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1.
Minerva Med ; 111(5): 443-454, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32955824

RESUMO

Mutation within the FMS-like tyrosine kinase 3 (FLT3) gene are one of the most frequent genetic alterations in acute myeloid leukemia. A high mutation fraction of FLT3-ITD molecules on the surface of leukemia cells is associated with short remissions and overall adverse outcomes in AML. In this article we summarize the clinical trial data of midostaurin - one of the FLT3 inhibitors. We review its use in various combinations both in relapsed/refractory acute myeloid leukemia as well as in the newly diagnosed patients and recollect the evidence of its use as maintenance therapy post allogenic stem cell transplantation. We enumerate the practical issues faced in the use of midostaurin like antifungal prophylaxis, dosage of concomitant chemotherapy agents as well as available data on sequencing of the FLT3 inhibitors. Lastly, we provide our perspective of the future directions for FLT3 inhibition especially midostaurin, the underlying resistance mechanisms and the need for standardization of the FLT3 tests.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Estaurosporina/análogos & derivados , Tirosina Quinase 3 Semelhante a fms/genética , Compostos de Anilina/uso terapêutico , Antraciclinas/uso terapêutico , Antifúngicos/uso terapêutico , Antineoplásicos/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Citarabina/uso terapêutico , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Equinocandinas/uso terapêutico , Previsões , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Quimioterapia de Manutenção , Mutação , Micoses/prevenção & controle , Inibidores de Proteínas Quinases/metabolismo , Pirazinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Estaurosporina/metabolismo , Estaurosporina/uso terapêutico , Triazóis/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores
2.
Sci Rep ; 10(1): 6238, 2020 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277126

RESUMO

Candida glabrata readily develops resistance to echinocandins. Identification, antifungal susceptibility testing (AST) and resistance mechanism to echinocandins among C. glabrata was determined in Kuwait. C. glabrata isolates (n = 75) were tested by Vitek2, multiplex PCR and/or PCR-sequencing of rDNA. AST to fluconazole, caspofungin, micafungin and amphotericin B was determined by Etest and to micafungin by broth microdilution (BMD). Mutations in hotspot-1/hotspot-2 of FKS1/FKS2 and ERG11 were detected by PCR-sequencing. All isolates were identified as C. glabrata sensu stricto. Seventy isolates were susceptible and five were resistant to micafungin by Etest and BMD (essential agreement, 93%; categorical agreement, 100%). Three micafungin-resistant isolates were resistant and two were susceptible dose-dependent to caspofungin. Four and one micafungin-resistant isolate contained S663P and ∆659 F mutation, respectively, in hotspot-1 of FKS2. Micafungin-resistant isolates were genotypically distinct strains. Only one of 36 fluconazole-resistant isolate contained nonsynonymous ERG11 mutations. Thirty-four of 36 fluconazole-resistant isolates were genotypically distinct strains. Our data show that micafungin susceptibility reliably identifies echinocandin-resistant isolates and may serve as a surrogate marker for predicting susceptibility/resistance of C. glabrata to caspofungin. All micafungin-resistant isolates also harbored a nonsynonymous/deletion mutation in hotspot-1 of FKS2. Fingerprinting data showed that echinocandin/fluconazole resistance development in C. glabrata is not clonal.


Assuntos
Antifúngicos/farmacologia , Candida glabrata/genética , Candidemia/epidemiologia , Farmacorresistência Fúngica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Candida glabrata/efeitos dos fármacos , Candida glabrata/isolamento & purificação , Candidemia/tratamento farmacológico , Candidemia/microbiologia , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Feminino , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Proteínas Fúngicas/genética , Glucosiltransferases/genética , Humanos , Kuweit/epidemiologia , Masculino , Micafungina/farmacologia , Micafungina/uso terapêutico , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Epidemiologia Molecular , Filogenia , Deleção de Sequência
3.
Int J Antimicrob Agents ; 55(3): 105901, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31954831

RESUMO

Antifungal combination is an interesting approach for the treatment of several fungal infections but there is currently little evidence to support combined therapy in Candida auris infections. The antibacterial colistin has recently been shown to interact synergistically with antifungals against Candida spp., including azole-resistant isolates. The current study evaluated the in vitro interaction between colistin and either caspofungin or micafungin against 15 C. auris isolates by a checkerboard methodology based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) reference method. Results were analysed by two approaches: calculation of the fractional inhibitory concentration index (FICI) and response surface analysis based on the Bliss model. The minimum inhibitory concentration (MIC) range (geometric mean [Gmean]) of caspofungin and micafungin was 0.25 to 1 µg/mL (0.691 µg/mL) and 0.03 to 0.125 µg/mL (0.114 µg/mL), respectively. No activity was observed for colistin alone with MIC of >64 µg/mL for all the isolates. When colistin was combined with caspofungin, synergistic interactions were observed for all strains with FICI values of 0.08 to 0.14. In contrast, indifferent interactions were observed for the combination of colistin with micafungin with FICI values of 0.51 to 1.01. Synergy was also demonstrated using the Bliss model against all isolates for the colistin-caspofungin combination and in 60% of isolates for the colistin-micafungin combination. Antagonism was not observed for any combination.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Colistina/farmacologia , Equinocandinas/farmacologia , Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Caspofungina/farmacologia , Caspofungina/uso terapêutico , Colistina/uso terapêutico , Sinergismo Farmacológico , Equinocandinas/uso terapêutico , Humanos , Micafungina/farmacologia , Micafungina/uso terapêutico
4.
Semin Respir Crit Care Med ; 41(1): 3-12, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32000280

RESUMO

Invasive candidiasis (IC) is the most frequent health care associated invasive fungal infection. It is also associated with high morbidity, mortality, and cost. The most frequent etiologic agent is Candida albicans, but non-albicans species are increasing and associated with reduced antifungal susceptibility and outbreaks. Candida auris is an emerging multidrug-resistant species recently described. IC presents as a spectrum of disease, going from fungemia to deep-seated candidiasis, and to septic shock with multiorgan failure. Diagnosis of IC is challenging. Several biomarkers and molecular methods are available for improving diagnosis. Early initial treatment with echinocandins is the treatment of choice. Step-down therapy when antifungal susceptibility is available is possible. Several new antifungal agents for the treatment of IC are in clinical development.


Assuntos
Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/epidemiologia , Candida/efeitos dos fármacos , Candidíase Invasiva/microbiologia , Farmacorresistência Fúngica Múltipla , Equinocandinas/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana
5.
Curr Top Microbiol Immunol ; 425: 255-275, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31875267

RESUMO

Antifungal therapy is a critical component of patient management for invasive fungal diseases. Yet, therapeutic choices are limited as only a few drug classes are available to treat systemic disease, and some infecting strains are resistant to one or more drug classes. The ideal antifungal inhibits a fungal-specific essential target not present in human cells to avoid off-target toxicities. The fungal cell wall is an ideal drug target because its integrity is critical to cell survival and a majority of biosynthetic enzymes and wall components is unique to fungi. Among currently approved antifungal agents and those in clinical development, drugs targeting biosynthetic enzymes of the cell wall show safe and efficacious antifungal properties, which validates the cell wall as a target. The echinocandins, which inhibit ß-1,3-glucan synthase, are recommended as first-line therapy for Candida infections. Newer cell wall-active drugs in clinical development encompass next-generation glucan synthase inhibitors including a novel echinocandin and an enfumafungin, an inhibitor of Gwt1, a key component of GPI anchor protein biosynthesis, and a classic inhibitor of chitin biosynthesis. As the cell wall is rich in potential drug discovery targets, it is primed to help deliver the next generation of antifungal drugs.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Parede Celular/efeitos dos fármacos , Fungos/citologia , Fungos/efeitos dos fármacos , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Humanos
6.
Curr Top Microbiol Immunol ; 425: 277-296, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31807895

RESUMO

Proper structure and function of the fungal cell wall are controlled by metabolic processes, as well as an interplay between a range of cellular organelles. Somewhat surprisingly, mitochondrial function has been shown to be important for proper cell wall biogenesis and integrity. Mitochondria also play a role in the susceptibility of fungi to cell wall-targeting drugs. This is true in a range of fungal species, including important human fungal pathogens. The biochemical mechanisms that explain the roles of mitochondria in cell wall biology have remained elusive, but studies to date strongly support the idea that mitochondrial control over cellular lipid homeostasis is at the core of these processes. Excitingly, recent evidence suggests that the mitochondria-lipid linkages drive resistance to the echinocandin drug caspofungin, a clinically important therapeutic that targets cell wall biosynthesis. Here, we review the state of affairs in mitochondria-fungal cell wall research and propose models that could be tested in future studies. Elucidating the mechanisms that drive fungal cell wall integrity through mitochondrial functions holds promise for developing new strategies to combat fungal infections, including the possibility to potentiate the effects of antifungal drugs and curb drug resistance.


Assuntos
Parede Celular , Fungos/citologia , Fungos/patogenicidade , Mitocôndrias/metabolismo , Micoses/microbiologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Parede Celular/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fungos/efeitos dos fármacos , Humanos , Micoses/tratamento farmacológico
7.
Mycopathologia ; 185(2): 377-388, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31853871

RESUMO

INTRODUCTION: Cases of invasive Trichosporon infections have increasingly emerged; it is now the second leading cause of yeast bloodstream infections after Candida spp., particularly in the immunosuppressed population, where it often causes breakthrough fungemia with high mortality. METHODS: We present a case report of a breakthrough Trichosporon asahii infection in a patient with acute myeloid leukemia and review all of the cases of breakthrough Trichosporon spp. infections published in the literature to date. RESULTS: We extracted 68 cases of breakthrough Trichosporon spp. infections, wherein 95.5% patients had hematological malignancy, 61.8% of them occurred in the presence of echinocandins, 22% of triazoles, 13.2% of amphotericin and 3% of other combinations of antifungals. The most prevalent manifestation was fungemia (94%); 82.8% of these were associated with the presence of a central venous catheter. The overall mortality was 68.7%; the patients who survived recovered from the neutropenic event. CONCLUSIONS: Invasive trichosporonosis is an acute fatal condition that occurs in immunosuppressed patients, usually under antifungal selective pressure. Typically, neutropenia and its underlying diseases are associated with adverse outcomes.


Assuntos
Leucemia Mieloide Aguda/complicações , Trichosporon/isolamento & purificação , Tricosporonose , Voriconazol/uso terapêutico , Adulto , Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Cateteres Venosos Centrais/efeitos adversos , Equinocandinas/uso terapêutico , Fungemia/patologia , Neoplasias Hematológicas/complicações , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Mortalidade , Neutropenia/complicações , Triazóis/uso terapêutico , Tricosporonose/complicações , Tricosporonose/tratamento farmacológico , Tricosporonose/patologia
8.
Int J Antimicrob Agents ; 55(1): 105820, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31622654

RESUMO

Evidence supporting the use of an echinocandin alone as an alternative agent for the treatment of Pneumocystis jirovecii pneumonia (PCP) is limited and controversial. This retrospective cohort study was conducted at National Taiwan University Hospital from 1 July 2015 to 31 December 2017. Using multivariable Cox regression analyses, the outcomes of patients receiving trimethoprim/sulfamethoxazole (TMP-SMZ) or anidulafungin single therapy as an alternative treatment for PCP were investigated. A total of 207 patients with PCP were screened and 170 patients were included in the final analysis, among whom 134 (78.8%) received TMP-SMZ and 36 (21.2%) received anidulafungin as alternative anti-PCP treatment. Overall 60-day mortality was 34.1% (58/170), and 60-day mortality did not differ significantly between the anidulafungin group (38.9%; 14/36) and the TMP-SMZ group (32.8%; 44/134) (P = 0.554). Age ≥60 years [hazard ratio (HR) = 1.840, 95% confidence interval (CI) 1.039-3.259; P = 0.036] and HIV infection (HR = 0.102, 95% CI 0.013-0.771; P = 0.027) independently predicted 60-day mortality. Patients with lower SpO2/FiO2 ratio (HR = 0.994, 95% CI 0.990-0.998; P = 0.005) showed a higher 60-day mortality. In the Kaplan-Meier survival analysis, anidulafungin as alternative anti-PCP treatment was not correlated with higher mortality (P = 0.605). Using TMP-SMZ or anidulafungin as alternative anti-PCP treatment had similar 60-day mortality. These findings suggest that anidulafungin therapy may be an effective and alternative treatment for PCP in patients who cannot tolerate TMP-SMZ.


Assuntos
Anidulafungina/uso terapêutico , Antifúngicos/uso terapêutico , Equinocandinas/uso terapêutico , Pneumocystis carinii/efeitos dos fármacos , Pneumonia por Pneumocystis/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pneumonia por Pneumocystis/microbiologia , Estudos Retrospectivos , Taiwan , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos , Adulto Jovem
9.
Med Mycol ; 58(2): 219-226, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31111912

RESUMO

Candidemia is widely reported as the fourth most common form of bloodstream infection worldwide. Reports of breakthrough cases of candidemia are increasing, especially in the context of a move away from azole antifungals as prophylactic or first line treatment toward the use of echinocandin agents. The global evaluation of echinocandin antifungal susceptibility since 2003 has included switches in testing methodologies and the move to a sentinel echinocandin approach for classification reporting. This study compiles previously unpublished data from echinocandin susceptibility testing of UK clinical isolates of C. glabrata received at the Public Health England Mycology Reference Laboratory from 2003 to 2016 and reevaluates the prevalence of resistance in light of currently accepted testing protocols. From 2015 onward, FKS gene mutation detection using a novel Pyrosequencing® assay was assessed as a predictor of echinocandin resistance alongside conventional susceptibility testing. Overall, our data show that echinocandin resistance in UK isolates of C. glabrata is a rare phenomenon and prevalence has not appreciably increased in the last 14 years. The pyrosequencing assay was able to successfully detect hot spot mutations in FKS1 and FKS2, although not all isolates that exhibited phenotypic resistance demonstrated detectable hot spot mutations. We propose that a rapid genomic based detection method for FKS mutations, as part of a multifactorial approach to susceptibility testing, could help provide accurate and timely management decisions especially in regions where echinocandin resistance has been reported to be emerging in this important pathogen.


Assuntos
Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Candidíase/microbiologia , Farmacorresistência Fúngica Múltipla/genética , Equinocandinas/farmacologia , Proteínas Fúngicas/genética , Antifúngicos/uso terapêutico , Candida glabrata/genética , Candidíase/tratamento farmacológico , Equinocandinas/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Testes de Sensibilidade Microbiana , Mutação , Prevalência , Reino Unido
10.
Int J Infect Dis ; 89: 137-145, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639522

RESUMO

OBJECTIVES: Recommendations in clinical practice guidelines (CPG) may differ and cause confusion. Our objective was to appraise CPGs for antifungal treatment of invasive candidiasis (IC) in non-neutropenic critically ill adult patients. METHODS: We systematically searched the literature for CPGs published between 2008 and 2018. We assessed the quality of each guideline using six domains of the AGREE II instrument. We extracted and compared recommendations for different treatment strategies and assessed content quality. RESULTS: Of 19 guidelines, the mean overall AGREE II score was 58%. The domain 'clarity of presentation' received the highest scores (88%) and 'applicability' the lowest (18%). CPGs provided detailed recommendations on antifungal prophylaxis (n = 10), with fluconazole recommended as initial prophylaxis in all seven CPGs citing a specific drug. Echinocandin was recommended as the initial drug in all 16 CPGs supporting empirical/pre-emptive treatment; and in 18 of 19 for targeted invasive candidiasis treatment. However, it remains unclear when to initiate prophylaxis, empirical or pre-emptive therapy or when to step down. CONCLUSIONS: The methodological quality of CPGs for antifungal treatment of IC in non-neutropenic critically ill patients is suboptimal. Some treatment recommendations were inconsistent across indications and require local guidance to help clinicians make better informed decisions.


Assuntos
Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Estado Terminal/terapia , Equinocandinas/uso terapêutico , Fluconazol/uso terapêutico , Humanos , Guias de Prática Clínica como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Infez Med ; 27(3): 251-257, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545768

RESUMO

The emergence of antibiotic resistance as a consequence of inappropriate use results in higher mortality rates and has become a major public health challenge worldwide. Antimicrobial stewardship programs (ASPs) aim to ensure proper use of antimicrobials and reduce health care costs. We assessed the impact of using a behavioral approach during a persuasive ASP on antibiotic appropriateness, consumption and costs. We conducted a prospective interventional cohort before-and-after study in the intensive care unit (ICU) of a 554-bed, university teaching hospital in Terni, Italy, 14 of which are located in the ICU. We describe a 10-month persuasive ASP intervention model used in a referral ICU with daily rounds. The aim of the study was to improve medication appropriateness through educational action and reduce the consumption of carbapenems and echinocandins by conducting post-prescription reviews, prescribing reviews and holding daily discussions with the ICU team. We analyzed the prescribing appropriateness of the ICU team in accordance with the decisions made by the Antimicrobial Stewardship (AMS) team to improve the quality of antibiotic prescribing during the first five months and the last five months of the surveillance period. The results were expressed as the defined daily dose (DDD) per 100 occupied bed-days and costs. The data were compared with those previously obtained during the pre-educational period (the year before ASP implementation). Comparisons were made between the decisions taken to improve antimicrobial treatments administered during the first half of the surveillance period (March-July) and those administered during the second half (August-December). In all, 116 decisions were made from March to July while only 65 were made from August to December (p-value 0.00001). A significant reduction was observed in the consumption of carbapenems and echinocandins (11.15% and 25.62%, respectively). Total antibiotic cost savings amounted to 57,541.16 euros. The persuasive ASP strategy positively influenced the prescribing behavior of physicians, thus improving the appropriateness of antibiotic therapy and reducing antimicrobial consumption.


Assuntos
Gestão de Antimicrobianos , Carbapenêmicos/uso terapêutico , Farmacorresistência Bacteriana , Equinocandinas/uso terapêutico , Prescrição Inadequada/prevenção & controle , Unidades de Terapia Intensiva , Carbapenêmicos/economia , Estudos Controlados Antes e Depois , Equinocandinas/economia , Hospitais de Ensino , Humanos , Itália , Modelos Organizacionais , Estudos Prospectivos , Fatores de Tempo
12.
Acta Biochim Pol ; 66(3): 361-364, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31518088

RESUMO

PURPOSE: Candida spp. are ranked as one of the four major causative agents of fungal infections. The number of infections caused by Candida species resistant to fluconazole, which is applied as the first line drug in candidiasis treatment, increases every year. In such cases the application of echinocandin is necessary. Echinocandin susceptibility testing has become a routine laboratory practice in many countries due to the increasing frequency of clinical failures during treatment with these drugs. METHODS: We performed anidulafungin, micafungin and caspofungin susceptibility testing according to the microdilution broth method on 240 Candida isolates collected in Polish hospitals. RESULTS: We identified 12 isolates resistant to all echinocandins within 240 examined isolates. Moreover, 6 of the examined samples were identified as rare Candida species and among them we observed very high echinocandin MIC values. CONCLUSION: Our research proves that in Poland there is a problem of echinocandin resistance. Moreover, we identified two species of Candida which are rare causative agents of human infections, and there was no reported incidence of such infections in Poland until now.


Assuntos
Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/epidemiologia , Farmacorresistência Fúngica/efeitos dos fármacos , Equinocandinas/uso terapêutico , Anidulafungina/uso terapêutico , Candida/isolamento & purificação , Candidíase/microbiologia , Caspofungina/uso terapêutico , Equinocandinas/efeitos adversos , Humanos , Micafungina/uso terapêutico , Testes de Sensibilidade Microbiana , Polônia/epidemiologia
13.
BMC Infect Dis ; 19(1): 570, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262263

RESUMO

BACKGROUND: Kodamaea ohmeri is a yeast is frequently mistaken for Candida, which belongs to the same family. This micro-organism has been reported to cause life-threatening infections in humans. CASE PRESENTATION: A 81-year-old woman developed a severe fungemic pulmonary infection due to Kodamaea ohmeri that was identified from bronchoalveolar fluid and blood cultures, which is unusual in immunocompetent patients. Because K. ohmeri was first wrongly identified as Candida albicans, the patient inadequately received caspofungin, which was clinically ineffective, especially as the strain was resistant to echinocandins. Clinical cure was obtained after treatment was switched to voriconazole. CONCLUSIONS: An increasing number of serious infections due to K. ohmeri has been reported in the literature, but the correct identification of this micro-organism remains difficult.


Assuntos
Fungemia/tratamento farmacológico , Fungemia/microbiologia , Saccharomycetales/patogenicidade , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Candida albicans/patogenicidade , Erros de Diagnóstico , Farmacorresistência Fúngica/efeitos dos fármacos , Equinocandinas/uso terapêutico , Feminino , Humanos , Testes de Sensibilidade Microbiana , Saccharomycetales/efeitos dos fármacos , Voriconazol/uso terapêutico
15.
Int J Infect Dis ; 86: 142-146, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31330325

RESUMO

OBJECTIVE: To describe the pharmacokinetic (PK) profile of anidulafungin and to evaluate its concentration in the peritoneal fluid (PF) of patients suspected of suffering from peritoneal infection undergoing abdominal surgery, in order to ensure that therapeutic levels are achieved within the peritoneal cavity. METHODS: A descriptive, open, prospective, observational, multicentre and non-interventional study was performed. Anidulafungin was used at conventional doses. Blood and PF samples were obtained on day 2 of treatment or on any of the following days. RESULTS: A total of 31 patients in a serious clinical condition, as demonstrated by high mean clinical severity scale scores (APACHE II and SOFA scores), were included in the study. The mean area under the curve (AUC) in PF was 30% (31±19%) of that determined in the plasma and the maximum concentration (Cmax) reached in PF (mg/l) was close to 1 (0.9±0.5). No adverse effects were observed in any of the 31 patients. CONCLUSIONS: Anidulafungin at conventional doses reaches PF concentrations that exceed the minimum inhibitory concentration of the usual Candida spp, which explains the proven efficacy of this echinocandin in the treatment of Candida peritonitis in critically ill patients.


Assuntos
Anidulafungina/farmacocinética , Antifúngicos/farmacocinética , Candidíase/tratamento farmacológico , Estado Terminal , Peritonite/tratamento farmacológico , APACHE , Idoso , Idoso de 80 Anos ou mais , Anidulafungina/uso terapêutico , Antifúngicos/uso terapêutico , Área Sob a Curva , Líquido Ascítico/metabolismo , Candida/efeitos dos fármacos , Equinocandinas/uso terapêutico , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Peritonite/microbiologia , Estudos Prospectivos
16.
J Infect Chemother ; 25(10): 743-749, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31257156

RESUMO

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


Assuntos
Antifúngicos/farmacologia , Candida/isolamento & purificação , Candidíase/tratamento farmacológico , Antifúngicos/uso terapêutico , Azóis/farmacologia , Azóis/uso terapêutico , Candida/efeitos dos fármacos , Candida/patogenicidade , Candidíase/epidemiologia , Candidíase/microbiologia , Farmacorresistência Fúngica Múltipla , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Humanos , Japão/epidemiologia , Testes de Sensibilidade Microbiana , Polienos/farmacologia , Polienos/uso terapêutico , Prevalência
18.
Int J Antimicrob Agents ; 53(6): 789-794, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30831231

RESUMO

OBJECTIVE: The aim of this meta-analysis was to assess the efficacy and safety of treatment with echinocandins compared with amphotericin B in paediatric patients with invasive candidiasis. METHODS: PubMed, Embase and Cochrane databases were searched up to August 2018. Only randomized controlled trials (RCTs) evaluating echinocandins and amphotericin B in the treatment of paediatric patients with invasive candidiasis were included. The outcomes were clinical responses and adverse effects. RESULTS: Five RCTs of 354 patients (191 patients in the echinocandins group and 163 patients in the amphotericin B group) were included in this study. Overall, no significant differences in clinical response were found between echinocandins and amphotericin B (odds ratio [OR], 1.38; 95% confidence interval [CI], 0.68-2.80; I2 = 39%). Similar results were also observed in the high-risk group (OR, 3.10; 95% CI, 0.10-97.23; I2 = 76%), the low-risk group (OR, 1.29; 95% CI, 0.36-4.62; I2 = 21%) and the neutropenia group (OR, 1.56; 95% CI, 0.75-3.26; I2 = 0%). The risk of discontinuing treatment because of adverse effects was significantly lower in the echinocandins group than in the amphotericin B group (OR, 0.30, 95% CI, 0.12-0.76; I2 = 0%). CONCLUSIONS: There were no differences in efficacy between the echinocandins group and the amphotericin B group in the treatment of invasive candidiasis in paediatric patients. However, the echinocandins group had a significantly lower risk of discontinuing treatment than the amphotericin B group.


Assuntos
Anfotericina B/uso terapêutico , Antifúngicos/uso terapêutico , Candidíase Invasiva/tratamento farmacológico , Equinocandinas/uso terapêutico , Adolescente , Anfotericina B/efeitos adversos , Antifúngicos/efeitos adversos , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Equinocandinas/efeitos adversos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Suspensão de Tratamento/estatística & dados numéricos
19.
Med Oral Patol Oral Cir Bucal ; 24(2): e172-e180, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818309

RESUMO

BACKGROUND: Candidiasis is one of the most common opportunistic oral infections that presents different acute and chronic clinical presentations with diverse diagnostic and therapeutic approaches. The present study carries out a bibliographic review on the therapeutic tools available against oral candidiasis and their usefulness in each clinical situation. MATERIAL AND METHODS: Recent studies on treatment of oral candidiasis were retrieved from PubMed and Cochrane Library. RESULTS: Nystatin and miconazole are the most commonly used topical antifungal drugs. Both antifungal drugs are very effective but need a long time of use to eradicate the infection. The pharmacological presentations of miconazole are more comfortable for patients but this drug may interact with other drugs and this fact should be assessed before use. Other topical alternatives for oral candidiasis, such as amphotericin B or clotrimazole, are not available in many countries. Oral fluconazole is effective in treating oral candidiasis that does not respond to topical treatment. Other systemic treatment alternatives, oral or intravenous, less used are itraconazole, voriconazole or posaconazole. Available novelties include echinocandins (anidulafungin, caspofungin) and isavuconazole. Echinocandins can only be used intravenously. Isavuconazole is available for oral and intravenous use. Other hopeful alternatives are new drugs, such as ibrexafungerp, or the use of antibodies, cytokines and antimicrobial peptides. CONCLUSIONS: Nystatin, miconazole, and fluconazole are very effective for treating oral candidiasis. There are systemic alternatives for treating recalcitrant infections, such as the new triazoles, echinocandins, or lipidic presentations of amphotericin B.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candidíase Bucal/tratamento farmacológico , Administração Intravenosa , Administração Oral , Administração Tópica , Anfotericina B/uso terapêutico , Anidulafungina/uso terapêutico , Azóis/uso terapêutico , Caspofungina/uso terapêutico , Clotrimazol/uso terapêutico , Bases de Dados Factuais , Interações Medicamentosas , Equinocandinas/uso terapêutico , Fluconazol/uso terapêutico , Humanos , Miconazol/uso terapêutico , Nitrilos/uso terapêutico , Nistatina/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico
20.
Intensive Care Med ; 45(6): 789-805, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30911804

RESUMO

INTRODUCTION: The term invasive candidiasis (IC) refers to both bloodstream and deep-seated invasive infections, such as peritonitis, caused by Candida species. Several guidelines on the management of candidemia and invasive infection due to Candida species have recently been published, but none of them focuses specifically on critically ill patients admitted to intensive care units (ICUs). MATERIAL AND METHODS: In the absence of available scientific evidence, the resulting recommendations are based solely on epidemiological and clinical evidence in conjunction with expert opinion. The task force used the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the recommendations and assign levels of evidence. The recommendations and their strength were decided by consensus and, if necessary, by vote (modified Delphi process). Descriptive statistics were used to analyze the results of the Delphi process. Statements obtaining > 80% agreement were considered to have achieved consensus. CONCLUSIONS: The heterogeneity of this patient population necessitated the creation of a mixed working group comprising experts in clinical microbiology, infectious diseases and intensive care medicine, all chosen on the basis of their expertise in the management of IC and/or research methodology. The working group's main goal was to provide clinicians with clear and practical recommendations to optimize microbiological diagnosis and treatment of IC. The Systemic Inflammation and Sepsis and Infection sections of the European Society of Intensive Care Medicine (ESICM) and the Critically Ill Patients Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) therefore decided to develop a set of recommendations for application in non-immunocompromised critically ill patients.


Assuntos
Antifúngicos/uso terapêutico , Candidíase Invasiva/terapia , Gerenciamento Clínico , Candidíase Invasiva/complicações , Estado Terminal/terapia , Técnica Delfos , Equinocandinas/uso terapêutico , Fluconazol/uso terapêutico , Humanos , Unidades de Terapia Intensiva/organização & administração , Unidades de Terapia Intensiva/estatística & dados numéricos , Sepse/complicações , Sepse/terapia
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