Potential risk factors for infection with Candida spp. in critically ill patients

The incidence, risk factors and prognostic factors for candidal infection were determined in a prospective study of 280 infected patients. Thirty-one (11%) patients were infected with Candida spp., sub-divided into 18 (58%) with C. albicans, and 13 (42%) with non-albicans spp. (six C. glabrata, three C. parapsilosis, and one each of C. krusei, C. tropicalis, C. guilliermondii and C. lusitaniae). Infection with Candida spp. was always associated with concurrent bacterial infection. By univariate logistic regression analysis, the degree of morbidity and the duration of mechanical ventilation were independent predictive factors for death, but infection with Candida spp., was not. Factors associated with Candida spp. infection were the degree of morbidity, intensive care unit length of stay, alterations of immune response, and the number of medical devices involved. By multivariate logistic regression analysis, the only independent risk factor for candidal infection was intensive care unit length of stay.     

Aromatic ethers of 1-aryl 2-(1H-azolyl)ethanol: study of antifungal activity

Aromatic ethers related to antifungal azole miconazole were synthesized and tested against various strains of Candida. We found that activity is related to the nature of the aromatic ring and the position of substituents on this ring. Activity is more strongly dependent on the substituent in the 2 position of the ethyl chain than on the aromatic group linked through the oxygen. Triazoles were always less potent than the corresponding imidazole analogues.     

Cutaneous distribution of orally administered itraconazole in guinea pigs, studied by autoradiography

Background Itraconazole is an orally active antifungal lipophilic drug with high affinity for sebum and keratinocytes. Aim The aim of the study was to investigate the routes of percutaneous egression and the sites of cutaneous action/storage of ³H-labelled itraconazole in an experimental animal model. Material and methods Hartley guinea pigs were dosed orally by gavage for 2 consecutive days at 10 mg/kg/day ³H-itraconazole dissolved in polyethylene glycol 200. At various time points after the second gavage, small full-thickness samples of dorsal skin were excised and processed using dry-apposing autoradiography. Results Our research revealed an accumulation of silver grains over the epidermis and its appendages (hair follicle and sebaceous gland), the dermal fat tissue and the hypodermal muscle tissue on tissue sections at 6, 24 and 48 h time intervals, whereas at the remaining time points (96, 168 and 336 h) the silver grain density was markedly decreased to background level. Discussion The present histological distribution data support the current method of oral treatment with itraconazole as the treatment schedule of choice to eradicate infective organisms residing in the deeper skin layers.     

Prosthetic valve endocarditis due to candida albicans treated successfully with medical treatment alone

Prosthetic valve endocarditis (PVE) caused by Candida species is associated with high morbidity and mortality. A combination of surgical resection and antifungal drug therapy is the golden standard for treatment, yet surgical intervention is not possible in all cases of Candida PVE. We report a case of PVE due to Candida albicans cured by medical treatment alone. This case suggests that, in some instances, Candida PVE can be managed medically with antifungal therapy. Such a conservative approach should be applied with caution and necessitates very close follow-up on a long-term basis.     

抗真菌剂三氮唑含硫化合物的合成

合成了１３个三氮唑含硫化合物，均为未见文献报道的新化合物，对所合成的化合物，选择三种常见真菌进行体外最低抑菌浓度（ＭＩＣ）的测定，结果表明它们均有较好的抗真菌活性，有些化合物抑菌活性极高，有进一步研究和开发前景。     

磺胺噻二嗪硫酮衍生物的合成及其抑菌活性

利用药物化学骈合原理设计并合成了一系列新的３，５－二取代１，３，５－噻二嗪－２－硫酮类化合物，其结构经红外光谱，紫外光谱及元素分析证实，抑菌活性试验显示了良好的抑菌活性。     

Antimicrobial properties of heartwood,bark/sapwood and leaves of Juniperus species

Hexane and methanol extracts of heartwood, bark/sapwood and leaves of twelve taxa of Juniperus from the United States were assayed for antifungal and antibacterial activities. The hexane extract of the heartwood of several junipers appeared comparable in antibacterial activity to streptomycin. Antibacterial activity of the hexane extracts from the bark/sapwood of J. monosperma and J. californica were comparable to streptomycin. No appreciable antibacterial activities were found in the leaf extracts from any species examined. No antifungal activities comparable to amphotericin B were found in either hexane or methanol extracts of the heartwood nor from the bark/sapwood. Antifungal activity against Cryptococcus neoformans comparable to amphotericin B was found in the hexane extract of the leaves of J. occidentalis var. australis. The methanol extracts from the leaves of J. osteosperma and J. californica had antifungal activities comparable to amphotericin B against Trichophyton mentagrophytes.     

Reduction of systemic fungal infections in patients with hematological malignancies,neutropenia, and prolonged fever by early amphotericin B therapy

Summary A rate on autopsy of up to 30% systemic fungal infections and difficulties in diagnosing systemic mycosis antemortem have led to the empiric use of amphotericin B in patients with hematological malignancies, prolonged fever, and neutropenia. Routine empiric antifungal treatment was initiated in our institution in 1982. Amphotericin B was given to granulocytopenic patients with hematological malignancies with (a) unremitting fever after 48–72 h of antibiotic treatment, (b) recurrent fever during antibiotic treatment, or (c) with newly detected pulmonary infiltrates, sinusitis, skin and retinal lesions suggestive of a fungal infection. With this approach the rate of systemic fungal infections decreased significantly from 10% (27 of 270 patients; 1973–1981) to 4% (6 of 153 patients; 1982–1986,P<0.02). The reduction of systemic fungal infections was most prominent in patients with acute myelogenous leukemia, where its proportion decreased from 16% (16 of 98 patients; 1973–1981) to 4% (2 of 50 patients; 1982–1986,P<0.023). Our data support the hypothesis that the incidence of systemic fungal infections in patients with hematological malignancies and especially in acute myelogenous leukemia can be reduced significantly by empirical treatment with amphotericin B.     

Fluconazole induces genotoxicity in cultured human peripheral blood mononuclear cells via immunomodulation of TNF-α, IL-6, and IL-10: new challenges for safe therapeutic regimens

Context: Fluconazole (FNZ) is a drug used in antifungal therapy. However, the minimum FNZ dose to interfering with immune responses or inducing DNA damage is still unknown.

Objective: This study investigated the toxicological profile of FNZ on cultured human peripheral blood mononuclear cells (PBMCs) treated with different concentrations of this azole.

Materials and methods: Cultured PBMCs were exposed to FNZ (6, 12, 30, 60 and 120?μg/mL) and the toxicological profile was assessed by the following parameters: cytotoxic and nuclear division index (necrotic, apoptotic and viable cells), DNA damage (alkaline comet test), mutagenic potential (micronucleus test), cytokine modulation (IL-1, IL-6, IL-10, TNF-α, IFN-γ), and predictive toxicity (Osiris^® and LAZAR^® programs).

Results: Our results demonstrated that FNZ induced cellular DNA damage and mutagenicity at concentrations above the plasma peak (>30?μg/mL) and 6?μg/mL, respectively, which was associated with increased TNF-α, and decrease IL-6 and IL-10 concentrations. These effects may be related to increased apoptosis and cytotoxic nuclear division index in the cultured PBMCs. In silico results indicated potential mutagenic, tumorigenic, irritant, and carcinogenic effects, which were partially confirmed by the above assays.

Discussion and conclusions: Together, these findings suggest the need to rationalize the use of FNZ, especially if it is used for long periods or with concomitant pathologies requiring azole therapy that may increase FNZ's plasma concentration.