Breakthrough Invasive Sinusitis by Hormographiella aspergillata in a Neutropenic Patient Receiving Voriconazole Therapy: A Case Report and Review of Breakthrough H. aspergillata Infections.

Breakthrough invasive infections occurs during the use of antifungals both in prophylaxis and therapy, it favors the emergence of new pathogens in the fungal landscape. Hormographiella aspergillata is considered a rare but emerging pathogen in the era of broad-spectrum antifungal use in patients with hematological malignancies. Here, we present a case report of invasive sinusitis due to Hormographiella aspergillata, manifesting as a breakthrough infection in a patient with severe aplastic anemia under treatment with voriconazole for invasive pulmonary aspergilosis. Also, we make a review of H. aspergillata breakthrough infections published in the literature.

Incidence of breakthrough fungal infections on isavuconazole prophylaxis compared to posaconazole and voriconazole.

BACKGROUND: Invasive fungal infections (IFIs) are a common infectious complication during the treatment of acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS) or post hematopoietic cell transplantation (HCT). For these patients, the National Comprehensive Cancer Network recommends posaconazole or voriconazole for IFI prophylaxis. In clinical practice, however, there has been increased use of isavuconazole due to favorable pharmacokinetic and pharmacodynamic parameters despite limited data for this indication. The comparative prophylactic efficacy of antifungals in this patient population has not been reported, and an analysis is warranted. METHODS: This retrospective, matched cohort, single-center study, included AML, MDS, or HCT patients who began treatment or underwent transplant between January 1, 2015 and July 31, 2021. Isavuconazole patients were matched 1:2 with patients receiving posaconazole or voriconazole prophylaxis. RESULTS: A total of 126 patients were included, 42 received isavuconazole, 81 received posaconazole, and three received voriconazole. The majority of patients were male receiving secondary IFI prophylaxis while receiving steroids for treatment of GVHD. The incidence of possible, probable or proven IFI was 16.7% in the isavuconazole group compared to 10.7% in the posaconazole and voriconazole group (OR 1.28, 95% CI -0.9-1.4; p = .67). Hepatotoxicity occurred in 16 total patients, 14 receiving posaconazole and two receiving isavuconazole. CONCLUSION: Patients who received isavuconazole prophylaxis during AML induction therapy or post-HCT experienced a similar incidence of breakthrough fungal infections compared to those who received posaconazole or voriconazole. These results suggest no difference in antifungal prophylactic efficacy; however larger prospective comparative studies are needed.

Successful treatment of Talaromyces marneffei pneumonia in a HIV-negative renal transplantation recipient: A case report.

RATIONALE: Talaromyces marneffei causes life-threatening opportunistic fungal infections in immunocompromised patients. It often has a poorer prognosis in non-human immunodeficiency virus (HIV)-infected than in HIV-infected individuals because of delayed diagnosis and improper treatment. PATIENT CONCERNS: A 51-year-old man presented with complaints of pyrexia, cough, and expectoration that had lasted for 15 day. This patient has been taking anti-rejection medication since kidney transplant in 2011. DIAGNOSIS: T marneffei pneumonia; post renal transplantation; renal insufficiency; hypertension. INTERVENTIONS: Intravenous moxifloxacin was administered on admission. After the etiology was established, moxifloxacin was discontinued and replaced with voriconazole. The tacrolimus dose was adjusted based on the blood concentration of tacrolimus and voriconazole. OUTCOMES: The patient was successfully treated and followed-up without recurrence for 1 year. LESSONS: A high degree of caution should be maintained for the possibility of T marneffei infection in immunodeficient non-HIV patients who live in or have traveled to T marneffei endemic areas. Early diagnosis and appropriate treatment can prevent progression of T marneffei infection and achieve a cure. Metagenomic next-generation sequencing (mNGS) can aid the physician in reaching an early pathogenic diagnosis. Close monitoring of tacrolimus and voriconazole blood levels during treatment remains a practical approach at this time.

Voriconazole is superior to combined itraconazole/isotretinoin therapy and itraconazole monotherapy in recalcitrant dermatophytosis.

BACKGROUND: There has been an emergence of recalcitrant, recurrent, and difficult-to-treat tinea. Monotherapy with oral antifungals leads to partial clearance or high recurrence of lesions. Isotretinoin is a good adjuvant to systemic antifungals in chronic dermatophytosis. Voriconazole could be a future alternative due to its efficacy against dermatophytes and little resistance. OBJECTIVE: To evaluate the efficacy and safety of oral itraconazole, combined itraconazole/isotretinoin therapy, and voriconazole for recalcitrant tinea. PATIENTS AND METHODS: This study included 90 patients with chronic, recurrent and/or recalcitrant tinea. They were equally divided into three groups: itraconazole monotherapy, combined itraconazole/isotretinoin therapy, and voriconazole monotherapy. All patients received treatments for 6 weeks. The clinical response was classified as either a complete or incomplete clinical cure. Potassium hydroxide microscopy and culture were performed to identify mycological cure. Patients with complete cure were followed up for another 6 months to detect any recurrence. RESULTS: Complete clinical cure was observed in 53.3% of the itraconazole group, 70% of the itraconazole/isotretinoin group, and 83.3% of the voriconazole group. Mycological cure was detected in 56.7% of the itraconazole group, 83.3% of the itraconazole/isotretinoin group, and 86.7% of the voriconazole group. There was a statistically significant difference between the three groups in favour of voriconazole, then the combined group. No significant adverse effects were observed. The recurrence rate was significantly lower in the voriconazole group compared with the other two groups. CONCLUSIONS: Voriconazole could be a future alternative for the treatment of recalcitrant dermatophytosis.

Single oral or intravenous administration of voriconazole achieved recommended therapeutic minimum inhibitory concentrations against Aspergillus in the common raven (Corvus corax).

OBJECTIVE: To determine the pharmacokinetics of voriconazole after single IV or orally administered boluses in common ravens (Corvus corax). ANIMALS: 8 healthy common ravens. PROCEDURES: Voriconazole (5 mg/mL, 10 mg/kg IV) was administered to 8 birds, and then plasma voriconazole concentrations were measured at various time points by high-pressure liquid chromatography with mass spectrometry. Starting 6 months later in a randomized 3-treatment 3-period regimen, birds received a single oral dose of voriconazole suspension (10 mg/mL; 6, 12, and 24 mg/kg PO). The study period was May 2015 to March 2016. RESULTS: Voriconazole (10 mg/kg IV) achieved an initial plasma concentration of 6.31 µg/mL when measured over 21 hours. After oral administration of voriconazole at 6, 12, and 24 mg/kg, the relative bioavailability was 67.5%, 209%, and 183%, respectively. For the 6-mg/kg dose, the maximum plasma concentration was reached at 30 minutes after administration and remained in the therapeutic range of 0.5 to 1 µg/mL for approximately 15 hours. The 12- and 24-mg/kg doses resulted in concentrations in a potentially toxic range. CLINICAL RELEVANCE: Voriconazole was well tolerated. All 4 doses resulted in plasma concentrations of voriconazole > 0.5 µg/mL, which is the minimum inhibitory concentration recommended for pathogenic species of Aspergillus fungi known to affect birds. A single dose of voriconazole administered as 10 mg/kg IV or 6 mg/kg PO resulted in recommended target plasma concentrations. Administration of voriconazole 6 mg/kg PO 2 to 3 times daily may be adequate for treatment without exceeding the toxic range.

Aspergillus spp. osteoarticular infections: an updated systematic review on the diagnosis, treatment and outcomes of 186 confirmed cases.

Aspergillus spp. osteoarticular infections are destructive opportunistic infections, while there is no clear consensus on their management. The purpose of this review is to investigate the current literature regarding Aspergillus spp. osteoarticular infections. An electronic search of the PubMed and Scopus databases was conducted considering studies that assessed osteoarticular infections from Aspergillus spp. We included only studies with biopsy proven documentation of positive cultures or histological findings for Aspergillus spp., and those with essential information for each case such as the anatomical location of the infection, the type of treatment (conservative, surgical, combination), the antifungal therapy, and the outcome. Overall, 148 studies from 1965 to 2021 including 186 patients were included in the review. One hundred and seven (57.5%) patients underwent surgical debridement in addition to antifungal therapy, while 79 (42.7%) patients were treated only conservatively. Complete infection resolution was reported in 107 (57.5%) patients, while partial resolution in 29 (15.5%) patients. Surgical debridement resulted in higher complete infection resolution rate compared to only antifungal therapy (70.0% vs. 40.5%, P < 0.001), while complete resolution rate was similar for antifungal monotherapy and combination/sequential therapy (58.3% vs. 54.5%; P = 0.76). Last, complete resolution rate was also similar for monotherapy with amphotericin B (58.1%) and voriconazole (58.6%; P = 0.95). The results of this study indicate that antifungal monotherapy has similar efficacy with combination/sequential therapy, while voriconazole has similar efficacy with amphotericin B. Moreover, surgical debridement of the infected focus results in better outcomes in terms of infection eradication compared to conservative treatment. LAY SUMMARY: Antifungal monotherapy has similar efficacy with combination/sequential therapy, and voriconazole has similar efficacy with amphotericin B for the treatment of Aspergillus spp. osteoarticular infections, while surgical debridement of the infected focus improves the infection eradication rate.

Optimization of Particle Properties of Nanocrystalline Solid Dispersion Based Dry Powder for Inhalation of Voriconazole.

A one-step spray drying based process was employed to generate ready-to-use nanocrystalline solid dispersion (NCSD) dry powder for inhalation (DPI) of voriconazole (VRC). The solid dispersion was prepared by spray drying VRC, MAN (mannitol) and soya lecithin (LEC) from mixture of methanol-water. Various formulation and process related parameters were screened, including LEC, inlet temperature, total solid content and feed flow rate to generate particles of geometric size ≤5 µm. Aerosil® 200 was explored as the quaternary excipient either during spray drying or by physically mixing with the optimized ternary NCSD. The powders were extensively characterized for solid form, primary particle size, assay, embedded nanocrystal size, morphology, porosity, density and moisture content. Aerodynamic properties were studied using next generation impactor (NGI), while surface elemental composition and topography were investigated using SEM-EDS (scanning electron microscopy- energy dispersive spectroscopy) and AFM (atomic force microscopy), respectively. At selected inlet temperature of 120 ˚C, total solid content and feed flow rate significantly impacted the size of primary NCSD particles. Size of primary particles increased with increase in total solid content and feed flow rate of the solution. VRC nanocrystals were obtained in polymorphic Form B whereas the matrix of MAN consisted of mixture of polymorphic Forms α, ß and δ. SEM-EDS analysis confirmed deposition of Aerosil® 200 on surface of spray dried particles. In addition to increased porosity and reduced density, increase in surface roughness of particles (evident from AFM topographic analysis) contributed to enhanced powder deposition at stages 3 and 4 in NGI. In comparison, physical blending of NCSD with Aerosil® 200 showed improvement in aerosolization due to flow enhancement property.

High dose nanocrystalline solid dispersion powder of voriconazole for inhalation.

In the current work, we aimed to deliver high dose of voriconazole (VRC) to lung through dry powder for inhalation (DPIs). Furthermore, the research tested the hypothesis that drug nanocrystals can escape the clearance mechanisms in lung by virtue of their size and rapid dissolution. High dose nanocrystalline solid dispersion (NCSD) based DPI of VRC was prepared using a novel spray drying process. Mannitol (MAN) and soya lecithin (LEC) were used as crystallization inducer and stabilizer, respectively. The powders were characterized for physicochemical and aerodynamic properties. Chemical interactions contributing to generation and stabilization of VRC nanocrystals in the matrix of MAN were established using computational studies. Performance of NCSD (VRC-N) was compared with microcrystalline solid dispersion (VRC-M) in terms of dissolution, uptake in A549 and RAW 264.7 cells. Plasma and lung distribution of VRC-N and VRC-M in Balb/c mice upon insufflation was compared with the intravenous product. In VRC-N, drug nanocrystals of size 645.86 ± 56.90 nm were successfully produced at VRC loading of 45%. MAN created physical barrier to crystal growth by interacting with N- of triazole and F- of pyrimidine ring of VRC. An increase in drug loading to 60% produced VRC crystals of size 4800 ± 200 nm (VRC-M). The optimized powders were crystalline and showed deposition at stage 2 and 3 in NGI. In comparison to VRC-M, more than 80% of VRC-N dissolved rapidly in around 5-10 mins, therefore, showed higher and lower drug uptake into A549 and RAW 264.7 cells, respectively. In contrast to intravenous product, insufflation of VRC-N and VRC-M led to higher drug concentrations in lung in comparison to plasma. VRC-N showed higher lung AUC0-24 due to escape of macrophage clearance.

Bioavailability enhancement of voriconazole using liposomal pastilles: Formulation and experimental design investigation.

Oral mucosa offers several advantages in the delivery of therapeutic molecules. It avoids presystemic metabolism, Nanoencapsulation techniques might be applied to conquer physical, chemical challenges and enhance drug penetration, formulation performance, prolonging drug residence time, and improving sensorial feeling. The present investigation is aimed to formulate liposomal pastilles with high bioavailability. Voriconazole Liposomes (VL) were produced by utilizing varied ratios of soya lecithin (SL) and cholesterol (CH) by solvent Injection method. RSM is utilized to identify the optimized formulation, as this design provides a thorough understanding of a process and also has great utilization in originating the robustness of the product. The main impact and interaction terms of the formulation variables were assessed quantitatively utilizing a mathematical-statistical approach indicating that both independent variables have significant ('P' value < 0.05) effects on particle size ('P' value: 0.0142), percentage entrapment efficiency ('P' value: 0.0120), percentage drug release through the dialysis membrane ('P' value: 0.0105), percentage drug release through porcine buccal mucosa ('P' value: 0.0171) and percentage zone of inhibition ('P' value: 0.0305). Optimal liposomal encapsulated in noticed in 15:10 lecithin: cholesterol concentration (VLP-6). Higher Lecithin and Cholesterol quantity in the liposome formulations resulted in lower drug entrapment efficiency and drug release when compared with middle levels of lecithin and cholesterol content formulation. The pastilles were prepared from the optimized liposomal formulation with a modified method reported in British Pharmaceutical Codex, 1907. These liposomal pastilles were subjected to evaluation of physicochemical parameters, In vitro drug release studies, stability studies, and In vivo bioavailability studies in comparison with pure voriconazole pastilles (PVP). The statistical data analysis results indicated that there was a significant difference in Tmax, Ka, t1/2 abs, t1/2 elim, AUC0-24, AUC0-∞, AUMC0-24 and AUMC0-∞, values among PVP and VLP-6. There was no significant difference in Cmax, Kel, MRT0-24 and MRT0-∞values among pure voriconazole pastilles and optimized liposomal formulation.

Review of the alternative therapies for onychomycosis and superficial fungal infections: posaconazole, fosravuconazole, voriconazole, oteseconazole.

Terbinafine and itraconazole are the most commonly used oral antifungals to treat onychomycosis and superficial dermatomycoses. Recently, poor response to oral terbinafine has been reported. We have summarized the most appropriate dosing regimens of posaconazole, fosravuconazole, voriconazole, and oteseconazole (VT-1161) to treat onychomycosis and superficial fungal infections. A structured search on PubMed and Google Scholar was conducted. Additionally, the bibliographies of selected articles were searched to identify relevant records. The number of records identified from the searches was 463, with 50 articles meeting the inclusion criteria for review. None of the new azoles are US FDA approved for onychomycosis treatment; however, an increasing number of studies have evaluated these agents. The efficacies (complete cure and mycologic cure) of the antifungal agents for dermatophyte great toenail onychomycosis treatment are terbinafine 250 mg/day × 12 weeks (Phase III trial) (38%, 70%), itraconazole 200 mg/day × 12 weeks (Phase III trial) (14%, 54%), posaconazole 200 mg/day × 24 weeks (Phase IIB) (54.1%, 70.3%), fosravuconazole 100 mg/day ravuconazole equivalent × 12 weeks (Phase III) (59.4%, 82.0%), and oteseconazole 300 mg/day loading dose × 2 weeks (Phase II), followed by 300 mg/week × 10 weeks (maintenance dose) (45%, 70%). Guidelines for monitoring are also presented.

The effect of biosynthesized selenium nanoparticles on the expression of CYP51A and HSP90 antifungal resistance genes in Aspergillus fumigatus and Aspergillus flavus.

The application of biological nanoparticles (NPs) can be considered as a way to overcome the problem of antifungal resistance in pathogenic fungi. This study takes a new approach to biosynthesized NPs influence on the expression of CYP51A and HSP90 antifungal resistance genes in Aspergillus fumigatus and A. flavus, and comparison with antifungal agents. Selenium NPs (Se-NPs) were biosynthesized using Aspergillus strains and their production was proved by several methods including, UV-Vis, XRD, FTIR, FESEM, and EDX techniques. The minimum inhibitory concentrations (MICs) of Aspergillus strains were determined using the CLSI M38-A2 broth microdilution method. The differences in expression levels of CYP51A and HSP90 genes were examined between untreated and treated of A. fumigatus and A. flavus using itraconazole and amphotericin B and biosynthesized Se-NPs through real-time PCR. After confirming the results of NPs synthesis, the MIC of itraconazole and amphotericin B against A. fumigatus and A. flavus was 4 µg/ml. Based on the real-time PCR results, the obtained ∆∆CTs for these strains were -0.18, -1.46, and -1.14. Whereas the MIC values for treated samples with Se-NPs have decreased to 0.5 µg/ml, and the ∆∆CTs for these were -0.25, -1.76, and -1.68. The expression of CYP51A and HSP90 genes was significantly down-regulated through the use of Se-NPs against A. fumigatus and A. flavus.

Effectiveness and antimicrobial susceptibility profiles during primary antimicrobial prophylaxis for pediatric acute myeloid leukemia.

Limited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0-18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome.

Formulation, optimization, and nephrotoxicity evaluation of an antifungal in situ nasal gel loaded with voriconazole‒clove oil transferosomal nanoparticles.

Fungal infections of the paranasal cavity are among the most widely spread illnesses nowadays. The aim of the current study was to estimate the effectiveness of an in situ gel loaded with voriconazole‒clove oil nano-transferosomes (VRC-CO-NT) in enhancing the activity of voriconazole against Aspergillus flavus, which causes rhinosinusitis. The nephrotoxic side effects of voriconazole may be reduced through the incorporation of the clove oil, which has antioxidant activity that protects tissue. The Box‒Behnken design was applied to formulate the VRC-CO-NT. The particle size, entrapment efficiency, antifungal inhibition zone, and serum creatinine concentration were considered dependent variables, and the soybean lecithin, VRC, and CO concentrations were considered independent ones. The final optimized formulation was loaded into a deacetylated gellan gum base and evaluated for its gelation, rheological properties, drug release profile, permeation capabilities, and in vivo nephrotoxicity. The optimum formulation was determined to be composed of 50 mg/mL lecithin, 18 mg/mL VRC, and 75 mg/mL CO, with a minimum particle size of 102.96 nm, an entrapment efficiency of 71.70%, an inhibition zone of 21.76 mm, and a serum creatinine level of 0.119 mmol/L. The optimized loaded in situ gel released 82.5% VRC after 12 hours and resulted in a 5.4-fold increase in drug permeation. The in vivo results obtained using rabbits resulted in a nonsignificant differentiation among the renal function parameters compared with the negative control group. In conclusion, nasal in situ gel loaded with VRC-CO-NT is considered an efficient novel carrier with enhanced antifungal properties with no signs of nephrotoxicity.

Combined Phialemonium curvatum and Acanthamoeba Keratitis: The Importance of Early Diagnosis and Specific Therapy.

PURPOSE: To report the clinical and confocal findings of a unique case of combined Phialemonium curvatum and Acanthamoeba keratitis and to highlight the role of the prompt diagnosis and specific medical treatment in preserving visual function. METHODS: A case report and literature review. RESULTS: A 54-year-old woman presented with a 3-day history of visual impairment, photophobia, and ocular pain in her right eye. Her best corrected visual acuity was 0.4 Logarithm of the Minimum Angle of Resolution scale, and the slit-lamp examination showed whitish corneal stromal infiltrate with satellite lesions. In vivo confocal microscopy evidenced Acanthamoeba cysts and fungal hyphae that resulted P. curvatum in the culture examination. The intensive medical treatment was started with topical 0.02% polyhexamethylene biguanide, voriconazole 1%, and moxifloxacin hydrochloride 0.5%. Progressive improvement of clinical and confocal pictures was registered with a complete recovery of visual function after 1 month. CONCLUSIONS: This is the first case report of combined P. curvatum and Acanthamoeba keratitis. The fast diagnosis with in vivo confocal microscopy allowed early and intensive specific treatment with recovery of corneal infection.

Efficacy of Voriconazole, Isavuconazole, Fluconazole, and Anidulafungin in the Treatment of Emerging Candida auris Using an Immunocompromised Murine Model of Disseminated Candidiasis.

Antifungal activity of anidulafungin, voriconazole, isavuconazole, and fluconazole in the treatment of Candida auris was determined in vitro and in vivo. MICs for anidulafungin, voriconazole, isavuconazole, fluconazole, and amphotericin B were 0.5, 1, >64, 0.25, and 4 µg/ml, respectively. Significant in vivo efficacy was observed in the anidulafungin- and voriconazole-treated groups in survival and reduction in kidney tissue fungal burden compared to that in the untreated group (P values of <0.001 and 0.044, respectively). Our data showed that anidulafungin and voriconazole had comparable efficacies against C. auris, whereas isavuconazole did not show significant in vivo activity.

Treatment of Cryptococcus gattii Infection Using Voriconazole.

We previously reported a 39-year-old man who presented with pulmonary and cerebral Cryptococcus gattii (genotype VGIIa) infection and was successfully treated with liposomal amphotericin B and flucytosine induction therapy. Following induction therapy, oral fluconazole treatment was initiated as consolidation therapy. However, the patient complained of progressively worsening headache, presenting an elevated cerebrospinal fluid (CSF) cell count. The minimum inhibitory concentrations of the CSF isolate were 8 and 0.12 µg/mL for fluconazole and voriconazole, respectively. The oral administration of voriconazole for more than 18 months alleviated his symptoms. Voriconazole might be useful for controlling refractory cases of C. gattii infection.

Axillary Digital Thermometers uplifted a multidrug-susceptible Candida auris outbreak among COVID-19 patients in Brazil.

OBJECTIVES: To describe the first outbreak of Candida auris in Brazil, including epidemiological, clinical and microbiological data. METHODS: After the first Candida auris-colonised patient was diagnosed in a COVID-19 ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation. Screening cultures for C. auris were collected from patients, healthcare workers and inanimate surfaces. Risk factors for C. auris colonisation were evaluated, and the fungemia episodes that occurred after the investigation were also analysed and described. Antifungal susceptibility of the C. auris isolates was determined, and they were genotyped with microsatellite analysis. RESULTS: Among body swabs collected from 47 patients, eight (n = 8/47, 17%) samples from the axillae were positive for C. auris. Among samples collected from inanimate surfaces, digital thermometers had the highest rate of positive cultures (n = 8/47, 17%). Antifungal susceptibility testing showed MICs of 0.5 to 1 mg/L for AMB, 0.03 to 0.06 mg/L for voriconazole, 2 to 4 mg/L for fluconazole and 0.03 to 0.06 mg/L for anidulafungin. Microsatellite analysis revealed that all C. auris isolates belong to the South Asian clade (Clade I) and had different genotypes. In multivariate analysis, having a colonised digital thermometer was the only independent risk factor associated with C. auris colonisation. Three episodes of C. auris fungemia occurred after the investigation, with 30-day attributable mortality of 33.3%. CONCLUSIONS: Emergence of C. auris in Salvador, Brazil, may be related to local C. auris clade I closely related genotypes. Contaminated axillary monitoring thermometers may facilitate the dissemination of C. auris reinforcing the concept that these reusable devices should be carefully cleaned with an effective disinfectant or replaced by other temperature monitoring methods.

Purpureocillium roseum sp. nov. A new ocular pathogen for humans and mice resistant to antifungals.

BACKGROUND: Infectious keratitis is the main cause of preventable blindness worldwide, with about 1.5-2.0 million new cases occurring per year. This inflammatory response may be due to infections caused by bacteria, fungi, viruses or parasites. Fungal keratitis is a poorly studied health problem. OBJECTIVES: This study aimed to identify a new fungal species by molecular methods and to explore the possible efficacy of the three most common antifungals used in human keratitis in Mexico by performing in vitro analysis. The capacity of this pathogen to cause corneal infection in a murine model was also evaluated. METHODS: The fungal strain was isolated from a patient with a corneal ulcer. To identify the fungus, taxonomic and phylogenetic analyses (nrDNA ITS and LSU data set) were performed. An antifungal susceptibility assay for amphotericin B, itraconazole and voriconazole was carried out. The fungal isolate was used to develop a keratitis model in BALB/c mice; entire eyes and ocular tissues were preserved and processed for histopathologic examination. RESULTS AND CONCLUSION: This fungal genus has hitherto not been reported with human keratitis in Mexico. We described a new species Purpurecillium roseum isolated from corneal infection. P roseum showed resistance to amphotericin B and itraconazole and was sensitive to voriconazole. In vivo study demonstrated that P roseum had capacity to developed corneal infection and to penetrate deeper corneal tissue. The global change in fungal infections has emphasised the need to develop better diagnostic mycology laboratories and to recognise the group of potential fungal pathogens.

CYP2C19 is involved in the effect of Wuzhi tablet (Schisandra sphenanthera extract) and its constituents on the pharmacokinetics of intravenous voriconazole.

The co-administration of voriconazole (VCZ) and Wuzhi tablet (WZ) is frequently prescribed for solid organ transplantation patients in China. However, the pharmacokinetic interactions between VCZ and WZ as well as its bioactive constituents, such as schisandrin A and schisandrol B, remain unknown. Therefore, the effects of WZ and the two lignans on the metabolism of VCZ and the potential role of cytochromeP450 (CYP450), especially cytochrome P450 2C19 (CYP2C19), were investigated. The results showed that WZ extensively inhibited the activities of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Noteworthy, 2.5 mg/mL WZ almost completely inhibited the activity of 2C19, and the inhibition ratio reached 78.6±3% and 63.5±4.6% for schisandrin A and schisandrol B at concentrations 100 µM, respectively. In addition, rats were treated with a single or consecutive 14 day oral dose of WZ (250 mg/kg), schisandrol B (10 mg/kg) and schisandrin A (10 mg/ kg). In rats treated with WZ, the AUC0-∞ value for intravenous VCZ dosing was increased by 80.2% (single dose, p < 0.05) and 66.4% (dosage for 14 day, p < 0.05) and the Cmax was increased by 10.5% (p < 0.05) and (20.6%, p < 0.05), respectively, much greater than that when VCZ (28 mg/kg) was given alone. Unexpectedly, the AUC and Cmax values after schisandrol B and schisandrin A treatment were significantly increased. However, the mRNA expression of liver CYP2C19 and the protein expression of liver CYP2C19 were surprisingly increased after treatment with WZ, schisandrol B and schisandrin A in rats. Therefore, attention should be paid to when WZ and VCZ are administered concomitantly, as dosage adjustment might become necessary. Further clinical study is warranted to validate the interaction between WZ and VCZ.

Voriconazole-natural latex dressings for treating infected Candida spp. skin ulcers.

Aim: This work aimed to develop a membrane based on voriconazole (VCZ)-loaded natural rubber latex (NRL) for treating infected ulcers with Candida spp. and study their interaction, drug release, antifungal activity against Candida parapsilosis and biological characterization. Materials & methods: VCZ-loaded NRL membrane was produced by casting method. Results: Infrared spectrum showed that the incorporation of VCZ into the NRL membrane maintained its characteristics. Its mechanical properties were considered suitable for dermal application. The VCZ was able to release from NRL membrane, maintaining its antifungal activity against C. parapsilosis, besides did not present hemolytic effects. Conclusion: The VCZ-NRL membrane showed good results in mechanical, antifungal and biological assays, representing an interesting alternative to treatment of infected wound with Candida spp.