RESUMEN
Microorganisms mainly exist in the form of biofilm in nature. Biofilm can contaminate food and drinking water system, as well as cause chronic wound infections, thereby posing a potential threat to public health safety. In the last two decades, researchers have made efforts to investigate the genetic contributors control different stages of biofilm development (adherence, initiation, maturation, and dispersal). As an opportunistic pathogen, C. albicans causes severe superficial or systemic infections with high morbidity and mortality under conditions of immune dysfunction. It has been reported that 80% of C. albicans infections are directly or indirectly associated with biofilm formation on host or abiotic surfaces including indwelling medical devices, resulting in high morbidity and mortality. Significantly, the outcome of C. albicans biofilm development includes enhanced invasion, exacerbated inflammatory responses and intrinsic resistance to antimicrobial chemotherapy. Thus, this review aimed at providing a comprehensive overview of the regulatory network controls microbial biofilm development, with C. albicans as a representative, served as reference for therapeutic targets.
Asunto(s)
Antifúngicos/uso terapéutico , Biopelículas , Candida albicans/fisiología , Candidiasis , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Candidiasis/tratamiento farmacológico , Candidiasis/metabolismo , Candidiasis/mortalidad , Proteínas Fúngicas/metabolismo , HumanosRESUMEN
BACKGROUND: The incidence of Candida bloodstream infections (BSIs), has increased over time. In this study, we aimed to describe the current epidemiology of Candida BSI in a large tertiary care hospital in Shanghai and to determine the risk factors of 28-day mortality and the impact of antifungal therapy on clinical outcomes. METHODS: All consecutive adult inpatients with Candida BSI at Ruijin Hospital between January 1, 2008, and December 31, 2018, were enrolled. Underlying diseases, clinical severity, species distribution, antifungal therapy, and their impact on the outcomes were analyzed. RESULTS: Among the 370 inpatients with 393 consecutive episodes of Candida BSI, the incidence of nosocomial Candida BSI was 0.39 episodes/1000 hospitalized patients. Of the 393 cases, 299 (76.1%) were treated with antifungal therapy (247 and 52 were treated with early appropriate and targeted antifungal therapy, respectively). The overall 28-day mortality rate was 28.5%, which was significantly lower in those who received early appropriate (25.5%) or targeted (23.1%) antifungal therapy than in those who did not (39.4%; P = 0.012 and P = 0.046, respectively). In multivariate Cox regression analysis, age, chronic renal failure, mechanical ventilation, and severe neutropenia were found to be independent risk factors of the 28-day mortality rate. Patients who received antifungal therapy had a lower mortality risk than did those who did not. CONCLUSIONS: The incidence of Candida BSI has increased steadily in the past 11 years at our tertiary care hospital in Shanghai. Antifungal therapy influenced short-term survival, but no significant difference in mortality was observed between patients who received early appropriate and targeted antifungal therapy.
Asunto(s)
Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Infección Hospitalaria/epidemiología , Infección Hospitalaria/microbiología , Sepsis/epidemiología , Sepsis/microbiología , Adulto , Anciano , Candidiasis/epidemiología , Candidiasis/microbiología , Candidiasis/mortalidad , China/epidemiología , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/mortalidad , Femenino , Humanos , Incidencia , Pacientes Internos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Sepsis/tratamiento farmacológico , Sepsis/mortalidad , Centros de Atención Terciaria , Resultado del TratamientoRESUMEN
BACKGROUND: Treatment of Candida albicans bloodstream infection with fluconazole is associated with significant mortality despite in vitro susceptibility to the drug. OBJECTIVES: We sought to determine whether tolerance to fluconazole is predictive of treatment failure. METHODS: We reviewed patients with monomicrobial C albicans bloodstream infection who received primary monotherapy with fluconazole. Tolerance to fluconazole, defined as the fraction of growth above the MIC, was quantified using the disc diffusion assay and digital image analyses. Survival analyses were performed with host and treatment factors as predictive variables. RESULTS: Among 44 patients included in the study, all-cause mortality was 29.5% at 30 days and 43.1% at 12 weeks. Forty-one isolates (93%) were susceptible to fluconazole (MIC50, 0.5 mg/L). Fluconazole tolerance was strongly associated with death for patients treated with fluconazole within 24 h of candidemia onset (33.3% vs 0%; p = .007), but not among patients whose treatment was started later. MIC did not correlate with survival, regardless of treatment delay. A Cox regression model including time to treatment, tolerance to fluconazole, fluconazole exposure and Pitt bacteraemia score provided good prediction of treatment outcome (area under the receiver-operator curve, 0.82). CONCLUSIONS: In patients with C albicans bloodstream infection, tolerance testing was predictive of fluconazole efficacy if the drug was started early. Further study is required to validate the utility of this metric to guide treatment choices.
Asunto(s)
Antifúngicos/uso terapéutico , Candidemia/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Fluconazol/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Candida albicans , Candidiasis/mortalidad , Estudios de Cohortes , Farmacorresistencia Fúngica , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Análisis de Supervivencia , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Invasive candidiasis is an increasingly frequent cause of serious and often fatal infections in hospitalized and immunosuppressed patients. Mortality rates associated with these infections have risen sharply due to the emergence of multidrug resistant (MDR) strains of C. albicans and other Candida spp., highlighting the urgent need of new antifungal therapies. Rhesus theta (θ) defensin-1 (RTD-1), a natural macrocyclic antimicrobial peptide, was recently shown to be rapidly fungicidal against clinical isolates of MDR C. albicans in vitro. Here we found that RTD-1 was rapidly fungicidal against blastospores of fluconazole/caspofungin resistant C. albicans strains, and was active against established C. albicans biofilms in vitro. In vivo, systemic administration of RTD-1, initiated at the time of infection or 24 h post-infection, promoted long term survival in candidemic mice whether infected with drug-sensitive or MDR strains of C. albicans. RTD-1 induced an early (4 h post treatment) increase in neutrophils in naive and infected mice. In vivo efficacy was associated with fungal clearance, restoration of dysregulated inflammatory cytokines including TNF-α, IL-1ß, IL-6, IL-10, and IL-17, and homeostatic reduction in numbers of circulating neutrophils and monocytes. Because these effects occurred using peptide doses that produced maximal plasma concentrations (Cmax) of less than 1% of RTD-1 levels required for in vitro antifungal activity in 50% mouse serum, while inducing a transient neutrophilia, we suggest that RTD-1 mediates its antifungal effects in vivo by host directed mechanisms rather than direct fungicidal activity. Results of this study suggest that θ-defensins represent a new class of host-directed compounds for treatment of disseminated candidiasis.
Asunto(s)
Candidiasis/tratamiento farmacológico , Candidiasis/mortalidad , Defensinas/uso terapéutico , Animales , Biopelículas/efectos de los fármacos , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Candidiasis/inmunología , Candidiasis/metabolismo , Defensinas/farmacocinética , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Farmacorresistencia Fúngica Múltiple/efectos de los fármacos , Femenino , Interacciones Huésped-Patógeno/efectos de los fármacos , Interacciones Huésped-Patógeno/inmunología , Macaca mulatta/inmunología , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Análisis de SupervivenciaRESUMEN
Candida auris is an emerging drug-resistant yeast responsible for hospital outbreaks. This statement reviews the evidence regarding diagnosis, treatment and prevention of this organism and provides consensus recommendations for clinicians and microbiologists in Australia and New Zealand. C. auris has been isolated in over 30 countries (including Australia). Bloodstream infections are the most frequently reported infections. Infections have crude mortality of 30-60%. Acquisition is generally healthcare-associated and risks include underlying chronic disease, immunocompromise and presence of indwelling medical devices. C. auris may be misidentified by conventional phenotypic methods. Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry or sequencing of the internal transcribed spacer regions and/or the D1/D2 regions of the 28S ribosomal DNA are therefore required for definitive laboratory identification. Antifungal drug resistance, particularly to fluconazole, is common, with variable resistance to amphotericin B and echinocandins. Echinocandins are currently recommended as first-line therapy for infection in adults and children ≥2 months of age. For neonates and infants <2 months of age, amphotericin B deoxycholate is recommended. Healthcare facilities with C. auris should implement a multimodal control response. Colonised or infected patients should be isolated in single rooms with Standard and Contact Precautions. Close contacts, patients transferred from facilities with endemic C. auris or admitted following stay in overseas healthcare institutions should be pre-emptively isolated and screened for colonisation. Composite swabs of the axilla and groin should be collected. Routine screening of healthcare workers and the environment is not recommended. Detergents and sporicidal disinfectants should be used for environmental decontamination.
Asunto(s)
Antifúngicos/uso terapéutico , Candida/aislamiento & purificación , Candidiasis/diagnóstico , Candidiasis/tratamiento farmacológico , Candidiasis/prevención & control , Factores de Edad , Australia , Candida/efectos de los fármacos , Candida/genética , Candidiasis/mortalidad , Infección Hospitalaria/prevención & control , ADN de Hongos/genética , Transmisión de Enfermedad Infecciosa/prevención & control , Farmacorresistencia Fúngica , Fluconazol/uso terapéutico , Humanos , Control de Infecciones/métodos , Pruebas de Sensibilidad Microbiana , Nueva Zelanda , Sociedades MédicasRESUMEN
Candida tropicalis is the second most common Candida species causing fungaemia in Taiwan, and decreased susceptibility to fluconazole has been reported. This study analysed the clinical characteristics of adult patients with C. tropicalis fungaemia and the antifungal susceptibilities of isolates at five tertiary hospitals in Taiwan (1 July 2011 to 30 June 2014). A standardised case record form was used retrospectively to collect demographic, clinical and microbiological characteristics, antifungal treatment and outcomes. MICs of non-duplicate isolates were determined using SensititreTM YeastOneTM and were interpreted using cut-off values recommended by the CLSI. A total 248 patients were diagnosed over the study period; 30-day crude mortality was 52.0%. Multivariate analysis showed that high Charlson comorbidity index ≥4 (ORâ¯=â¯2.09, 95% CI 1.22-3.59; Pâ¯=â¯0.008), neutropenia (ORâ¯=â¯4.61, 95% CI 1.42-15.00; Pâ¯=â¯0.011) and treatment with an azole-based regimen (ORâ¯=â¯0.39, 95% CI 0.17-0.90; Pâ¯=â¯0.028) were significantly associated with 30-day mortality. A total of 33.9% of isolates were non-susceptible to fluconazole (MIC50, 2 mg/L; MIC90, 16 mg/L; MIC range, 0.25 to >256 mg/L), whilst 56.9% to voriconazole (MIC50, 0.25 mg/L; MIC90, 1 mg/L; MIC range, 0.015 to >8 mg/L) according to CLSI clinical breakpoints. There was no significant correlation between overall mortality and MICs of fluconazole or voriconazole. This study showed high mortality in patients with C. tropicalis fungaemia, and azole-based antifungal treatment could improve outcomes regardless of fluconazole MICs of infecting isolates compared with patients without any treatment within 48 h.
Asunto(s)
Antifúngicos/uso terapéutico , Candida tropicalis/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Fluconazol/uso terapéutico , Fungemia/tratamiento farmacológico , Voriconazol/uso terapéutico , Anciano , Candidiasis/mortalidad , Farmacorresistencia Fúngica , Femenino , Fungemia/microbiología , Fungemia/mortalidad , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Estudios Retrospectivos , TaiwánRESUMEN
Prolonged empiric and etiotropic therapy of multidrug-resistant or pan-resistant bacterial flora in different gestation age newborns has led to the growth of resistant fungalflora in intencive care units (ICU). According to risk factors and rating scales every child of ICU undergoing the abdominal cavity surgery is threatened the development of a fungal infection and requires antifungal therapy appointment or causal prophylactic. In recent years, before the advent of medications of the group of echinocandins, therapy of invasive fungal infections has been a challenge. Currently alternative drug to diflucane in neonates and infants is micafungine (mycamine) in the dose of 2-8 mg/kg/day, depending on the signs of infestation and severity of the condition.
Asunto(s)
Antifúngicos/uso terapéutico , Candidiasis/prevención & control , Anomalías Congénitas/cirugía , Equinocandinas/uso terapéutico , Lipopéptidos/uso terapéutico , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Antifúngicos/administración & dosificación , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Candidiasis/microbiología , Candidiasis/mortalidad , Anomalías Congénitas/mortalidad , Equinocandinas/administración & dosificación , Humanos , Lactante , Recién Nacido , Lipopéptidos/administración & dosificación , Micafungina , Pruebas de Sensibilidad Microbiana , Resultado del TratamientoRESUMEN
FKS mutant Candida isolates were recovered from 24% (6/25) of abdominal candidiasis patients exposed to echinocandin. Candida glabrata (29%) and Candida albicans (14%) mutants were identified. Multidrug-resistant bacteria were recovered from 83% of FKS mutant infections. Mutations were associated with prolonged echinocandin exposure (P = 0.01), breakthrough infections (P = 0.03), and therapeutic failures despite source control interventions (100%). Abdominal candidiasis is a hidden reservoir for the emergence of echinocandin-resistant Candida.
Asunto(s)
Absceso Abdominal/microbiología , Antifúngicos/uso terapéutico , Candida albicans/efectos de los fármacos , Candida glabrata/efectos de los fármacos , Candidiasis/microbiología , Equinocandinas/uso terapéutico , Peritonitis/microbiología , Absceso Abdominal/tratamiento farmacológico , Absceso Abdominal/mortalidad , Absceso Abdominal/patología , Adulto , Anciano , Candida albicans/genética , Candida albicans/crecimiento & desarrollo , Candida glabrata/genética , Candida glabrata/crecimiento & desarrollo , Candidiasis/tratamiento farmacológico , Candidiasis/mortalidad , Candidiasis/patología , Farmacorresistencia Fúngica/genética , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mutación , Peritonitis/tratamiento farmacológico , Peritonitis/mortalidad , Peritonitis/patología , Análisis de SupervivenciaRESUMEN
BACKGROUND: Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified. METHODS: The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article. RESULTS: In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY. CONCLUSIONS: De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.
Asunto(s)
Antifúngicos/economía , Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Equinocandinas/economía , Equinocandinas/uso terapéutico , Lipopéptidos/economía , Lipopéptidos/uso terapéutico , Antifúngicos/administración & dosificación , Candidiasis/economía , Candidiasis/mortalidad , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Equinocandinas/administración & dosificación , Fluconazol/economía , Fluconazol/uso terapéutico , Servicios de Salud/economía , Servicios de Salud/estadística & datos numéricos , Humanos , Esperanza de Vida , Lipopéptidos/administración & dosificación , Micafungina , Pruebas de Sensibilidad Microbiana , Años de Vida Ajustados por Calidad de VidaRESUMEN
BACKGROUND: Candida albicans is the predominant isolate in many neonatal fungal bloodstream infections (BSIs), so fluconazole is used as empiric antifungal therapy. AIM: To determine the predominant organisms, antifungal sensitivity patterns, clinical and demographic risk factors and crude mortality rate in neonatal fungal BSI cases. SUBJECTS AND METHODS: This is a review of all neonatal fungal BSI cases between January 2007 and December 2011. RESULTS: Fifty-nine patients were included in the study. Candida parapsilosis (54.2%) was isolated in majority of the cases, followed by C. albicans (27.1%). Fluconazole resistance was present in 16 of 32 cases of C. parapsilosis versus 1 of 16 cases of C. albicans (P = 0.003). Mortality rate was 45.8%. Surgical problems were present in 55.9%. Death was significantly associated with lower birth weight (P = 0.046) and necrotizing enterocolitis (P = 0.034). CONCLUSIONS: The increase in neonatal fungal BSI and resistant organisms highlights the need to review use of routine empiric fluconazole and to implement preventive measures.
Asunto(s)
Antifúngicos/uso terapéutico , Candida/aislamiento & purificación , Candidemia/diagnóstico , Candidiasis/diagnóstico , Antifúngicos/farmacología , Peso al Nacer , Candida/clasificación , Candida/efectos de los fármacos , Candidemia/tratamiento farmacológico , Candidemia/epidemiología , Candidemia/microbiología , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Candidiasis/mortalidad , Farmacorresistencia Fúngica , Femenino , Fluconazol/farmacología , Fluconazol/uso terapéutico , Humanos , Incidencia , Recién Nacido , Masculino , Pruebas de Sensibilidad Microbiana , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Factores de Riesgo , Factores Socioeconómicos , Sudáfrica/epidemiología , Resultado del Tratamiento , Triazoles/farmacología , Triazoles/uso terapéutico , VoriconazolRESUMEN
OBJECTIVES: NanoDisk-amphotericin B (ND-AMB) is a protein-phospholipid bioparticle containing a "super aggregate" form of antifungal AMB. While lipid-based formulations of AMB, including liposomal AMB (L-AMB), are safer than the deoxycholate (DOC) solubilized form (DOC-AMB), the potency of lipid-based formulations is attenuated. We have developed an AMB-based therapy that is both well tolerated and fully efficacious. METHODS: Potency was determined using broth culture growth-inhibition assays and candidacidal kinetics by quantitative culture plating. Toxicology studies were performed in healthy mice. Efficacy was assessed using both immune-competent and leukopenic murine models of systemic Candida albicans infection. RESULTS: ND-AMB C. albicans and Aspergillus fumigatus minimum inhibitory concentrations were fourfold and sixfold lower, respectively, than that observed for L-AMB. ND-AMB exhibited candidacidal activity at 0.125 mg/L, 16-fold lower than L-AMB. In mice, ND-AMB produced no statistically significant kidney or liver toxicity at 15 mg/kg, the highest dose tested. When evaluated in immune-competent mice infected with C. albicans, ND-AMB was at least as effective as DOC-AMB or L-AMB. In a leukopenic model of candidiasis, the 50% effective dose of ND-AMB was around threefold lower than L-AMB. CONCLUSION: These results indicate that ND-AMB exhibits a more favorable safety profile while maintaining uncompromised antifungal properties compared to both DOC-AMB and L-AMB. ND-AMB is a promising therapy for the treatment of invasive fungal infections.
Asunto(s)
Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Nanoestructuras/uso terapéutico , Anfotericina B/química , Anfotericina B/toxicidad , Animales , Antifúngicos/química , Antifúngicos/toxicidad , Candida albicans , Candidiasis/tratamiento farmacológico , Candidiasis/mortalidad , Femenino , Estimación de Kaplan-Meier , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Nanoestructuras/química , Nanoestructuras/toxicidad , Pruebas de ToxicidadRESUMEN
Since nystatin (NYT) is used only topically owing to its toxicity upon systemic administration, a study was initiated aiming to develop a formulation of NYT that could be used systemically against invasive mycoses. The present research is a continuation of previous in vitro investigation of the antifungal effect of nystatin-Intralipid (NYT-IL) against Candida, exploring its in vivo activity. NYT-IL was tested in murine systemic candidiasis induced in naïve as well as cyclophosphamide-immunosuppressed female ICR mice. The infection was assessed by survival rate (SR), mean survival time (MST) and qualitative and quantitative fungal organ colonisation. Mice were treated by intravenous administration of various doses of NYT-IL for 5 consecutive days starting either 24h or 48 h after the initiation of infection. The experiments showed that NYT-IL is therapeutically effective in the murine candidiasis model. NYT-IL was found to be less toxic in vivo than NYT and therefore higher doses of NYT-IL could be used. The efficacy of NYT-IL was expressed in treated naïve and immunosuppressed mice by increased SR, prolonged MST and reduced fungal organ colonisation. Early initiation of treatment increased efficacy. In summary, the Intralipid formulation of NYT can be administered parenterally and is effective against systemic experimental Candida infection.
Asunto(s)
Antifúngicos/farmacología , Candidiasis/tratamiento farmacológico , Emulsiones Grasas Intravenosas/farmacología , Nistatina/farmacología , Fosfolípidos/farmacología , Aceite de Soja/farmacología , Animales , Antifúngicos/administración & dosificación , Antifúngicos/química , Antifúngicos/uso terapéutico , Candidiasis/inmunología , Candidiasis/mortalidad , Candidiasis/patología , Recuento de Colonia Microbiana , Ciclofosfamida/inmunología , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Sistemas de Liberación de Medicamentos , Emulsiones/administración & dosificación , Emulsiones/química , Emulsiones/farmacología , Emulsiones/uso terapéutico , Emulsiones Grasas Intravenosas/administración & dosificación , Emulsiones Grasas Intravenosas/química , Emulsiones Grasas Intravenosas/uso terapéutico , Femenino , Huésped Inmunocomprometido/fisiología , Inmunosupresores/inmunología , Ratones , Ratones Endogámicos ICR , Nistatina/administración & dosificación , Nistatina/química , Nistatina/uso terapéutico , Fosfolípidos/administración & dosificación , Fosfolípidos/química , Fosfolípidos/uso terapéutico , Aceite de Soja/administración & dosificación , Aceite de Soja/química , Aceite de Soja/uso terapéutico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The efficacy of allicin compared with fluconazole in alleviating systemic Candida albicans infections was evaluated both in vitro and in vivo through a systemic candidiasis mouse model. Determination of in vitro minimum inhibitory concentrations (MICs) for different C. albicans isolates revealed that both allicin and fluconazole showed different MICs that ranged from 0.05 to 12.5 µg mL(-1) and 0.25 to 16 µg mL(-1) , respectively. A time-kill study showed a significant effect of allicin (P<0.01) against C. albicans, comparable to that of fluconazole. Scanning electron microscopy observation revealed that, similar to fluconazole, allicin produced structural destruction of C. albicans cell surface at low MIC and lysis or puncture at high MIC concentrations. Treatment of BALB/c mice systemically infected with C. albicans showed that although the allicin treatment (at 5 mg kg(-1) day(-1) ) was slightly less efficacious than fluconazole treatment in terms of the fungal load reduction and host survival time, it was still effective against C. albicans in terms of mean survival time, which increased from 8.4 to 15.8 days. These results demonstrate the efficacy of anticandidal effects of allicin both in vitro and in an animal model of candidiasis and affirm the potential of allicin as an adjuvant therapy to fluconazole.
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Candida albicans/efectos de los fármacos , Fluconazol/farmacología , Fluconazol/uso terapéutico , Ácidos Sulfínicos/farmacología , Ácidos Sulfínicos/uso terapéutico , Animales , Candida albicans/citología , Candidiasis/tratamiento farmacológico , Candidiasis/mortalidad , Modelos Animales de Enfermedad , Disulfuros , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Viabilidad Microbiana/efectos de los fármacos , Microscopía Electrónica de Rastreo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Information on the species causing Candida peritonitis, their in vitro susceptibility, antifungal strategies in this setting and patient outcome is still scarce. AmarCand was a prospective, non-interventional study in 271 adult intensive-care unit (ICU) patients with proven invasive Candida infection who received systemic antifungal therapy (France, 2005-2006). Of these ICU patients, 93 (median age 65 years, simplified acute physiology score II 52) had Candida peritonitis, including 73 nosocomial peritonitis, 53 concomitant bacterial peritoneal infections and 26 candidaemias. Candida species were C. albicans (n = 63/108 isolates, 58%), C. glabrata (n = 22, 20%), C. krusei (n = 9), C. kefyr (n = 5), C. parapsilosis (n = 3), C. tropicalis (n = 3), C. ciferii (n = 2) and C. lusitaniae (n = 1). Of tested isolates, 28% were fluconazole-resistant or susceptible dose-dependent (C. albicans 3/32, C. glabrata 9/14, C. krusei 4/4). Empiric antifungal treatment was started 1 day (median) after peritonitis diagnosis, with fluconazole (n = 2 patients), caspofungin (n = 12), voriconazole (n = 3), amphotericin B (n = 2), or a combination (n = 4). Following susceptibility testing, empiric antifungal treatment was judged inadequate in 9/45 (20%) patients and modified in 30 patients (fluconazole was replaced by caspofungin (n = 14) or voriconazole (n = 4)). Mortality in ICU was 38% (35/93) and was not influenced by type of Candida species, fluconazole susceptibility, time to treatment, candidaemia, nosocomial acquisition, or concomitant bacterial infection. No specific factors for death were identified. In summary, a high proportion of fluconazole-resistant or susceptible dose-dependent strains was cultured. These results confirm the high mortality rates of Candida peritonitis and plead for additional investigation in this population. Antifungal treatment for severe cases of Candida peritonitis in ICU patients remains the standard care.
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Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antifúngicos/farmacología , Candida/clasificación , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Candidiasis/microbiología , Candidiasis/mortalidad , Infección Hospitalaria/tratamiento farmacológico , Infección Hospitalaria/microbiología , Infección Hospitalaria/mortalidad , Femenino , Francia , Humanos , Unidades de Cuidados Intensivos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Peritonitis/microbiología , Peritonitis/mortalidad , Estudios Prospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
The objectives of this study were to investigate the participation of Candida albicans and non-albicans as colonization and sepsis agents, along with the risk factors associated with the neonates in the neonatal intensive care unit of the clinical hospital of the Federal University of Uberlândia. Epidemiological surveillance was implemented through the National Healthcare Safety Network between August 2007 and April 2008. The incidence rate for sepsis with microbiological criteria was 6.7/1,000 patients/day, which was shown as only one case of candidemia. Approximately 19% of the neonates were colonized by Candida, which was identified as Candida albicans (50%) and Candida not-albicans (50%). The significant risk factors for Candida spp colonization were gestational age of between 26 and 30 weeks, previous antibiotic use and umbilical central vascular catheter. The overall mortality among the neonates hospitalized with sepsis over the study period was 11.8%. However, the neonate with candidemia did not die.
Asunto(s)
Antifúngicos/farmacología , Candida/aislamiento & purificación , Candidiasis/microbiología , Infección Hospitalaria/microbiología , Unidades de Cuidado Intensivo Neonatal , Brasil , Candida/clasificación , Candidiasis/epidemiología , Candidiasis/mortalidad , Infección Hospitalaria/epidemiología , Fungemia/epidemiología , Fungemia/microbiología , Hospitales de Enseñanza , Humanos , Incidencia , Recién Nacido , Pruebas de Sensibilidad Microbiana , Factores de Riesgo , Vigilancia de Guardia , Sepsis/epidemiología , Sepsis/microbiologíaRESUMEN
Os objetivos desse estudo foram investigar a participação de Candida albicans e não-albicans como agente de colonização e sepse, bem como os fatores de risco associados aos neonatos internados na Unidade de Terapia Intensiva Neonatal do Hospital de Clínicas da Universidade Federal de Uberlândia. Foi realizada vigilância epidemiológica pelo sistema National Healthcare Safety Network no período entre agosto de 2007 e abril de 2008. A taxa de incidência de sepse com critério microbiológico foi de 6,7/1.000 paciente/dia, constatando-se apenas um caso de candidemia. Aproximadamente, 19 por cento dos neonatos estavam colonizados por Candida, identificadas como Candida albicans (50 por cento) e Candida não-albicans (50 por cento). Os fatores de risco significantes para colonização por Candida spp foram a idade gestacional entre 26 e 30 semanas, o uso prévio de antibiótico e o cateter vascular central umbilical. A mortalidade total foi de 11,8 por cento nos neonatos internados durante o período de estudo com sepse, porém o recém-nascido com candidemia não evoluiu para óbito.
The objectives of this study were to investigate the participation of Candida albicans and non-albicans as colonization and sepsis agents, along with the risk factors associated with the neonates in the neonatal intensive care unit of the clinical hospital of the Federal University of Uberlândia. Epidemiological surveillance was implemented through the National Healthcare Safety Network between August 2007 and April 2008. The incidence rate for sepsis with microbiological criteria was 6.7/1,000 patients/day, which was shown as only one case of candidemia. Approximately 19 percent of the neonates were colonized by Candida, which was identified as Candida albicans (50 percent) and Candida not-albicans (50 percent). The significant risk factors for Candida spp colonization were gestational age of between 26 and 30 weeks, previous antibiotic use and umbilical central vascular catheter. The overall mortality among the neonates hospitalized with sepsis over the study period was 11.8 percent. However, the neonate with candidemia did not die.
Asunto(s)
Humanos , Recién Nacido , Antifúngicos/farmacología , Candida/aislamiento & purificación , Candidiasis/microbiología , Infección Hospitalaria/microbiología , Unidades de Cuidado Intensivo Neonatal , Brasil , Candida/clasificación , Candidiasis/epidemiología , Candidiasis/mortalidad , Infección Hospitalaria/epidemiología , Fungemia/epidemiología , Fungemia/microbiología , Hospitales de Enseñanza , Incidencia , Pruebas de Sensibilidad Microbiana , Factores de Riesgo , Vigilancia de Guardia , Sepsis/epidemiología , Sepsis/microbiologíaRESUMEN
The risk factors for and clinical features of bloodstream infection with uncommon Candida spp. (species other than C. albicans, C. glabrata, C. parapsilosis, C. tropicals and C. krusei) are incompletely defined. To identify clinical variables associated with these species that might guide management, 57 cases of candidaemia resulting from uncommon Candida spp. were analysed in comparison with 517 episodes of Candida albicans candidaemia (2001-2004). Infection with uncommon Candida spp. (5.3% of candidaemia cases), as compared with C. albicans candidaemia, was significantly more likely to be outpatient-acquired than inpatient-acquired (15 of 57 vs. 65 of 517 episodes, p 0.01). Prior exposure to fluconazole was uncommon (n=1). Candida dubliniensis was the commonest species (n=22, 39%), followed by Candida guilliermondii (n=11, 19%) and Candida lusitaniae (n=7, 12%).C. dubliniensis candidaemia was independently associated with recent intravenous drug use (p 0.01) and chronic liver disease (p 0.03), and infection with species other than C. dubliniensis was independently associated with age<65 years (p 0.02), male sex (p 0.03) and human immunodeficiency virus infection (p 0.05). Presence of sepsis at diagnosis and crude 30-day mortality rates were similar for C. dubliniensis-related, non-C. dubliniensis-related and C. albicans-related candidaemia. Haematological malignancy was the commonest predisposing factor in C. guilliermondii (n=3, 27%) and C. lusitaniae (n=3, 43%) candidaemia. The 30-day mortality rate of C. lusitaniae candidaemia was higher than the overall death rate for all uncommon Candida spp. (42.9% vs. 25%, p not significant). All isolates were susceptible to amphotericin B, voriconazole, posaconazole, and caspofungin; five strains (9%) had fluconazole MIC values of 16-32 mg/L. Candidaemia due to uncommon Candida spp. is emerging among hospital outpatients; certain clinical variables may assist in recognition of this entity.
Asunto(s)
Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Candida , Candidiasis , Fungemia , Anciano , Australia/epidemiología , Candida/clasificación , Candida/efectos de los fármacos , Candida/aislamiento & purificación , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Candidiasis/mortalidad , Femenino , Fungemia/tratamiento farmacológico , Fungemia/microbiología , Fungemia/mortalidad , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Técnicas de Tipificación Micológica , Vigilancia de la Población , Factores de Riesgo , Especificidad de la EspecieRESUMEN
The balance between saturated and unsaturated fatty acids plays a crucial role in determining the membrane fluidity. In the diploid fungal pathogen Candida albicans, the gene for fatty acid Delta9 desaturase, OLE1, is essential for viability. Using a reverse genetic approach, termed the fitness test, we identified a group of structurally related synthetic compounds that induce specific hypersensitivity of the OLE1(+/-) strain. Genetic repression of OLE1 and chemical inhibition by two selected compounds, ECC145 and ECC188, resulted in a marked decrease in the total unsaturated fatty acids and impaired hyphal development. The resulting auxotroph of both was suppressed by the exogenous monounsaturated fatty acids (16:1Delta9 and 18:1Delta9). These correlations suggest that both compounds affect the level of unsaturated fatty acids, likely by impairing Ole1p directly or indirectly. However, the residual levels of monounsaturated fatty acids (MUFAs) resulted from chemical inhibition were significantly higher than OLE1 repression, indicating even partial inhibition of MUFAs is sufficient to stop cellular proliferation. Although the essentiality of OLE1 was suppressed by MUFAs in vitro, we demonstrated that it was required for virulence in a murine model of systemic candidiasis even when the animals were supplemented with a high fat diet. Thus, the fungal fatty acid desaturase is an attractive antifungal drug target. Taking advantage of the inhibitors and the relevant conditional shut-off strains, we validated several chemical genetic interactions observed in the fitness test profiles that reveal novel genetic interactions between OLE1/unsaturated fatty acids and other cellular processes.
Asunto(s)
Antifúngicos/farmacología , Candida albicans/genética , Ácidos Grasos Insaturados/biosíntesis , Perfilación de la Expresión Génica , Regulación Fúngica de la Expresión Génica/efectos de los fármacos , Animales , Antifúngicos/química , Candida albicans/metabolismo , Candida albicans/patogenicidad , Candidiasis/microbiología , Candidiasis/mortalidad , Cerulenina/farmacología , Análisis por Conglomerados , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismo , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Hifa/efectos de los fármacos , Hifa/genética , Hifa/crecimiento & desarrollo , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Mutación , Estearoil-CoA Desaturasa , Tasa de Supervivencia , Tiazoles/química , Tiazoles/farmacología , Factores de Tiempo , Triazoles/química , Triazoles/farmacología , Virulencia/genéticaRESUMEN
1. The aim of the present study was to investigate the effects of ascorbic acid (AA) on the antifungal activity of fluconazole (FCZ) in a systemic murine candidiasis model as well as in vitro. 2. The murine model was established by infusion of Candida albicans via the tail vein. Control mice received no further treatment. Other groups of mice were injected with FCZ (0.5 mg/kg, i.p.) and then treated or not with 50 or 500 mg/kg AA intragastrically (i.g.) or i.p. In all groups, FCZ was administered i.p. 2 h after fungal inoculation, whereas AA was administered 6 h after fungal inoculation. Survival rate, kidney fungal burden and renal pathological changes were evaluated. 3. The in vitro effects of AA (5, 1 and 0.2 mmol/L) on the growth of various Candida strains in the presence of FCZ (0.125-64 microg/mL) were also investigated. The in vitro effects of two anti-oxidants, namely N-acetylcysteine (NAC; 5, 1 and 0.2 mmol/L) and reduced glutathione (GSH; 5, 1 and 0.2 mmol/L), on FCZ activity were evaluated to determine the mechanism of action of AA. 4. Intragastric administration of AA (50 or 500 mg/kg) significantly decreased the antifungal effect of 0.5 mg/kg FCZ. Although i.p. administration of AA (50 or 500 mg/kg) had no significant effect on the survival of mice, it dose-dependently inhibited the activity of FCZ, with significant inhibition observed with 500 mg/kg AA. 5. In vitro, AA decreased the activity of FCZ against various Candida strains. Both NAC and GSH dose-dependently decreased the activity of FCZ. 6. The results of the present study indicate that AA inhibits the antifungal activity of FCZ, suggesting that the two should not be used together clinically for the treatment of candidiasis.
Asunto(s)
Antifúngicos/uso terapéutico , Ácido Ascórbico/farmacología , Candidiasis/tratamiento farmacológico , Fluconazol/uso terapéutico , Animales , Antifúngicos/farmacología , Antioxidantes/farmacología , Candida albicans/efectos de los fármacos , Candidiasis/mortalidad , Modelos Animales de Enfermedad , Antagonismo de Drogas , Evaluación Preclínica de Medicamentos , Farmacorresistencia Fúngica/efectos de los fármacos , Fluconazol/farmacología , Ratones , Pruebas de Sensibilidad MicrobianaRESUMEN
Invasive fungal infection is an important cause of mortality and morbidity in very low birthweight (VLBW) infants. Extremely preterm and extremely low birthweight infants are at highest risk because of the intensive and invasive nature of the care that these infants receive. Additional specific risk factors include prolonged use of parenteral nutrition and exposure to broad-spectrum antibiotics and histamine type 2 receptor blockers. Diagnosis is difficult and often delayed, and this may contribute to the high levels of deep-organ dissemination and associated mortality and morbidity. The most commonly used antifungal agents are amphotericin B and fluconazole. Recent research has assessed the value of early empirical and prophylactic treatment. However, although systemic antifungal prophylaxis reduces the incidence of invasive fungal infection, there is no evidence of effect on mortality. Concern exists about the impact that widespread use of prophylaxis may have on the emergence of antifungal resistance.