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Candida spp. are responsible for most of the fungal infections in humans. Available since 1990, fluconazole is well established as a leading drug in the setting of prevention and treatment of mucosal and invasive candidiasis. Fluconazole displays predictable pharmacokinetics and an excellent tolerance profile in all groups, including the elderly and children. Fluconazole is a fungistatic drug against yeasts and lacks activity against moulds. Candida krusei is intrinsically resistant to fluconazole, and other species, notably Candida glabrata, often manifest reduced susceptibility. Emergence of azole-resistant strains as well as discovery of new antifungal drugs (new triazoles and echinocandins) have raised important questions about its use as a first line drug. The aim of this review is to summarize the main available data on the position of fluconazole in the prophylaxis or curative treatment of invasive Candida spp. infections. Fluconazole is still a major drug for antifungal prophylaxis in the setting of transplantation (solid organ and bone marrow), intensive care unit, and in neutropenic patients. Prophylactic fluconazole still has a place in HIV-positive patients in viro-immunological failure with recurrent mucosal candidiasis. Fluconazole can be used in adult neutropenic patients with systemic candidiasis, as long as the species identified is a priori susceptible. Among non-neutropenic patients with candidaemia fluconazole is one of the first line drugs for susceptible species. Cases reports and uncontrolled studies have also reported its efficacy in the setting of osteoarthritis, endophthalmitis, meningitis, endocarditis and peritonitis caused by Candida spp. among immunocompetent adults. In paediatrics, fluconazole is a well tolerated and major prophylactic drug for high-risk neonates, as well as an alternative treatment for neonatal candidiasis. Importantly 15 years after its introduction in the antifungal armamentarium, fluconazole is still a first line treatment option in several cases of invasive candidiasis. Its prophylactic use should however be limited to selected high-risk patients to limit the risk of emergence of azole-resistant strains.

We investigated the in vitro interaction of terbinafine with itraconazole, fluconazole, amphotericin B and 5-flucytosine, against Aspergillus spp. We tested three isolates of Aspergillus fumigatus (one resistant to itraconazole), and two each of Aspergillus flavus, Aspergillus niger and Aspergillus terreus. We employed a broth microdilution-based method derived from an in vivo validated method capable of detecting itraconazole resistance in A. fumigatus. We studied the effect on the MICs by calculation of the fractional inhibitory concentration (FIC) and fractional fungicidal concentration (FFC) (99.99% kill). Itraconazole and terbinafine were synergic or additive in all strains (FIC = 0.15-1.0). Fluconazole and terbinafine were synergic with A. fumigatus, A. terreus and A. flavus (FIC = 0.3-0.5) and indifferent with A. niger (FIC = 2) isolates. Amphotericin B and terbinafine were mostly indifferent or antagonistic (FIC = 1.0-4.02). Flucytosine and terbinafine were usually indifferent or antagonistic (FIC = 0.63-8.5). FFCs were generally in accord with FICs. The use of terbinafine in combination therapy for Aspergillus infections with azoles seems promising, whereas terbinafine and amphotericin B or flucytosine in combination were less effective.

The activities of amphotericin B and itraconazole were studied in a temporarily neutropenic murine model of disseminated Absidia corymbifera infection, caused by two different strains. Amphotericin B MICs were 0.25 mg/L for both strains and itraconazole MICs were 1 and 2 mg/L. Amphotericin B was effective in vivo with both isolates. Itraconazole was less effective.

ABSTRACTWe have attempted to validate in Aspergillus flavusthe main in vitro methodologies that have been used to detect resistance in Aspergillus fumigatus. We developed a murine model with two A. flavusisolates, one that was apparently resistant in vitro to amphotericin B (AFL5) and another that was resistant to itraconazole (AFL8). No correlation was found for amphotericin B in AFL5, since the in vivo response was compatible with a susceptible isolate. Modification of the in vitro susceptibility test methodology for amphotericin B was unsuccessful. Although AFL8 was apparently resistant to itraconazole in vitro, it was found to be susceptible in vivo. Additional in vitro work has detected weaknesses in the in vitro susceptibility methodology validated for A. fumigatuswhen applied to A. flavus. The principal problems are that changes in the inoculum have a large effect on the MICs of itraconazole for some A. flavusstrains and that a trailing end point and spore sediment often appear when an inoculum with a higher colony count is used. We propose a modified method using a final inoculum of 2.5 × 104CFU per ml of RPMI 1640 medium with 2% glucose buffered to pH 7.0 in a microtiter format, incubated for 48 h with no growth end point. Validation of this methodology requires one or more itraconazole-resistant A. flavusisolates, which have yet to be identified.

ABSTRACTWe compared four doses of amphotericin B lipid complex (ABLC) with three doses of fluconazole in temporarily neutropenic mice in a murine model of disseminated candidiasis due to four different isolates ofCandida tropicalis. The mice were infected with a 90% lethal dose of four strains of C. tropicalisfor which the fluconazole MICs ranged from 1 to >125 mg/liter 3 days after receiving 200 mg of cyclophosphamide/kg of body weight. Treatment was started 18 h after infection and lasted for 7 days. ABLC (1, 2, 5, and 10 mg/kg) was administered once a day intravenously, fluconazole was administered by oral gavage once daily (25 and 50 mg/kg/day) or twice daily (125 mg/kg). MICs determined in five different ways with 24- and 48-h endpoints were also compared. The overall survival rates were controls, 14%; fluconazole, 64%; and ABLC, 82%. Treatment with ABLC at 2 to 10 mg/kg increased survival compared to controls (P= <0.0001) and was also superior to fluconazole at 25 and 50 mg/kg (P= 0.006). In the fluconazole-resistant C. tropicalismodel (MIC, 128 μg/ml), ABLC at 2 to 10 mg/kg was superior to fluconazole at 250 mg/kg and ABLC at 10 mg/kg was superior to all fluconazole doses (P= <0.05). Fluconazole at 250 mg/kg daily was superior to both 25 and 50 mg/kg at reducing mortality with most isolates. ABLC was superior to fluconazole (P= <0.01), and fluconazole at 250 mg/kg was superior to fluconazole at both 25 and 50 mg/kg (P= 0.02) in all models at reducing C. tropicaliscounts in the kidneys. Neither drug consistently sterilized the brain or kidneys. A 48-h endpoint reading with the NCCLS susceptibility testing microtiter variation overestimates resistance to fluconazole. ABLC is an effective treatment for fluconazole-resistant C. tropicalisat all doses tested.

Amphotericin B has been the standard therapy for invasive aspergillosis since its introduction in 1957. It is only moderately effective. Many susceptibility tests have been used but little variation has been noted between strains. We have studied three strains of Aspergillus fumigatusand one of Aspergillus terreusin a neutropenic mouse model of invasive aspergillosis and attempted to correlate the variable efficacy in vivowith MICs generated by over 30 different susceptibility test formats. One strain of A. fumigatus(AF65) and the strain of A. terreus(AT49) were 'resistant' and the remaining two strains of A. fumigatus(AF210 and AF294) were 'susceptible' in vivo. Only AT49 had elevated MICs of amphotericin (MIC 2 mg/L) by 41 of 54 in vitrotesting systems. With each test format, including Etest, there was no distinction between MICs obtained for AF65, AF210 and AF294 (MICs 0.125-64 mg/L depending on the test). Thus despite extensive efforts we have been unable to correlate susceptible test results with in vivooutcome in A. fumigatusbut we have with A. terreus, with some test formats. This suggests that, at present, amphotericin B susceptibility testing of A. fumigatus is of limited clinical value and further work needs to be done to find testing systems that can identify the 'resistance' documented in vivo.

Although several typing methods have been described for Shiga-like toxin-producingEscherichia coli O157, the methods are somewhat cumbersome. Using 22 isolates ofEscherichia coli O157 and five otherEscherichia coli isolates, two primers (M13 core sequence and 970-11) were found to give excellent differentiation between isolates using random amplified polymorphic DNA (RAPD). Using only the presence or absence of variable bands, a matrix of 20 variable characters was identified. From these characters, similarity coefficients were calculated and a phenogram constructed. All of theEscherichia coli O157 isolates were easily distinguished from the non-O157Escherichia coli isolates. Using a 95% similarity cutoff, we found 13 RAPD types among the 22Escherichia coli O157 isolates. Isolates thought to be identical by toxin and phage typing as well as by epidemiological association were distinguished, and others thought to be distinct by lack of epidemiological association were identical. RAPD using M13 and 970-11 primers is a potentially useful typing tool forEscherichia coli isolates of serotype O157 and possibly otherEscherichia coli isolates.

Aspergillus species are widespread in the environment and have the capacity to cause life-threatening invasive disease, notably in the immunocompromised patient. In this review, an initial consideration of environmental sources of aspergilli will be followed by examination of the significance of Aspergillus isolated from human cultures. A review of the various disease patterns seen in the immunocompetent and immunocompromised leads on to discussion of what is known about pathogenesis and determinants of virulence. Finally, to give some idea of the scale of the problem, we consider the occurrence of three types of disease due to aspergilli, namely, allergic bronchopulmonary aspergillosis, pulmonary aspergilloma, and invasive aspergillosis.

An enzyme-linked immunosorbent assay (ELISA) developed to determine aflatoxin in food was adapted to analyse rapidly human serum for aflatoxin.Sera from subjects in the U.K., Nigeria and Nepal were studied. No aflatoxin was found in U.K. sera, whilst 76% and 100% respectively of Nigerian and Nepalese samples were found positive for aflatoxin.Study was also made of maternal and cord sera from Thai subjects. Only 6% of maternal blood had detectable aflatoxin whilst 49% of cord sera were found positive for aflatoxin. This is evidence of trans-placental transfer of aflatoxin in humans and possibly of concentration of aflatoxin by the feto-placental unit.

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.

AbstractGoera schmidin. sp. from Thailand is described together with drawings of the greatly modified male genitalia and maxillary palpi. SEM micrographs of scales on the wings of Goeridae are presented. Distributional data are given for the Goeridae known to occur in Canada and the United States.

From a number of Trichoptera predominantly from Thailand, collected by W.L. and J.G. Peters, Florida A & M University, and Fred W. Knapp, University of Kentucky, the following new species are selected for description: Dipseudopsis ulmeri, akhila, petersorum, thailandica, and knappiof the family Dipseudopsidae and Pahamunaya jihmita, Pseudoneureclipsis saccheda, and Polycentropus vanachakuniof the family Polycentropodidae. Unless designated otherwise types will be deposited in the California Academy of Sciences, San Francisco, California. Some paratypes are in the Canadian National Collection of Insects, Ottawa.

AbstractFive new species of western Rhyacophila, leechi, siskiyou, lurella, arcella, and tehama, are described; siskiyouis remarkably different from other described species. The vedracomplex, comprising five species, is discussed with descriptions of two new species.

The in-vitro activity of the triazole antifungal agent voriconazole was compared with itraconazole and amphotericin B against 60 aspergillus isolates. Susceptibility tests were performed using two methods: a macrodilution and a microdulution method. For macrodilution methodology, geometric mean (GM) MIC values and ranges were 0.4 and 0.125-4 mg/L for voriconazole, 0.24 and 0.06-->16 mg/L for itraconazole, and 1.04 and 0.5-4 mg/L for amphotericin B. For the microdilution method, GM MICs and ranges were 0.66 and 0.125-2 mg/L for voriconazole, 0.27 and 0.06-->16 mg/L for itraconazole, and 1.62 and 0.25-32 mg/L for amphotericin B. In conclusion, voriconazole is active against Aspergillus spp. in vitro, and at similar concentrations to itraconazole.

The in-vitro activity of amphotericin B, itraconazole and voriconazole against 130 clinical and 20 environmental Aspergillus fumigatus isolates was tested with an agar dilution method using RPMI 1640 medium. Itraconazole-susceptible (AF71) and -resistant (AF90) isolates were included in each test and all isolates were tested in duplicate. Geometric mean MIC values (ranges) at 48 h and 72 h were, respectively, amphotericin B, 0.91 (0.25-2) and 1.50 (1-4) mg/L; itraconazole, 0.25 (0.06-1) and 0.48 (0.125-8) mg/L; and voriconazole, 0.56 (0.25-8) and 0.78 (0.25-8) mg/L. The reproducibility of the results was high for all drugs. In-vitro resistance of A. fumigatus to the tested antifungal agents was uncommon and the MICs of itraconazole were half those of voriconazole (P < 0.01).

Endemic mycoses remain a major public health problem in several countries and they are becoming increasingly frequent with the spread of HIV infection. Amphotericin B remains the drug of choice during the acute stage of life-threatening endemic mycoses occurring in both immunocompetent and immunocompromised hosts. Ketoconazole is effective in non-AIDS patients with non-life-threatening histoplasmosis, blastomycosis, or paracoccidioidomycosis. Itraconazole is the treatment of choice for non-life-threatening Histoplasma capsulatum or Blastomyces dermatitidis infections occurring in immunocompetent individuals and is the most efficient secondary prophylaxis of histoplasmosis in AIDS patients. Itraconazole is also effective in lymphocutaneous and visceral sporotrichosis, in paracoccidioidomycosis, for Penicillum marneffei infection, and is an alternative to amphotericin B for Histoplasma duboisii infection. Coccidioidomycosis may be effectively treated with prolonged and sometimes life-long itraconazole or fluconazole therapy. Fluconazole has relatively poor efficacy against histoplasmosis, blastomycosis and sporotrichosis. New antifungal agents have been tested in vitro or in animal models and may soon be evaluated in clinical trials.

Abstract: The dependence of selectivity on HC1 flow and operating pressure for an 850 C SiH2Cl2/ HC1 based SEG process has been investigated. The polysilicon nuclei density (#/cm2 measured by optical microscope) on large unpatterned areas of deposited SiO2 was used to quantify the selectivity of different process conditions. Three distinct selectivity regimes were identified: (a) a non-selective regime with >106 nuclei/cm2, (b) a pattern dependent regime with <106 nuclei/cm2, and (c) an intrinsically selective regime with <1 nuclei/cm2. The intermediate, pattern dependent, selectivity regime was characterized by a much lower density of silicon nuclei in and around patterned areas where windows of Si are exposed, thus making a loss of selectivity more difficult to detect. This phenomenon is shown to arise from feature scale (<100 micron) lateral fluxes of gas phase species. An intrinsically selective regime suitable for VLSI manufacturing, which avoids the high nuclei density associated with the pattern dependent regime, is identified.