Systematic review and meta-analysis on synthetic antifungal versus keratolytic agents for topical treatment of Pityriasis Versicolor

Background@#Pityriasis versicolor is a common fungal infection of the superficial skin layer caused by Malassezia furfur, a normal commensal in the skin. Keratolytic agents are popular, cheap, and readily available over-the-counter treatments for pityriasis versicolor. Conventional antifungal agents are more expensive, requiring prescription, and may induce resistant strains. However, evidence of their comparative safety and efficacy is still lacking. @*Objectives@#To assess the efficacy and safety of synthetic antifungals compared to keratolytic agents in the topical treatment of pityriasis versicolor through a systematic review.@*Methods@#We searched the following databases: MEDLINE (from 1966) through PubMed, CENTRAL (Issue 9 of 12, September 2021), EMBASE (from 1974), LILACS (from 1987); Herdin (from 1970), www.clinicaltrials.gov, www. isrctn.com, www.trialregister.nl. We contacted researchers in the field, hand searched relevant conference abstracts, and the Journal of the Philippine Dermatological Society 1992-2019. We included all randomized controlled trials involving patients with diagnosed active pityriasis versicolor where topical antifungal was compared with a topical keratolytic for treatment. Two review authors independently applied eligibility criteria, assessed risk of bias using the Cochrane collaboration tool, and extracted data from included studies. We used RevMan 5.3 to pool dichotomous outcomes using risk ratios (RR) and continuous outcomes using the mean difference (MD), using random-effects meta-analysis. We tested for statistical heterogeneity using both the Chi² test and the I² test. We presented results using forest plots with 95% confidence intervals. We planned to create a funnel plot to determine publication bias but were unable to due to few studies. A Summary of Findings table was created using GRADE profile software for the primary outcomes. @*Results@#We included 8 RCTs with a total of 617 participants that compared azole preparations (ketoconazole, bifonazole and econazole) versus keratolytic agents (selenium sulfide, adapalene, salicylic-benzoic acid). Pooled data showed that azoles did not significantly differ from keratolytic agents for clinical cure (RR 0.99, 0.88, 1.12; 4 RCTs, N=274, I2=55%; very low-quality evidence), and adverse events (0.59 [0.17, 2.06]; very low-quality evidence) based on 6 RCTs (N=536). There were two patients given a keratolytic agent (selenium sulfide shampoo) who had acute dermatitis and discontinued treatment. @*Conclusion@#It is uncertain whether topical azoles are as effective as keratolytic agents in clinical clearance and occurrence of adverse events in patients with pityriasis versicolor. A wider search of grey literature and local studies are warranted. Larger RCTs with low risk of bias are recommended.

Perfiles de expresión de los genes ERG11, MDR1 y AFR1 en Cryptococcus neoformans var. grubii aislados de pacientes con HIV / Gene expression profiles of ERG11, MDR1 y AFR1 in Cryptococcus neoformans var. grubbi isolated from HIV patients

Introducción. El fluconazol es el antifúngico más utilizado para la prevención y el tratamiento de infecciones causadas por el género Cryptococcus, agente etiológico de la criptococosis. La resistencia al fluconazol en los aislamientos de Cryptoccocus neoformans puede hacer fracasar el tratamiento y generar recaídas de la infección. Objetivo. Evaluar los perfiles de expresión de los genes AFR1, MDR1 y ERG11 en aislamientos clínicos de C. neoformans var. grubii, durante la respuesta in vitro a la inducción con fluconazol. Materiales y métodos. Se estudiaron 14 aislamientos de C. neoformans var. grubii provenientes de pacientes con HIV, de los cuales 6 eran sensibles al fluconaol y 8 presentaban sensibilidad disminuida. Los niveles de expresión de los genes ERG11, AFR1 y MDR1 se determinaron mediante PCR en tiempo real. Resultados. Los aislamientos resistentes al fluconazol mostraron sobreexpresión de los genes AFR1 y MDR1, mientras que la expresión de los fenotipos de resistencia evaluados se mantuvo homogénea en ERG11, en todos los aislamientos de C. neoformans var. grubii. Conclusiones. La sobreexpresión de los genes AFR1 y MDR1 que codifican las bombas de eflujo, contribuye a la resistencia al fluconazol en los aislamientos estudiados. Sin embargo, los patrones de resistencia que se registran en este hongo, sumado a los casos de recaídas en pacientes con HIV, no pueden atribuirse únicamente a los casos de resistencia por exposición al fármaco. Otros mecanismos podrían también estar involucrados en este fenómeno, como la resistencia emergente (resistencia mediante otros genes ERG) y la heterorresistencia, los cuales deben ser estudiados en estos aislamientos.

Introduction: Fluconazole is the most used antifungal drug for prevention and treatment of Cryptococcus spp. infections, the etiological agent of cryptococcosis. Resistance to fluconazole among Cryptococcus neoformans isolates can lead to treatment failure and generate relapses. Objective: To evaluate the expression profles of the AFR1, MDR1 and ERG11 genes in C. neoformans var. grubii clinical isolates during the in vitro response to fluconazole induction. Materials and methods: Fourteen C. neoformans var. grubii isolates recovered from HIV patients were studied, in which 6 showed sensitivities to fluconazole and 8 decreased sensitivity. The expression levels of ERG11, AFR1 and MDR1 genes were determined by real-time PCR from extracted mRNA. Results: AFR1 and MDR1 genes from C. neoformans var. grubii were overexpressed in fluconazole resistant isolates, whereas ERG11 maintains homogeneous expression in all the evaluated resistance phenotypes of C. neoformans var. grubii isolates. Conclusions: The overexpression of AFR1 and MDR1 genes, which codify for efflux pumps, contributes to fluconazole resistance in the studied isolates. However, the resistance patterns in this fungus and the relapse cases in HIV patients cannot be attributed solely to the exposure to the drug. Heteroresistance and the emerging resistance (resistance through other ERG genes), might be other mechanisms involved in this phenomenon, which must be studied in these isolations.

Synthesis of New Thiazole Derivatives Bearing Thiazolidin-4(5H)-One Structure and Evaluation of Their Antimicrobial Activity

The first report about antimicrobial resistance was published in the 1940s. And today, the antimicrobial resistance has become a worldwide problem. Because of this problem, there is a need to develop new drugs. That's why we synthesized some novel thiazolidine-4-one derivatives and evaluated their antimicrobial activity. The final compounds were obtained by reacting 2-[(4,5-diphenylthiazol-2-yl)imino]thiazolidin-4-one with some aryl aldehydes. The synthesized compounds were investigated for their antimicrobial activity against four Candida species, five gram-negative and four gram-positive bacterial species. The lead compounds (4a- h) were obtained with a yield of at least 70%. All compounds showed antimicrobial activity. Compound 4f (MIC: 31.25 µg/ml) exhibited more efficacy than the other compounds against C. glabrata (ATCC 24433). Compound 4b (MIC: 62.5 µg/ml) was the most active compound against all bacterial species, particularly K. pneumoniae (NCTC 9633). Whereas, compound 4c (MIC: <31.25 µg/ml) was observed as the most active compound against E. coli (ATCC 25922). In general, all compounds (4a-4h) showed antimicrobial activity against all fungi and bacterial species. Compounds 4b (2,6-dichlorobenzylidene), 4c (2,6-dihydroxybenzylidene), 4f (1H-pyrrol-2- yl)methylene), 4g (4-triflouromethylbenzylidene) and 4h (2,3,4-trimethoxybenzylidene) were determined as the most active compounds

Épidémiologie des candidoses systémiques dans les services à haut risque au CHU et au centre anti cancer de Batna ­Algérie / Epidemiology of systemic candidiasis in high-risk departments at the university hospital and cancer center of Batna -Algeria

Introduction : Les candidoses systémiques sont des affections graves responsables d'une mortalité élevée. L'objectif de ce travail est de décrire l'épidémiologie des candidoses systémiques dans les services à haut risque au CHU et au CAC de BATNA. Patients et méthodes : Il s'agit d'une étude prospective descriptive durant une période de trois ans (1er janvier 2016 au 31 décembre 2018). Les patients inclus sont ceux ayant au moins un prélèvement profond positif á Candida spp. Résultats : Un total de 69 cas de candidoses systémiques correspondant à 75 isolats et concernant 63 patients a pu être analysé. L'incidence globale était de 2,62 cas pour 1000 admissions. Les principaux motifs d'hospitalisation étaient les hémopathies malignes et le choc septique. La présence d'une colonisation ( 2 sites), une antibiothérapie á large spectre, d'un cathéter intra vasculaire, une corticothérapie, une chimiothérapie, une neutropénie étaient les facteurs de risque les plus retrouvés. L'analyse des souches isolées a montré la prédominance des espèces non albicans. L'index de colonisation ≥ 0,5 a été significativement associé au risque de candidose systémique. L'utilisation des Azolés a été associée á un taux de mortalité le plus élevé (19%). Le taux de mortalité est significativement élevé 51%. Conclusion : Les facteurs de risque et un index de colonisation ≥ 0,5 dans les services á haut risque constituent un facteur prédictif de candidose systémique. La prise en charge thérapeutique doit être instaurée pour réduire le taux de mortalité et éviter les complications liées á ces infections.

Background: Systemic candidiasis are serious conditions responsible for high mortality. The objective of this work is to describe the epidemiology of systemic candidiasis in high-risk departments at the UHC and the ACC of BATNA. Patients and methods: This is a descriptive prospective study over a period of three years (January 1, 2016 to December 31, 2018). The patients included are those with at least one positive deep sample for Candida spp. Results: 69 cases of systemic candidiasis corresponding to 75 isolates and concerning 63 patients could be analyzed. The overall incidence was 2.62 cases per 1,000 admissions. The main reasons for hospitalization were hematologic malignancies and septic shock. The presence of colonization ( 2 sites), broad-spectrum antibiotic therapy, an intravascular catheter, corticosteroid therapy, chemotherapy, neutropenia were the most common risk factors. Analysis of the isolated strains showed the predominance of nonalbicans species. Colonization index ≥ 0.5 was significantly associated with the risk of systemic candidiasis. Azole's use was associated with the highest mortality rate (19%). The mortality rate is significantly high 51%. Conclusion. Risk factors and a colonization index ≥ 0.5 in high-risk wards are a predictor of systemic candidiasis. Therapeutic care must be instituted to reduce the mortality rate and avoid complications linked to these infections

Azoles de antes y ahora: una revisión / Azoles of then and now: a review

Resumen Los azoles son fármacos que inhiben la enzima 14α-esteroldemetilasa, impidiendo la unión de ergosterol; esto altera la estructura y función de la pared celular fúngica. Especialmente el grupo de los triazoles: fluconazol, itraconazol, voriconazol, posaconazol e isavuconazol, son una alternativa farmacológica para el tratamiento de la enfermedad fúngica invasora causada por Aspergillus spp, Candida spp, Cryptococcus spp, patógenos emergentes como los Mucorales, y de micosis endémicas como las ocasionadas por Histoplasma spp y Coccidioides spp. Los efectos adversos de los triazoles son menos frecuentes comparados con los ocasionados por anfotericina B, un antifúngico de uso común para estas micosis. Los principales efectos adversos de los triazoles son hepáticos, gastrointestinales y cardiovasculares como la prolongación del intervalo QT. Las interacciones farmacológicas son usuales y se presentan con moléculas que usan sustratos del citocromo CYP3A4, lo que incluye anti-retrovirales, anti-tuberculosos e inmunomoduladores. En este trabajo se revisan la historia, características farmacológicas y los ensayos clínicos que evidencian su eficacia clínica en los diferentes escenarios clínicos.

Abstract The azoles are drugs that inhibit the 14α-sterol-demethylase enzyme preventing the binding of ergosterol, altering the functionality and structure of the fungal cell wall. Especially the group of triazoles: fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole, are a pharmacological alternative for the treatment of the invasive fungal disease, caused by Aspergillus spp, Candida spp, Cryptococcus spp, by emerging pathogens for example, the Mucoral and finally of endemic mycosis as those caused by Histoplasma spp. and Coccidioides spp. The adverse effects of the triazoles are less frequent compared to those caused by amphotericin B, the main ones being hepatics, gastrointestinals and cardiovasculars, such as the prolongation of the QT interval. The pharmacological interactions are common and occur with molecules that use the substrates of the CYP3A4 cytochrome, for example: antiretroviral, anti-tuberculous and immunomodulators. The history, pharmacological characteristics and clinical trials are reviewed.

Systematic review and meta-analysis on Synthetic Antifungal versus Keratolytic Agents for Topical Treatment of Pityriasis Versicolor

Background@#Pityriasis versicolor is a common fungal infection of the superficial skin layer caused by Malassezia furfur, a normal commensal in the skin. Keratolytic agents are popular, cheap, and readily available over-the-counter treatments for pityriasis versicolor. Conventional antifungal agents are more expensive, requiring prescription, and may induce resistant strains. However, evidence of their comparative safety and efficacy is still lacking. @*Objectives@#To assess the efficacy and safety of synthetic antifungals compared to keratolytic agents in the topical treatment of pityriasis versicolor through a systematic review. @*Methods@#We searched the following databases: MEDLINE (from 1966) through PubMed, CENTRAL (Issue 9 of 12, September 2021), EMBASE (from 1974), LILACS (from 1987); Herdin (from 1970), www.clinicaltrials.gov, www. isrctn.com, www.trialregister.nl. We contacted researchers in the field, hand searched relevant conference abstracts, and the Journal of the Philippine Dermatological Society 1992-2019. We included all randomized controlled trials involving patients with diagnosed active pityriasis versicolor where topical antifungal was compared with a topical keratolytic for treatment. Two review authors independently applied eligibility criteria, assessed risk of bias using the Cochrane collaboration tool, and extracted data from included studies. We used RevMan 5.3 to pool dichotomous outcomes using risk ratios (RR) and continuous outcomes using the mean difference (MD), using random-effects meta-analysis. We tested for statistical heterogeneity using both the Chi² test and the I² test. We presented results using forest plots with 95% confidence intervals. We planned to create a funnel plot to determine publication bias but were unable to due to few studies. A Summary of Findings table was created using GRADE profile software for the primary outcomes. @*Results@#We included 8 RCTs with a total of 617 participants that compared azole preparations (ketoconazole, bifonazole and econazole) versus keratolytic agents (selenium sulfide, adapalene, salicylic-benzoic acid). Pooled data showed that azoles did not significantly differ from keratolytic agents for clinical cure (RR 0.99, 0.88, 1.12; 4 RCTs, N=274, I2=55%; very low-quality evidence), and adverse events (0.59 [0.17, 2.06]; very low-quality evidence) based on 6 RCTs (N=536). There were two patients given a keratolytic agent (selenium sulfide shampoo) who had acute dermatitis and discontinued treatment. @*Conclusion@#It is uncertain whether topical azoles are as effective as keratolytic agents in clinical clearance and occurrence of adverse events in patients with pityriasis versicolor. A wider search of grey literature and local studies are warranted. Larger RCTs with low risk of bias are recommended.

Satureja khuzistanica Jamzad essential oil and its anti-candidal activities against clinical isolates of Candida albicans isolated from women with candidiasis / Actividad anti-Candida de los aceites esenciales del Jamzad Satureja khuzistanica contra aislados clínicos de Candida albicans obtenidos de mujeres con candidiasis

Satureja khuzistanica Jamzad is known as antiseptic and analgesic agent in folk medicine. The aim of this investigation was to evaluate the anti-candidal activity of S. khuzistanica aerial parts essential oil against clinical isolates of Candida albicans, which were isolated from women with chronic recurrent candidiasis. For this purpose, the chemical composition of hydro-distilled essential oil was determined by GC and GC-MS analysis. Then, the anti-candidal activity of essential oil and its main component (carvacrol) were determined. Carvacrol (94.1%) was the main component of essential oil, followed by β-bisabolene, p-cymene and γ-terpinene. S. khuzistanica essential oil had strong anti-candidal activity against clinical isolates of C. albicans via inhibition of germ tube formation and induction the huge punctures in the cytoplasmic structures. The cell membranes were intact in presence of essential oil or carvacrol. S. khuzistanica essential oil as the main source of carvacrol can be used for treatment of C. albicans related infections.

Satureja khuzistanica Jamzad es conocido como analgésico y antiséptico en la medicina tradicional. El objetivo de esta investigación fue evaluar el efecto anti- Candida de los aceites esenciales obtenidos de las partes aéreas de S. khuzistanica sobre aislados clínicos de Candida albicans, obtenidos de mujeres con candida diasis crónica recurrente. Para este propósito la composición química de aceites esenciales hidrodestilados fueron determinados por análisis GC y GC-MS. Luego la actividad anti-candidasica de los aceites esenciales y de su componente principal (carvacrol) fue determiando. Carvacrol (94.1%) fue el principal compuesto del aceite esencial seguido por β-bisaboleno, p-cimeno and γ-terpineno. El aceite esencial de S. khuzistanica tuvo fuerte actividad anti-candida contra aislados clínicos de C. albicans via la inhibicion de tubo germinal y la inducción de estructuras puntiformes en la membrana citoplásmatica. Las membranas celulares quedaron intactas en presencia del aceite esencial o del carvacrol. El aceite esencial de S. khuzistanica como fuente principal de carvacrol podría ser usado como tratamiento de infecciones relacionadas con Candida albicans.

Two natural molecules preferentially inhibit azole-resistant Candida albicans with MDR1 hyperactivation / 中国天然药物

Antifungal drug resistance is a significant clinical problem, and antifungal agents that can evade resistance are urgently needed. In infective niches, resistant organisms often co-existed with sensitive ones, or a subpopulation of antibiotic-susceptible organisms may evolve into resistant ones during antibiotic treatment and eventually dominate the whole population. In this study, we established a co-culture assay in which an azole-resistant Candida albicans strain was mixed with a susceptible strain labeled with green fluorescent protein to mimic in vivo conditions and screen for antifungal drugs. Fluconazole was used as a positive control to verify the validity of this co-culture assay. Five natural molecules exhibited antifungal activity against both susceptible and resistant C. albicans. Two of these compounds, retigeric acid B (RAB) and riccardin D (RD), preferentially inhibited C. albicans strains in which the efflux pump MDR1 was activated. This selectivity was attributed to greater intracellular accumulation of the drugs in the resistant strains. Changes in sterol and lipid compositions were observed in the resistant strains compared to the susceptible strain, and might increase cell permeability to RAB and RD. In addition, RAB and RD interfered with the sterol pathway, further aggregating the decrease in ergosterol in the sterol synthesis pathway in the MDR1-activated strains. Our findings here provide an alternative for combating resistant pathogenic fungi.

Candida species: the silent enemy

Candida species are known to causeserious infections in immunocompromised patients but uncommon cases have been reported in immunocompetent individuals regardless of the harmless co-existence of the fungi with the host. Recently, the incidence rate of candidiasis has increased dramatically alongside the emergence of antifungal resistance. Although conventional methods to ensure prompt diagnosis of candidiasisfor effective therapy have been established, thescientific world is witnessing progress in the development of more accurate, timelyand cost-effective methods that is coinciding with the molecular revolutionand advanced DNA analysis. Moreover, the challenges of resistance of Candida to available antifungal agents are being met with the deployment of molecular techniques to investigate the mechanisms of resistance. This review is an attempt to provide up-to-date information on the persistent problems of Candidawith highlights on the clinical importance, molecular diagnosis,and resistance to candidate antifungal drugs;azoles and echinocandins

Paracoccidioidomicosis. Una enfermedad multisistémica / Paracoccidioidomycosis. A multisystemic disease

Resumen La paracoccidioidomicosis es una enfermedad crónica, sistémica y progresiva, sólo descrita en América Latina. Su presentación clínica crónica multifocal es la más prevalente, afectando mayormente a hombres adultos y comprometiendo principalmente a pulmones, sin embargo, puede diseminarse a cualquier órgano generando múltiples complicaciones en el paciente. Presentamos el caso de un paciente masculino, inmunocompetente, caficultor, quien debuta con compromiso de la glándula suprarrenal y en quien posteriormente se documenta compromiso pulmonar. El diagnóstico se confirmó mediante biopsia de lesiones en glándula suprarrenal, inmunodifusión en gel de agar y reacción en cadena de la polimerasa, la cual mostró compromiso por Paracoccidioides brasiliensis. (Acta Med Colomb 2018; 43: 111-114).

Abstract Paracoccidioidomycosis is a chronic, systemic and progressive disease which is described only in Latin America. Its chronic and multifocal clinical presentation is the most prevalent, affecting mainly adult men and compromising mainly lungs; however, it can spread to any organ generating multiple complications in the patient. The case of an immunocompetent male patient, coffee grower, who debuted with compromise of the adrenal gland and in who subsequently pulmonary involvement was documented, is presented. The diagnosis was confirmed by biopsy of lesions in the adrenal gland, agar gel immunodiffusion and polymerase chain reaction, which showed compromise by Paracoccidioides brasilensis. (Acta Med Colomb 2018; 43: 111-114).

A new coumarin derivative, 4-acetatecoumarin, with antifungal activity and association study against Aspergillus spp

Abstract Fungal infections have become a concern for health professionals, and the emergence of resistant strains has been reported for all known classes of antifungal drugs. Among the fungi causing disease, we highlight those that belong to the genus Aspergillus. For these reasons, the search for new antifungals is important. This study examines the effects of a coumarin derivative, 4-acetatecoumarin (Cou-UMB16) both alone and together with antifungal drugs, and its mode of action against Aspergillus spp. Cou-UMB16 was tested to evaluate its effects on mycelia growth, and germination of Aspergillus spp. fungal conidia. We investigated its possible action on cell walls, on the cell membrane, and also the capacity of this coumarin derivative to enhance the activity of antifungal drugs. Our results suggest that Cou-UMB16 inhibits Aspergillus spp. virulence factors (mycelia growth and germination of conidia) and affects the structure of the fungal cell wall. When applying Cou-UMB16 in combination with azoles, both synergistic and additive effects were observed. This study concludes that Cou-UMB16 inhibits mycelial growth and spore germination, and that the activity is due to its action on the fungal cell wall, and that Cou-UMB16 could act as an antifungal modifier.

Characterisation of an ABC transporter of a resistant Candida glabrata clinical isolate

BACKGROUND Candida glabrata ranks second in epidemiological surveillance studies, and is considered one of the main human yeast pathogens. Treatment of Candida infections represents a contemporary public health problem due to the limited availability of an antifungal arsenal, toxicity effects and increasing cases of resistance. C. glabrata presents intrinsic fluconazole resistance and is a significant concern in clinical practice and in hospital environments. OBJECTIVE The aim of this study was to characterise the azole resistance mechanism presented by a C. glabrata clinical isolate from a Brazilian university hospital. METHODS Azole susceptibility assays, chemosensitisation, flow cytometry and mass spectrometry were performed. FINDINGS Our study demonstrated extremely high resistance to all azoles tested: fluconazole, voriconazole, posaconazole and itraconazole. This isolate was chemosensitised by FK506, a classical inhibitor of ABC transporters related to azole resistance, and Rhodamine 6G extrusion was observed. A mass spectrometry assay confirmed the ABC protein identification suggesting the probable role of efflux pumps in this resistance phenotype. MAIN CONCLUSIONS This study emphasizes the importance of ABC proteins and their relation to the resistance mechanism in hospital environments and they may be an important target for the development of compounds able to unsettle drug extrusion.

In vitro anti-tuberculosis activity of azole drugs against Mycobacterium tuberculosis clinical isolates / Actividad in vitro de azoles contra aislamientos clínicos de Mycobacterium tuberculosis

Background: Latent tuberculosis has been associated with the persistence of dormant Mycobacterium tuberculosis in the organism of infected individuals, who are reservoirs of the bacilli and the source for spreading the disease in the community. New active anti-TB drugs exerting their metabolic action at different stages and on latent/dormant bacilli are urgently required to avoid endogenous reactivations and to be part of treatments of multi- and extensively-drug resistant tuberculosis (M/XDR-TB). It was previously reported that azole drugs are active against M. tuberculosis. For that reason, the aims of this study were to determine the in vitro activity of azole drugs, imidazole (clotrimazole, CLO and econazole, ECO) and nitroimidazole (metronidazole, MZ and ipronidazole, IPZ), against a collection of MDR M. tuberculosis clinical isolates; and to analyze their potential use in both the LTB and the active forms of M/XDR-TB treatments. Methods: A total of 55 MDR M. tuberculosis isolates and H37Rv were included. MZ and IPZ activity against M. tuberculosis isolates were tested using anaerobic culture conditions. The activity of ECO and CLO was measured by the minimal inhibitory concentration (MIC) using a microdilution colorimetric method. Results: MZ and IPZ showed bacteriostatic activity against M. tuberculosis strains. MIC5o and MIC90 to ECO was 4.0 µg/ml, while MIC50 to CLO was 4.0 µg/ml and MIC90 was 8.0 µg/ml respectively. Conclusion: All azole compounds tested in the study showed inhibitory activity against MDR M. tuberculosis clinical isolates.

Introducción: La tuberculosis (TB) latente ha sido asociada a la persistencia de Mycobacterium tuberculosis durmientes en el organismo de las personas infectadas, las cuales constituyen un reservorio del bacilo y una fuente de diseminación de la enfermedad en la comunidad. Urge la necesidad de contar con nuevos fármacos antituberculosos con acción sobre el bacilo en estado latente/durmiente, a fin de evitar reactivaciones endógenas y para ser incluidas en el tratamiento de la TB multirresistente y extensivamente resistente (M/XDR-TB). Se ha reportado que los azoles son activos contra M. tuberculosis. Por esta razón, los objetivos del presente estudio fueron determinar la actividad in vitro sobre aislamientos clínicos de M/XDR-TB de distintos azoles, incluyendo los imidazoles econazol (ECO) y clotrimazol (CLO) y los 5-nitro-imidazoles ipronidazol (IPZ) y metronidazol (MZ), así como analizar su potencial uso contra las formas latente y activa de esta enfermedad. Métodos: Fueron incluidos 55 aislamientos clínicos de M. tuberculosis MDR y la cepa de referencia H37Rv. Se evaluó la actividad del MZ y el IPZ sobre los aislamientos en condiciones de cultivo anaeróbico, mientras que la actividad del ECO y el CLO fue estimada determinando la concentración inhibitoria mínima (CIM) mediante el método colorimétrico de microdilución en placa. Resultados: El MZ y el IPZ presentaron actividad bacteriostática frente a las cepas de M. tuberculosis. La CIM50 y CIM90 del ECO fue de 4 µg/ml, mientras que el CLO presentó una CIM50 de 4 µg/ml y una CIM90 de 8 µg/ml. Conclusión: Todos los compuestos azólicos evaluados presentaron actividad inhibitoria frente a aislamientos clínicos de M. tuberculosis.

Antifungal pharmacodynamics: Latin America's perspective

Abstract The current increment of invasive fungal infections and the availability of new broad-spectrum antifungal agents has increased the use of these agents by non-expert practitioners, without an impact on mortality. To improve efficacy while minimizing prescription errors and to reduce the high monetary cost to the health systems, the principles of pharmacokinetics (PK) and pharmacodynamics (PD) are necessary. A systematic review of the PD of antifungals agents was performed aiming at the practicing physician without expertise in this field. The initial section of this review focuses on the general concepts of antimicrobial PD. In vitro studies, fungal susceptibility and antifungal serum concentrations are related with different doses and dosing schedules, determining the PD indices and the magnitude required to obtain a specific outcome. Herein the PD of the most used antifungal drug classes in Latin America (polyenes, azoles, and echinocandins) is discussed.

Regulation of ERG3, ERG6, and ERG11 genes in antifungal-resistant isolates of candida parapsilosis

Background: Candida parapsilosis is one of the five common strains of yeasts involved in invasive candidiasis. The expression analysis of sterol biosynthesis pathway genes, which are associated with resistance, can assist the better understanding of antifungal resistance mechanisms

Methods: The antifungal susceptibility of 120 clinical C. parapsilosis isolates was examined. The changes in the gene expression related to resistance were analyzed

Results: Eight strains were resistant to fluconazole [FLC], itraconazole [ITC], and amphotericin B [AMB]. The regulation variations included increased mRNA levels of ERG3, ERG6, and ERG11 and decreased mRNA levels of ERG3 and ERG6 in response to FLC. ERG11 mRNA level increases in response to ITC and AMB

Conclusion: The mechanism of resistance to azoles in C. parapsilosis is very similar to C. Albicans. This feature may help to design new treatment strategy for candidiasis

Extracellular phospholipase production of oral Candida albicans isolates from smokers, diabetics, asthmatics, denture wearers and healthy individuals following brief exposure to polyene, echinocandin and azole antimycotics

Abstract Objective Candida albicans is the primary causative agent of oral candidosis, and one of its key virulent attributes is considered to be its ability to produce extracellular phospholipases that facilitate cellular invasion. Oral candidosis can be treated with polyenes, and azoles, and the more recently introduced echinocandins. However, once administered, the intraoral concentration of these drugs tend to be sub-therapeutic and rather transient due to factors such as the diluent effect of saliva and cleansing effect of the oral musculature. Hence, intra-orally, the pathogenic yeasts may undergo a brief exposure to antifungal drugs. We, therefore, evaluated the phospholipase production of oral C. albicans isolates following brief exposure to sub-therapeutic concentrations of the foregoing antifungals. Materials and methods Fifty C. albicans oral isolates obtained from smokers, diabetics, asthmatics using steroid inhalers, partial denture wearers and healthy individuals were exposed to sub-therapeutic concentrations of nystatin, amphotericin B, caspofungin, ketoconazole and fluconazole for one hour. Thereafter the drugs were removed and the phospholipase production was determined by a plate assay using an egg yolk-agar medium. Results The phospholipase production of these isolates was significantly suppressed with a percentage reduction of 10.65, 12.14, 11.45 and 6.40% following exposure to nystatin, amphotericin B, caspofungin and ketoconazole, respectively. This suppression was not significant following exposure to fluconazole. Conclusions Despite the sub-therapeutic, intra oral, bioavailability of polyenes, echinocandins and ketoconazole, they are likely to produce a persistent antifungal effect by suppressing phospholipase production, which is a key virulent attribute of this common pathogenic yeast.

Azole resistance in Candida spp. isolated from Catú Lake, Ceará, Brazil: an efflux-pump-mediated mechanism

Abstract Since, there is no study reporting the mechanism of azole resistance among yeasts isolated from aquatic environments; the present study aims to investigate the occurrence of antifungal resistance among yeasts isolated from an aquatic environment, and assess the efflux-pump activity of the azole-resistant strains to better understand the mechanism of resistance for this group of drugs. For this purpose, monthly water and sediment samples were collected from Catú Lake, Ceará, Brazil, from March 2011 to February 2012. The obtained yeasts were identified based on morphological and biochemical characteristics. Of the 46 isolates, 37 were Candida spp., 4 were Trichosporon asahii, 3 were Cryptococcus laurentii, 1 Rhodotorula mucilaginosa, and 1 was Kodamaea ohmeri. These isolates were subjected to broth microdilution assay with amphotericin B, itraconazole, and fluconazole, according to the methodology standardized by the Clinical and Laboratory Standards Institute (CLSI). The minimum inhibitory concentrations (MICs) of amphotericin B, itraconazole, and fluconazole were 0.03125–2 µg/mL, 0.0625 to ≥16 µg/mL, and 0.5 to ≥64 µg/mL, respectively, and 13 resistant azole-resistant Candida isolates were detected. A reduction in the azole MICs leading to the phenotypical reversal of the azole resistance was observed upon addition of efflux-pump inhibitors. These findings suggest that the azole resistance among environmental Candida spp. is most likely associated with the overexpression of efflux-pumps.

Novel point mutations in the ERG11 gene in clinical isolates of azole resistant Candida species

The azoles are the class of medications most commonly used to fight infections caused by Candida sp. Typically, resistance can be attributed to mutations in ERG11 gene (CYP51) which encodes the cytochrome P450 14α-demethylase, the primary target for the activity of azoles. The objective of this study was to identify mutations in the coding region of theERG11 gene in clinical isolates of Candidaspecies known to be resistant to azoles. We identified three new synonymous mutations in the ERG11 gene in the isolates of Candida glabrata (C108G, C423T and A1581G) and two new nonsynonymous mutations in the isolates of Candida krusei - A497C (Y166S) and G1570A (G524R). The functional consequence of these nonsynonymous mutations was predicted using evolutionary conservation scores. The G524R mutation did not have effect on 14α-demethylase functionality, while the Y166S mutation was found to affect the enzyme. This observation suggests a possible link between the mutation and dose-dependent sensitivity to voriconazole in the clinical isolate of C. krusei. Although the presence of the Y166S in phenotype of reduced azole sensitivity observed in isolate C. kruseidemands investigation, it might contribute to the search of new therapeutic agents against resistant Candida isolates.

Paracoccidioidomycosis treatment / Tratamento da paracoccidioidomicose

SUMMARYConsidered to be an emerging endemic mycosis in Latin America, paracoccidioidomycosis is characterized by a chronic course and involvement of multiple organs in immunocompromised hosts. Infection sequelae are mainly related to pulmonary and adrenal insufficiency. The host-parasite interaction results in different expressions of the immune response depending on parasite pathogenicity, fungal load and genetic characteristics of the host. A few controlled and case series reports have shown that azoles and fast-acting sulfa derivatives are useful treatment alternatives in milder forms of the disease. For moderate/severe cases, more prolonged treatments or even parenteral routes are required especially when there is involvement of the digestive tract mucosa, resulting in poor drug absorption. Although comparative studies have reported that shorter treatment regimens with itraconazole are able to induce cure in chronically-infected patients, there are still treatment challenges such as the need for more controlled studies involving acute cases, the search for new drugs and combinations, and the search for compounds capable of modulating the immune response in severe cases as well as the paradoxical reactions.

RESUMOConsiderada micose endêmica emergente na América Latina, a paracoccidioidomicose é caracterizada por uma evolução crônica e envolvimento de múltiplos órgãos em pacientes com comprometimento imunológico. Sequelas da infecção estão relacionadas principalmente à insuficiência pulmonar e adrenal. A interação hospedeiro-parasito resulta em diferentes expressões da resposta imune dependendo da patogenicidade do parasito, carga fúngica e características genéticas do hospedeiro. Alguns estudos controlados e séries de casos têm demonstrado que azóis de ação rápida e derivados de sulfa constituem alternativas terapêuticas úteis nas formas mais leves da doença. Para casos moderados/graves, tratamentos mais prolongados ou mesmo por via parenteral são necessários especialmente quando há envolvimento de mucosa do trato digestivo, resultando em absorção deficiente de drogas. Embora estudos comparativos tenham relatado que esquemas terapêuticos mais curtos com itraconazol sejam capazes de induzir cura em pacientes cronicamente infectados, ainda existem desafios no tratamento, tais como a necessidade de maior número de estudos controlados envolvendo casos agudos, busca por novas drogas e combinações, compostos capazes de modular a resposta imune nos casos graves, e reações paradoxais.

Synergistic effects of tacrolimus and azole antifungal compounds in fluconazole-susceptible and fluconazole-resistant Candida glabrata isolates

In vitro interaction between tacrolimus (FK506) and four azoles (fluconazole, ketoconazole, itraconazole and voriconazole) against thirty clinical isolates of both fluconazole susceptible and -resistant Candida glabrata were evaluated by the checkerboard microdilution method. Synergistic, indifferent or antagonism interactions were found for combinations of the antifungal agents and FK506. A larger synergistic effect was observed for the combinations of FK506 with itraconazole and voriconazole (43%), followed by that of the combination with ketoconazole (37%), against fluconazole-susceptible isolates. For fluconazole-resistant C. glabrata, a higher synergistic effect was obtained from FK506 combined with ketoconazole (77%), itraconazole (73%), voriconazole (63%) and fluconazole (60%). The synergisms that we observed in vitro, notably against fluconazole-resistant C. glabrata isolates, are promising and warrant further analysis of their applications in experimental in vivo studies.