Super bioavailability (SUBA) itraconazole (S-ITZ), which releases drug in the duodenum, and conventional itraconazole (C-ITZ), which releases drug in the stomach, were compared in two pharmacokinetic (PK) studies: a 3-day loading dose study and a 15-day steady-state administration study. These were crossover oral bioequivalence studies performed under fed conditions in healthy adult volunteers. In the loading dose study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered three times daily for 3 days and once on day 4 (n = 15). For the steady-state administration study, C-ITZ (two doses of 100 mg each) and S-ITZ (two doses of 65 mg each) were administered twice daily for 14 days and a last dose was administered 30 min after a meal on day 15 (n = 16). Blood samples collected throughout both studies were analyzed for ITZ and hydroxy-ITZ (OH-ITZ) levels. Least-squares geometric means were used to compare the maximum peak concentration of drug after administration at steady state prior to administration of the subsequent dose (Cmax_ss), the minimum drug level after administration prior to the subsequent dose (Ctrough), and the area under the curve over the dosing interval (AUCtau) of each formulation. The ratios of itraconazole (ITZ) and OH-ITZ for S-ITZ to C-ITZ were between 107% and 118% in both studies for Cmax_ss, Ctrough, and AUCtau, which were within the U.S. FDA-required bioequivalence range of 80% to 125%. At the end of the steady-state administration study, 13 of 16 volunteers obtained higher mean ITZ blood Ctrough levels of >1,000 ng/ml when they were administered S-ITZ (81%) than when they were administered C-ITZ (44%). The study drugs were well tolerated in both studies, with similar adverse events (AEs). All treatment-emergent AEs resolved after study completion. One volunteer receiving C-ITZ discontinued due to a treatment-unrelated AE in the steady-state administration study. No serious AEs were reported. Total, trough, and peak ITZ and OH-ITZ exposures were similar between the two formulations. Therefore, SUBA-ITZ, which has 35% less drug than C-ITZ, was bioequivalent to C-ITZ in healthy adult volunteers and exhibited a safety profile similar to that of C-ITZ.

We analyzed the relationship between itraconazole (ITZ) and hydroxy-itraconazole (OH-ITZ) levels in 1,223 human samples. Overall, there was a statistically significant correlation between ITZ and OH-ITZ levels (Pearson's r, 0.7838), and OH-ITZ levels were generally higher than ITZ levels (median OH-ITZ:ITZ ratio, 1.73; range, 0.13 to 8.96). However, marked variability was observed throughout the range of ITZ concentrations. Thus, it is difficult to predict OH-ITZ concentrations based solely on ITZ levels.

Pulmonary aspergillosis has been increasingly reported following severe respiratory viral infections. Millions have been infected by SARS-CoV-2, placing large numbers of patients at-risk for COVID-19 associated pulmonary aspergillosis (CAPA). Prompt recognition of this syndrome and is paramount to improve outcomes.

We compared prophylactic or continuous therapy with the investigational drug VT-1161 to that with posaconazole in treating murine mucormycosis due to Rhizopus arrhizus var. arrhizus In the prophylaxis studies, only VT-1161 resulted in improved survival and lowered tissue fungal burden of immunosuppressed infected mice. In the continuous therapy, VT-1161 outperformed posaconazole in prolonging mouse survival time despite its comparable effect in lowering tissue fungal burden. These results support the further development of VT-1161 against mucormycosis.

We studied the efficacy of the investigational drug VT-1161 against mucormycosis. VT-1161 had more potent in vitro activity against Rhizopus arrhizus var. arrhizus than against R. arrhizus var. delemar. VT-1161 treatment demonstrated dose-dependent plasma drug levels with prolonged survival time and lowered tissue fungal burden in immunosuppressed mice infected with R. arrhizus var. arrhizus and was as effective as high-dose liposomal amphotericin B treatment. These results support further development of VT-1161 against mucormycosis.

There is increased concern that the quality, generalizability and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either Rhizopus delemar or Mucor circinelloides. The only difference detected was that when DKA mice were infected with M. circinelloides, female mice were more resistant to infection than male mice (median survival time of 5 vs. 2 days for female and male mice, respectively). However, a 100% lethality was detected among infected animals of both sexes. Treatment with either liposomal amphotericin B (L-AMB) or posaconazole (POSA) protected mice from infection and eliminated the difference seen between infected but untreated female and male mice. Treatment with L-AMB consistently outperformed POSA in prolonging survival and reducing tissue fungal burden of DKA and neutropenic mice infected with R. delemar or M. circinelloides, in both mouse sexes. While little difference was detected in cytokine levels among both sexes, mucormycosis infection in the DKA mouse model induced more inflammatory cytokines/chemokines involved in neutrophil (CXCL1) and macrophage (CXCL2) recruitment vs. uninfected mice. As expected, this inflammatory response was reduced in the neutropenic mouse model. Our studies show that there are few differences between female and male DKA or neutropenic mice infected with mucormycosis with no effect on the outcome of treatment or host immune response.

Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19-associated fungal infections.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities.