Fusarium (n ‫؍‬ 67) and Scedosporium (n ‫؍‬ 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species of Fusarium (4 isolates unspeciated) and 28 Scedosporium apiospermum, 7 Scedosporium aurantiacum, and 28 Scedosporium prolificans species were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC 90 values (g/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, for Fusarium of 0.12, >16, >16, >8, >8, 8, and 4 g/ml. E1210 was very potent against the Scedosporium spp. tested. The E1210 MEC 90 was 0.12 g/ml for S. apiospermum, but 1 to >8 g/ml for other tested agents. Against S. aurantiacum, the MEC 50 for E1210 was 0.06 g/ml versus 0.5 to >8 g/ml for the comparators. Against S. prolificans, the MEC 90 for E1210 was only 0.12 g/ml, compared to >4 g/ml for amphotericin B and >8 g/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ؎2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole and F. oxysporum species complex (SC) (60%), posaconazole and S. aurantiacum (85.7%), and voriconazole and S. aurantiacum (85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole-and amphotericin B-resistant strains of Fusarium spp. and Scedosporium spp. Furthermore, in vitro susceptibility testing of E1210 against isolates of Fusarium and Scedosporium may be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.

For more than a century, diabetic patients have been considered immunosuppressed due to defects in phagocytosis and microbial killing. We confirmed that diabetic mice were hypersusceptible to bacteremia caused by Gram-negative bacteria (GNB), dying at inocula nonlethal to nondiabetic mice. Contrary to the pervasive paradigm that diabetes impedes phagocytic function, the bacterial burden was no greater in diabetic mice despite excess mortality. However, diabetic mice did exhibit dramatically increased levels of proinflammatory cytokines in response to GNB infections, and immunosuppressing these cytokines with dexamethasone restored their resistance to infection, both of which are consistent with excess inflammation. Furthermore, disruption of the receptor for advanced glycation end products (RAGE), which is stimulated by heightened levels of AGEs in diabetic hosts, protected diabetic but not nondiabetic mice from GNB infection. Thus, rather than immunosuppression, diabetes drives lethal hyperinflammation in response to GNB by signaling through RAGE. As such, interventions to improve the outcomes from GNB infections should seek to suppress the immune response in diabetic hosts.

E1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents against Aspergillus spp. by using and itraconazole-R strains of A. fumigatus SC (MEC range, 0.03 to 0.12 g/ml), A. niger SC (MEC, 0.008 g/ml), and A. terreus SC (MEC, 0.015 g/ml). In conclusion, E1210 was a very potent and broad-spectrum antifungal agent regardless of in vitro method applied, with excellent activity against AMB-R and itraconazole-R strains of Aspergillus spp.

Two concentration-controlled trials (CCTs) defined the relationship between plasma concentrations of 3'-deoxy-3'-fluorothymidine (alovudine) and changes in surrogate markers of antiretroviral activity. In an initial open-label CCT involving 14 subjects infected with human immunodeficiency virus (HIV), unacceptable hematologic toxicity occurred when the area under the concentration-time curve during a 12-h dosing interval (AUC12) was > or = 300 ng*h/mL. Consequently, 46 subjects were assigned to AUC12s of 50, 100, or 200 ng*h/mL for up to 16 weeks in a prospective, randomized, double-blind CCT. Alovudine caused a concentration-dependent reduction in p24 antigen and peripheral blood mononuclear cell HIV titers within 4 weeks of start of treatment. The AUC12 producing a 50% reduction in p24 (108 ng*h/mL) had a trough concentration identical to the reported IC50 of alovudine in HIV-infected H9 cells. It may be possible to predict the antiretroviral activity of certain nucleoside analogues as a function of plasma drug concentration.

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