Class of 2012 Abstract / Specific Aims: The primary aim of this study was to determine the incidence of posaconazole and voriconazole concentration monitoring that occurs in transplant patients receiving antifungal prophylaxis therapy. The secondary aim was to determine whether voriconazole and posaconazole serum concentrations were used for dose adjustments. Methods: Patients status post either a liquid or solid organ transplant over the age of 1 year who received invasive fungal infection prophylaxis with either posaconazole or voriconazole between the dates of February 1, 2010 through January 31, 2011 while admitted to academic medical center were included in this descriptive retrospective study. This study has been approved by the Institutional Review Board. Data collected on each subject included demographic information, type of transplant, posaconazole or voriconazole concentrations, and duration and dosage adjustments. Main Results: 54 subjects were identified who received either voriconazole or posaconazole for fungal prophylaxis after transplant. For subjects who were prescribed posaconazole (N = 8), concentration monitoring was performed in 50% of subjects and 0% of posaconazole dose adjustments were based on concentrations. For subjects who were prescribed voriconazole, concentration monitoring and dose adjustments based on voriconazole concentrations were performed in 20% and 78% of subjects respectively. Adverse outcomes associated with the use of antifungal therapy were reported in 0% of the posaconazole therapy group and 17% of the voriconazole therapy group. Conclusions: Both posaconazole and voriconazole concentrations were obtained from patients who were receiving antifungal therapy for invasive fungal infection prophylaxis. Adjustments of prophylactic doses are not well characterized.

Orientador: Ricardo de Souza Cavalcante / Resumo: Introdução. A candidemia tem-se tornado cada vez mais frequente nos hospitais e apresentado elevada mortalidade. Conhecer a epidemiologia e os fatores prognósticos permite melhor manejo clínico desta infecção. Diante disto, este estudo teve por objetivo avaliar a incidência da candidemia em um hospital de ensino durante os últimos anos, a mortalidade, a prevalência das espécies causadoras da infecção, bem como os fatores prognósticos. Métodos. Este foi um estudo de coorte não concorrente, com pacientes atendidos no Hospital das Clínicas da Faculdade de Medicina de Botucatu (HCFMB), que apresentaram diagnóstico de candidemia durante sua internação, entre os anos de 2012 e 2019. Os dados clínicos foram obtidos a partir do prontuário médico. Para a avaliação dos fatores associados ao prognóstico, em análise univariada e múltipla, foi utilizado o modelo de Regressão Proporcional de Cox. Foram consideradas significativas as variáveis com valores de p inferiores a 0,05. Resultados. Ocorreram 314 episódios de candidemia em 288 pacientes. A taxa de incidência foi de 1,66/1000 admissões. A espécie mais prevalente foi Candida albicans (38,8%), seguida de complexo C. parapsilosis (20,4%), C. tropicalis (15,3%), C. glabrata (10,8%) e C. krusei (2,5%). Na população pediátrica houve predomínio de complexo C. parapsilosis (p<0,0001) e C. glabrata nos adultos (p=0,002). A taxa de mortalidade em 30 dias foi de 43,4%, sendo maior em adultos do que pacientes pediátricos (19,3% vs 54,0%; p<0,01)... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction. Candidemia has become increasingly frequent in hospitals and has shown high mortality. Knowing the epidemiology and prognostic factors allows better clinical management of this infection. In view of this, this study aimed to evaluate the incidence of candidemia in a teaching hospital during the past few years, mortality, the prevalence of species causing the infection, as well as prognostic factors. Methods. Non-concurrent cohort study was carried out, with inpatients at the Hospital das Clínicas, Faculdade de Medicina de Botucatu (HCFMB), who presented a diagnosis of candidemia during their hospitalization, between the years 2012 and 2019. The clinical data were obtained from the medical records. For the assessment of factors associated with prognosis, in univariate and multiple analysis, the Cox Proportional Regression model was used. Variables with p values below 0.05 were considered significant. Results. There were 314 episodes of candidemia in 288 patients. The incidence rate was 1.66 / 1000 admissions. The most prevalent species was Candida albicans (38.8%), followed by C. parapsilosis complex (20.4%), C. tropicalis (15.3%), C. glabrata (10.8%) and C. krusei (2.5%). In the pediatric population, there was a predominance of the C. parapsilosis complex (p <0.0001) and C. glabrata in adults (p=0.002). The 30-day mortality rate was 43.4%, being higher in adults than pediatric patients (19.3% vs 54.0%; p<0.01). Independent factors of mortality were liver cirrhos... (Complete abstract click electronic access below) / Mestre

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. Infectious Diseases Society of America considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. Coccidioidomycosis, also known as San Joaquin Valley fever, is a systemic infection endemic to parts of the southwestern United States and elsewhere in the Western Hemisphere. Residence in and recent travel to these areas are critical elements for the accurate recognition of patients who develop this infection. In this practice guideline, we have organized our recommendations to address actionable questions concerning the entire spectrum of clinical syndromes. These can range from initial pulmonary infection, which eventually resolves whether or not antifungal therapy is administered, to a variety of pulmonary and extrapulmonary complications. Additional recommendations address management of coccidioidomycosis occurring for special at-risk populations. Finally, preemptive management strategies are outlined in certain at-risk populations and after unintentional laboratory exposure.

Orientador: James Venturini / Resumo: A paracoccidioidomicose (PCM) é micose sistêmica causada por fungos do gênero Paracoccidioides. As principais formas clínicas da doença são aguda/subaguda e crônica (FC), sendo que nessa última, a maioria dos pacientes desenvolvem fibrose pulmonar e enfisema. Estudos prévios demonstraram que pacientes FC, na forma ativa da doença, apresentam elevada produção de mediadores inflamatórios, incluindo a IL-1β. Essa citocina, diferente das demais, é produzidas por uma plataforma protéica intracelular denominada inflamassoma que pode ser ativadas por patógenos e sinais de dano do hospedeiro. Considerando-se que os mecanismos de ativação do inflamassoma em pacientes com PCM não são conhecidos, o presente estudo teve por objetivo determinar a expressão de genes envolvidos na ativação do inflamassoma e a produção de citocinas por monócitos e macrófagos alveolares de pacientes com PCM em diferentes momentos do tratamento antifúngico.Nossos resultados demonstram a ativação do NLRP3-inflamassoma, caracterizada pela elevada expressão de NLRP3, CASP1 e IL1B por monócitos. Esses achados corroboram a contribuição do NLRP3-inflamassoma na patogênese da PCM também em pacientes. / Abstract: Paracoccidioidomycosis (PCM) is a systemic mycosis caused by species of the genus Paracoccidioides . The main clinical forms of the disease are acute/subacute (AF) and chronic (CF), and in the latter, most patients develop pulmonary fibrosis and emphysema. Previous studies showed that CF patients in active disease, exhibit elevated production of inflammatory mediators, including IL-1β. This cytokine, different from the others, are produced by an intracellular multiprotein platform called inflammasome that can be activated by pathogens and host signs of damage. Considering that the activation mechanisms of the inflammasome in patients with PCM are not know, this study aimed to determine the expression of genes involved in inflammasome activation and cytokine production by monocytes and alveolar macrophages from PCM patients at different times of antifungal treatment. Our results demonstrate the activation of the NLRP3 inflammasome-characterized by high expression of NLRP3, CASP1 and IL1B by monocytes. These findings corroborate the contribution of NRLP3-inflamassome in pathogenesis of PCM also in patients. / Mestre

Les levures du genre Candida figurent parmi les pathogènes majeurs isolés chez les patients en soins intensifs et sont responsables d'infections systémiques : les candidoses invasives. Le retard et le manque de fiabilité du diagnostic sont susceptibles d'aggraver l'état du patient et d'augmenter le risque de décès à court terme. Pour respecter les objectifs de traitement, les experts recommandent de traiter le plus précocement possible les patients à haut risque de candidose invasive. Cette attitude permet de proposer un traitement précoce aux malades atteints, mais peut entraîner un traitement inutile et coûteux et favoriser l'émergence de souches de moindre sensibilité aux antifongiques utilisés.Ce travail applique des méthodes statistiques modernes à des données observationnelles longitudinales. Il étudie l'impact des traitements antifongiques systémiques sur la répartition des quatre principales espèces de Candida dans les différents prélèvements de patients en réanimation médicale, sur leur sensibilité à ces antifongiques, sur le diagnostic des candidémies ainsi que sur le pronostic des patients. Les analyses de séries de données temporelles à l'aide de modèles ARIMA (moyenne mobile autorégressive intégrée) ont confirmé l'impact négatif de l'utilisation des antifongiques sur la sensibilité des principales espèces de Candida ainsi que la modification de leur répartition sur une période de dix ans. L'utilisation de modèles hiérarchiques sur données répétées a montré que le traitement influence négativement la détection des levures et augmente le délai de positivité des hémocultures dans le diagnostic des candidémies. Enfin, l'utilisation des méthodes d'inférence causale a montré qu'un traitement antifongique préventif n'a pas d'impact sur le pronostic des patients non neutropéniques, non transplantés et qu'il est possible de commencer une désescalade précoce du traitement antifongique entre le premier et le cinquième jour après son initiation sans aggraver le pronostic. / Candida species are among the main pathogens isolated from patients in intensive care units (ICUs) and are responsible for a serious systemic infection: invasive candidiasis. A late and unreliable diagnosis of invasive candidiasis aggravates the patient's status and increases the risk of short-term death. The current guidelines recommend an early treatment of patients with high risks of invasive candidiasis, even in absence of documented fungal infection. However, increased antifungal drug consumption is correlated with increased costs and the emergence of drug resistance whereas there is yet no consensus about the benefits of the probabilistic antifungal treatment.The present work used modern statistical methods on longitudinal observational data. It investigated the impact of systemic antifungal treatment (SAT) on the distribution of the four Candida species most frequently isolated from ICU patients', their susceptibilities to SATs, the diagnosis of candidemia, and the prognosis of ICU patients. The use of autoregressive integrated moving average (ARIMA) models for time series confirmed the negative impact of SAT use on the susceptibilities of the four Candida species and on their relative distribution over a ten-year period. Hierarchical models for repeated measures showed that SAT has a negative impact on the diagnosis of candidemia: it decreases the rate of positive blood cultures and increases the time to positivity of these cultures. Finally, the use of causal inference models showed that early SAT has no impact on non-neutropenic, non-transplanted patient prognosis and that SAT de-escalation within 5 days after its initiation in critically ill patients is safe and does not influence the prognosis.