Vulvovaginal candidiasis (VVC) is an opportunistic mucosal infection caused by Candida albicans that affects large numbers of otherwise healthy women of childbearing age. Acute episodes of VVC often occur during pregnancy and during the luteal phase of the menstrual cycle, when levels of progesterone and estrogen are elevated. Although estrogen-dependent experimental rodent models of C. albicans vaginal infection are used for many applications, the role of reproductive hormones and/or their limits in the acquisition of vaginal candidiasis remain unclear. This study examined the effects of estrogen and progesterone on several aspects of an experimental infection together with relative cell-mediated immune responses. Results showed that while decreasing estrogen concentrations eventually influenced infection-induced vaginal titers of C. albicans and rates of infection in inoculated animals, the experimental infection could not be achieved in mice treated with various concentrations of progesterone alone. Furthermore, progesterone had no effect on (i) the induction and persistence of the infection in the presence of estrogen, (ii) delayed-type hypersensitivity in primary-infected mice, or (iii) the partial protection from a secondary vaginal infection under pseudoestrus conditions. Other results with estrogen showed that a persistent infection could be established with a wide range of C. albicans inocula under supraphysiologic and near-physiologic (at estrus) concentrations of estrogen and that vaginal fungus titers or rates of infection were similar if pseudoestrus was initiated several days before or after inoculation. However, the pseudoestrus state had to be maintained for the infection to persist. Finally, estrogen was found to reduce the ability of vaginal epithelial cells to inhibit the growth of C. albicans. These results suggest that estrogen, but not progesterone, is an important factor in hormone-associated susceptibility to C. albicans vaginitis.Vulvovaginal candidiasis (VVC) is a significant problem for women of childbearing age; approximately 75% of all women experience at least one episode of VVC during their lifetime (24,26). Several exogenous factors, including antibiotic or oral contraceptive usage, pregnancy, hormone replacement therapy (HRT), and uncontrolled diabetes mellitus, predispose women to VVC (24,26). In the absence of these factors, clinical observations show that VVC most often occurs in women during the luteal phase of the menstrual cycle, when estrogen and progesterone levels are elevated (11). In contrast, premenarchal and postmenopausal women not receiving HRT rarely suffer from VVC (23). There also exists a subset of women (5 to 10%) who experience recurrent VVC

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We investigated the antifungal activities of itraconazole and voriconazole on Aspergillus species by time kill studies, and the results were compared with those obtained forCandida species. Exposure of Aspergillus fumigatus conidia to varying concentrations (1.25 to 10 μg/ml) of itraconazole and voriconazole resulted in cellular death; the cytocidal effect was time and concentration dependent. In contrast, no killing of Candida albicans occurred in the presence of itraconazole and voriconazole at concentrations as high as 10 μg/ml, although candidal growth was inhibited compared to the drug-free control. Amphotericin B (1.25 to 10 μg/ml), on the other hand, killed both A. fumigatus and C. albicans. Similar results were obtained for non-A. fumigatus aspergilli and non-C. albicans Candida species. These observations indicate that both itraconazole and voriconazole are cytocidal agents for Aspergillus species but not for Candidaspecies, suggesting that azoles possess organism-dependent fungicidal activities.

Oropharyngeal candidiasis (OPC), as opposed to vulvovaginal candidiasis (VVC), is a common opportunistic infection in human immunodeficiency virus (HIV)-positive persons that correlates with reduced CD4 T cell counts. Although cell-mediated immunity (CMI) by CD4 Th1-type cells is considered to be the predominant host defense against mucosal candidiasis, the immune factors associated with susceptibility to OPC in HIV-positive persons are not well understood. This study investigated Candida-specific systemic CMI in HIV-positive persons with OPC and/or VVC. Reductions in delayed skin test reactivity to Candida antigen were observed in HIV-positive persons with CD4 cell counts <200 cells/microL, irrespective of the presence of mucosal infection. Likewise, despite the correlate of OPC with reduced CD4 cell counts in HIV-positive persons, differences in Candida-specific peripheral blood mononuclear cell proliferation and Th1/Th2 cytokine production between HIV-positive and HIV-negative persons were not consistent in a manner to suggest that deficiencies in Candida-specific systemic CMI account solely for the susceptibility to OPC.

Vaginal Candida glabrata infections have increased significantly in recent years and are particularly common in women with uncontrolled diabetes mellitus. Efforts to understand the pathogenesis and treatment of this infection have been hindered by the lack of experimental animal models. Before onset of hyperglycemia, nonobese diabetic (NOD) mice inoculated intravaginally with clinical C. glabrata isolates were shown to support high vaginal titers of C. glabrata for > 14 days with evidence for superficial invasion of vaginal epithelial tissue. In contrast, congenic diabetic-resistant mice and mice susceptible to Candida albicans infections were significantly less susceptible to vaginal infection by C. glabrata, suggesting a potential link between the susceptibility of NOD mice to diabetes and their susceptibility to vaginal C. glabrata infections. This animal model of C. glabrata vaginitis provides a means to study the genetics and pathogenesis of C. glabrata infections and to evaluate the efficacy of antimycotic agents against C. glabrata.

Clostridium difficile is a leading cause of infectious diarrhea in hematopoietic stem cell transplant (HSCT) recipients. Asymptomatic colonization of the gastrointestinal tract occurs before development of C. difficile infection (CDI). This prospective study examines the rates, risk factors, and outcomes of colonization with toxigenic and nontoxigenic strains of C. difficile in HSCT patients. This 18-month study was conducted in the HSCT unit at the Karmanos Cancer Center and Wayne State University in Detroit. Stool samples from the patients who consented for the study were taken at admission and weekly until discharge. Anaerobic culture for C. difficile and identification of toxigenic strains by PCR were performed on the stool samples. Demographic information and clinical and laboratory data were collected. Of the 150 patients included in the study, 29% were colonized with C. difficile at admission; 12% with a toxigenic strain and 17% with a nontoxigenic strain. Over a 90-day follow-up, 12 of 44 (26%) patients colonized with any C. difficile strain at admission developed CDI compared with 13 of 106 (12%) of patients not colonized (odds ratio [OR], 2.70; 95% confidence interval [95% CI], 1.11 to 6.48; P = .025). Eleven of 18 (61%) patients colonized with the toxigenic strain and 1 of 26 (4%) of those colonized with nontoxigenic strain developed CDI (OR, 39.30; 95% CI, 4.30 to 359.0; P < .001) at a median of 12 days. On univariate and multivariate analyses, none of the traditional factors associated with high risk for C. difficile colonization or CDI were found to be significant. Recurrent CDI occurred in 28% of cases. Asymptomatic colonization with C. difficile at admission was high in our HSCT population. Colonization with toxigenic C. difficile was predictive of CDI, whereas colonization with a nontoxigenic C. difficile appeared protective. These findings may have implications for infection control strategies and for novel approaches for the prevention and preemptive treatment of CDI in the HSCT patient population.

The efficacy of voriconazole in combination with amphotericin B or micafungin was studied in a transiently neutropenic guinea-pig model of invasive pulmonary aspergillosis. Guinea-pigs treated with the antifungal drugs, alone or in two-drug combinations, had an improved survival rate and reduced fungal burden in the lungs compared to untreated control animals. The efficacy of monotherapy and combination therapy was similar; activity was neither enhanced nor reduced with the two-drug combinations. Further studies of efficacy, dosing and optimal regimens for antifungal combinations are warranted.

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