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Background. Breakthrough zygomycosis is increasingly observed among patients at high risk for fungal infection who are receiving voriconazole, reflecting either selective pressure or voriconazole-associated alterations in Zygomycetes virulence. We tested the latter hypothesis, using 2 phylogenetically disparate zygomycosis models. Methods. Three Zygomycetes strains were exposed to voriconazole by serial passages on voriconazole-containing medium. The virulence of voriconazole-exposed Zygomycetes strains was compared with that of voriconazolenonexposed strains in Drosophila and murine models of zygomycosis by assessment of survival curves, pulmonary fungal burdens, and expression of inflammation-associated genes. Results. Among Toll-deficient (Tl-/-) and wild-type fruit flies, infection with Zygomycetes isolates that had been exposed to voriconazole yielded significantly lower survival rates than infection with Zygomycetes strains grown in drug-free media. In contrast, exposure of Rhizopus oryzae to itraconazole, amphotericin B, or caspofungin and exposure of Aspergillus fumigatus to voriconazole did not alter the virulence of these isolates in fruit flies. In the murine model, infection with a R. oryzae strain preexposed to voriconazole was associated with decreased survival rates and increased pulmonary fungal burdens, compared with infection with a voriconazole-nonexposed R. oryzae strain. In addition, enhanced angioinvasion, inflammation, and expression of genes involved in stress response and tissue repair were found in mouse lungs infected with voriconazole-exposed R. oryzae. Conclusions. Exposure of Zygomycetes organisms to voriconazole selectively enhanced their virulence. The mechanisms underlying these phenotypic changes should be studied further. [ABSTRACT FROM AUTHOR]

Background. Zygomycosis is an emerging opportunistic mycosis among immunocompromised patients with a particularly poor prognosis. Methods. We analyzed the impact of delaying effective amphotericin B-based therapy on outcome among 70 consecutive patients with hematologic malignancy who had zygomycosis in our institution during the period 1989- 2006. We used classification and regression tree analysis to identify the mortality breakpoint between early and delayed treatment. Results. Delayed amphotericin B-based therapy (i.e., initiating treatment ⩾6 days after diagnosis) resulted in a 2-fold increase in mortality rate at 12 weeks after diagnosis, compared with early treatment (82.9% vs. 48.6%); this remained constant across the years of the study and was an independent predictor of poor outcome (odds ratio, 8.1; 95% confidence interval, 1.7-38.2; Pp.008) in multivariate analysis. Active malignancy (Pp.003) and monocytopenia (Pp.01) at the time of diagnosis of infection were also independently associated with a poor outcome, whereas salvage posaconazole-based therapy (Pp.01) and neutrophil recovery (Pp.009)were predictive of a favorable outcome. Conclusions. Because discriminating between zygomycosis and aspergillosis in a timely fashion is difficult, the pursuit of aggressive diagnostic strategies and prompt initiation of antifungal agents with activity against Zygomycetes should be considered for patients with hematological malignancy who are at an increased risk for zygomycosis. [ABSTRACT FROM AUTHOR]

There is limited information on the utility of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for the diagnosis and management of invasive mould infections (IMIs). We retrospectively evaluated patients with IMIs who underwent FDG-PET in our institution (n=13; December 1999 to April 2004), and reviewed the available literature (n=9). In 16 non-neutropenic patients with available FDG-PET imaging studies (11 from our institution), FDG-PET revealed an occult IMI site (n=3; 2 unidentified CNS involvement) and was helpful in guiding the duration of treatment (n=8). Prospective evaluation of the role of FDG-PET in the work-up and management of IMIs is needed. [ABSTRACT FROM AUTHOR]

Abstract: Although the extensive use of Aspergillus-active antifungals has been recently associated with an increase in zygomycosis in several cancer centers, the frequency of this opportunistic mycosis began to rise earlier, since the mid 1990s. The reasons for that emergence are unclear. Recent evidence suggests that endosymbiotic bacteria of Rhizopus species produce toxins that enhance fungal pathogenicity. We postulate that, although Zygomycetes appear equally ubiquitous and virulent to Aspergillus, zygomycosis was rare in the past in immunosuppressed patients specifically because of the widespread use of antibacterials in this patient population. Such use may have resulted in inhibition of endosymbiotic, toxin-producing bacteria and led indirectly in attenuation of Zygomycetes virulence. Thus, the growing rates of antimicrobial resistance over the past decade selected for multidrug-resistant endosymbiotic bacteria of Zygomycetes, which could facilitate the emergence of zygomycosis. This hypothesis, if true, will be the first paradigm of modulation of virulence of opportunistic fungi by antibacterials. [Copyright &y& Elsevier]

Background. Anecdotal evidence suggests a rise in zygomycosis in association with voriconazole (VRC) use in immunosuppressed patients. Methods. We performed prospective surveillance of patients with zygomycosis (group A; ) and compared np27 them with contemporaneous patients with invasive aspergillosis (group B; ) and with matched contempo- np54 raneous high-risk patients without fungal infection (group C; ). We also performed molecular typing and in np54 vitro susceptibility testing of Zygomycetes isolates. Results. Nearly all patients with zygomycosis either had leukemia ( ) or were allogeneic bone marrow np14 transplant recipients ( ). The Zygomycetes isolates (74% of which were of the genus Rhizopus) had different np13 molecular fingerprinting profiles, and all were VRC resistant. In multivariate analysis of groups A and C, VRC prophylaxis (odds ratio [OR], 10.37 [95% confidence interval {CI}], 2.76-38.97]; ), diabetes (OR, 8.39 Pp.001 [95% CI, 2.04-34.35]; ), and malnutrition (OR, 3.70 [95% CI, 1.03-13.27]; ) were found to be Pp.003 Pp.045 independent risk factors for zygomycosis. Between patients with zygomycosis (after excluding 6 patients with mixed mold infections) and patients with aspergillosis, VRC prophylaxis (OR, 20.30 [95% CI, 3.85-108.15]; ) Pp.0001 and sinusitis (OR, 76.72 [95% CI, 6.48-908.15]; ) were the only factors that favored the diagnosis of Pp.001 zygomycosis. Conclusions. Zygomycosis should be considered in immunosuppressed patients who develop sinusitis while receiving VRC prophylaxis, especially those with diabetes and malnutrition. [ABSTRACT FROM AUTHOR]