Early versus delayed antiretroviral treatment in HIV-positive people with cryptococcal meningitis.

BACKGROUND: There remains uncertainty about the optimum timing of antiretroviral therapy (ART) initiation in HIV-positive people with cryptococcal meningitis. This uncertainty is the result of conflicting data on the mortality risk and occurrence of immune reconstitution inflammatory syndrome (IRIS) when ART is initiated less than four weeks after cryptococcal meningitis treatment is commenced. OBJECTIVES: To compare the outcomes of early initiation of ART (less than four weeks after starting antifungal treatment) versus delayed initiation of ART (four weeks or more after starting antifungal treatment) in HIV-positive people with concurrent cryptococcal meningitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase for trials published between 1 January 1980 and 7 August 2017. We additionally searched international trial registries, including ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP), and conference abstracts from the International AIDS Society (IAS) and the Conference on Retroviruses and Opportunistic Infections (CROI) for ongoing or unpublished studies between 2015 and 2017. We reviewed reference lists of included studies to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared early versus delayed ART initiation in HIV-positive people with cryptococcal meningitis. Children, adults, and adolescents from any setting were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria and extracted data. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs). We presented time-to-death data as hazard ratios with 95% CIs. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Four trials including 294 adult participants met the inclusion criteria of this review. Participants were predominantly from low- and middle-income countries. Two trials treated cryptococcal meningitis with amphotericin B and fluconazole; a third trial used fluconazole monotherapy; and the fourth trial did not specify the antifungal used.Early ART initiation may increase all-cause mortality compared to delayed ART initiation (RR 1.42, 95% CI 1.02 to 1.97; 294 participants, 4 trials; low-certainty evidence). Early ART initiation may reduce relapse of cryptococcal meningitis compared to delayed ART initiation (RR 0.27, 95% CI 0.07 to 1.04; 205 participants, 2 trials, low-certainty evidence). We are uncertain whether early ART initiation increases or reduces cryptococcal IRIS events compared to delayed ART initiation (RR 3.56, 95% CI 0.51 to 25.02; 205 participants, 2 trials; I2 = 54%; very low-certainty evidence). We are uncertain if early ART initiation increases or reduces virological suppression at six months compared to delayed ART initiation (RR 0.93, 95% CI 0.72 to 1.22; 205 participants, 2 trials; I2 statistic = 0%; very low-certainty evidence).We were unable to pool results related to rate of fungal clearance for the two trials that reported this outcome; individual trial results indicated that there was no difference in cerebrospinal fluid fungal clearance between trial arms. Similarly, we were unable to pool results on adverse events for the trials reporting on this outcome; individual trial results indicated no difference in the occurrence of grade 3 to 5 adverse events between trial arms.Three of the four included trials had an overall low or unclear risk of bias related to the primary outcome of all-cause mortality. However, we assessed one trial as at high risk of bias due to selective outcome reporting and other bias. This, in addition to the few clinical events and imprecision of effect estimates, led to downgrading of the evidence to low or very low certainty. AUTHORS' CONCLUSIONS: The results of this review are relevant to HIV-positive adults with cryptococcal meningitis in low- and middle-income countries. These data suggest a higher risk of mortality among people who initiate ART within four weeks of cryptococcal meningitis diagnosis. However, it is unclear if this higher mortality risk is related to cryptococcal meningitis-IRIS

The transcription factor Pdr802 regulates Titan cell formation and pathogenicity of Cryptococcus neoformans

The pathogenic yeast Cryptococcus neoformansC. neoforman

Antifungal properties in some Malaysian herbal plants

Cassia obtusifolia is a plant that belongs to bean family (Leguminosae). Old folks used to use this plant as a treatment for skin diseases such as ringworm. The common part that is used by the folks is the leaf. Thus, I only use C.obtusifo/ia leaves for my research study. Water extract and ethanol extract of C.obtusifolia leaves is performed in this study. The C.obtusifo/ia leaves were collected at Kampung Sungai Keladi, 2 kilometer from Kota Bharu. The leaves were then washed with tap water before it is rinsed with distilled water. The cleaned leaves were dried in an oven to remove the water contained in the leaves so that the pure component of the plant can be collected. The dried leaves were grinded and ready for extraction process by using sohlex apparatus. Distilled water is used as solvent to form water extract. The extraction process takes approximately 7 days. The residue of the leaves was dried in an oven with temperature of 42°C. After 3 days, when the residue dried, it was mixed with ethanol 95% to form ethanolic extract. Then it was filtered to separate the residue and the extract solution. This is done by using 2 layers of gauze which is placed on top of filter paper in a funnel. These two e~cts were concentrated by means of evaporation. This process is done by using evaporator apparatus. The concentrated water extract was put in universal bottles approximately 1/3 full and it was kept in a freezer before it was lyophilysed. As for ethanol extract, it was put in petri dishes and placed in an oven in order to remove the excess ethanol. Since 95% ethanol was used as solvent, the ethanol extract is naturally oily. The process takes several weeks (approximately 3 weeks). The water extract will be in powder form while ethanol extract will be in oily liquid form. Three concentration of both extract was prepared (1.00 mg/ml, 0.10 mg/ml and 0.01 mglml). Since the folks used to use this plant together with the lime ("kapur''), it is believed that the lime helps in enhancing the effect of the plant. Based on this practice, I tried to add the lime to the water extract and ethanol extract to see their reaction. This mixed-extract was also prepared in three concentrations as water and ethanol extract. The extracts were tested in vitro to fungi. Three types of pathogenic fungi were used for this research namely Cryptococcus neoformans, Candida albican and Candida tropicalis. The test is done by means of agar disc diffusion method. Sabauraud Dextrose Agar (SDA) was used as medium for fungus. Fungal inoculum suspension was prepared from 48 hours old cultures and sterile distilled water. The suspension was adjusted with saline to approximate a density of 1.0 McFarland turbidity standard. The sterile swab was moisten with adjusted inoculum suspension and the surface of the plates was streaked with the swab in two different directions (at 90 degree angles) to cover the entire surface. The tests were done by means of disc diffusion method with three incubation periods (3, 5 and 7 days) and three incubation temperature (28°C, 30°C and 3JOC). The result was red by measuring the zone of inhibition (clear zone) around the test disc. Amphoterism B was used as standard antifungal. TLC was performed at the end of this research

Antibacterial and Antifungal Activity of Ashwagandha (Withania somnifera L.): A review

Approaches for studying antimicrobial susceptibility and discovering new antimicrobial agents from the plants and other natural sources have been extensively utilized. Withania somnifera (L.) Dunal, commonly known as Ashwagandha or Indian ginseng or winter cherry, is a popular medicinal plant in Ayurvedic medicine. The principal active compounds include several withanolide-type compounds. Various plant parts, like roots and less often leaves and fruits of Ashwagandha, have been used as plant-derived medicines. The plant possesses various pharmacological activities including antimicrobial activity. Many bacterial and fungal species have been used as a test microorganism for the assessment of the antimicrobial activity of extracts and purified compounds of various plant parts of Ashwagandha. In this article, we tried to compile and to discuss the information about the antimicrobial activity of W. somnifera. This will provide the platform for the researchers to select plants, plant parts, solvent system, test microorganisms, method of evaluation and other related factors affecting the analysis

Sinergismo in vitro entre hidrazonas, ajoeno y posaconazol sobre aislados de Cryptococcus spp

El objetivo de este trabajo fue estudiar la susceptibilidad in vitro de aislados de Cryptocococus spp con una nueva clase de antifúngicos, hidrazonas esteroidales y comparar su actividad antifúngica en combinación con ajoeno y posaconazol contra aislados de Cryptococcus spp. Se utilizaron tres aislados del género Cryptococcus 42794, 4050 y 44192 y se evaluaron su sensibilidad y efectos sinérgicos con las hidrazonas esteroidales, ajoeno y posaconazol, según el documento M27-A2 del CLSI. Se incluyeron las cepas Candida albicans (ATCC 90028) y Candida parapsilosis (ATCC 22019) como controles. Se observó con las hidrazonas (H1, H2, H3, H4) un efecto plateau a partir de 10 μM (CMI). Sin embargo, con la H4 se obtuvo bajo porcentaje de inhibición del crecimiento. Con el ajoeno, se obtuvieron valores de CMI de 25 y 50 μM. El posaconazol mostró altos valores de inhibición y un valor de CMI de 6 μM para 42794 y 44192 y un CMI de 20 μM para el aislado 4050. Se obtuvieron efectos sinérgicos al combinar posaconazol con ajoeno, ajoeno con hidrazona 3 y posaconazol con hidrazona 3. Los valores de concentración inhibitoria fraccional fueron de 0,24; 0,16 y 0,09 respectivamente, indicando un marcado efecto sinérgico. Se obtuvieron efectos sinérgicos importantes entre el posaconazol con ajoeno, ajoeno con hidrazona 3 y posaconazol con hidrazona 3, lo cual sería muy útil para futuros estudios clínicos

A synthetic peptide as a novel anticryptococcal agent.

Summary An engineered, killer decapeptide (KP) has been synthesized based on the sequence of a recombinant, single-chain anti-idiotypic antibody (KT-scFv) acting as a functional internal image of a yeast killer toxin. Killer decapeptide exerted a strong fungicidal activity against Candida albicans, which was attributed to peptide interaction with β-glucan. As this polysaccharide is also a critical component of the cryptococcal cell wall, we wondered whether KP was also active against Cryptococcus neoformans, a human pathogen of increasing medical importance. We found that KP was able to kill both capsular and acapsular C. neoformans cells in vitro. Furthermore, KP impaired the production of specific C. neoformans virulence factors including protease and urease activity and capsule formation, rendering the fungus more susceptible to natural effector cells. In vivo treatment with KP significantly reduced fungal burden in mice with cryptococcosis and, importantly, protected the majority of immunosuppressed animals from an otherwise lethal infection. Given the relevance of cryptococcosis in immunocompromised individuals and the inability of conventional drugs to completely resolve the infection, the results of the present study indicate KP as an ideal candidate for further studies on novel anticryptococcal agents

Determining potential link between environmental and clinical isolates of Cryptococcus neoformans/Cryptococcus gattii species complexes using phenotypic and genotypic characterisation

Opportunistic infections due to Cryptococcus neoformans and C. gattii species complexes continue to rise unabated among HIV/AIDS patients, despite improved antifungal therapies. Here, we collected a total of 20 environmental and 25 presumptive clinical cryptococcal isolates from cerebrospinal fluid (CSF) samples of 175 patients enrolled in an ongoing clinical trial Ambition 1 Project (Botswana-Harvard Partnership). Identity confirmation of the isolates was done using MALDI-TOF MS and PCR. We describe the diversity of the isolates by PCR fingerprinting and sequencing (Oxford Nanopore Technology) of the intergenic spacer region. Mating types of the isolates were determined by amplification of the MAT locus. We report an unusual prevalence of 42.1% of C. neoformans x C. deneoformans hybrids Serotype AD (n = 16), followed by 39.5% of C. neoformans Serotype A (n = 15), 5.3% of C. deneoformans, Serotype D (n = 2), 7.9% of C. gattii (n = 3), and 5.3% of C. tetragattii (n = 2) in 38 representative isolates that have been characterized. Mating type-specific PCR performed on 38 representative environmental and clinical isolates revealed that 16 (42.1%) were MATa/MATα hybrids, 17 (44.7%) were MATα, and five (13.2%) possessed MATa mating type. We used conventional and NGS platforms to demonstrate a potential link between environmental and clinical isolates and lay a foundation to further describe mating patterns/history in Botswana.University of Botswana through Office of Research and Development (ORD).https://www.tandfonline.com/loi/tmyb20hj2024School of Health Systems and Public Health (SHSPH)SDG-03:Good heatlh and well-bein

PLoS One

ObjectivesAcute meningitis and encephalitis (AME) are common diseases with the main pathogens being viruses and bacteria. As specific treatments are different, it is important to develop clinical prediction rules to distinguish aseptic from bacterial or fungal infection. In this study we evaluated the incidence rates, seasonal variety and the main etiologic agents of AME, and identified factors that could be used to predict the etiologic agents.MethodsA population-based AME syndrome surveillance system was set up in Guigang City, Guangxi, involving 12 hospitals serving the study communities. All patients meeting the case definition were investigated. Blood and/or cerebrospinal fluid were tested for bacterial pathogens using culture or RT-PCR and serological tests for viruses using enzyme-linked immunosorbent assays. Laboratory testing variables were grouped using factor analysis. Multinomial logistic regression was used to predict the etiology of AME.ResultsFrom May 2007 to June 2012, the annual incidence rate of AME syndrome, and disease specifically caused by Japanese encephalitis (JE), other viruses, bacteria and fungi were 12.55, 0.58, 4.57, 0.45 and 0.14 per 100,000 population, respectively. The top three identified viral etiologic agents were enterovirus, mumps virus, and JE virus, and for bacteria/fungi were Streptococcus sp., Cryptococcus neoformans and Staphylococcus sp. The incidence of JE and other viruses affected younger populations and peaked from April to August. Alteration of consciousness and leukocytosis were more likely to be caused by JE, bacteria and fungi whereas CSF inflammation was associated with bacterial/fungal infection.ConclusionsWith limited predictive validity of symptoms and signs and routine laboratory tests, specific tests for JE virus, mumps virus and enteroviruses are required to evaluate the immunization impact and plan for further intervention. CSF bacterial culture cannot be omitted in guiding clinical decisions regarding patient treatment.26633824PMC466924