Double-, single- and none-carbapenem-containing regimens for the treatment of carbapenem-resistant Enterobacterales (CRE) bloodstream infections: a retrospective cohort.

OBJECTIVES: To investigate the effect of double-, single- and none-carbapenem-containing antimicrobial regimens in the treatment of patients with carbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSIs). METHODS: We conducted a retrospective cohort study from 2013 to 2020 in two Brazilian hospitals. Patients ≥18 years old with CRE BSI were included and excluded if death or treatment duration for ≤48 h after BSI or non-Class A-producing carbapenemase isolates. We evaluated the impact of different carbapenem-containing regimens on 30 day mortality through a propensity score adjusted model and a Cox proportional hazards model. RESULTS: Two-hundred and seventy-nine patients were included for analyses: 47 (16.9%), 149 (53.4%) and 83 (29.8%) were treated with double-, single- and none-carbapenem-containing regimens, respectively. One-hundred and seventeen (41.9%) patients died in 30 days. Treatment with a single-carbapenem regimen was associated with a lower risk of death in 30 days compared with therapies containing no carbapenem [adjusted HR (aHR) 0.66, 95% CI 0.44-0.99, P = 0.048], when adjusted for Charlson score and ICU admission at baseline, while double-carbapenem regimens were not associated with a lower risk of death (aHR 0.78, 95% CI 0.46-1.32, P = 0.35). Propensity score adjusted model results went in the same direction. CONCLUSIONS: Double-carbapenem- was not superior to single-carbapenem-containing regimens in patients with CRE BSIs. Single-carbapenem-containing schemes were associated with a lower mortality risk.

Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial.

OBJECTIVES: To evaluate the effect of melatonin versus placebo on the incidence of acute kidney injury (AKI) in patients treated with polymyxin B. METHODS: We performed a single-centre, double-blind, randomized clinical trial (NCT03725267) of 30-mg oral melatonin versus placebo for patients treated with intravenous polymyxin B. Patients aged ≥18 years receiving polymyxin B for ≤48 hours were eligible. Melatonin or placebo pills were administered until the end of polymyxin B treatment or for a maximum of 14 days. The main outcome was any level of AKI. RESULTS: Eighty-eight patients were randomized: 44 in the melatonin group and 44 in the placebo group. The study ended prematurely because of polymyxin B shortage during the COVID-19 pandemic. The patients' mean age was 63.6 ± 17.3 years, and 60.2% of the patients were men. Forty-six (52.3%, 23 in each group) patients developed AKI during the follow-up period. The incidence rate of AKI was 81.9/1000 and 77.4/1000 patients per day in melatonin and placebo groups, respectively (hazard ratio, 1.09; 95% CI, 0.61-1.94; p 0.78). Renal failure and 30-day mortality were similar between the groups. Moreover, the incidence of AKI was not different in pre-specified sub-groups. DISCUSSION: Melatonin initiated in the first 48 hours of therapy did not reduce the incidence of AKI in patients treated with polymyxin B.

Antimicrobial stewardship programme associated with earlier prescription of in vitro susceptible therapy and lower 14-day mortality in patients with carbapenem-resistant Enterobacterales bacteraemia: a cohort study.

OBJECTIVES: This study analysed the impact of antimicrobial stewardship team (AST) evaluation on time to susceptible in vitro therapy and mortality of patients with carbapenem-resistant Enterobacterales (CRE) bacteraemia. METHODS: We performed a retrospective cohort study (February 2018 to July 2020) to evaluate the impact of AST evaluation, along with other clinical and microbiological variables, on time to appropriate antibiotics, 14-day mortality and in-hospital mortality in patients aged >18 years with CRE bacteraemia. A Cox regression model was used for multivariate analysis. RESULTS: A total of 142 patients were included. The proportion of patients who received appropriate antibiotics in the first 5 days after bacteraemia was 82/92 (89.1%) versus 29/50 (58.0%) evaluated and not evaluated by the AST, respectively (P < 0.01). AST evaluation reduced the median time to appropriate therapy (49.8 h vs. 71.1 h; P = 0.01). AST intervention was independently associated with earlier prescription of appropriate therapy (P = 0.02) when controlled for septic shock (P < 0.01) and CRE isolation in the previous 90 days (P = 0.04). Regarding mortality, 51 patients (35.9%) died within 14 days (25.8% vs. 44.7% with and without AST intervention, respectively; P = 0.02) and 82 patients (57.7%) in hospital (52.2% vs. 68.0% evaluated and not evaluated by the AST, respectively; P = 0.08). AST intervention was independently protective for 14-day mortality (P = 0.03) when controlled for septic shock status (P < 0.01). CONCLUSION: AST guidance improves the quality of antibiotic prescriptions and clinical outcomes in patients with CRE bacteraemia.

Pictorial Review of Thoracic Parasitic Diseases: A Radiologic Guide.

Parasitoses are infectious diseases of global distribution, with predominance in areas of poor sanitation. Parasites cause damage through direct tissue injury and the inflammatory response generated by their migration and establishment in various organs. Thoracic involvement by parasitic disease can generate both specific and nonspecific clinical, laboratorial, and radiologic manifestations, which often makes their diagnosis challenging. The correct diagnosis is crucial for definition of treatment, which sometimes requires rapid intervention. Based on a literature review of the last few decades, this article aimed to characterize the main radiologic findings related to thoracic manifestations of parasitic diseases, correlating them with radiographic and tomographic images of patients with confirmed diagnosis of such pathologies. The included parasitic diseases are malaria, Chagas disease, toxoplasmosis, amoebiasis, ascariasis, toxocariasis, strongyloidiasis, dirofilariasis, cysticercosis, echinococcosis, schistosomiasis, and paragonimiasis.

Design of Novel Inhibitors of Human Thymidine Phosphorylase: Synthesis, Enzyme Inhibition, in Vitro Toxicity, and Impact on Human Glioblastoma Cancer.

Overexpressed human thymidine phosphorylase (hTP) has been associated with cancer aggressiveness and poor prognosis by triggering proangiogenic and antiapoptotic signaling. Designed as transition-state analogues by mimicking the oxacarbenium ion, novel pyrimidine-2,4-diones were synthesized and evaluated as inhibitors of hTP activity. The most potent compound (8g) inhibited hTP in the submicromolar range with a noncompetitive inhibition mode with both thymidine and inorganic phosphate substrates. Furthermore, compound 8g was devoid of apparent toxicity to a panel of mammalian cells, showed no genotoxicity signals, and had low probability of drug-drug interactions and moderate in vitro metabolic rates. Finally, treatment with 8g (50 mg/(kg day)) for 2 weeks (5 days/week) significantly reduced tumor growth using an in vivo glioblastoma model. To the best of our knowledge, this active compound is the most potent in vitro hTP inhibitor with a kinetic profile that cannot be reversed by the accumulation of any enzyme substrates.

Impact of polymyxin-B-associated acute kidney injury in 1-year mortality and renal function recovery.

The objective of this study was to evaluate the impact of polymyxin B (PMB) -associated acute kidney injury (AKI) in 1-year mortality and renal function recovery. Patients >18 years old who survived the first 30 days after PMB therapy were followed for 1 year. The impact of AKI and renal failure (using RIFLE score) in 1-year mortality was analysed, along with other confounding variables. Variables with a P-value ≤0.2 were included in a forward stepwise Cox regression model. In the subgroup of patients who developed AKI, we evaluated renal function recovery. A total of 234 patients were included for analyses. Of these, 108 (46.1%) died, in a median time of 63 (38.3-102.5) days. The use of other nephrotoxic drugs along with PMB (P = 0.05), renal failure (P = 0.03), dialysis (P < 0.01) and re-exposure to PMB (P<0.01), were all significantly related to 1-year mortality, while male gender had a protective effect (P = 0.01). Independent factors related to death were age (adjusted hazard ratio (aHR) 1.02, 95% confidence interval (CI) 1.00-1.03, P = 0.02), re-exposure to PMB (aHR 2.69, 95% CI 1.82-3.95, P<0.01), and male gender (aHR0.6, 95% CI 0.41-0.87, P = 0.01), when controlled for renal failure (aHR 1.28, 95% CI 0.78-2.10, P = 0.34).Thirty one of 94 (33%) patients who developed AKI had renal function recovery within 1 year. Mortality rates were high in the first year after PMB use and only one-third of patients who developed AKI returned to baseline renal function. Strategies to reduce renal toxicity are urgently needed in these patients.

Pre-clinical evaluation of quinoxaline-derived chalcones in tuberculosis.

New effective compounds for tuberculosis treatment are needed. This study evaluated the effects of a series of quinoxaline-derived chalcones against laboratorial strains and clinical isolates of M. tuberculosis. Six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratorial strain. The three compounds (N9, N15 and N23) with the lowest MIC values were further tested against clinical isolates and laboratory strains with mutations in katG or inhA genes. From these data, N9 was selected as the lead compound for further investigation. Importantly, this chalcone displayed a synergistic effect when combined with moxifloxacin. Noteworthy, the anti-tubercular effects of N9 did not rely on inhibition of mycolic acids synthesis, circumventing important mechanisms of resistance. Interactions with cytochrome P450 isoforms and toxic effects were assessed in silico and in vitro. The chalcone N9 was not predicted to elicit any mutagenic, genotoxic, irritant, or reproductive effects, according to in silico analysis. Additionally, N9 did not cause mutagenicity or genotoxicity, as revealed by Salmonella/microsome and alkaline comet assays, respectively. Moreover, N9 did not inhibit the cytochrome P450 isoforms CYP3A4/5, CYP2C9, and CYP2C19. N9 can be considered a potential lead molecule for development of a new anti-tubercular therapeutic agent.

Profilaxia pré-exposição no controle do HIV: uma revisão de efetividade e potenciais complicações / Preexposure prophylaxis for HIV control: a review of effectiveness and potential complications

INTRODUÇÃO. A infecção por HIV permanece sendo um problema de saúde mundial. Dessa forma, a Profilaxia Pré-Exposição (PrEP) surgiu como um método complementar de prevenção. Este trabalho tem como objetivo avaliar a eficácia da PrEP contra a infecção por HIV, o contexto de resistência viral e incidência de infecções sexualmente transmissíveis. MÉTODOS. Revisão narrativa, com busca de artigos na plataforma PubMed, utilizando os descritores HIV AND PrEP, filtrando para artigos do tipo ensaio clínico ou coorte prospectiva, realizados em humanos, publicados há, no máximo, 10 anos e em língua inglesa. RESULTADOS. A eficácia da PrEP contra infecção por HIV foi avaliada por 8 estudos. Elevados níveis de proteção contra o HIV foram demonstrados, com taxas de efetividade variando entre 73% e 85% considerando aderência adequada ao tratamento profilático. A resistência viral foi reportada em 7 estudos que avaliaram pacientes infectados por HIV durante o uso da PrEP, 6 deles identificaram casos de resistência viral, variando conforme os níveis de aderência obtidos e o perfil de uso dos pacientes. Um estudo feito em Montreal, Canadá, verificou maior incidência de infecções sexualmente transmissíveis em indivíduos usuários de PrEP, com um aumento generalizado de 72%. CONCLUSÃO. A PrEP é uma medida eficaz na proteção contra o HIV, sendo uma importante ferramenta de saúde pública no controle da doença. Apesar de sua efetividade, a PrEP não é isenta de limitações, repercutindo em riscos elevados de infecções sexualmente transmissíveis associadas e resistência viral. O papel do profissional de saúde é fundamental na indicação adequada e acompanhamento de pessoas que podem se beneficiar do uso da PrEP.

AIMS. HIV infection is a worldwide health issue, in that scenario PrEP has emerged as a complementary method of prevention. This review aims to evaluate the effectiveness of Pre-exposure prophylaxis (PrEP) against HIV infection, the viral resistance context, and the incidence of associated sexually transmitted infections. METHODS. It was conducted a narrative review on the PubMed platform using the descriptors HIV AND PrEP. Included studies were clinical trials or prospective cohorts, performed in humans, published in a maximum of 10 years and in English language. RESULTS. The effectiveness of PrEP against HIV infection was evaluated by 8 studies. High levels of protection against HIV have been demonstrated, with effectiveness rates varying between 73% and 85% in studies with proper adherence to the prophylactic treatment. Viral resistance was reported in 7 studies evaluating HIV-infected patients during the use of PrEP, 6 of which have identified cases of viral resistance, varying according to adherence levels achieved and patient profile. A study in Montréal, Canada, found a higher incidence of sexually transmitted infections in individuals using PrEP, with a generalized increase of 72%. CONCLUSION. PrEP is an effective way of prevention and an important public health tool for disease control. Despite its effectiveness, PrEP has limitations: it reflects higher risks of sexually transmitted diseases and viral resistance. Health professionals play a central role indicating PrEP and following-up people who can benefit from its use.

Classificação dos alimentos quanto ao processamento industrial: uma revisão bibliográfica / Food classification for industrial processing: a review

Introdução: O processamento artificial de alimentos tem sido considerado um fator de risco importante na saúde. O objetivo deste estudo é revisar a literatura científica quanto à definição da classificação dos alimentos referente ao seu grau de processamento industrial. Métodos: revisão narrativa de artigos publicados nas bases de dados indexadas MEDLINE (PubMed) e LILACS e guias alimentares disponíveis na página online da Food and Agriculture Organization of the United Nations (FAO). A estratégia de busca utilizada compreendeu os seguintes descritores: Processed food OR Unprocessed food OR Artisanal food OR Minimally processed food OR Highly processed OR Ultra-processed food OR Industrial food processing. Não houve restrição quanto ao idioma utilizado nas publicações. Resultados: foram identificados 1301 artigos nas bases de dados PubMed e LILACS e 35 na página da FAO. Definições de alimentos processados ou ultraprocessados foram encontradas em diretrizes de apenas 8 dos 34 países avaliados nessa revisão. Apenas três diretrizes eram baseadas na classificação NOVA, utilizada no Brasil. Os demais países que utilizam classificações baseadas no grau de processamento industrial se pautam em definições variadas, baseadas na quantidade de aditivos, açucares, gorduras e outras substâncias. Além disso, apenas quatro países utilizam a classificação de ultraprocessados para alimentos altamente industrializados. Conclusões: apesar dos riscos já evidenciados em relação ao consumo destes alimentos, as evidências demonstram que o conceito em relação ao grau de processamento industrial de alimentos não apresenta uma definição padronizada.

Introduction: artificial food processing has been considered a major health risk factor. The objective of this study is to review the scientific literature regarding the definition of food classification related to its degree of industrial processing. Methods: narrative review. Articles published in MEDLINE (PubMed) and LILACS indexed databases and food guides available on the Food and Agriculture Organization of the United Nations (FAO) website were evaluated. The search strategy used included the following descriptors: Processed food OR Unprocessed food OR Artisanal food OR Minimally processed food OR Highly processed OR Ultra-processed food OR Industrial food processing. There was no restriction on the language used in the publications. Results: 1301 articles in the PubMed and LILACS databases and 35 on the FAO website were identified. Food classifications based on the degree of industrial processing were found in only 8 of 34 countries included in this review. Of those, only three guidelines were based on the NOVA classification, currently used in Brazil. Other countries with food classifications based on industrial processing used definitions characterized by the addition of sugars, chemical additives, fats and other substances. Furthermore, only four countries used definitions for ultraprocessed foods specifically. Conclusion: the evidence demonstrates the concept in relation to industrial processing does not present a standard definition, despite the risks already evidenced in relation to the consumption of these.