Decrease of voriconazole trough levels during therapy with enteral nutrition: a case report.

BACKGROUND: Voriconazole (VRCZ) is the first-line therapy for chronic pulmonary aspergillosis and is available in both intravenous and oral formulations. The bioavailability of the oral form is estimated to be over 90% in healthy volunteers. Some drugs are reported to interact with enteral nutrition (EN), but there are few reports about the trough levels of VRCZ during EN therapy. Here, we describe changes in the VRCZ trough levels in a patient receiving continuous EN therapy. CASE PRESENTATION: The patient was a 58-year-old man with esophageal cancer and a history of partial pulmonary resection due to aspergilloma. He was taking oral VRCZ tablets and his VRCZ trough level was about 2 µg/mL before esophageal cancer surgery. Following esophagectomy, VRCZ was restarted on postoperative day 16. Crushed VRCZ tablets were administered via a jejunostomy tube because of swallowing difficulty. He was also receiving EN, which was interrupted only during the administration of VRCZ. When we checked his VRCZ level 5 days after restarting VRCZ, the trough level was 0.80 µg/mL. After increasing the VRCZ dose, reducing EN, and changing the administration route from jejunostomy tube to oral, his trough level increased to 1.87 µg/mL. CONCLUSIONS: A decrease in the VRCZ trough level was observed when VRCZ was administered via a jejunostomy tube while the patient was receiving continuous EN. Careful monitoring of VRCZ levels is needed in such cases.

High detection rate of azole-resistant Aspergillus fumigatus after treatment with azole antifungal drugs among patients with chronic pulmonary aspergillosis in a single hospital setting with low azole resistance.

The prevalence of azole-resistant Aspergillus fumigatus (ARAF) among chronic pulmonary aspergillosis (CPA) patients treated with azoles in Japan is unknown. The aim of this study was to determine the detection rate of ARAF in isolates from CPA patients who were treated with azoles for varying durations. The potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104) between February 2012 and February 2019, at National Hospital Organization Tokyo National Hospital. The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF among all isolates was 8.3% (n = 10). Of the 10 resistant isolates, eight were ITCZ-resistant and five were VRCZ-resistant. Among 47 isolates obtained from 36 CPA patients who were treated with ITCZ (for an average of 256 days) and/or VRCZ (for an average of 29 days), the resistance rates were 17.0% and 10.6%, respectively. In addition, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients, particularly in those with ongoing long-term azole treatment, at the time of azole antifungal therapy failure.

Aspergillus fumigatus can acquire azole resistance during long-term treatment with azole drugs in patients with chronic pulmonary aspergillosis (CPA). The aim of this study was to determine the detection rate of azole-resistant A. fumigatus (ARAF) in isolates from CPA patients who had been treated with azoles. In addition, a potential mechanism of acquiring resistance was examined by sequencing cyp51A and hmg1, two genes associated with ARAF. A. fumigatus isolates (n = 120) were collected from CPA patients (n = 104). The isolates were tested for susceptibility to the azole drugs itraconazole (ITCZ) and voriconazole (VRCZ). The detection rate of ARAF from all isolates was 8.3% (n = 10). Greater than 10% of the 47 isolates obtained from 36 CPA patients who had been treated with azoles exhibited resistance. Furthermore, 46.2% of 13 isolates obtained from CPA patients with ongoing azole treatment at the time of antifungal therapy failure were resistant to azoles. Among the 10 ARAF isolates, a point mutation was detected in cyp51A in seven isolates and in hmg1 in two isolates. ARAF was detected at a high rate in CPA patients undergoing long-term azole treatment at the time of antifungal therapy failure.

CRISPR/Cas9 Genome Editing To Demonstrate the Contribution of Cyp51A Gly138Ser to Azole Resistance in Aspergillus fumigatus.

A pan-azole-resistant Aspergillus fumigatus strain with the cyp51A mutations Gly138Ser and Asn248Lys was isolated from a patient receiving long-term voriconazole treatment. PCR fragments containing cyp51A with the mutations were introduced along with the Cas9 protein and single guide RNA into the azole-resistant/susceptible strains. Recombinant strains showed increased susceptibility via the replacement of Ser138 by glycine. Genetic recombination, which has been hampered thus far in clinical isolates, can now be achieved using CRISPR/Cas9 genome editing.

Multi-azole resistant Aspergillus fumigatus harboring Cyp51A TR46/Y121F/T289A isolated in Japan.

Multi-azole resistant Aspergillus fumigatus carrying TR46/Y121F/T289A was isolated from a patient in Japan in Dec 2013. This strain grouped into the same clade of the ones which were clinically isolated in France and Germany. A. fumigatus harboring this mutation could be rapidly diffused outside the Eurasian continent.

[Chromoblastomycosis caused by Fonsecaea monophora].

Fonsecaea species are major etiologic agents of Chromoblastomycosis (CBM). By genetic analysis, the genus Fonsecaea has recently been revised and classified into F. pedorosoi, F. monophora and F. nubica. Here we report a severe chronic case of CBM caused by F. monophora. A 55-year-old Filipino male developed progressive skin lesions on the left lateral ankle in 1973, when he worked at a coconut plantation in the Philippines. In 1999, he received medical treatments for enlarged, multiple lesions on the left lower limb. When he moved to Japan in 2005, the lesions were remarkably improved and he discontinued taking the medicine. On our first examination in October 2008, a large, reddish, cicatricial plaque was observed on the left lower aspect of his leg. Several tumorous lesions surrounded the plaque, indicating that the therapies performed before had been insufficient. In addition, there were many patchy scars scattered on the thigh and the upper part of the lower leg. The diagnosis of CBM was made by the presence of muriform cells. Black, pulverulent colonies were yielded in culture of skin scrapings and tissues. Although the fungus could not be identified by microscopic morphology, r-RNA ITS sequence analysis enabled identification of Fonsecaea monophora. The patient responded well to oral voriconazole combined with local thermotherapy using pocket warmers. The tumoral masses subsided in 6 months, leaving pink scars with negative fungal culture. Voriconazole treatment was continued for 18 months. It seems that drugs are insufficiently delivered in the cicatricial lesions because of the paucity of blood flow, suggesting that a long-term follow-up is necessary for such a case.

Oral candidiasis of HIV-infected children undergoing sequential HIV therapies.

Candida oral flora from 52 Brazilian HIV-infected children was characterized while they received antiviral monotherapy therapy and subsequently, HAART with the use of protease inhibitor. There was a significant increase in non-C. albicans Candida isolates from 9.6-28.8% (P=0.005) after the children were placed on protease inhibitor therapy. Although Candida albicans still remained the most commonly isolated species, relative presence of C. tropicalis (n=9) followed by C. parapsilosis (n=8) markedly increased in association with protease inhibitor therapy. Furthermore, rare Candida species including C. dubliniensis, C. norvegensis, C. humicula and C. rugosa also appeared after the onset of protease inhibitor therapy. Subsequent investigation of the antifungal sensitivity of these diverse isolates, derived during protease inhibitor therapy, demonstrated some variation in antifungal sensitivity. With notable exceptions, the majority were sensitive to amphotericin B while most C. albicans and non-C. albicans Candida isolates were also susceptible to fluconazole, itraconazole and ketoconazole. Amongst exceptions was a single C. tropicalis isolates which was resistant to fluconazole (MIC>64 microl/ml) and one C. albicans-B isolate which showed cross-resistance to all azoles and amphotericin.

Effects of dietary fish oil on lipid peroxidation and serum triacylglycerol levels in psychologically stressed mice.

OBJECTIVE: The intake of omega-3 polyunsaturated fatty acids and psychological stress can each induce tissue lipid peroxidation. In our present study, we investigated their combined effects on the oxidative status of mouse tissues. METHODS: Mice were group-housed (four mice/cage) and fed a diet containing fish oil (as a source of omega-3 polyunsaturated fatty acids), soybean oil, or olive oil for 3 wk. These animals were then 1) housed under the same conditions (four per cage, control group) or 2) individually housed to generate psychological stress conditions (isolation stress). After 2 wk of isolation stress, the levels of thiobarbituric acid-reactive substances (an index of lipid peroxidation) and antioxidants in the liver and kidney and the serum levels of triacylglycerol were measured. RESULTS: Fish oil-fed mice showed increased levels of thiobarbituric acid-reactive substances in their livers and kidneys compared with soybean oil- or olive oil-fed mice. These increases in thiobarbituric acid-reactive substance levels in the fish oil-fed mice were less profound under isolation stress conditions when compared with the group-housed animals on the same diet. In the fish oil-fed mice, isolation stress led to an increase in liver vitamin E levels when compared with their group-housed counterparts. The fish oil-fed mice exhibited lower serum triacylglycerol levels compared with the soybean oil- or olive oil-fed mice, and this decrease was more profound under conditions of isolation stress when compared with group-housing conditions. CONCLUSION: Dietary fish oil combined with isolation stress results in lower levels of lipid peroxidation in the liver and kidney compared with dietary fish oil alone.