Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020).

OBJECTIVES: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France. METHODS: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality. RESULTS: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). Solid-organ transplant patients were most likely to have disseminated infections and a positive serum cryptococcal antigen result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265; p 0.029). The crude 90-day case-fatality ratio was 27.2% (95% CI, 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26]; p < 0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7]; p 0.002), and malignancy (aOR: 2.4 [1.14-5.07]; p 0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71]; p 0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80]; p 0.006). DISCUSSION: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management.

Improving health literacy of antifungal use-Comparison of the readability of antifungal medicines information from Australia, EU, UK, and US of 16 antifungal agents across 5 classes (allylamines, azoles, echinocandins, polyenes, and others).

Adherence to antifungals is poor in high endemic regions where antifungal resistance is high. Poor readability of prescription/over-the-counter (OTC) antifungals may contribute to poor adherence, due to the patient not fully understanding the purpose, importance, and dosage of their antifungal medicine. As there are no reports on the readability of antifungals, this study examined the readability of patient-facing antifungal information. Antifungals (n = 16; five classes [allylamines, azoles, echinocandins, polyenes, and others-flucytosine and griseofulvin]) were selected. Readability of four sources of information, (i) summary of product characteristics, (ii) patient information leaflets (PILs), (iii) OTC patient information, and (iv) patient web-based information, was calculated using Readable software, to obtain readability scores [(i) Flesch Reading Ease [FRE], (ii) Flesch-Kinkaid Grade Level [FKGL], (iii) Gunning Fog Index, and (iv) Simple Measure of Gobbledygook (SMOG) Index) and text metrics [word count, sentence count, words/sentence, and syllables/word]. PILs, web-based resources, and OTC patient information had good readability (FRE mean ± sd = 52.8 ± 6.7, 58.6 ± 6.9, and 57.3 ± 7.4, respectively), just falling short of the ≥ 60 target. For FKGL (target ≤ 8.0), PILs, web-based resources, and OTC patient information also had good readability (mean ± sd = 8.5 ± 1.0, 7.2 ± 0.86, and 7.8 ± 0.1, respectively). Improved readability scores observed correlate with reduced words, words/sentence and syllables/word. Improving readability may lead to improved patient health literacy. Healthcare professionals, academics, and publishers preparing written materials regarding antifungals for the lay/patient community are encouraged to employ readability calculators to check the readability of their work, so that the final material is within recommended readability reference parameters, to support the health literacy of their patients/readers.

Yeast and mould infections can be difficult-to-treat, due to resistance. Our study shows that patient information on antifungals is fairly easy-to-read. Such information helps the patient know how best to take the medicine and help avoid resistance. Authors should always try to write clearly for patients.

Ibrexafungerp for the Treatment of Vulvovaginal Candidiasis: Design, Development and Place in Therapy.

Vulvovaginal candidiasis (VVC) is experienced by an estimated 75% of women at least once in their lifetime and is recurrent, defined as three or more infections per year (RVVC) in 5-9%. Candida albicans is the most common causative agent, but up to 19% of infections may be related to non-albicans species. Available treatment options for VVC have consisted of oral and topical azoles (except for topical nystatin, a polyene). Oral polyenes are not absorbed and therefore not effective for VVC. Fluconazole is the only oral medication FDA approved for VVC. None of these treatments are FDA approved for RVVC. Ibrexafungerp, a triterpenoid fungicidal agent, was FDA approved in 2021, becoming the first oral non-azole agent for VVC. Ibrexafungerp reaches concentrations up to 9-fold higher in vaginal tissues versus plasma. In Phase 2 clinical trials, ibrexafungerp had a clinical cure rate comparable to fluconazole at day 10, but significantly better at day 25. In Phase 3 clinical trials, ibrexafungerp had both a higher clinical and mycologic cure rate versus placebo at both days 10 and 25. In December 2022, Ibrexafungerp received FDA approval for once monthly dosing to decrease the incidence of RVVC. This approval was based on data from the CANDLE STUDY, which showed 65.4% resolution of symptoms and culture negative success through week 24, compared to 53.1% of placebo. Ibrexafungerp provides an alternative oral option for treatment of acute, severe VVC. It is the only FDA approved antifungal for RVVC. Currently, the population likely to benefit from this drug are those with azole allergy, non-albicans or azole resistant albicans species, or other azole contraindications such as drug interactions (like statins or tricyclics). Side effects are mostly gastrointestinal and mild in nature. Ibrexafungerp, like fluconazole, should be used with caution in women who are or may become pregnant.

Comparison of mortality between echinocandins and polyenes for an initial treatment of candidemia: A systematic review and meta-analysis.

BACKGROUND: Current guidelines recommend echinocandins for the initial treatment of candidemia. However, polyenes are often chosen in clinical settings because of their fungicidal and anti-biofilm effects. Therefore, we performed a systematic review and meta-analysis to evaluate whether echinocandins are superior to polyenes in terms of mortality for the initial treatment of candidemia. METHODS: We systematically searched the Scopus, EMBASE, Cochrane Central Register of Controlled Trials, PubMed, and CINAHL databases until July 1, 2020. We compared the mortality rates of patients who received echinocandins and polyenes. As a subgroup analysis, we compared the mortality rates following the use of echinocandins versus liposomal amphotericin B. RESULTS: Fifteen studies involving 854 patients were included. Various Candida species were detected, and the rates of resistance of echinocandins and polyenes against the overall detected isolates were 1.0% and 0%, respectively. The overall mortality recorded in 15 studies was 41.0%, and the mortality was significantly higher for polyenes than echinocandins (odd ratios [OR] 1.68, 95% confidential interval [CI] 1.17-2.42). Furthermore, liposomal amphotericin B showed higher mortality in the initial treatment than echinocandins (OR 1.42; 95% CI 0.84-2.39). CONCLUSIONS: We revealed an association between echinocandin treatment and reduced mortality in the initial treatment of candidemia when causative fungi were not considered. Our findings partially support current guidelines recommending echinocandins for the treatment of candidemia.

Antifungals in Clinical Use and the Pipeline.

Over the past 15 years, there has been an increase in the development and utilization of newer antifungal agents. The ideal antifungal, however, in regard to spectrum of activity, pharmacokinetic/pharmacodynamic properties, development of resistance, safety, and drug interaction profile remains elusive. This article reviews pharmacologic aspects of Food and Drug Administration-approved polyenes, flucytosine, azoles, and echinocandins as well as promising pipeline antifungal agents. Unique properties of these newer agents are highlighted. The clinical role of established and investigational antifungal agents as treatment and/or prevention of invasive fungal infections is discussed.

Network meta-analysis of triazole, polyene, and echinocandin antifungal agents in invasive fungal infection prophylaxis in patients with hematological malignancies.

BACKGROUND AND AIM: Triazole, polyene, and echinocandin antifungal agents are extensively used to treat invasive fungal infections (IFIs); however, the optimal prophylaxis option is not clear. This study aimed to determine the optimal agent against IFIs for patients with hematological malignancies. METHODS: Randomized controlled trials (RCTs) comparing the effectiveness of triazole, polyene, and echinocandin antifungal agents with each other or placebo for IFIs in patients with hematological malignancies were searched. This Bayesian network meta-analysis was performed for all agents. RESULTS: The network meta-analyses showed that all triazoles, amphotericin B, and caspofungin, but not micafungin, reduced IFIs. Posaconazole was superior to fluconazole [odds ratio (OR), 0.30; 95% credible interval (CrI), 0.12-0.60], itraconazole (OR, 0.40; 95% CrI, 0.15-0.85), and amphotericin B (OR, 4.97; 95% CrI, 1.73-11.35). It also reduced all-cause mortality compared with fluconazole (OR, 0.35; 95% CrI, 0.08-0.96) and itraconazole (OR, 0.33; 95% CrI, 0.07-0.94), and reduced the risk of adverse events compared with fluconazole (OR, 0.02; 95% CrI, 0.00-0.03), itraconazole (OR, 0.01; 95% CrI, 0.00-0.02), posaconazole (OR, 0.02; 95% CrI, 0.00-0.03), voriconazole (OR, 0.005; 95% CrI, 0.00 to 0.01), amphotericin B (OR, 0.004; 95% CrI, 0.00-0.01), and caspofungin (OR, 0.05; 95% CrI, 0.00-0.42) despite no significant difference in the need for empirical treatment and the proportion of successful treatment. CONCLUSIONS: Posaconazole might be an optimal prophylaxis agent because it reduced IFIs, all-cause mortality, and adverse events, despite no difference in the need for empirical treatment and the proportion of successful treatment.

1,3-Cyclohexadien-1-Als: Synthesis, Reactivity and Bioactivities.

In synthetic organic chemistry, there are very useful basic compounds known as building blocks. One of the main reactions wherein they are applied for the synthesis of complex molecules is the Diels-Alder cycloaddition. This reaction is between a diene and a dienophile. Among the most important dienes are the cyclic dienes, as they facilitate the reaction. This review considers the synthesis and reactivity of one of these dienes with special characteristics-it is cyclic and has an electron withdrawing group. This building block has been used for the synthesis of biologically active compounds and is present in natural compounds with interesting properties.

Guideline: Vulvovaginal candidosis (AWMF 015/072, level S2k).

Approximately 70-75% of women will have vulvovaginal candidosis (VVC) at least once in their lifetime. In premenopausal, pregnant, asymptomatic and healthy women and women with acute VVC, Candida albicans is the predominant species. The diagnosis of VVC should be based on clinical symptoms and microscopic detection of pseudohyphae. Symptoms alone do not allow reliable differentiation of the causes of vaginitis. In recurrent or complicated cases, diagnostics should involve fungal culture with species identification. Serological determination of antibody titres has no role in VVC. Before the induction of therapy, VVC should always be medically confirmed. Acute VVC can be treated with local imidazoles, polyenes or ciclopirox olamine, using vaginal tablets, ovules or creams. Triazoles can also be prescribed orally, together with antifungal creams, for the treatment of the vulva. Commonly available antimycotics are generally well tolerated, and the different regimens show similarly good results. Antiseptics are potentially effective but act against the physiological vaginal flora. Neither a woman with asymptomatic colonisation nor an asymptomatic sexual partner should be treated. Women with chronic recurrent Candida albicans vulvovaginitis should undergo dose-reducing maintenance therapy with oral triazoles. Unnecessary antimycotic therapies should always be avoided, and non-albicans vaginitis should be treated with alternative antifungal agents. In the last 6 weeks of pregnancy, women should receive antifungal treatment to reduce the risk of vertical transmission, oral thrush and diaper dermatitis of the newborn. Local treatment is preferred during pregnancy.

New Polyenes from the Marine-Derived Fungus Talaromyces cyanescens with Anti-Neuroinflammatory and Cytotoxic Activities.

Three new polyene compounds, talacyanols A-C (1-3), along with two known compounds, ramulosin (4) and eurothiocin A (5), were isolated from the marine fungus Talaromyces cyanescens derived from a seaweed Caulerpa sp. Structures of 1-5 were established by one-dimensional and two-dimensional (1D/2D) NMR, HR-ESIMS, and the modified Mosher's methods, as well as comparison with previously reported literature data. All the compounds (1-5) were tested for their in vitro cytotoxic and anti-neuroinflammatory activities. Among them, 1 showed moderate cytotoxic activity against a panel of cancer cell lines (HCT-15, NUGC-3, NCI-H23, ACHN, PC-3, and MDA-MB-231) with GI50 values ranging from 44.4 to 91.6 µM, whereas compounds 2 and 5 exhibited anti-neuroinflammatory effect without cytotoxicity against all the tested cell lines.

Eficacia y seguridad del uso de amfotericina B liposomal en el tratamiento de pacientes adultos con diagnóstico de histoplasmosis diseminada con evento adverso serio a amfotericina B deoxicolato / Efficacy and safety of the use of liposomal amphotericin B in the treatment of adult patients diagnosed with disseminated histoplasmosis with a serious adverse event A amphotericin B deoxycholate

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología sanitaria de eficacia y seguridad de amfotericina B liposomal (L-AMB) en comparación con amfotericina B deoxicolato (D-AMB) e itraconazol, para el tratamiento de pacientes adultos con diagnóstico de histoplasmosis diseminada con evento adverso serio a D-AMB. La histoplasmosis es una enfermedad fúngica endémica en determinadas regiones de América del Norte y Sur. Uno de los países comprometidos con histoplasmosis endémica es Estados Unidos, donde existe una incidencia acumulada entre 3.4 a 6.1 casos por 100,000 habitantes. Aunque el Perú tiene zonas endémicas de histoplasmosis, no se tiene certeza de la prevalencia de la enfermedad (solo reportes nacionales tipos series de caso). Tampoco se tiene una aproximación de casos atendidos por EsSalud. El grado de respuesta inmune del paciente es muy importante para el desarrollo de la histoplasmosis. Los pacientes inmunosuprimidos son propensos a desarrollar la infección diseminada. Es necesario contextualizar la histoplasmosis diseminada (HD) dentro de las características de la propia enfermedad. La HD pertenece al grupo de las micosis profundas, es una enfermedad de baja prevalencia, catalogada como olvidada por la Organización Mundial de la Salud (OMS), de difícil diagnóstico y manejo, donde la enfermedad puede comprometer en gran medida el estado general de los pacientes. Afecta a pacientes con inmunosupresión como infección por el virus de la inmunodeficiencia humana (VIH), tratamiento anti-neoplásico, trasplantados, entre otros. La HD puede clasificarse en: leve, moderada o severa; dependiendo del compromiso clínico del paciente. El manejo del paciente con HD posee dos etapas. Primero es el manejo de la fase de inducción donde se recomienda utilizar amfotericina B (deoxicolato o liposomal) durante 1 a 2 semanas. Segundo es el manejo de la fase de consolidación donde se recomienda utilizar itraconazol durante 12 meses (itraconazol se encuentra dentro del Petitorio Farmacológico de EsSalud). No se tienen evaluaciones de tecnologías sanitarias (ETS) previas del IETSI que evalúen medicamentos para manejo de pacientes con HD. En el contexto de EsSalud, durante la fase de inducción del tratamiento de HD se utiliza la amfotericina B deoxicolato (D-AMB). Sin embargo, D-AMB posee eventos adversos (EA) como: nefrotoxicidad, anemia, alteraciones metabólicas como hipokalemia, entre otras. De presentarse algún EA, como: nefrotoxicidad, elevación de su nivel de creatinina sérica o trastornos hidroelectrolíticos como hipokalemia, se retira el fármaco y se estabiliza al paciente. Posteriormente, dependiendo de la evolución del mismo, se decide la re-inserción de la D-AMB; dado que es la única opción de tratamiento para los pacientes con HD. Ante esta situación, los especialistas sugieren la necesidad de una ETS que evalúe el uso de amfotericina B liposomal (L-AMB) en la fase de inducción del tratamiento de pacientes adultos con diagnóstico de HD y EA serios a D-AMB. Considerando la opinión de los especialistas y/o las recomendaciones de guías de práctica clínica (GPC) es que se consideraron como comparadores adecuados a D-AMB e itraconazol. METODOLOGÍA: Para la elaboración del presente dictamen, se realizó una búsqueda bibliográfica sistemática y jerárquica de la literatura con respecto a la eficacia y seguridad de L-AMB, comparado con D-AMB e itraconazol, en pacientes adultos con diagnóstico de HD y evento adverso serio a D-AMB. Se inició la búsqueda mediante la revisión de la información del producto farmacéutico en la FDA, EMA y DIGEMID en el Perú. Se llevó a cabo una búsqueda sistemática en las principales bases de datos bibliográficas, tales como PubMed, Cochrane Library, LILACS. Asimismo, se realizó una búsqueda manual en las páginas web de los grupos dedicados a la investigación y educación en salud que elaboran guías de práctica clínica: National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Haute Authorité de Santé (HAS), Institute for Clinical and Economic Review (ICER), Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWIG), Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde (CONECIT) y el Ministerio de Salud del Perú (MINSA). Así como en el repositorio de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Además, se realizó una búsqueda de las guías de las principales sociedades o instituciones especializadas en infectología; tales como: la Infectious Diseases Society of America (IDSA); las Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV que son recomendaciones del Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH) y de la American Thoracic Society (ATS). Por último, se revisó la página web www.clinicaltrials.gov en busca de ensayos clínicos en desarrollo o cuyos resultados aún no hayan sido publicados y que ayuden a responder a la pregunta PICO del presente dictamen, con el objetivo de disminuir el sesgo de publicación. RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de L-AMB comparado con D-AMB o itraconazol, en el tratamiento de pacientes adultos con diagnóstico de HD y evento adverso a D-AMB. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y EC). CONCLUSIONES: En la presente evaluación de tecnología sanitaria se evaluó la evidencia disponible con relación a la eficacia y seguridad de L-AMB, comparada con D-AMB e itraconazol, para el tratamiento (fase de inducción) de pacientes adultos con diagnóstico de HD, con EA serio a D-AMB. Se identificaron tres GPC realizadas por la IDSA en 2007, la ATS en 2011 y CDC/NIH/IDSA en 2019 que brindaron recomendaciones sobre el tratamiento de pacientes con HD; y un ECA de fase III de (Johnson et al. 2012) que compara el uso de L-AMB y D-AMB en pacientes con HD e infección por VIH. No se encontraron estudios que comparen L-AMB versus itraconazol, como manejo de los pacientes con HD. Respecto a las GPC, las tres recomendaron el uso de L-AMB (dosis entre 3 mg/kg/día y 5 mg/kg/día) para el manejo de pacientes con HD moderada a severa, en fase de inducción durante un periodo de 1 a 2 semanas. La GPC de la IDSA menciona que D-AMB debe reservarse para los pacientes con bajo riesgo de nefrotoxicidad y la GPC de la ATS contempla el uso de L-AMB en pacientes adultos con HD que desarrollaron nefrotoxicidad a D-AMB (tengan o no VIH). Las tres GPC también recomiendan el uso de itraconazol para pacientes con HD leve, a dosis de 200 mg 3 veces al día, durante 3 días; así como el monitoreo de las concentraciones séricas de itraconazol. Respecto al ECA de fase III de Johnson et al., los resultados reportados sugieren que L-AMB produciría mejor respuesta clínica, menos eventos adversos y menor mortalidad que D-AMB; sin embargo, las limitaciones del ECA afectan tanto la validez interna como la validez externa al momento de extrapolarse a la población de interés del presente dictamen. La evidencia disponible hasta la fecha es escasa y no permite afirmar con certeza que L-AMB es más eficaz y seguro que D-AMB o itraconazol en pacientes adultos con HD y EA serios a D-AMB. Sin embargo, la evidencia indirecta sobre la incidencia de nefrotoxicidad sugiere que L-AMB sería más segura que D-AMB en este desenlace. Si, además, se tiene en cuenta que la población de interés del presente dictamen ya ha presentado EA serios ante el uso de D-AMB, L-AMB podría considerarse como una alternativa de tratamiento para esta población. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI, aprueba el uso de L-AMB como tratamiento para la fase de inducción en pacientes adultos con HD moderada-severa y con EA serio después de usar D-AMB, según lo establecido en el Anexo N° 1. Para el manejo de pacientes con HD leve, las GPC revisadas en el presente dictamen indican el uso de itraconazol, el cual es un medicamento que se encuentra dentro del Petitorio Farmacológico de EsSalud. La vigencia del presente dictamen preliminar es de un año a partir de la publicación. La continuación de dicha aprobación está sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Antifungal drugs: An updated review of central nervous system pharmacokinetics.

Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.

N-alkylated linear heptamethine polyenes as potent non-azole leads against Candida albicans fungal infections.

In this study, eighteen heptamethine dyes were synthesised and their antifungal activities were evaluated against three clinically relevant yeast species.. The eighteen dyes were placed within classes based on their core subunit i.e. 2,3,3-trimethylindolenine (5a-f), 1,1,2-trimethyl-1H-benzo[e]indole (6a-f), or 2-methylbenzothiazole (7a-f). The results presented herein imply that the three families of cyanine dyes, in particular compounds 5a-f, show high potential as selective scaffolds to treat C. albicans infections. This opens up the opportunity for further optimisation and investigation of this class compounds for potential antifungal treatment.

Choosing the Right Antifungal Agent in ICU Patients.

Fungi are responsible for around 20% of microbiologically documented infections in intensive care units (ICU). In the last decade, the incidence of invasive fungal infections (IFI), including candidemia, has increased steadily because of increased numbers of both immunocompromised and ICU patients. To improve the outcomes of patients with IFI, intensivists need to be aware of the inherent challenges. This narrative review summarizes the features of routinely used treatments directed against IFI in non-neutropenic ICU patients, which include three classes of antifungals: polyenes, azoles, and echinocandins. ICU patients' pathophysiological changes are responsible for deep changes in the pharmacokinetics of antifungals. Moreover, drug interactions affect the response to antifungal treatments. Consequently, appropriate antifungal dosage is a challenge under these special conditions. Dosages should be based on renal and liver function, and serum concentrations should be monitored. This review summarizes recent guidelines, focusing on bedside management.

Candida auris: A pathogen difficult to identify, treat, and eradicate and its characteristics in Japanese strains.

Candida auris is a multidrug-resistant and emergent pathogen that has caused healthcare-associated infection outbreaks. Recently, C. auris has spread worldwide; nevertheless, it was unexpectedly rare before 2009. Based on the molecular epidemiological analysis, C. auris may independently emerge at specific areas at first and recently may be transmitted to other continents. As C. auris cannot be detected using conventional methods, internally transcribed spacers, D1/D2 regions of the 26S rDNA sequencing, and/or matrix-assisted laser desorption ionization time-of-flight mass spectrometry method can be selected as comparatively accessible choices. Thus, detection of C. auris using the conventional method might be underestimated. In Japan, all C. auris strains were isolated from ear specimen and not from invasive mycoses. Japan strains were classified as an East Asian clade under a single clone. Although colonization, virulence, and infection pattern are almost the same as with other Candida species, its antifungal resistance is different. Fluconazole resistance is notably common, but resistance to all three classes of antifungals (azole, polyene, and echinocandin) rarely exists. Once C. auris is detected, screening, emphasis on hand hygiene adherence, use of single-patient room isolation, contact precaution, surveillance, and eradication from the environment and patients are appropriately required for infection control.

Antifungal resistance in Aspergillus terreus: A current scenario.

Invasive aspergillosis caused by intrinsically resistant non-fumigatus Aspergillus species displays a poor outcome in immunocompromised patients. The polyene antifungal amphotericin B (AmB) remains to be "gold standard" in the treatment of invasive fungal infections. Aspergillus terreus is innately resistant to AmB, in vivo and in vitro. Till now, the exact mode of action in polyene resistance is not well understood. This review highlights the underlying molecular basis of AmB resistance in A. terreus, displaying data obtained from AmB susceptible A. terreus and AmB resistant A. terreus strains. The effect of AmB on main cellular and molecular functions such as fungal respiration and stress response pathways will be discussed in detail and resistance mechanisms will be highlighted. The fungal stress response machinery seems to be a major player in the onset of AmB resistance in A. terreus.

Trends in antifungal use in US hospitals, 2006-12.

Background: Although trends in antibiotic use have been characterized, less is known about antifungal use. Data on antifungal use are important for understanding practice patterns, assessing emergence of antifungal resistance and developing antifungal stewardship programmes. We estimated national trends in inpatient antifungal use in the USA. Methods: Using billing data for antifungals from the Truven Health MarketScan® Hospital Drug Database during 2006-12, we estimated the proportion of discharges at which antifungals were given and days of therapy (DOT)/1000 patient days (PDs) by antifungal drug type, year, patient and facility characteristics. We created national estimates using weights generated from Centers for Medicare and Medicaid Services data and assessed trends over time. Results: Overall, 2.7% of all inpatients and 7.7% of those in ICUs received antifungals. The estimated DOT/1000 PDs for any antifungal was 35.0 for all inpatients and 73.7 for ICU patients. Azoles accounted for 80% of all antifungal use (28.5/1000 PDs), followed by echinocandins (5.0/1000 PDs). By multivariable trend analysis, DOT/1000 PDs for azoles (-21%) and polyenes (-47%) decreased between 2006 and 2012, whereas echinocandins increased 11% during 2006-10 and declined after 2011. Unspecified septicaemia, HIV and antineoplastic therapy were among the top primary diagnosis codes for patients who received antifungals. Conclusions: Antifungals were most frequently used in ICU settings and fluconazole accounted for a large, but declining, proportion of antifungal use. Antifungal stewardship efforts may have the most impact if focused in ICUs, among certain patient groups (e.g. HIV and malignancy) and on stopping empirical antifungal therapy for unspecified sepsis when not indicated.

A synthetic polymeric biolubricant imparts chondroprotection in a rat meniscal tear model.

Intra-articular injection of hyaluronic acid (HA) is used to treat osteoarthritis (OA) as a viscosupplement, yet it only provides short-term benefit because HA is cleaved by hyaluronidase and cleared out of the joint after several days. Therefore, we developed a new polymer biolubricant based on poly-oxanorbornane carboxylate to enhance joint lubrication for a prolonged time. Rheological and biotribological studies of the biolubricant reveal viscoelastic properties and coefficient of friction equivalent and superior to that of healthy synovial fluid, respectively. Furthermore, in an ex vivo bovine cartilage plug model, the biolubricant exhibits superior long-term reduction of friction and wear prevention compared to saline and healthy synovial fluid. ISO 10993 biocompatibility tests demonstrate that the biolubricant polymer is non-toxic. In an in vivo rat medial meniscal tear OA model, where the performance of the leading HA viscosupplement (Synvisc-one®) is comparable to the saline control, treatment with the biolubricant affords significant chondroprotection compared to the saline control.

Drugs in Clinical Development for Fungal Infections.

Despite increasing rates of invasive fungal infections being reported globally, only a single antifungal drug has been approved during the last decade. Resistance, toxicity, drug interactions and restricted routes of administration remain unresolved issues. This review focuses on new antifungal compounds which are currently in various clinical phases of development. We discuss two azoles with a tetrazole moiety that allows selective activity against the fungal CYP: VT-1161 for Candida infections and VT-1129 for cryptococcal meningoencephalitis. We also discuss two glucan synthesis inhibitors: CD101, an echinocandin with an increased half-life, and SCY-078 with oral bioavailability and increased activity against echinocandin-resistant isolates. Among the polyenes, we discuss MAT023, an encochleated amphotericin B formulation that allows oral administration. Two novel classes of antifungal drugs are also described: glycosylphosphatidylinositol inhibitors, and the leading drug APX001, which disrupt the integrity of the fungal wall; and the orotomides, inhibitors of pyrimidine synthesis with the leading drug F901318. Finally, a chitin synthesis inhibitor and progress on human monoclonal antifungal antibodies are discussed.

Elfamycins: inhibitors of elongation factor-Tu.

Elfamycins are a relatively understudied group of antibiotics that target the essential process of translation through impairment of EF-Tu function. For the most part, the utility of these compounds has been as laboratory tools for the study of EF-Tu and the ribosome, as their poor pharmacokinetic profile and solubility has prevented implementation as therapeutic agents. However, due to the slowing of the antibiotic pipeline and the rapid emergence of resistance to approved antibiotics, this group is being reconsidered. Some researchers are using screens for novel naturally produced variants, while others are making directed, systematic chemical improvements on publically disclosed compounds. As an example of the latter approach, a GE2270 A derivative, LFF571, has completed phase 2 clinical trials, thus demonstrating the potential for elfamycins to become more prominent antibiotics in the future.