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SARS-CoV-2 infection triggers distinct patterns of disease development characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SLs) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n = 55), COVID-19 patients (n = 204), and convalescent individuals (n = 77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, a predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, and neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) species (d18:1/24:1) and (d18:1/24:0)were associated with increased risk. Moreover, we observed the enhanced expression of key enzymes involved in the SL pathway in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.
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COVID-19 , Esfingomielinas , Humanos , Pronóstico , SARS-CoV-2/metabolismo , Ceramidas/metabolismo , Esfingolípidos/metabolismo , BiomarcadoresRESUMEN
BACKGROUND: Sex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients. METHODS: A cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome. RESULTS: There were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings. CONCLUSIONS: These original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.
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COVID-19 has a broad spectrum of clinical manifestations associated with the host immune response heterogeneity. Despite the advances in COVID-19 research, it is still crucial to seek a panel of molecular markers that enable accurate stratification of COVID-19 patients. Here, we performed a study that combined analysis of blood transcriptome, demographic data, clinical aspects and laboratory findings from 66 participants classified into different degrees of COVID-19 severity and healthy subjects. We identified a perturbation in blood-leukocyte transcriptional profile associated with COVID-19 aggravation, which was mainly related to processes that disfavoured lymphocyte activation and favoured neutrophil activation. This transcriptional profile stratified patients according to COVID-19 severity. Hence, it enabled identification of a turning point in transcriptional dynamics that distinguished disease outcomes and non-hospitalized from hospitalized moderate patients. Central genes of this unique neutrophil signature were S100A9, ANXA3, CEACAM6, VNN1, OLFM4, IL1R2, TCN1 and CD177. Our study indicates the molecular changes that are linked with the differing clinical aspects presented by humans when suffering from COVID-19, which involve neutrophil activation.
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COVID-19 , Humanos , COVID-19/genética , Neutrófilos , Transcriptoma , BiomarcadoresRESUMEN
COVID-19 is associated with a dysregulated immune response. Currently, several medicines are licensed for the treatment of this disease. Due to their significant role in inhibiting pro-inflammatory cytokines and lipid mediators, glucocorticoids (GCs) have attracted a great deal of attention. Similarly, the endocannabinoid (eCB) system regulates various physiological processes including the immunological response. Additionally, during inflammatory and thrombotic processes, phospholipids from cell membranes are cleaved to produce platelet-activating factor (PAF), another lipid mediator. Nonetheless, the effect of GCs on this lipid pathway during COVID-19 therapy is still unknown. This is a cross-sectional study involving COVID-19 patients (n = 200) and healthy controls (n = 35). Target tandem mass spectrometry of plasma lipid mediators demonstrated that COVID-19 severity affected eCBs and PAF synthesis. This increased synthesis of eCB was adversely linked with systemic inflammatory markers IL-6 and sTREM-1 levels and neutrophil counts. The use of GCs altered these lipid pathways by reducing PAF and increasing 2-AG production. Corroborating this, transcriptome analysis of GC-treated patients blood leukocytes showed differential modulation of monoacylglycerol lipase and phospholipase A2 gene expression. Altogether, these findings offer a breakthrough in our understanding of COVID-19 pathophysiology, indicating that GCs may promote additional protective pharmacological effects by influencing the eCB and PAF pathways involved in the disease course.
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COVID-19 , Factor de Activación Plaquetaria , Humanos , Estudios Transversales , Endocannabinoides , Glucocorticoides/uso terapéuticoRESUMEN
Lipid and cholinergic mediators are inflammatory regulators, but their role in the immunopathology of COVID-19 is still unclear. Here, we used human blood and tracheal aspirate (TA) to investigate whether acetylcholine (Ach), fatty acids (FAs), and their derived lipid mediators (LMs) are associated with COVID-19 severity. First, we analyzed the perturbation profile induced by SARS-CoV-2 infection in the transcriptional profile of genes related to the ACh and FA/LM pathways. Blood and TA were used for metabolomic and lipidomic analyses and for quantification of leukocytes, cytokines, and ACh. Differential expression and coexpression gene network data revealed a unique transcriptional profile associated with ACh and FA/LM production, release, and cellular signaling. Transcriptomic data were corroborated by laboratory findings: SARS-CoV-2 infection increased plasma and TA levels of arachidonic acid, 5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid, 11-hydroxy-5Z,8Z,12E,14Z-eicosatetraenoic acid, and ACh. TA samples also exhibited high levels of PGE2, thromboxane B2, 12-oxo-5Z,8Z,10E,14Z-eicosatetraenoic acid, and 6-trans-leukotriene B4 Bioinformatics and experimental approaches demonstrated robust correlation between transcriptional profile in Ach and FA/LM pathways and parameters of severe COVID-19. As expected, the increased neutrophil-to-lymphocyte ratio, neutrophil counts, and cytokine levels (IL-6, IL-10, IL-1ß, and IL-8) correlated with worse clinical scores. Glucocorticoids protected severe and critical patients and correlated with reduced Ach levels in plasma and TA samples. We demonstrated that pulmonary and systemic hyperinflammation in severe COVID-19 are associated with high levels of Ach and FA/LM. Glucocorticoids favored the survival of patients with severe/critical disease, and this effect was associated with a reduction in ACh levels.
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Acetilcolina , COVID-19 , Ácido Araquidónico , Ácidos Araquidónicos/farmacología , Ácidos Grasos , Glucocorticoides , Humanos , SARS-CoV-2RESUMEN
COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.
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COVID-19 , SARS-CoV-2 , Antiinflamatorios/farmacología , Apoptosis , Humanos , Macrófagos/metabolismo , FagocitosisRESUMEN
Patients with COVID-19 predominantly have a respiratory tract infection and acute lung failure is the most severe complication. While the molecular basis of SARS-CoV-2 immunopathology is still unknown, it is well established that lung infection is associated with hyper-inflammation and tissue damage. Matrix metalloproteinases (MMPs) contribute to tissue destruction in many pathological situations, and the activity of MMPs in the lung leads to the release of bioactive mediators with inflammatory properties. We sought to characterize a scenario in which MMPs could influence the lung pathogenesis of COVID-19. Although we observed high diversity of MMPs in lung tissue from COVID-19 patients by proteomics, we specified the expression and enzyme activity of MMP-2 in tracheal-aspirate fluid (TAF) samples from intubated COVID-19 and non-COVID-19 patients. Moreover, the expression of MMP-8 was positively correlated with MMP-2 levels and possible shedding of the immunosuppression mediator sHLA-G and sTREM-1. Together, overexpression of the MMP-2/MMP-8 axis, in addition to neutrophil infiltration and products, such as reactive oxygen species (ROS), increased lipid peroxidation that could promote intensive destruction of lung tissue in severe COVID-19. Thus, the inhibition of MMPs can be a novel target and promising treatment strategy in severe COVID-19.
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COVID-19 , Metaloproteinasa 2 de la Matriz , Antígenos HLA-G , Humanos , Inmunidad , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 8 de la Matriz/metabolismo , Estrés Oxidativo , SARS-CoV-2RESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring viral replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in postmortem lung tissue. These results indicated that SARS-CoV-2 infection of blood-circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host.
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COVID-19 , SARS-CoV-2 , Síndrome de Liberación de Citoquinas , Humanos , Leucocitos Mononucleares , MonocitosRESUMEN
Uncontrolled inflammatory responses play a critical role in coronavirus disease (COVID-19). In this context, because the triggering-receptor expressed on myeloid cells-1 (TREM-1) is considered an intrinsic amplifier of inflammatory signals, this study investigated the role of soluble TREM-1 (sTREM-1) as a biomarker of the severity and mortality of COVID-19. Based on their clinical scores, we enrolled COVID-19 positive patients (n = 237) classified into mild, moderate, severe, and critical groups. Clinical data and patient characteristics were obtained from medical records, and their plasma inflammatory mediator profiles were evaluated with immunoassays. Plasma levels of sTREM-1 were significantly higher among patients with severe disease compared to all other groups. Additionally, levels of sTREM-1 showed a significant positive correlation with other inflammatory parameters, such as IL-6, IL-10, IL-8, and neutrophil counts, and a significant negative correlation was observed with lymphocyte counts. Most interestingly, sTREM-1 was found to be a strong predictive biomarker of the severity of COVID-19 and was related to the worst outcome and death. Systemic levels of sTREM-1 were significantly correlated with the expression of matrix metalloproteinases (MMP)-8, which can release TREM-1 from the surface of peripheral blood cells. Our findings indicated that quantification of sTREM-1 could be used as a predictive tool for disease outcome, thus improving the timing of clinical and pharmacological interventions in patients with COVID-19.
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Biomarcadores/sangre , COVID-19/diagnóstico , COVID-19/mortalidad , Leucocitos/metabolismo , Metaloproteinasa 8 de la Matriz/metabolismo , Índice de Severidad de la Enfermedad , Receptor Activador Expresado en Células Mieloides 1/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Femenino , Humanos , Inflamación , Interleucina-10/sangre , Interleucina-6/sangre , Interleucina-8/sangre , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Estudios Prospectivos , SARS-CoV-2 , Receptor Activador Expresado en Células Mieloides 1/metabolismo , Adulto JovenRESUMEN
OBJECTIVE: To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes. DESIGN: We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate. RESULTS: Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0-6.0) days for the colchicine group and 6.5 (4.0-9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0-9.0) days for the colchicine group and 9.0 (7.0-12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26). CONCLUSION: Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19. TRIAL REGISTRATION NUMBER: RBR-8jyhxh.
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Tratamiento Farmacológico de COVID-19 , Colchicina/administración & dosificación , Tiempo de Internación , Terapia por Inhalación de Oxígeno , SARS-CoV-2/genética , Índice de Severidad de la Enfermedad , Adulto , Anciano , COVID-19/mortalidad , COVID-19/virología , Colchicina/efectos adversos , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Resultado del TratamientoRESUMEN
Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1ß, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.
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COVID-19/patología , COVID-19/virología , Inflamasomas/metabolismo , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Apoptosis , Comorbilidad , Citocinas/biosíntesis , Humanos , Pulmón/patología , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Cambios Post Mortem , Resultado del TratamientoRESUMEN
Pneumonia bacteriana comunitária e hospitalar em adultos são problemas de saúde pública crescentes, com inúmeras internações anualmente e causas frequentes de morbimortalidade. A rápida caracterização do quadro clínico deve ser acompanhada de decisão quanto à necessidade de internação do paciente e o tratamento deve ser baseado na gravidade da apresentação e aspectos epidemiológicos. O acompanhamento clínico é imprescindível, tanto ambulatorialmente quanto na internação, atento aos critérios de falha terapêutica e necessidade de revisão da terapêutica inicialmente instituída. Particularmente na pneumonia hospitalar (nosocomial), o diagnóstico é um desafio e a análise do tempo do início do quadro é fundamental para o direcionamento empírico do tratamento. Ênfase na prevenção é uma tentativa de redução na frequência dos casos.
Community and hospital acquired bacterial pneumonia in adults are increasing public health problems, with numerous hospitalizations annually and frequent causes of morbidity and mortality. Rapid characterization of the clinical picture must be accompanied by a decision regarding the need for patient hospitalization and treatment should be based on severity of presentation and epidemiological aspects. The follow up is essential, both outpatient and in hospital, in keeping with the criteria of treatment failure and need for review of initial treatment. Particularly in hospital-acquired pneumonia (nosocomial), the diagnosisis a challenge and analysis of time of onset is crucial for directing empirical treatment. Emphasison prevention is an attempt to reduce the frequency of cases.
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Humanos , Masculino , Femenino , Adulto , Enfermedades Transmisibles , Infección Hospitalaria , Infecciones Comunitarias Adquiridas , Neumonía Bacteriana/diagnóstico , Neumonía Bacteriana/etiologíaRESUMEN
A administração inadequada de antimicrobianos é capaz de comprometer a resposta clínica do paciente, aumentar custos com internação e contribuir para o surgimento de bactérias multirresistentes. Nesse contexto, o uso racional de antimicrobianos é benéfico para o paciente infectado e também para a instituição de saúde. A indicação desta classe de drogas deve levar em conta o hospedeiro, o agente infeccioso e o antimicrobiano propriamente dito. Assim, sua utilização deve ser baseada no conhecimento dos conceitos de colonização, contaminação e infecção, noções de microbiologia clínica, coleta de culturas, microbiota habitual do corpo humano, e mecanismos, espectro de ação, farmacocinética, farmacodinâmica e efeitos colaterais dos antimicrobianos. A revisão desses tópicos procura fornecer subsídios para escolha do antimicrobiano mais adequado para o tipo de infecção, tempo de tratamento previsto, critérios de falha e resposta clínica à droga prescrita, além de nortear possível troca de terapia ao longo do tratamento.
The inadequate administration of antimicrobials may compromise the clinical response of the patient, increase the costs during hospitalization and contribute to the appearance of multiresistant bacteria. In this context, the use of rational antimicrobials is beneficial to the infected patient and also to the health institution. The prescription of this drug type must take in account the host, the infectious agent and the antimicrobial itself. Thus, its utilization must be based on the knowledge of the concepts of colonization, contamination and infection, notions of clinical microbiology, culture collection, and habitual microbiota of the human body, and mechanisms, action specter, pharmacokinetics, pharmacodynamics and side effects of the antimicrobials. The revision of these topics pursuits to provide subsidies to the choice of the most adequate antimicrobial to the type of infection, foreseen treatment time, failure criteria and clinical answer to the prescribed drug, besides guide possible change of therapy along the treatment.
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Humanos , Antibacterianos , Utilización de MedicamentosRESUMEN
A infecção do trato urinário (ITU) é uma das causas mais comuns de infecção na população geral. É mais prevalente no sexo feminino, mas também acomete pacientes do sexo masculino principalmente quando associada à manipulação do trato urinário e à doença prostática. A ITU pode ser classificada quanto à localização em ITU baixa (cistite) e ITU alta (pielonefrite) e quanto à presença de fatores complicadores em ITU não complicada e ITU complicada. A ITU é complicada quando estão presentes alterações estruturais ou funcionais do trato urinário ou quando se desenvolve em ambiente hospitalar. Na ITU não complicada a Escherichia coli é a bactéria responsável pela maioria das infecções enquanto nas ITUs complicadas o espectro de bactérias envolvido é bem mais amplo incluindo bactérias Grampositivas e Gram negativas e com elevada frequência organismos multirresistentes. ITU é definida pela presença de 100.000 ufc/mL. Os sinais e sintomas associados à ITU incluem polaciúria, urgência miccional, disúria, hematúria e piúria. A escolha da terapia antimicrobiana para a ITU varia de acordo com a apresentação da infecção, hospedeiro e agente. Estratégias envolvendo diferentes esquemas terapêuticos de acordo com grupos específicos de pacientes maximizam os benefícios terapêuticos, além de reduzir os custos, as incidências de efeitos adversos e o surgimento de microrganismos resistentes.
Urinary Tract Infection (UTI) is one of the most common causes of infection in the general population. Itis more prevalent in females, but also affects male patients especially when associated with manipulation of the urinary tract and prostate disease. The UTI can be classified according to location in lower UTI (cystitis) and high UTI (pyelonephritis) and according the presence of complicating factors in uncomplicated UTI and complicated UTI. The ITU is complicated when structural or functional abnormalities of the urinary tract are present or when it develops in the hospital. In uncomplicated UTI, Escherichia coli is the bacteria responsible for most infections while in complicated UTIs the bacterial spectrum involved is much broader including Gram positive and Gram-negative and high-frequency multi-resistant organisms. UTI is defined by the presence of 100000 cfu/mL. Signs and symptoms associated with UTI include urinary frequency, urinary urgency, dysuria, hematuria and pyuria. The choice of antimicrobial therapy for UTI varies with the presentation of the infection, host and agent. Strategies involving different treatment regimens according to specific patient groups maximize the therapeutic benefits and reduce costs, the incidences of adverse effects and the emergency of resistant organisms.