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Concept: Antifungals

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BACKGROUND: Incorporation of the solubilizing excipient, sulfobutylether-beta-cyclodextrin (SBECD), in the intravenous (IV) formulation of voriconazole has resulted in the recommendation that this formulation be used with caution in patients with creatinine clearances (Clcr) < 50 mL/min. This study evaluated the safety of IV voriconazole compared with two other IV antifungals not containing SBECD in patients with compromised renal function. METHODS: A total of 128 patients aged 11--93 years who had a baseline Clcr < 50 mL/min between January 1, 2007 and December 31, 2010 were identified from a database of a university-affiliated inpatient healthcare system; of these, 55 patients received caspofungin, 54 patients received fluconazole, and 19 patients received voriconazole. Changes in serum creatinine (Scr) and Clcr levels while on therapy were compared with baseline values and between groups. RESULTS: The groups had similar characteristics apart from the larger proportion of females that received fluconazole. Baseline Scr was higher in those receiving caspofungin, but maximal increases of Scr and decreases in Clcr were greatest for the fluconazole group. Acute kidney injury (AKI), assessed by RIFLE criteria, was more frequent in the fluconazole vs. the caspofungin group (p < 0.01); incidence of AKI in the voriconazole group was not significantly different than found in the other two groups. The infecting organism was a predictor of AKI and formulation with SBECD was not. CONCLUSIONS: Treatment of fungal infections in patients with compromised renal function with an SBECD-containing antifungal agent was not associated with AKI in clinical practice. Since the infecting organism was associated with AKI, decision on which antifungal to use should be determined by susceptibilities to the organism and not the incorporation of SBECD in the IV formulation.

Concepts: Renal failure, Renal physiology, Blood urea nitrogen, Antifungals, Candidiasis, Antifungal drug, Athlete's foot, Griseofulvin

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F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.

Concepts: Pharmacology, Clinical trial, Aspergillosis, Aspergillus, Antifungals, Antifungal drug, Athlete's foot, Griseofulvin

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The European Conference on Infections in Leukemia (ECIL) provides recommendations for diagnostic strategies and prophylactic, pre-emptive or targeted therapy strategies for various types of infection in patients with hematological malignancies or hematopoietic stem cell transplantation recipients. Meetings are held every two years since 2005 and evidence-based recommendations are elaborated after evaluation of the literature and discussion among specialists of nearly all European countries. In this manuscript, the ECIL group presents the 2015-update of the recommendations for the targeted treatment of invasive candidiasis, aspergillosis and mucormycosis. Current data now allow a very strong recommendation in favor of echinocandins for first line therapy of candidemia irrespective of the underlying predisposing factors. Anidulafungin has been given the same grading as the other echinocandins for hemato-oncological patients. The beneficial role of catheter removal in candidemia is strengthened. Aspergillus guidelines now recommend the use of either voriconazole or isavuconazole for first line treatment of invasive aspergillosis, while first line combination antifungal therapy is not routinely recommended. As only few new data were published since the last ECIL guidelines, no major changes were brought to mucormycosis recommendations.

Concepts: Cancer, Bone marrow, Chemotherapy, Hematology, Hematopoietic stem cell transplantation, Aspergillosis, Antifungals, Candidiasis

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SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpine antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibility by broth micro-dilution, antifungal carry-over, and time-kill dynamics were determined for 3 reference (ATCC) strains (C. albicans 90028, C. parapsilosis 90018, and C. tropicalis 750), a Quality Control (QC) strain (C krusei 6258), and 4 other strains (C. albicans MYA-2732, 64124, 76485 and C.glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16x MIC80, and FLU and VORI were evaluated at 4x MIC80 The time to reach 50%, 90%, and 99.9% growth from starting innoculum was determined. Net change in CFU/mL was used to determine EC50, EC90, and Emax SCY-078 MIC range was between 0.0625 - 1 μg/mL and generally similar to CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against 7 isolates at ≥4x MIC (kill ≥3log10) and achieved a 1.7 log10 reduction in CFUs/mL against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5 log10 reduction in CFUs/mL against C. albicans 90028. Reductions of 50% in CFUs/mL were achieved rapidly (1-2.8 h); fungicidal endpoints were reached at 12.1 - 21.8 h at ≥4x MIC. EC90 was reached at ∼5x MIC at each time point to 24 h. EC50 and EC90 were generally similar (8-24 h). Time-kill behavior of CASP was similar to SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.

Concepts: Candida albicans, Antifungals, Candidiasis, Candida, Fungemia, Antifungal drug, Fluconazole, Candida krusei

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Because of the low prevalence of onychomycosis in children, little is known about the efficacy and safety of systemic antifungals in this population. PubMed and Embase databases and the references of related publications were searched in March 2012 for clinical trials (CTs), retrospective analyses (RAs), and case reports (CRs) on the use of systemic antifungals for onychomycosis in children (<18 years). Twenty-six studies (5 CTs, 3 RAs, and 18 CRs) were published between 1976 and 2011. Most of these studies reported the use of systemic terbinafine and itraconazole for the treatment of onychomycosis in children. Therapy with systemic antifungals alone in children age 1 to 17 years resulted in a complete cure rate of 70.8% (n = 151), whereas combined systemic and topical antifungal therapy in one infant and 19 children age 8 and older resulted in a complete cure rate of 80.0% (n = 20). The efficacy and safety profiles of terbinafine, itraconazole, griseofulvin, and fluconazole in children were similar to those previously reported for adults. In conclusion, based on the little information available on onychomycosis in children, systemic antifungal therapies in children are safe and cure rates are similar to the rates achieved in adults.

Concepts: Medicine, Therapy, Antifungals, Antifungal drug, Onychomycosis, Athlete's foot, Fluconazole, Griseofulvin

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Rhodotorula species are emergent fungal pathogens capable of causing invasive infections, primarily fungemia. They are particularly problematic in immunosuppressed patients when using a central venous catheter. In this study, we evaluated the species distribution of 51 clinical and 8 environmental Rhodotorula species isolates using the ID32C system and internal transcribed spacer (ITS) sequencing. Antifungal susceptibility testing and biofilm formation capability using a crystal violet staining assay were performed. Using ITS sequencing as the gold standard, the clinical isolates were identified as follows: 44 R. mucilaginosa isolates, 2 R. glutinis isolates, 2 R. minuta isolates, 2 R. dairenensis isolates, and 1 Rhodosporidium fluviale isolate. The environmental isolates included 7 R. mucilaginosa isolates and 1 R. slooffiae isolate. Using the ID32C system, along with a nitrate assimilation test, only 90.3% of the isolates tested were correctly identified. In the biofilm formation assay, R. mucilaginosa and R. minuta exhibited greater biofilm formation ability compared to the other Rhodotorula species; the clinical isolates of R. mucilaginosa showed greater biofilm formation compared to the environmental isolates (P = 0.04). Amphotericin B showed good in vitro activity (MIC ≤ 1 μg/ml) against planktonic cells, whereas voriconazole and posaconazole showed poor activity (MIC(50)/MIC(90), 2/4 μg/ml). Caspofungin and fluconazole MICs were consistently high for all isolates tested (≥64 μg/ml and ≥ 4 μg/ml, respectively). In this study, we emphasized the importance of molecular methods to correctly identify Rhodotorula species isolates and non-R. mucilaginosa species in particular. The antifungal susceptibility profile reinforces amphotericin B as the antifungal drug of choice for the treatment of Rhodotorula infections. To our knowledge, this is the first study evaluating putative differences in the ability of biofilm formation among different Rhodotorula species.

Concepts: Molecular biology, Biofilm, Catheter, Antifungals, Flucytosine, Candidiasis, Ergosterol, Antifungal drug

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We aim in this study to provide levels of susceptibility of 162 bloodstream isolates of non-Candida albicans and non-C. tropicalis species from a sentinel program conducted in 11 hospitals in Brazil. Additionally, we compared the broth microdilution (BMD) method of the European Committee of Susceptibility Testing (EUCAST) with Clinical Laboratory Standards Institute (CLSI) BMD method for fluconazole, itraconazole, voriconazole, and amphotericin B. The study included 103 C. parapsilosis, 38 C. glabrata, 8 C. orthopsilosis, and 7 C. krusei isolates, and single isolates of Pichia anomala, C. famata, C. lusitaniae, C. kefyr, C. guilliermondii, and C. metapsilosis. Of note, we observed cross-resistance between fluconazole and voriconazole for two isolates being one C. parapsilosis and one C. glabrata. Good essential agreement (EA) was observed between the EUCAST and the CLSI results for C. parapsilosis and for fluconazole, itraconazole, voriconazole, and amphotericin B, respectively: 98%, 99%, 98%, and 97%. Otherwise, for C. glabrata, the EA for fluconazole was 84.2% and for voriconazole 89.4%. Because data from Brazil are scarce, our results contribute to the consolidation of the database of candidemia agents and monitoring of trends in the profile of drug resistance.

Concepts: Laboratory, Amphotericin B, The Europeans, Antifungals, Candidiasis, Ergosterol, Triazole, World Health Organization essential medicines

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We report the detection of high-titre anti-Histoplasma capsulatum IgM in the serum of three young adult males occupationally exposed to bat guano. Multidrug treatment with trimethoprim- sulfamethoxazole was started, followed by ciprofloxacin, clarithromycin, metamizole sodium, rifampicin/isoniazid/pyrazinamide, moxifloxacin and lastly amphotericin B and ceftriaxone. Despite treatment the condition of one patient deteriorated, and he died 23 days after exposure. The other two patients recovered after receiving similar therapy with the addition of voriconazole. They are currently being treated with itraconazole for a 1-year period.

Concepts: Patient, Amphotericin B, Bat, Antifungals, Ergosterol, Histoplasmosis, Guano, World Health Organization essential medicines

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An antibacterial is a substance that kills bacteria or slows their growth. An antifungal are the agents that drugs use for treatment of fungal infections. 5- Chloro-1,3-benzoxazol-2(3H)-one (5-Chloro Benzoxazolinone) contains an azole ring structure. Numbers of azole compounds are reported as antibacterial and antifungal agents. Benzoxazolinones naturally occurs in plants. It plays role as defense compounds against bacteria, fungi and insects. Here is synthesis of six Benzoxazolinone derivatives with various substituents. Benzoxazolinone substituted with p-Aminobenzoic acids and sulphanilamide derivatives. The above both substituents are reported as potent antimicrobial agents. Attachment it with azole leads to increase its potency. The other substituents are with 2,4-dichlorobezylchloride. The same rings are found in miconazole and this may lead to increase its antifungal activity. Fluconazole also contains triazole moiety and triazole is having other number of activity like antimicrobial, anti-inflammatory, local anesthetic, antiviral, anticancer, antimalerial etc. Here there is substitution of azole ring at 5-Chloro position in that might increase antibacterial and antifungal activity. Here is the synthesis and interpretation of six final compounds and three intermediates. Synthesis of 5-Chloro Benzoxazolinone derivatives substituted with Halogenated rings, sulphonated and benzylated derivatives and azole derivatives. There was synthesis of P2A, P2B, P4A, P4B, P5A and P6A compounds and their Structures were characterized by UV-Visible, IR, MASS spectroscopy and NMR spectroscopy. The antibacterial activity of all six compounds is measured against various gm+ve and gm-ve bacteria and against fungi.Compound P4A and P4B has good antibacterial and anti fungal activity, half of the Ampicillin and Cephalexin. P4A, P4B, P6A has good activity against S.aureus and E.coli. Compound P2B has good antifungal activity, half of the Miconazole against C.albicans. P2A, P2B, P5A, P6A has almost equal antibacterial activity.

Concepts: Bacteria, Microbiology, Fungus, Meningitis, Antifungals, Antifungal drug, Fluconazole, Itraconazole

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Molecular epidemiology studies on cryptococcemia are limited. This study aimed to describe the clinical features of patients with bloodstream infections by Cryptococcus sp. in a public tertiary hospital in Mato Grosso do Sul, as well as identify the fungus' molecular type and determine its antifungal susceptibility. Molecular typing was performed using URA5 restriction fragment length polymorphism PCR, and antifungal susceptibility was determined by microdilution method standardized by the Clinical and Laboratory Standards Institute. Over 14 years, 48 patients were diagnosed with cryptococcemia. The majority (72.9 %) was male with a median age of 40 years; 81.3 % of the patients had HIV/AIDS and 72.9 % died. Cryptococcus neoformans was the most commonly isolated species (97.9 %). Molecular analysis identified the genotypes C. neoformans VNI (93.7 %), C. neoformans VNII (4.2 %), and Cryptococcus gattii VGII (2.1 %). In vitro, these fungi were not resistant to fluconazole, itraconazole, voriconazole, and amphotericin B. This is the first description of the molecular types of cryptococcemia agents in central-west Brazil. Its high lethality, especially in HIV-negative patients, suggests that early diagnosis and prompt antifungal therapy are crucial for a good clinical outcome.

Concepts: Fungus, Cryptococcus neoformans, Antifungals, Flucytosine, Basidiomycota, Cryptococcus, Fluconazole, Cryptococcosis