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To develop and validate a one-step, rapid and simple reversed-phase high-performance liquid chromatography (HPLC)-based protocol for the simultaneous measurement of voriconazole (VCZ), posaconazole (POSA), itraconazole (ITC) in serum/plasma. Calibration standards (CS) and quality control samples were prepared in drug-free serum by spiking with the triazoles at different concentrations. HPLC was performed with C18 column, isocratic mobile phase after extraction with cold acetonitrile. The standardized method was tested in 2693 patients’ serum/plasma samples. Linearity of CS for ITC, VCZ and POSA was proportional to the nominal concentration (correlation coefficient > 0.999). Limit of detection (mg/L) for ITC, VCZ and POSA was 0.25, 0.25 and 0.125, respectively. The lower limit of quantification (mg/L) for ITC, VCZ and POSA was 0.5, 0.5 and 0.25, respectively. Precision and accuracy were in acceptable range with 100% average percentage recovery. No interferences from endogenous substances and other antimicrobial compounds were noted. In clinical samples, the therapeutic range achieved for VCZ was 39.9%. Whereas, 61.1% and 44% of samples with ITC and POSA, respectively, were in the sub-therapeutic range. We developed a rapid and simple HPLC method to quantify common triazoles in a single chromatographic run allowing simultaneous measurement of different antifungals in a small volume of serum/plasma. Thus, therapeutic drug monitoring requests can be processed in one run without changing the protocol parameters, column or column conditioning thereby improving turnaround time.

The South-Asian epidemic of anti-fungal therapeutic failures (AFTF) is on the rise. Although many demographic, environmental, and socioeconomic factors have been implicated in the genesis of this problem, two pharmacological issues warrant attention. While detailed discussions on the role of topical corticosteroid (TCS) in the changing landscape of the superficial mycotic infections in this region have been making headlines, another equally, rather more important pharmacological factor seems to have been undermined by the hype around TCS. The fastidious pharmacokinetic properties and related practical aspects of the triazole group of oral and topical antifungals, especially oral itraconazole seem to contribute significantly to the persistence of AFTF epidemic. In this paper, we shall discuss the broad aspects of the spectral precariousness of oral triazole antifungals with special emphasis to itraconazole, a concept known as the 'azole menace' in the overall pathogenesis and tenacity of the AFTF epidemic. This article is protected by copyright. All rights reserved.

The study found that the leading role in the etiology of infectious diseases of the upper and lower respiratory tract belonged to the viridans group streptococci and fungi of the genus Candida. The proportion of fungi of the genus Candida was 28.8 % in patients with pharyngitis, 22.6 % in those with bronchitis and 37.4 % in individuals with pneumonia, which in 77–85.6 % of ca-ses were present in associations with bacteria. There is a high level of resistance of fungi of genus Candida to triazole antifungals., В ходе исследования выявлено, что ведущая роль в этиологии инфекционных заболеваний верхних и нижних дыхательных путей принадлежала Streptococcus viridans и грибам рода Candida. Удельный вес грибов рода Candida составлял 28,8 % у больных фарингитами, 22,6 % — у больных бронхитами и 37,4 % — у больных пневмонией, которые в 77–85,6 % случаев были представлены ассоциациями с бактериями. Отмечался высокий уровень резистентности грибов рода Candida к триазольным антимикотикам., Під час дослідження виявлено, що провідна роль в етіології інфекційних захворювань верхніх і нижніх дихальних шляхів належала Streptococcus viridans і грибам роду Candida. Питома вага грибів роду Candida становила 28,8 % у хворих на фарингіти, 22,6 % — у хворих на бронхіти і 37,4 % — у хворих на пневмонію, які у 77–85,6 % випадків були представлені в асоціаціях із бактеріями. Відмічається високий рівень резистентності грибів роду Candida до триазольних антимікотиків.

Despite the availability of antifungal treatments, fungal infections are still causing morbidity all around the globe with unacceptably high mortality rates. A major driver for the rising incidence of serious fungal infections is due to a substantial increase in immunocompromised individuals with autoimmune diseases, cancers and transplants. Because of growing resistance in fungus to frontline triazole antifungals and the association of fungal disease with the immunocompromised host, adjunctive host-directed therapy is seen as a promising choice to improve patient outcomes. Immunotherapeutic treatments being explored as adjunct therapies to existing antifungal treatments include cytokine therapy, monoclonal antibodies and cellular immunotherapy. In this review, we give a brief overview of potential immunotherapies and recent developments in the field, which are needed to tackle the growing problem of fungal diseases.

The environmental mold Aspergillus fumigatus is the primary cause of invasive aspergillosis. In patients with high-risk conditions, including stem cell and organ transplant recipients, mortality exceeds 50%. Triazole antifungals have greatly improved survival (1); however, triazole-resistant A. fumigatus infections are increasingly reported worldwide and are associated with increased treatment failure and mortality (2). Of particular concern are resistant A. fumigatus isolates carrying either TR34/L98H or TR46/Y121F/T289A genetic resistance markers, which have been associated with environmental triazole fungicide use rather than previous patient exposure to antifungals (3,4). Reports of these triazole-resistant A. fumigatus strains have become common in Europe (2,3), but U.S. reports are limited (5). Because of the risk posed to immunocompromised patients, understanding the prevalence of such isolates in patients is important to guide clinical and public health decision-making. In 2011, CDC initiated passive laboratory monitoring for U.S. triazole-resistant A. fumigatus isolates through outreach to clinical laboratories. This system identified five TR34/L98H isolates collected from 2016 to 2017 (6), in addition to two other U.S. isolates collected in 2010 and 2014 and reported in 2015 (5). Four of these seven isolates were reported from Pennsylvania, two from Virginia, and one from California. Three isolates were collected from patients with invasive pulmonary aspergillosis, and four patients had no known previous triazole exposure. A. fumigatus resistant to all triazole medications is emerging in the United States, and clinicians and public health personnel need to be aware that resistant infections are possible even in patients not previously exposed to these medications.

Coccidioidal meningitis remains a difficult clinical problem, and despite life-long therapy with triazole antifungals, relapses of disease and medication intolerance occur necessitating salvage treatment. We report two patients with recurrent coccidioidal meningitis who improved following a 2-week course of liposomal amphotericin B monotherapy and discuss potential advantages of this treatment option.

Aspergillus fumigatus is a ubiquitous saprophytic fungus. Inhalation of A. fumigatus spores can lead to Invasive Aspergillosis (IA) in people with weakened immune systems. The use of triazole antifungals with the demethylation inhibitor (DMI) mode of action to treat IA is being hampered by the spread of DMI-resistant “ARAf” (azole-resistant Aspergillus fumigatus) genotypes. DMIs are also used in the environment, for example, as fungicides to protect yield and quality in agronomic settings, which may lead to exposure of A. fumigatus to DMI residues. An agronomic setting can be a “hotspot” for ARAf if it provides a suitable substrate and favourable conditions for the growth of A. fumigatus in the presence of DMI fungicides at concentrations capable of selecting ARAf genotypes at the expense of the susceptible wild-type, followed by the release of predominantly resistant spores. Agronomic settings that do not provide these conditions are considered “coldspots". Identifying and mitigating hotspots will be key to securing the agronomic use of DMIs without compromising their use in medicine. We provide a review of studies of the prevalence of ARAf in various agronomic settings and discuss the mitigation options for confirmed hotspots, particularly those relating to the management of crop waste.

Background Invasive mold infections (IMIs) are an increasing cause of morbidity and mortality worldwide.1 Pharmacological differences among the currently available mold-active triazoles make treatment selection complex.1 To the best of our knowledge, this is the first study to assess patient preferences for mold-active triazoles in IMI treatment. Methods Patients were included if they were aged ≥ 18 years with investigator-confirmed invasive aspergillosis or invasive mucormycosis; had received voriconazole, isavuconazonium sulfate or posaconazole within ≤ 1 week previously; and were outpatients for ≥ 3 weeks. Participants were presented with 14 choice cards, each with two hypothetical treatments with varying levels of attributes, and asked to select their preferred treatment. Preference weights for attribute levels were analyzed using conditional logit regression and used to calculate the impact of changes in attribute levels on patient choices; relative attribute importance (RAI); and patient willingness to pay (WTP; monthly out-of-pocket cost) for an attribute improvement. Results Of 50 participants, 52% were female and the mean age was 47.3 years; 40%, 40%, and 28% had used posaconazole, voriconazole and isavuconazonium sulfate, respectively (Figure 1). Route of administration (27% RAI), treatment duration (22% RAI), and chance of symptom relief after treatment (20% RAI) were the most important attributes for patients (Figure 2). The odds ratios for patients choosing oral suspension or tablets/capsules over IV infusion were 5.6 and 4.5, respectively (P < 0.001) (Figure 3); patients were willing to pay an additional $205/month or $180/month out of pocket for these respective routes of administration over IV (Figure 4). The odds ratio for patients choosing a 30-day over a 90-day treatment were 4.1 (P < 0.001) (Figure 3); this decrease in duration was valued by patients at $168/month (Figure 4). For a 50% vs. 30% chance of symptom relief, the odds ratio was 3.5 (P < 0.001) (Figure 3) and WTP was $147.89/month (Figure 4). Conclusion Patients considered route of administration, treatment duration and chance of symptom relief to be the most important IMI treatment attributes among mold-active triazoles. 1Jenks JD et al. (2019) Med Mycol 57:S168–S178 Disclosures All authors: No reported disclosures.

Candida spp. are currently the fourth most common cause of bloodstream infections in US hospitals, and the third most common cause of bloodstream infections in the intensive care unit. Over the last 2 decades there has been a shift towards a greater involvement of non-Candida albicans spp. as the cause of candidemia. Several of these non-albicans spp. (e.g., C. glabrata and C. krusei ) exhibit resistance to traditional triazole antifungals like fluconazole, and cross-resistance with newer triazoles, focusing attention on the first-line use of antifungals such as the echinocandins, which possess improved activity against fluconazole-resistant strains. Recent treatment guidelines from the Infectious Diseases Society of America (IDSA) recommend an echinocandin as primary therapy for nonneutropenic or neutropenic patients with moderately severe to severe candidiasis and for patients at risk for infection with a triazole-resistant strain. However, further improvement in candidemia-associated mortality will only be attainable with the development and validation of new diagnostic tools that will allow earlier detection, discrimination, and treatment of invasive candidiasis. Clinicians should remain vigilant to wider emergence of Candida spp. with echinocandin resistance.

Antifungal susceptibility testing of Candida spp has been standardized and refined and now may play an important role in managing Candida infections. Important new developments include standardizing methods for testing echinocandins, fluconazole, and voriconazole and establishing interpretive breakpoints for these agents. Refinements in broth microdilution technology include the ability to read results after 24-hour incubation for several agents, addition of new azoles and echinocandins to commercially available microdilution trays, and automation of the entire testing process. Cross-resistance studies have identified important relationships among the triazole antifungals, and international collaboration offers the promise of harmonization and the development of an international standard for the testing of yeasts.

A 22-year-old woman with cystic fibrosis developed QTc interval prolongation following lung transplantation in the setting of voriconazole therapy. After the discontinuation of voriconazole and initiation of isavuconazole, her QTc interval normalized. This case highlights the unique property of QTc interval shortening by isavuconazole among the triazole antifungals.

Objective: To report the first case of disseminated Trichosporon spp infection in a newborn infant in Brazil, discussing a few aspects concerning management and treatment. A new spectrum of pathogens associated with severe infections in neonatal ICU has arisen, afflicting mainly newborn infants weighing less than 1,000 g at birth. Infection with Trichosporon asahii is rare and often fatal in this group of patients. Description: A case of Trichosporon spp fatal infection in a newborn weighing 815 g at birth is reported. Literature search in the main databases returned only nine articles, reporting 14 cases of infection with this fungus in preterm newborns. Conclusions: The rate of invasive fungal infection is around 6% in this group of patients, Trichosporon infection being a likely occurrence. Mortality rate in these cases is extremely high, but early treatment with triazole antifungals improves prognosis significantly. J Pediatr (Rio J). 2009;85(5):459-461: Newborn infant, premature infant, low birth weight, sepsis.

OBJETIVO: Apresentar o primeiro caso de infecção disseminada por Trichosporon spp em um recém-nascido no Brasil, discutindo alguns aspectos de manejo e tratamento. Um novo espectro de agentes infecciosos associado a infecções graves em UTI neonatais tem surgido. Ele atinge particularmente recém-nascidos com peso de nascimento abaixo de 1.000 g. A infecção por Trichosporon asahii é rara e quase sempre fatal nesse grupo. DESCRIÇÃO: É apresentado o caso de um recém-nascido de 815 g com infecção fatal por Trichosporon spp. Na literatura pesquisada nos principais bancos de dados, apenas nove artigos foram encontrados, com descrição de 14 casos de infecção por esse fungo em recém-nascidos prematuros. CONCLUSÕES: A taxa de infecção fúngica invasiva é de cerca de 6% no grupo de risco referido acima, sendo a causada por Trichosporon uma possibilidade. A taxa de mortalidade desses casos é muito alta, mas o tratamento precoce com triazólicos melhora muito o seu prognóstico. OBJECTIVE: To report the first case of disseminated Trichosporon spp infection in a newborn infant in Brazil, discussing a few aspects concerning management and treatment. A new spectrum of pathogens associated with severe infections in neonatal ICU has arisen, afflicting mainly newborn infants weighing less than 1,000 g at birth. Infection with Trichosporon asahii is rare and often fatal in this group of patients. DESCRIPTION: A case of Trichosporon spp fatal infection in a newborn weighing 815 g at birth is reported. Literature search in the main databases returned only nine articles, reporting 14 cases of infection with this fungus in preterm newborns. CONCLUSIONS: The rate of invasive fungal infection is around 6% in this group of patients, Trichosporon infection being a likely occurrence. Mortality rate in these cases is extremely high, but early treatment with triazole antifungals improves prognosis significantly.

Voriconazole (VRC) is a second-generation triazole licensed to treat patients with invasive aspergillosis, invasive candiadiasis caused by Candida species with reduced susceptibility to fluconazole, and serious infections caused by Scedosporium and Fusarium species [1, 2]. Recently, prophylaxis of invasive fungal infections (IFIs) in high risk allogeneic hematopoietic stem cell transplant recipients was added as a new indication for VRC [3]. According to the British Society for Medical Microbiology (BSMM), trough concentrations > 1 mg/L and < 4–6 mg/L are required to maximize efficacy and to minimize drugrelated toxicity [4]. In patients treated for IFIs with the recommended oral/intravenous VRC dosage regimen, large interand intra-individual variability has been found in VRC trough plasma concentrations, ranging from undetectable concentrations to 11 mg/L [5]. Oral bioavailability is a major determinant of variability of VRC plasma concentrations [6]. In healthy individuals, oral bioavailability is reported to be high, approximately 96%, when administered in a fasting state (1 h before/after meal) [2]. However, in patients, oral bioavailability might be much lower, as these patients are frequently suffering from gastro-intestinal complications [6, 7]. Other factors that contribute to the variability in VRC plasma concentrations are the Michaelis-Menten (non-linear) pharmacokinetics of VRC, polymorphisms of the gene encoding the CYP2C19 enzyme, drug-drug interactions, liver disease and age [4]. The large variability in VRC plasma concentrations together with the narrow therapeutic window for treating patients with IFIs, makes individualized dosing adjustments based on therapeutic drug monitoring (TDM) of VRC necessary to optimize therapeutic response and to minimize the probability of neurotoxicity [6]. According to the BSMM, VRC plasma concentrations should be measured in the first 5 days of therapy and regularly thereafter [4]. In Table 1, an overview is given of the analytical methods that are suitable for measuring VRC in plasma, including bioassays [8–11], HPLC [12–19] and LC-MSMS [20– 29] methods. Currently, chromatographic methods are predominantly used, as can also be derived from proficiency testing results [30]. These techniques are accurate, precise and allow the simultaneous analysis of multiple antifungal drugs. However, these methods also include some disadvantages, such as the limited availability of chromatographic instruments in the core clinical laboratory, the need for skilled laboratory technicians, the use of (sometimes) time consuming sample preparation steps and the need aCurrent address: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium *Corresponding author: Veronique Stove, Department of Laboratory Medicine, Ghent University Hospital, De Pintelaan 185 (2P8), 9000 Ghent, Belgium, Phone: +32 9 3325871, Fax: +32 3324985, E-mail: Veronique.Stove@UGent.be Lien Cattoir and Alain G. Verstraete: Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium; and Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium Gregoire Fauvarque: Department of Laboratory Medicine, Ghent University Hospital, Ghent, Belgium Simon Degandt and Timothy Ghys: Clinical Laboratory, General Hospital Sint-Lucas Ghent, Ghent, Belgium

Alkylthio and alkylsulfonyl derivatives of antifungal SM-8668 ( 3 ) were synthesized and estimated for their activities in vitro and in vivo . Derivatives having pentylthio, heptylthio or nonylthio group showed potent activities against both candidiasis and aspergillosis. The introduction of hydroxyl group at the end of their alkyl chain made their activities stronger.

10535Background: Antifungal prophylaxis is recommended for intermediate and high-risk patients with acute lymphoblastic leukemia (ALL) during periods of prolonged neutropenia such as induction ther...

We report on the first case of eumycetoma caused by the organism Leptosphaeria tompkinsii to be diagnosed and possibly acquired within the United Kingdom. Conventional culture of fungal grains and surgical tissue specimens was negative and the diagnosis was achieved using panfungal polymerase chain reaction and sequencing technology. Despite limited surgical resection and prolonged antifungal therapy with voriconazole, the patient developed progressive disease with mycetoma bone involvement. This case highlights the usefulness of molecular diagnostic techniques in eumycetoma where organisms may fail to grow with conventional culture or be difficult to identify morphologically. It also reminds us that eumycetoma is a difficult infection to treat and despite optimism regarding the efficacy of the newer triazole antifungals in this condition, treatment failures may still occur.

Optically active epoxide (2R,3S)-4, a key intermediate for the preparation of triazole antifungal agents (4R,5R)-1 and (2R,3R)-2 (X=2,4-F2), was synthesized. The Friedel-Crafts reaction between the (S)-lactic acid derivative (S)-10 and m-difluorobenzene gave the (R)-2-chloropropiophenone derivative (R)-11, which was converted into (2R,3R)-18 with sodium triazolide gave (2R,3S)-4. Similarly, the 4-chlorophenyl analog (2R,3S)-4′ was prepared.

A new series of thiazole-containing triazole antifungals was synthesized and evaluated for antifungal activity against a variety of clinically isolated pathogenic fungi in vitro and against systemic candidosis in vivo. Among these compounds, (+/-)-1-(2,4-difluorophenyl)-1-[4-(2,4-difluorophenyl) thiazol-2-yl]-2-(1H-1,2,4-triazol-1-yl)ethanol (ER24161) showed the most potent and well-balanced in vitro activities and excellent in vivo efficacy. We also achieved an enantioselective synthesis of the more potent enantiomer of ER-24161.

Killing activity of amphotericin B, fluconazole, voriconazole, posaconazole, and 5-fluorocytosine was determined against 6 Candida parapsilosis , 3 Candida orthopsilosis , and 4 Candida metapsilosis clinical isolates. After 24 h, 1 of 6 C. parapsilosis , 1 of 3 C. orthopsilosis , and 3 of 4 C. metapsilosis isolates were killed at 1 to 4 μg/mL (1–8× MIC) amphotericin B. The remaining isolates were killed by 2 to 4 μg/mL amphotericin B after 48 h. Fluconazole was fungistatic at ≥1× MIC (0.5–2 μg/mL) against C. parapsilosis and at ≥2× MIC (4–8 μg/mL) against C. orthopsilosis and C. metapsilosis isolates. Voriconazole inhibited C. parapsilosis at ≥1× MIC (0.015–0.12 μg/mL), but the other 2 species were inhibited only at 4 to 8× MIC (0.25–0.5 μg/mL). Against C. orthopsilosis and C. metapsilosis , posaconazole was fungistatic close to the MIC (0.03–0.06 and 0.015–0.03 μg/mL, respectively). Against C. orthopsilosis and C. metapsilosis , fluconazole and voriconazole, but not posaconazole, seem to be less active in vitro than against C. parapsilosis .

Polyene antifungals have been the cornerstone treatment for invasive aspergillosis for over 40 years. Whilst new treatment options have somewhat changed their role, lipid-associated amphotericin B regimens remain important therapeutic options for aspergillosis due to their broad-spectrum of activity and limited cross-resistance with triazole antifungals. Recent studies have demonstrated the importance of accurate speciation of Aspergillus species during amphotericin B therapy, as some non-fumigatus species, particularly A. terreus and A. flavus are relatively resistant to polyenes. Furthermore, insights into the pharmacokinetic/pharmacodynamic behaviour of the polyenes suggest a limited role for dosage escalation in the treatment of invasive pulmonary aspergillosis. The continued development of new formulation approaches and interest in aerosolised delivery strategies may open new opportunities for the use of polyenes in the prevention of fungal pneumonia caused by a wide range of moulds, including Aspergillus species.

The work describes a new enzyme-mediated approach to optically active epoxide (2 R ,3 S )- 6 , which is an important key intermediate in the preparation of single enantiomers of chiral azole antifungals. The conversion of (2 R ,3 S )- 6 into (−)-genaconazole is reported as an example of its synthetic relevance.

Triazole antifungals are commonly used in the treatment of candidiasis. Fluconazole (FCZ) is one of the most frequently prescribed therapy for vaginal fungal infections. Rarely, FCZ has been shown to cause fixed drug eruptions (FDE).

Optically active epoxide 1, an important intermediate for the preparation of antifungal triazole-amides 2, was synthesized starting from the (S)-lactic acid- derived ketone 9 and taking advantage of the Payne rearrangement of the epoxyalocohol 8.