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Mycotic keratitis in human cornea has been rarely reported to be associated with a co-infection of filamentous fungi and yeast. This paper aims to report a case of mycotic keratitis concurrently infected by Exserohilum mcginnisii and Candida parapsilosis.
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The last decade has been remarkable for the dramatic increase in the prevalence of serious fungal infections in patients with haematological disorders and neutropenic cancer patients. The mortality rate of deep-seated infection has been in excess of 90% and there is no doubt that this is one of the greatest challenges currently facing haematologists and oncologists. The development of the lipid-based drugs - liposomal amphotericin (AmBisome(R)), amphotericin B lipid complex, ABLC (Abelcet(R)), amphotericin B colloidal dispersion, Amphocil (ABCD(R)), has meant that doses of amphotericin B can be safely escalated for the first time whilst the problems of nephrotoxicity, infusion related reactions (including chills, rigors, fevers and hypoxia) can be reduced. These toxicities are variably reduced with AmBisome more than Abelcet and more than Amphocil and there is little information from randomised trials other than for AmBisome. AmBisome used in the setting of persistent fever and neutropenia not responding after 3-4 days of intravenous antibiotics, is associated with less breakthrough systemic fungal infections. There is also much less need for premedication, including steroids, compared with amphotericin B and Abelcet. The use of intermittent doses of Ambisome given prophylactically is now being explored. A new and exciting era of antifungal therapy is opening up with new compounds, such as itraconazole voriconazole, posaconazole and echinocandins, being investigated and for the first time, we also have options for combination therapy and prophylaxis.
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It is believed that most microbial infections are caused by pathogens organized in biofilms. Recently, it was shown that the dimorphic fungus Histoplasma capsulatum, estimated to be the most common cause of fungal respiratory diseases, is also able to form biofilm. Although the antifungal therapy commonly used is effective, refractory cases and recurrences have been reported. In the search for new compounds with antimicrobial activity, the sesquiterpene farnesol has gained prominence for its antifungal action. This study aimed to evaluate the in vitro susceptibility of H. capsulatum var. capsulatum to the antifungal agents itraconazole and amphotericin B, and farnesol alone and combined, as well as to determine the in vitro antifungal activity of these compounds against biofilms of this pathogen. The results show that farnesol has antifungal activity against H. capsulatum in the yeast and filamentous phases, with MIC values ranging from 0.0078 to 0.00312 µM. A synergistic effect (fractional inhibitory concentration index ≤0.5) between itraconazole and farnesol was found against 100 and 83.3 % of the isolates in yeast and mycelial forms, respectively, while synergism between amphotericin B and farnesol was only observed against 37.5 and 44.4 % of the isolates in yeast and filamentous forms, respectively. Afterwards, the antifungal drugs, itraconazole and amphotericin B, and farnesol alone, and the combination of itraconazole and farnesol, were tested against mature biofilms of H. capsulatum, through XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide) metabolic assay, and the itraconazole and amphotericin B showed lower antibiofilm activity when compared to farnesol alone and farnesol combined with itraconazole. In conclusion, farnesol showed promising results as an antifungal agent against H. capsulatum and also showed adjuvant action, especially when combined with itraconazole, increasing the fungal susceptibility to this drug.
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Aspergillosis, an opportunistic mycosis caused by the Aspergillus genus, affects mainly the respiratory system and is considered one of the most significant causes of mortality in captive penguins. This study aimed to examine a 6-yr period of cases of aspergillosis in penguins at the Centro de Recuperação de Animais Marinhos (CRAM-FURG), Rio Grande, Brazil. A retrospective cohort study was conducted using the institution's records of penguins received from January 2004 to December 2009. Animals were categorized according to the outcome "aspergillosis," and analyzed by age group, sex, oil fouling, origin, prophylactic administration of itraconazole, period in captivity, body mass, hematocrit, and total plasma proteins. A total of 327 Magellanic penguins (Spheniscus magellanicus) was studied, 66 of which died of aspergillosis. Proportionate mortality by aspergillosis was 48.5%, and incidence density was 7.3 lethal aspergillosis cases per 100 penguins/mo. Approximately 75% of the aspergillosis cases occurred in penguins that had been transferred from other rehabilitation centers, and this was considered a significant risk factor for the disease. Significant differences were also observed between the groups in regard to the period of time spent in captivity until death, hematocrit and total plasma proteins upon admission to the center, and body mass gain during the period in captivity. The findings demonstrate the negative impacts of aspergillosis on the rehabilitation of Magellanic penguins, with a high incidence density and substantial mortality.
A prospective double-blind randomized study was conducted in autologous HSCT recipients who were divided into prophylaxis and empirical treatment groups, and we investigated the efficacy of itraconazole prophylaxis in pediatric autologous HSCT.
A 26-year-old white man with life-threatening pulmonary blastomycosis developed elevation of his liver enzymes after the addition of amphotericin B to his initial itraconazole therapy. The hepatotoxicity resolved rapidly with discontinuation of the amphotericin B, and the blastomycosis was successfully treated with itraconazole alone.
In vitro susceptibility to fluconazole of Candida species isolated from 83 HIV-infected patients treated with fluconazole because of recurrent Candida stomatitis was monitored over a period of two years. A microdilution assay with high-resolution antifungal assay (HR) medium and RPMI 1640-medium were compared. In vitro less susceptible and fluconazole resistant C. species were observed in 23 patient at the end of the study. The Candida isolates recovered from oral rinsing fluids at the beginning and the end of study were tested for crossresistance to itraconazole and ketoconazole. Susceptibility to ketoconazole and to itraconazole was reduced using RPMI 1640-medium. Susceptibility of the isolates to fluconazole was not influenced by the assay medium. In 21 patients in vitro fluconazole resistant or less susceptible C. albicans were observed. 9 of 21 isolates showed crossresistance to itroconazole and ketoconazole, in 10 isolates only crossresistance to itraconazole was observed. During fluconazole treatment double infections due to combination of C. albicans and C. glabrata or C. krusei increased from 20% to 78% C. krusei was resistant to the three azoles. C. glabrata was less susceptible (4-8 mg/l) or resistant (> 8 mg/l) to fluconazole and resistant to itraconazole and ketoconazole High dosed intravenous fluconazole treatment with 400 to 600 mg daily failed in 11 patients with fluconazole resistant C. albicans and in 3 (3/10) patients with les susceptible C. albicans isolates.
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Local therapy is a valuable and strategic approach in the treatment of lung associated diseases and dry powder inhalation (DPI) formulations play the key role in this plan. Transfersome has been introduced as a novel biocompatible vesicular system with potential for administration in pulmonary drug delivery. The present study was designed to prepare Itraconazole-loaded nanotrantransfersomal DPI formulation.
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Twenty isolates of aspergillus were tested against saperconazole and 16 of these against itraconazole and amphotericin B using a macrodilution broth method. For 18 (90%) of 20 isolates tested against saperconazole, MICs were less than or equal to 3.1 mg/l and for 15 (75%) of 20 isolates MFCs were less than or equal to 3.1 mg/l. For 9 (56%) of 16 isolates tested against itraconazole, MICs were less than or equal to 3.1 mg/l, and for 4 (33%) of 12 isolates MFCs were less than or equal to 3.1 mg/l. For all 16 isolates tested against amphotericin B MICs and MFCs were less than or equal to 4.0 mg/l; for 11 of 16 isolates MICs were less than or equal to 2.0 mg/l. Saperconazole appears to be highly active against Aspergillus spp. in vitro, with a bimodal distribution of MICs and MFCs.
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Topical or systemic antifungal therapy was administered to patients diagnosed with Malassezia folliculitis during the 5-year period between March 2007 and October 2013. The diagnosis of Malassezia folliculitis was established on the basis of characteristic clinical features and direct microscopic findings (10 or more yeast-like fungi per follicle). Treatment consisted of topical application of 2% ketoconazole cream or 100 mg oral itraconazole based on symptom severity and patients' preferences. Treatment was given until papules flattened, and flat papules were examined to determine whether the patient's clinical condition had "improved" and the treatment had been "effective". The subjects were 44 patients (35 men, 9 women), with a mean disease period of 25±15 days. In regard to the lesion site, the frontal portion of the chest was the most common, accounting for 60% of all patients. The mean period required for improvement was 27±16 days in 37 patients receiving the topical antifungal agent and 14±4 days in the 7 patients receiving the systemic antifungal agent. The results were "improved" and the treatment was "effective" in all patients. Neither treatment resulted in any adverse reactions. Although administration of oral agents has been recommended for the treatment of Malassezia folliculitis, this study revealed that beneficial results are safely obtained with topical antifungal therapy alone, similar to those of systemic antifungal agents.
Corneal traumatism was the principal risk factor for fungal keratitis in young and middle-aged farmers. Fusarium solani is the predominant cause in Sfax. Early diagnosis, coupled with appropriate treatment, is crucial for increasing the chance of complete recovery.
The consumption of a bread meal before the administration of itraconazole caused a significant increase in its bioavailability, as well as increases in the peak plasma concentration and lag time for itraconazole absorption. On the contrary, consumption of a rice meal before the administration of itraconazole caused a significant decrease in its bioavailability.
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Four children with an osteomyelitic process in the jaw bones while on cytotoxic chemotherapy were treated by radical surgery and antimicrobial chemotherapy.
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Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disorder caused by immunologic reactions to antigens released by Aspergillus fumigatus, a ubiquitous fungi colonizing the tracheobronchial tree of asthmatic patients. The clinical presentation is usually poorly controlled asthma, recurrent pulmonary opacities and bronchiectasis. The prevalence of ABPA in asthma clinics may be as high as 13% with a global burden of almost 5 million patients. A. fumigatus-specific IgE level is the most sensitive test in diagnosis of ABPA, and all asthmatic patients should be routinely screened with A. fumigatus-specific IgE levels for early diagnosis. The goals of managing ABPA include control of asthma, prevention and treatment of acute exacerbations, and preventing the development or progression of bronchiectasis. Glucocorticoids are the treatment of choice with itraconazole reserved for those with recurrent exacerbations and glucocorticoid-dependent disease. There is a dire need for newer treatment approaches including oral antifungal agents and immunomodulatory therapy.
Pulmonary blastomycosis is an uncommon pathologic condition that is quite rare in Africa compared to endemic regions of Canada and the upper Midwest of the U.S. We describe a 45-year-old patient who complained of productive cough, hemoptysis, and dorsal rachiodynia. Chest imaging revealed a necrotic tissue-density pulmonary mass involving both the upper and lower right lobes. Chest MRI showed signal abnormality of the third thoracic vertebral body and the greater trochanter, consistent with metastatic lesions. Clinical and radiological findings were strongly suggestive of lung cancer. Diagnosis of pulmonary blastomycosis was made by visualization of yeast in bronchial biopsies and further confirmed by culture of bronchoalveolar lavage specimens. The patient was treated with itraconazole and his clinical condition improved markedly. Pulmonary blastomycosis is unusual in Africa and that fact caused a considerable delay in diagnosis. We suggest that this disease may be more common in Africa than has been previously suspected.
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We examined the features of 36 new cases of sporotrichosis identified from two hospital centers in Abancay. Furthermore, we searched for relevant studies of cases of sporotrichosis in the endemic region using healthcare databases and literature sources. We analyzed a detailed subset of data on cases collected in Abancay, neighboring provinces, and other regions of Peru.
C. albicans was the predominant Candida species isolated from this series of patients with VVC. Resistance of vaginal C. albicans isolates to antifungal agents was infrequent.
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Human pythiosis is a life-threatening disease for which no standard treatment protocols with proven efficacy exist. We present the results of our institutional pythiosis treatment protocol, composed of surgery, antifungal agents, iron chelator (only vascular cases) and immunotherapy.
Interest in antifungal therapeutic-drug monitoring has increased due to studies demonstrating associations between concentrations and outcomes. We reviewed the antifungal drug concentration database at our institution to gain a better understanding of achievable triazole drug levels. Antifungal concentrations were measured by high-performance liquid chromatography (HPLC), ultraperformance liquid chromatography and single-quadrupole mass spectrometry (UPLC/MS), or a bioassay. For this study, only confirmed human bloodstream (serum or plasma) and cerebral spinal fluid (CSF) concentrations of voriconazole, posaconazole, and itraconazole were analyzed. The largest numbers of bloodstream and CSF samples were found for voriconazole (14,370 and 173, respectively). Voriconazole bloodstream concentrations within the range of 1 to 5.5 μg/ml represented 50.6% of samples. Levels below the lower limit of quantification (0.2 μg/ml) were observed in 14.6% of samples, and 10.4% of samples had levels of ≥5.5 μg/ml. CSF voriconazole levels ranged from undetectable to 15.3 μg/ml and were <0.2 μg/ml in 11% of samples. Posaconazole bloodstream concentrations were ≥0.7 and ≥1.25 μg/ml in 41.6% and 18.9% of samples, respectively. Posaconazole was detected in only 4 of 22 CSF samples (undetectable to 0.56 μg/ml). Itraconazole levels, as measured by UPLC/MS, were ≥0.5 μg/ml in 43.3% and were undetectable in 33.9% of bloodstream samples. In contrast, when measured by a bioassay, itraconazole/hydroxyitraconazole bloodstream concentrations were ≥1.0 μg/ml in 72.9% of samples and were undetectable in 18% of samples. These results indicate that there is marked variability in bloodstream concentrations achieved with these three azoles. In addition, many levels within the bloodstream for each azole and for voriconazole and posaconazole in the CSF were undetectable or below thresholds associated with efficacy.
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Saksenaea is a monotypic genus belonging to the order Mucorales and capable of producing severe human infections. Through a polyphasic study based on analysis of the sequences of the internal transcribed spacer (ITS) region, domains D1 and D2 of the 28S rRNA gene, and the elongation factor 1α (EF-1α) gene, as well as by evaluation of relevant morphological and physiological characteristics of a set of clinical and environmental strains, we have demonstrated that Saksenaea vasiformis is a complex of species. We propose as new species Saksenaea oblongispora, characterized by oblong sporangiospores and unable to grow at 42°C, and Saksenaea erythrospora, characterized by large sporangiophores and sporangia and by ellipsoid sporangiospores, biconcave in the lateral view. Itraconazole, posaconazole, and terbinafine were active against all isolates included in the study, while amphotericin B, voriconazole, and the echinocandins showed low activity.
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A retrospective (25 years) report of mycetomas was conducted in children less than 15 years of age. Each of the cases was studied clinically and proven with microbiologic tests: direct examinations (to identify and classify the grains), cultures and identification based on morphology and biochemical tests. The therapeutic experience of the cases was also reviewed.
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A great deal of attention at the XI International Conference on AIDS was focused on new approaches to managing and preventing AIDS-related opportunistic infections (OIs). Aside from a similar prevalence of Pneumocystis carinii pneumonia (PCP) in developed countries, a different spectrum of OIs is seen in less developed areas, such as Latin America, where many endemic diseases are included among OIs. Candidiasis has been the most common fungal pathogen, but a broader spectrum of mycoses is being seen, with fluconazole and itraconazole being the mainstays for treating these infections. Ganciclovir and foscarnet are still used to treat cytomegalovirus retinitis, but introduction of cidofovir represents a significant advance in treating this disease. Mycobacterium avium complex (MAC) is the third most common OI in developed countries, and delays in diagnosis and starting treatment are common. Trimethoprim-sulfamethoxazole (TMP/SMX) remains the drug of choice for PCP prophylaxis. Liposomal doxorubicin with or without other chemotherapy agents has been approved for treating Kaposi's sarcoma. A three-drug regimen of amphotericin B, flucytosine, and itraconazole is effective for treatment of HIV-infected patients with cryptococcosis. Bacterial infections can be treated with appropriate antibiotics, but adding intravenous immune globulin may decrease the occurrence of infections and increase the time between new infections.
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The results of the laboratory diagnosis of secondary infections of the bronchi and lungs due to Candida krusei strains isolated from patients with respiratory tract tuberculosis are presented. The activity of fluconazole, amphothericin B, itraconazole, ketoconazole, myconazole and 5-fluorocytosin against the C. krusei isolates from a tuberculosis clinic within 2003-2008 was tested. A decrease in the number of the C. krusei isolates susceptible to fluconazole from 30% in 2003 to 0% in 2008 was recorded.
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Invasive fungal rhinosinusitis, a rare infection, is a life threatening disease. Delay in diagnosis may consequently lead to high morbidity and mortality.
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Pharmacokinetic interactions involving anti-infective drugs may be important in the intensive care unit (ICU). Although some interactions involve absorption or distribution, the most clinically relevant interactions during anti-infective treatment involve the elimination phase. Cytochrome P450 (CYP) 1A2, 2C9, 2C19, 2D6 and 3A4 are the major isoforms responsible for oxidative metabolism of drugs. Macrolides (especially troleandomycin and erythromycin versus CYP3A4), fluoroquinolones (especially enoxacin, ciprofloxacin and norfloxacin versus CYP1A2) and azole antifungals (especially fluconazole versus CYP2C9 and CYP2C19, and ketoconazole and itraconazole versus CYP3A4) are all inhibitors of CYP-mediated metabolism and may therefore be responsible for toxicity of other coadministered drugs by decreasing their clearance. On the other hand, rifampicin is a nonspecific inducer of CYP-mediated metabolism (especially of CYP2C9, CYP2C19 and CYP3A4) and may therefore cause therapeutic failure of other coadministered drugs by increasing their clearance. Drugs frequently used in the ICU that are at risk of clinically relevant pharrmacokinetic interactions with anti-infective agents include some benzodiazepines (especially midazolam and triazolam), immunosuppressive agents (cyclosporin, tacrolimus), antiasthmatic agents (theophylline), opioid analgesics (alfentanil), anticonvulsants (phenytoin, carbamazepine), calcium antagonists (verapamil, nifedipine, felodipine) and anticoagulants (warfarin). Some lipophilic anti-infective agents inhibit (clarithromycin, itraconazole) or induce (rifampicin) the transmembrane transporter P-glycoprotein, which promotes excretion from renal tubular and intestinal cells. This results in a decrease or increase, respectively, in the clearance of P-glycoprotein substrates at the renal level and an increase or decrease, respectively, of their oral bioavailability at the intestinal level. Hydrophilic anti-infective agents are often eliminated unchanged by renal glomerular filtration and tubular secretion, and are therefore involved in competition for excretion. Beta-lactams are known to compete with other drugs for renal tubular secretion mediated by the organic anion transport system, but this is frequently not of major concern, given their wide therapeutic index. However, there is a risk of nephrotoxicity and neurotoxicity with some cephalosporins and carbapenems. Therapeutic failure with these hydrophilic compounds may be due to haemodynamically active coadministered drugs, such as dopamine, dobutamine and furosemide, which increase their renal clearance by means of enhanced cardiac output and/or renal blood flow. Therefore, coadministration of some drugs should be avoided, or at least careful therapeutic drug monitoring should be performed when available. Monitoring may be especially helpful when there is some coexisting pathophysiological condition affecting drug disposition, for example malabsorption or marked instability of the systemic circulation or of renal or hepatic function.
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A high performance liquid chromatography (HPLC) method was developed to quantify free fatty acids (FFA) in a pharmaceutical suspension formulated with phospholipids as stabilizing agents. Specifically, a suspension of crystalline itraconazole microparticles stabilized with Lipoid E80 was used as a model system to study the physicochemical stability of an aqueous, phospholipid-based suspension for injection. The hydrolysis of the phospholipids during storage at elevated temperatures (40 degrees C) necessitated the development of a suitable HPLC method for the determination of free fatty acid content in the suspension samples. HPLC methods using two types of aerosol detectors were investigated for the above purpose. Reversed-phase separation coupled with either an evaporative light scattering detector (ELSD) or a Corona(Plus) charged aerosol detector (CAD) was used. A comparison of the methods indicated that the CAD method provided better sensitivity, precision, recovery, and linearity for the parameters evaluated. As a result, this method was chosen for the stability study of itraconazole suspension and has been incorporated in subsequent formulation studies.
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Polymerase chain reaction (PCR) and DNA typing of the fungal gene between the internal transcribed spacer 2 (ITS2) and the 5.8S ribosomal DNA of the scraping were performed. PCR amplified a band with a sequence that was 99% homologous with Malassezia restricta. Antifungal agents, topical 5% pimaricin ointment and 0.2% miconazole, and oral itraconazole 150 mg/day, were applied, and the corneal ulcer disappeared within 5 weeks.
A 64-year-old woman with a history of old tuberculosis, had a fungus ball shadow with meniscus sign in the upper right lung field on a chest X-ray film in 1991. Based on the chest X-ray findings, pulmonary aspergilloma was suspected. Because the size of the intracavitary fungus ball increased, the patient was treated with itraconazole over one year in 1995, but there was no improvement. One month later, she was admitted because of fever, hemoptysis and productive cough, and chest X-ray showed an enlargement of intracavitary mass and infiltrative shadow in the right lung. Chronic necrotizing aspergillosis was diagnosed on the basis of her clinical and radiographic features, and positive serological test. Although itraconazol and amphotericin B were given, cavity and intracavitary fungus ball shadow kept growing. Combination therapy of antifungal drugs and ulinastatin markedly improved symptoms and resulted in complete disappearance of the fungus ball on chest CT scan.
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Candidiasis and aspergillosis are the most common fungal infections in hematopoietic stem cell transplant recipients and other hematology/oncology patients. Strategies for reducing the morbidity and mortality associated with these infections include antifungal prophylaxis, empiric therapy in patients with persistent fever and neutropenia, and preemptive therapy. Antifungal therapies include amphotericin B deoxycholate, lipid formulations of amphotericin B, the triazoles (fluconazole, itraconazole, and voriconazole), and the echinocandins (caspofungin and the investigational agents micafungin and anidulafungin). Fluconazole is a reasonable choice for the treatment of invasive candidiasis if the patient has not previously received a triazole and the institution has a low incidence of triazole resistance. If resistance is a concern, an echinocandin, such as caspofungin, is an appropriate option. Voriconazole may be the initial choice in most patients with invasive aspergillosis. If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin.
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An overview of studies where continuous or pulse itraconazole therapy has been used in the treatment of fingernail and toenail onychomycosis.