures that create a thermal restriction zone for most fungal species. Conditions associated with increased susceptibility generally reflect major disturbances of immune function involving both the cellular and humoral innate and adaptive arms, which implies considerable redundancy in host defense mechanisms against fungi. In general, tissue fungal invasion is controlled through either neutrophil or granulomatous inflammation, depending on the fungal species. Neutrophils are critical against Candida spp. and Aspergillus spp. while macrophages are essential for controlling mycoses due to Cryptococcus spp., Histoplasma spp., and other fungi. The increasing number of immunocompromised patients together with climate change could significantly increase the prevalence of fungal diseases. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Mucormycosis Infections during the Second Wave of COVID-19: Experience from a Tertiary Care Centre in India

Background: Mucormycosis is an uncommon fungal infection with high morbidity and mortality. There had been a sudden surge in the cases of mucormycosis during the second wave of Coronavirus Disease 2019 (COVID-19) in India. Objective: The etiology, pathophysiology, and correlations of mucormycosis at tertiary hospital in India is explored in the present study. Methods: In this retrospective observational study, all coronavirus disease associated mucormycosis (CAM) cases admitted at this center between April 2021 to June 2021 were included. The cases were evaluated in terms of their background, most common presentations, chief underlying etiologies, severity of disease, comorbidities, investigation profiles, prognosis, and treatment provided. Results: Among the total 231 cases reported with mucormycosis, age group of 40 - 50 years (28%) was the most afflicted and the 20 30 year was the least. Men (68%) were more afflicted than Women. 66% patients had a history of vaccination against COVID-19. 63% patients presented with a High-Resolution Computerized Tomography (HRCT) score of 9-16. 60% required oxygen support and 71% required steroids. Diabetes mellitus was the most prevalent comorbidity. Conclusion: The salience of the second inferno wave of COVID-19 was witness to COVID-19 patients who had pre existing diabetes mellitus. Individuals with diabetes in general foster more extreme COVID-19 infections and end up using corticosteroids. In any case, the corticosteroids – alongside diabetes – increment the danger of getting mucormycosis. The specific pathophysiology of COVID-19 may represent co-morbidity with Invasive Fungal diseases (IFI).

Incidence and risk factors for inappropriate use of non-culture based fungal assays: Implication for diagnostic stewardship

Background Non-culture-based fungal assays (NCBFAs) have been used increasingly to help diagnose invasive fungal diseases. However, little is known about inappropriate use of NCBFAs. We aimed to investigate inappropriate use of NCBFAs in a tertiary academic hospital. Methods This retrospective cohort study included patients who underwent testing with beta-D glucan (BDG) between Jan and Mar 2018, or galactomannan antigen (GMA) or cryptococcal antigen (CRAG) between Jan and Jun 2018. Testing was deemed appropriate if the clinical presentation was compatible with a fungal infection and there was a predisposing host factor at the time of ordering. We compared patients with appropriate and inappropriate use of NCBFAs using the multivariate logistic regression analysis. Results 470 patients (BDG, 394; GMA, 138; CRAG, 164) met inclusion criteria and were evaluated. About 80% of NCBFAs were deemed inappropriate. Ordering by transplant medicine physicians, repetitions of the test, the absence of predisposing factors for fungal infections, and the absence of recommendations from infectious diseases consultants were associated with an increased risk of inappropriate NCBFA use. Conclusions We found a large proportion of NCBFAs were deemed inappropriate. There is an opportunity for diagnostic stewardship to reduce avoidable fungal testing among patients at low risk for fungal infection.

Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-d-Glucanemia

Circulating endotoxin, also called lipopolysaccharide (LPS) and (1→3)-β-d-Glucan (β-d-glucan), major constituents of bacterial and fungal cell walls, respectively, are determined as biomarkers for Gram-negative sepsis and invasive fungal diseases [...]

Pneumonia Caused by Lichtheimia Ramosa During the COVID-19 Pandemic in Hubei Province, China：A Case Report and Literature Review

BackgroundMucor infection cannot be ignored in patients with pulmonary shadowing with cavitation .This paper reports a case of mucormycosis during the COVID-19 pandemic in Hubei Province, China. Case PresentationA anesthesiology doctor was initially diagnosed as COVID-19 due to changes in lung imaging. Later Lichtheimia ramose was found by Metagenomic next generation sequencing (mNGS) in the Bronchoalveolar lavage fluid (BALF).After adjusting amphotericin B for anti-infective treatment, the patient's infection lesions were shranked and the symptoms were significantly relieved. ConclusionThe diagnosis of invasive fungal infections is very difficult, mNGS can make an accurate pathogenic diagnosis of invasive fungal diseases for the clinic and provide a basis for clinical treatment.

Activity of Amphotericin B Formulations and Voriconazole, alone or in combination, against Biofilms of Scedosporium and Fusarium spp.

Scedosporium and Fusarium species are emerging opportunistic pathogens, causing invasive fungal diseases in humans, particularly in immunocompromised patients. Biofilm-related infections are associated with increased morbidity and mortality. We herein assessed the ability of Scedosporium apiospermum ( SA ) and Fusarium solani species complex ( FSSC ) isolates to form biofilms and evaluated the efficacy of deoxycholate amphotericin B (D-AMB), liposomal amphotericin B (L-AMB) and voriconazole (VRC), alone or in combination, against mature biofilms. Biofilm formation was assessed by safranin staining and spectrophotometric measurement of optical density. Planktonic and biofilm damage was assessed by XTT reduction assay. Planktonic cell and biofilm MIC50’s were determined as the minimum concentrations that caused ≥50% fungal damage compared to untreated controls. The combined activity of L-AMB (0.5-32 mg/L) with VRC (0.125-64 mg/L) against biofilms was determined by the checkerboard microdilution method and analyzed by the Bliss independence model. Biofilm MIC50’s of D-AMB and L-AMB against SA isolates were 1 and 2 mg/L and against FSSC isolates were 0.5 and 1 mg/L, respectively. Biofilm MIC50’s of VRC against SA and FSSC were 32 mg/L and >256 mg/L, respectively. Synergistic effects were observed at 2-4 mg/L of L-AMB combined with 4-16 mg/L of VRC against SA biofilms (mean ΔE±standard error: 17% ± 3.7%). Antagonistic interactions were found at 0.5-4 mg/L of L-AMB combined with 0.125-16 mg/L of VRC against FSSC isolates with -28% ± 2%. D-AMB and L-AMB were more efficacious against SA and FSSC biofilms than VRC.

Aiming for a bull’s-eye: Targeting antifungals to fungi with dectin-decorated liposomes

Globally, there are several million individuals with life-threatening invasive fungal diseases such as candidiasis, aspergillosis, cryptococcosis, Pneumocystis pneumonia (PCP), and mucormycosis. The mortality rate for these diseases generally exceeds 40%. Annual medical costs to treat these invasive fungal diseases in the United States exceed several billion dollars. In addition to AIDS patients, the risks of invasive mycoses are increasingly found in immune-impaired individuals or in immunosuppressed patients following stem cell or organ transplant or implantation of medical devices. Current antifungal drug therapies are not meeting the challenge, because (1) at safe doses, they do not provide sufficient fungal clearance to prevent reemergence of infection; (2) most become toxic with extended use; (3) drug-resistant fungal isolates are emerging; and (4) only one new class of antifungal drugs has been approved for clinical use in the last 2 decades. DectiSomes represent a novel design of drug delivery to drastically increase drug efficacy. Antifungals packaged in liposomes are targeted specifically to where the pathogen is, through binding to the fungal cell walls or exopolysaccharide matrices using the carbohydrate recognition domains of pathogen receptors. Relative to untargeted liposomal drug, DectiSomes show order of magnitude increases in the binding to and killing of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus in vitro and similarly improved efficacy in mouse models of pulmonary aspergillosis. DectiSomes have the potential to usher in a new antifungal drug treatment paradigm.

Pneumonia caused by Lichtheimia ramosa during the COVID-19 pandemic in Hubei Province, China：mNGS assists diagnosis

BackgroundRecently, COVID-19 is still pandemic in worldwide. India has reported multiple cases of COVID-19 combined with mucormycosis(MM)(1). This paper reports a case during the COVID-19 pandemic in Hubei Province, China. Case PresentationA anesthesiology doctor was initially diagnosed as COVID-19 due to changes in lung imaging. Later Lichtheimia ramose was found by Metagenomic next generation sequencing (mNGS) in the Bronchoalveolar lavage fluid (BALF).After adjusting amphotericin B for anti-infective treatment, the patient's infection lesions were shranked and the symptoms were significantly relieved.ConclusionThe diagnosis of invasive fungal infections is very difficult, mNGS can make an accurate pathogenic diagnosis of invasive fungal diseases for the clinic and provide a basis for clinical treatment.