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Influenza-associated pulmonary aspergillosis (IAPA) is a feared complication in patients with influenza tracheobronchitis, especially those receiving corticosteroids. Herein, we established a novel IAPA mouse model with low-inoculum Aspergillus infection and compared outcomes in mice with and without cortisone acetate (CA) immunosuppression. CA was an independent predictor of increased morbidity/mortality in mice with IAPA. Early antifungal treatment with liposomal amphotericin B was pivotal to improve IAPA outcomes in CA-immunosuppressed mice, even after prior antiviral therapy with oseltamivir. In summary, our model recapitulates key clinical features of IAPA and provides a robust preclinical platform to study the pathogenesis and treatment of IAPA. [ABSTRACT FROM AUTHOR]

In invasive pulmonary aspergillosis, direct invasion and occlusion of pulmonary vasculature by Aspergillus hyphae causes tissue hypoxia, which is enhanced by secreted fungal metabolites that downregulate compensatory angiogenic signaling pathways. We assessed the effects of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) on survival rates, fungal burden, and in situ angiogenesis in a murine invasive pulmonary aspergillosis model. bFGF and VEGF monotherapy significantly increased survival rates and potentiated the activity of amphotericin B. bFGF-containing regimens were associated with reduced tissue fungal burdens. bFGF and VEGF reversed the antiangiogenic activity of Aspergillus fumigatus; however, VEGF induced the formation of immature neovessels, providing an explanation for its lesser efficacy. Treatment with bFGF plus amphotericin B was associated with neutrophil influx into Aspergillus-infected pulmonary tissue, suggesting that this combination limits fungal growth through neutrophil trafficking. Vasculogenic pathways are unexplored targets for the treatment of invasive pulmonary aspergillosis and may potentiate both innate immunity and antifungal drug activity against A. fumigatus. [ABSTRACT FROM PUBLISHER]

Pharmacological immune checkpoint blockade has revolutionized oncological therapies, and its remarkable success has sparked interest in expanding checkpoint inhibitor therapy in infectious diseases. Herein, we evaluated the efficacy of programmed cell death protein 1 (PD-1) blockade in a murine invasive pulmonary aspergillosis model. We found that, compared with isotype-treated infected control mice, anti-PD-1-treated mice had improved survival, reduced fungal burden, increased lung concentrations of proinflammatory cytokines and neutrophil-attracting chemokines, and enhanced pulmonary leukocyte accumulation. Furthermore, combined treatment with anti-PD-1 and caspofungin resulted in a significant survival benefit compared with caspofungin or anti-PD-1 therapy alone, indicating a synergistic effect between PD-1 inhibitors and immunomodulatory antifungal agents. [ABSTRACT FROM AUTHOR]

Clinical-grade T cells are genetically modified ex vivo to express chimeric antigen receptors (CARs) to redirect their specificity to target tumor-associated antigens in vivo. We now have developed this molecular strategy to render cytotoxic T cells specific for fungi. We adapted the pattern-recognition receptor Dectin-1 to activate T cells via chimeric CD28 and CD3-ζ (designated "D-CAR") upon binding with carbohydrate in the cell wall of Aspergillus germ-lings. T cells genetically modified with the Sleeping Beauty system to express D-CAR stably were propagated selectively on artificial activating and propagating cells using an approach similar to that approved by the Food and Drug Administration for manufacturing CD19-specific CAR+ T cells for clinical trials. The D-CAR+ T cells exhibited specificity for β-glucan which led to damage and inhibition of hyphal growth of Aspergillus in vitro and in vivo. Treatment of D-CAR+ T cells with steroids did not compromise antifungal activity significantly. These data support the targeting of carbohydrate antigens by CAFT T cells and provide a clinically appealing strategy to enhance immunity for opportunistic fungal infections using T-cell gene therapy. [ABSTRACT FROM AUTHOR]

Background Myocutaneous mucormycosis is encountered in settings of extreme mechanical forces such as combat-related blast injuries or natural catastrophes. It is unclear whether the virulence of Mucorales is affected by mechano-biological factors such as shear forces (SF). Methods Spores of clinical strains of Rhizopus arrhizus , Rhizomucor pusillus , and Mucor circinelloides (107/mL in PBS) were either kept in static culture (control) or exposed to shear forces (SF) by magnetic stirring for 30 minutes. Mycelial expansion was monitored in the IncuCyte time-lapse microscopy system. For in vivo studies, the dorsal thorax of wild-type Drosophila melanogaster flies (n = 66–76 per condition) was pricked with a needle dipped in control or SF-exposed spore solutions. Flies were also infected with non-exposed spores suspended in cell-free supernatant taken from SF-exposed spores. Survival was monitored for 7 days post-infection. Results Growth rates and morphogenesis of all isolates were not altered by SF. However, SF-exposed spores of all tested Mucorales isolates exhibited increased pathogenicity in the fly model (7-day survival: SF 8–14%, control 36–44%, P < 0.001). Introducing different resting periods after SF resulted in gradual attenuation of the hyper-virulent phenotype, with survival rates of infected flies returning to the level seen with non-SF-exposed spores after 120 min post-SF resting (Panel A). To gain a mechanistic insight, we added cyclosporine A (CsA, 100 µg/mL) during shear challenge. Compared with SF-exposed spores, CsA addition improved 7-day survival of R. arrhizus -infected flies from 1% to 29% (P < 0.001), whereas the pathogenicity of non-SF-exposed spores was not influenced by CsA. Interestingly, supernatants from SF-exposed R. arrhizus rendered non-exposed spores hyper-virulent (Panel B, P = 0.003). Conclusion SF induces a transient hypervirulent phenotype of Mucorales. Our findings suggest that soluble mediators contribute to increased pathogenicity. Largely attenuated hyper-virulence in the presence of CsA corroborated the previously described relevance of the calcineurin pathway in fungal mechano-biology. RNA sequencing studies are in progress to identify epigenetic alterations in Mucorales following SF. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Background Checkpoint blockade (CPB) has brought a revolution in modern oncology and may offer new strategies for antifungal immunotherapy. In vitro studies have demonstrated that blockade of the PD-1/PDL-1 interaction increased IFN-γ secretion in response to Aspergillus antigens, suggesting a potential role for anti-PD-1 therapy in promoting anti- Aspergillus immunity. We sought to evaluate the therapeutic efficacy of low-dose anti-PD-1 therapy in a murine IPA model. Methods Eight- to twelve-week-old female BALB/c mice were immunosuppressed with cyclophosphamide and cortisone acetate and infected intra-nasally with 5 × 104 of A. fumigatus Af293 conidia (panel A). Mice were then treated intraperitoneally with 4 doses of either 200 µL PBS (PBS control), 250 µg/kg BW IgG antibody (isotype control), or a monoclonal PD-1 antibody (anti-PD-1). Survival was monitored daily until day 8 post-infection. 24–28 mice per treatment were assessed in 3 independent experiments. Pulmonary fungal burden was determined by 18S qPCR either on day 8 post-infection or upon death. Additional mice were sacrificed on day 1 and 4 post-infection to assess serum concentrations of selected cytokines by ELISA. Results Infected mice receiving treatment with either PBS or the isotype antibody exhibited 8 day survival rates of 33% and 36%, respectively. In contrast, 68% of the mice in the PD-1 antibody treatment group survived (panel B). Accordingly, pulmonary fungal burden was significantly reduced in anti-PD-1 vs. isotype-treated infected mice (median spore equivalent: 0.39 vs. 2.06 × 109, P = 0.015). No signs of toxicity or early mortality were seen in anti-PD-1-treated mice, and no elevated serum levels of pro-inflammatory cytokines TNF-α and INF-γ were found in those mice (compared with isotype-treated infected mice). Conclusion We found that anti-PD-1 immune checkpoint blockade has independent beneficial effects in untreated immunosuppressed mice with IPA. We are in the process of measuring pulmonary cytokines to deepen our understanding of protective anti- Aspergillus immunity conferred by low-dose CPB. In addition, future studies would address the combined application of CPB and conventional antifungal drugs that have immune-regulatory activity such as echinocandins. Disclosures All Authors: No reported Disclosures. [ABSTRACT FROM AUTHOR]

Objectives: Candida auris is an emerging, often MDR, yeast pathogen. Efficient animal models are needed to study its pathogenicity and treatment. Therefore, we developed a C. auris fruit fly infection model.Methods: TollI-RXA/Tollr632 female flies were infected with 10 different C. auris strains from the CDC Antimicrobial Resistance bank panel. We used three clinical Candida albicans strains as controls. For drug protection assays, fly survival was assessed along with measurement of fungal burden (cfu/g tissue) and histopathology in C. auris-infected flies fed with fluconazole- or posaconazole-containing food.Results: Despite slower in vitro growth, all 10 C. auris isolates caused significantly greater mortality than C. albicans in infected flies, with >80% of C. auris-infected flies dying by day 7 post-infection (versus 67% with C. albicans, P < 0.001-0.005). Comparison of C. auris isolates from different geographical clades revealed more rapid in vitro growth of South American isolates and greater virulence in infected flies, whereas the aggregative capacity of C. auris strains had minimal impact on their growth and pathogenicity. Survival protection and decreased fungal burden of fluconazole- or posaconazole-fed flies infected with two C. auris strains were in line with the isolates' disparate in vitro azole susceptibility. High reproducibility of survival curves for both non-treated and antifungal-treated infected flies was seen, with coefficients of variation of 0.00-0.31 for 7 day mortality.Conclusions: Toll-deficient flies could provide a fast, reliable and inexpensive model to study pathogenesis and drug activity in C. auris candidiasis. [ABSTRACT FROM AUTHOR]

Background. Azole-resistant aspergillosis in high-risk patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) is a cause of concern. Methods. We examined changes over time in triazole minimum inhibitory concentrations (MICs) of 290 sequential Aspergillus isolates recovered from respiratory sources during 1999-2002 (before introduction of the Aspergillus-potent triazoles voriconazole and posaconazole) and 2003-2015 at MD Anderson Cancer Center. We also tested for polymorphisms in ergosterol biosynthetic genes (cyp51A, erg3C, erg1) in the 37 Aspergillus fumigatus isolates isolated from both periods that had non-wild-type (WT) MICs. For the 107 patients with hematologic cancer and/or HSCT with invasive pulmonary aspergillosis, we correlated in vitro susceptibility with 42-day mortality. Results. Non-WT MICs were found in 37 (13%) isolates and was only low level (MIC <8 mg/L) in all isolates. Higher-triazole MICs were more frequent in the second period and were Aspergillus-species specific, and only encountered in A. fumigatus. No polymorphisms in cyp51A, erg3C, erg1 genes were identified. There was no correlation between in vitro MICs with 42-day mortality in patients with invasive pulmonary aspergillosis, irrespective of antifungal treatment. Asian race (odds ratio [OR], 20.9; 95% confidence interval [CI], 2.5-173.5; P = .005) and azole exposure in the prior 3 months (OR, 9.6; 95% CI, 1.9-48.5; P = .006) were associated with azole resistance. Conclusions. Non-WT azole MICs in Aspergillus are increasing and this is associated with prior azole exposure in patients with hematologic cancer or HSCT. However, no correlation of MIC with outcome of aspergillosis was found in our patient cohort. [ABSTRACT FROM AUTHOR]

Background: Mucormycosis is a destructive invasive mold infection afflicting patients with diabetes and hematologic malignancies. Patients with diabetes are often treated with statins, which have been shown to have antifungal properties. We sought to examine the effects of statins on Rhizopus oryzae, a common cause of mucormycosis.Methods: Clinical strains of R. oryzae were exposed to lovastatin, atorvastatin, and simvastatin and the minimum inhibitory concentrations (MICs) were determined. R. oryzae germination, DNA fragmentation, susceptibility to oxidative stress, and ability to damage endothelial cells were assessed. We further investigated the impact of exposure to lovastatin on the virulence of R. oryzaeResults: All statins had MICs of >64 µg/mL against R. oryzae Exposure of R. oryzae to statins decreased germling formation, induced DNA fragmentation, and attenuated damage to endothelial cells independently of the expression of GRP78 and CotH. Additionally, R. oryzae exposed to lovastatin showed macroscopic loss of melanin, yielded increased susceptibility to the oxidative agent peroxide, and had attenuated virulence in both fly and mouse models of mucormycosis.Conclusions: Exposure of R. oryzae to statins at concentrations below their MICs decreased virulence both in vitro and in vivo. Further investigation is warranted into the use of statins as adjunctive therapy in mucormycosis. [ABSTRACT FROM AUTHOR]

High concentrations of methylprednisolone (0.32 mg/mL) accelerated growth and attenuated spontaneous apoptosis of Exserohilum rostratum in vitro. Injection of E. rostratum conidia preexposed to 0.32 mg/mL of methylprednisolone for 7 days in immunocompetent flies led to increased mortality and a higher fungal burden. Exposure to methylprednisolone could enhance the virulence of E. rostratum. [ABSTRACT FROM AUTHOR]

High concentrations of methylprednisolone (0.32 mg/mL) accelerated growth and attenuated spontaneous apoptosis of Exserohilum rostratum in vitro. Injection of E. rostratum conidia preexposed to 0.32 mg/mL of methylprednisolone for 7 days in immunocompetent flies led to increased mortality and a higher fungal burden. Exposure to methylprednisolone could enhance the virulence of E. rostratum. [ABSTRACT FROM PUBLISHER]

We examined the qualitative polymorphonuclear neutrophil (PMN)-associated immune impairment in patients with chronic lymphocytic leukemia (CLL) by characterizing phagocytic killing of key non-opsonized bacterial ( Staphylococcus aureus and Pseudomonas aeruginosa) and fungal ( Candida albicans and Aspergillus fumigatus) pathogens. Neutrophils were collected from 47 non-neutropenic patients with CLL (PMN count > 1000/mm3) and age-matched and young healthy controls (five each). A subset of patients (13%) had prior or subsequent infections. We found that the patients with CLL had diminished PMN microbicidal response against bacteria but not against fungi compared with the controls. Compared to patients with effective PMN responses, we did not identify differences of basal PMN pathogen-associated molecular pattern receptor gene expression, soluble pathogen-associated molecular pattern gene expression or inflammatory cytokine signatures in patients with impaired PMN responses when PMNs were analyzed in multiplex real-time polymerase chain reaction assays. However, differences in PMN microbicidal response against A. fumigatus in patients with CLL were associated with the degree of hypogammaglobulinemia. [ABSTRACT FROM AUTHOR]

Background. Mini-host models are simple experimental systems to study host-pathogen interactions. We adapted a Drosophila melanogaster infection model to evaluate the in vivo effect of different mechanisms of linezolid (LNZ) resistance in Staphylococcus aureus.Methods. Fly survival was evaluated after infection with LNZ-resistant S. aureus strains NRS119 (which has mutations in 23S ribosomal RNA [rRNA]), CM-05 and 004-737X (which carry cfr), LNZ-susceptible derivatives of CM-05 and 004-737X (which lack cfr), and ATCC 29213 (an LNZ-susceptible control). Flies were then fed food mixed with LNZ (concentration, 15–500 µg/mL). Results were compared to those in mouse peritonitis, using LNZ via oral gavage at 80 and 120 mg/kg every 12 hours.Results. LNZ at 500 µg/mL in fly food protected against all strains, while concentrations of 15–250 µg/mL failed to protect against NRS119 (survival, 1.6%–20%). An in vivo effect of cfr was only detected at concentrations of 30 and 15 µg/mL. In the mouse peritonitis model, LNZ (at doses that mimic human pharmacokinetics) protected mice from challenge with the cfr+ 004-737X strain but was ineffective against the NRS119 strain, which carried 23S rRNA mutations.Conclusions. The fly model offers promising advantages to dissect the in vivo effect of LNZ resistance in S. aureus, and findings from this model appear to be concordant with those from the mouse peritonitis model. [ABSTRACT FROM AUTHOR]

Abstract: Background: USA300 is a uniquely successful methicillin-resistant Staphylococcus aureus (MRSA) clone that has been associated with Panton-Valentine leukocidin (PVL) production and severe infections. However, conflicting experimental and epidemiological data exist regarding the virulence of USA300 relative to other MRSA clones. We aimed to address this issue using Drosophila melanogaster as a model host to study strain and PVL-dependent variations in virulence among MRSA clinical isolates. Results: We studied the relative virulence of 39 MRSA isolates: 17 (43%) were PFGE type USA300. Lethal MRSA infection was reproducibly induced both in wild-type (WT) and Toll-deficient D. melanogaster. USA300 strains had significantly lower lethality than non-USA300 strains in a WT background but not in Toll-deficient flies. PFGE type (USA300 versus non-USA300) and PVL status did not affect the response to treatment with linezolid. Virulence was similar in strains with high vancomycin MIC (≥2 μg/mL) versus those with vancomycin MIC<2 μg/mL. Conclusions: D. melanogaster is a potentially useful model host to study pathogenicity and response to antibiotic treatment in S. aureus. Our results imply that the attenuated virulence of PVL+/USA300 requires intact host innate immunity. [Copyright &y& Elsevier]

Abstract: Introduction: Invasive pulmonary aspergillosis (IPA) is a leading cause of infection-associated death in immunosuppressed patients. Early detection and early administration of antifungal therapy are critical factors in improving outcome for patients with IPA. Here, we evaluated the imaging properties of a 111In-labeled cyclic peptide targeted to Aspergillus fumigatus in an immunosuppressed murine model of IPA. Methods: A cyclic peptide c(CGGRLGPFC)-NH2 was labeled with 111In by means of diethylenetriaminepentaacetic acid (DTPA). Two days after intranasal inoculation of 17.5×106 conidia of A. fumigatus, mice were injected 111In-DTPA-c(CGGRLGPFC)-NH2 intravenously. Biodistribution data were obtained at 2 h, and γ-images were acquired at 10 min and 2 h after radiotracer injection. Healthy mice were used as controls. In addition, a group of infected mice were co-injected with the radiotracer and unlabeled c(CGGRLGPFC)-NH2 to evaluate the inhibition of radiotracer''s binding to infected lungs. Autoradiographs of lungs from infected and healthy mice were compared with corresponding photographs of transaxial sections of the lung tissues stained for A. fumigatus hyphae. Results: The labeling efficiency was >98%, with specific radioactivity of up to 74 MBq/nmol peptide. Significantly higher uptake of 111In-DTPA-c(CGGRLGPFC)-NH2 was observed in the lungs of mice infected with A. fumigatus than in those of healthy mice (0.37±0.06 %ID/g vs. 0.14±0.02 %ID/g, P=.00044). Simultaneous injection with unlabeled peptide reduced radioactivity in the infected lungs by 41% (P=.0037). Increased radioactivity in the lungs of infected mice was visible in γ images at both 10 min and 2 h after radiotracer injection. Moreover, autoradiography confirmed radiotracer uptake in infected lungs, but not in the lungs of healthy mice or infected mice co-injected with unlabeled peptide. Conclusions: γ-Imaging with 111In-DTPA-c(CGGRLGPFC)-NH2 clearly delineated experimental IPA in mice. Peptides directly targeting fungi therefore may be valuable agents for noninvasive detection of opportunistic mycoses. [Copyright &y& Elsevier]

Candida species are the predominant fungal pathogens in humans and an important cause of mortality in immunocompromised patients. We developed a model of candidiasis in Toll (Tl)-deficient Drosophila melanogaster. Similar to the situation in humans, C. parapsilosis was less virulent than C. albicans when injected into Tl mutant flies. In agreement with findings in the mouse model of invasive candidiasis, cph1/cph1 and efg1/efg1 C. albicans mutants had attenuated virulence, and the efg1/efg1 cph1/cph1 double mutant was almost avirulent in Tl mutant flies. Furthermore, the conditional tet-NRG1 C. albicans strain displayed significantly attenuated virulence in flies fed food without doxycycline; virulence was restored to wild-type levels when the strain was injected into Tl mutant flies fed doxycycline-containing food. Fluconazole (FLC) mixed into food significantly protected Tl mutant flies injected with FLC-susceptible C. albicans strains, but FLC had no activity in flies injected with FLC-resistant C. krusei strains. The D. melanogaster model is a promising minihost model for large-scale studies of virulence mechanisms and antifungal drug activity in candidiasis. [ABSTRACT FROM AUTHOR]

Background Efficient animal models are needed in order to investigate fungal pathogenicity and antifungal therapy in the context of epithelial injury, e.g. due to anticancer chemotherapy. Using a Gal4 enhancer trap (GET) zebrafish line facilitating metronidazole (MTZ)-inducible ablation of epithelial (periderm) cells, we aimed to establish a mucositis model predisposing larvae for fungal invasion. Methods 4 days post-fertilization Et(Gal4-VP16)zc1044A;Tg(UAS-1b:nfsB-mCherry)c264 zebrafish larvae were exposed to 10 mM MTZ in E3 medium for 5 h. After washing, larvae were incubated in Candida albicans or Rhizopus arrhizus spore suspensions (5 × 105–5 × 107/mL) for 16 h. Thereafter, larvae were washed again and survival was monitored until 72 h post-infection. Fungal burden was assessed by 18S qPCR and histopathology. For drug protection studies, 5 µg/mL amphotericin B (AMB) or posaconazole (PCZ) was added to the medium of R. arrhizus -infected larvae at 16 h post-infection. Results In MTZ-treated GET larvae, inoculum-dependent mortality was found for both R. arrhizus (panel A) and C. albicans (panel B). High inter-experiment reproducibility of survival rates was seen (CV < 0.3). Using a GFP-expressing R. arrhizus strain, fungal invasion of the larval tissue was verified by fluorescence microscopy (panel C). PCZ and AMB improved survival rates of R. arrhizus -infected (5 × 106/mL) larvae from 46% to 85% and 51% to 86%, respectively (P < 0.001). Similarly, significantly reduced fungal burden in AMB and PCZ-treated larvae was documented by qPCR (panel D) and histopathology. In additional validation experiments, the hypo-virulent phenotypes of a CotH-depleted R. arrhizus strain and filamentation-defective C. albicans mutants (Δefg1 and Δcph1) were recapitulated in zebrafish larvae with epithelial cell loss. Conclusion We have established a robust and reliable model of invasive mycoses by controlled ablation of epithelial cells in zebrafish larvae, allowing for rapid immersion-based interrogation of different infection and treatment options. Our proof-of-concept experiments suggest that GET zebrafish larvae are positioned as an appealing high-throughput in vivo system for antifungal drug screening or comparative virulence studies. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]

Abstract: Invasive aspergillosis (IA) can occur despite prior prophylactic or empiric use of triazoles or amphotericin B (AMB). Although profound immunosuppression may account for breakthrough IA, resistance of Aspergillus to antifungals may also play a role. To examine this question, we measured the minimal inhibitory concentration of 105 Aspergillus isolates recovered from 105 cancer patients (64 with IA, 41 with Aspergillus colonization) to AMB, itraconazole (ITC), and voriconazole (VRC) using the National Committee for Clinical Laboratory Standards (NCCLS) M38-A microdilution and E-test methods. We also determined the minimal fungicidal concentration (MFC) of these agents and the minimal effective concentration (MEC) of caspofungin (CAS) using standardized methods. We then collected information regarding pre-exposure to AMB or triazoles (fluconazole, ITC, VRC) within 3 months before Aspergillus isolation. Pre-exposure of cancer patients to AMB or triazoles was associated with increased frequency of non-fumigatus Aspergillus species. Aspergillus isolates recovered from patients who previously received AMB exhibited higher E-test AMB MICs compared with isolates from patients without prior AMB exposure (P = 0.01). In addition, the AMB MICs by E-test were higher in triazole–pre-exposed patients compared with those not exposed to triazoles (P = 0.001). The ITC and VRC MICs by E-test were not affected by prior AMB or triazole exposure. Finally, neither the AMB, ITC, and VRC MICs and MFCs by NCCLS method nor CAS MECs showed such changes. In conclusion, cancer patients with positive Aspergillus cultures who are pre-exposed to AMB or triazoles have high frequency of non-fumigatus Aspergillus species. These Aspergillus isolates were found to be AMB-resistant by the more sensitive E-test method. [Copyright &y& Elsevier]

Invasive aspergillosis (IA) is the most important opportunistic mycosis in immunosuppressed patients. The lack of a sufficient number of effective antifungals and our incomplete understanding of the pathogenesis of IA contribute to its overall unfavorable prognosis. Studies of drug efficacy against IA and Aspergillus virulence rely on conventional animal models that are laborious and use limited numbers of animals; alternative, less cumbersome in vivo models are desirable. Using different inoculation models of IA, we found that Tolldeficient Drosophila flies exposed to voriconazole (VRC), the preferred drug for the treatment of IA in humans, had significantly better survival rates and lower tissue fungal burdens than did those not exposed to VRC. Furthermore, Toll-deficient Drosophila flies infected with an alb-deleted hypovirulent Aspergillus mutant had significantly better survival rates than did those infected with a wild-type Aspergillus strain. Therefore, the Drosophila fly is a fast, high-throughput in vivo model for the study of drug efficacy against IA and Aspergillus virulence. [ABSTRACT FROM AUTHOR]

We investigated the in vitro activity of sequential itraconazole and caspofungin against 10 isolates of Aspergillus fumigatus. Previous exposure of A. fumigatus to itraconazole resulted in dose-dependent enhanced effects of caspofungin and vice versa. Our finding suggests a preferential role for azole-caspofungin sequential combinations and merits further in vivo investigation. [Copyright &y& Elsevier]

We compared the in vitro pharmacodynamics of isavuconazole, voriconazole, and posaconazole against 92 clinical isolates from documented cases of invasive aspergillosis, mucormycosis, fusariosis, and phaeohyphomycosis. Whereas inhibitory and fungicidal concentrations of these triazoles were predictably similar with the exception of Mucorales , isavuconazole appeared to have improved pharmacodynamics against Fusarium solani. [ABSTRACT FROM AUTHOR]