Live, Attenuated, Tetravalent Butantan-Dengue Vaccine in Children and Adults.

BACKGROUND: Butantan-Dengue Vaccine (Butantan-DV) is an investigational, single-dose, live, attenuated, tetravalent vaccine against dengue disease, but data on its overall efficacy are needed. METHODS: In an ongoing phase 3, double-blind trial in Brazil, we randomly assigned participants to receive Butantan-DV or placebo, with stratification according to age (2 to 6 years, 7 to 17 years, and 18 to 59 years); 5 years of follow-up is planned. The objectives of the trial were to evaluate overall vaccine efficacy against symptomatic, virologically confirmed dengue of any serotype occurring more than 28 days after vaccination (the primary efficacy end point), regardless of serostatus at baseline, and to describe safety up to day 21 (the primary safety end point). Here, vaccine efficacy was assessed on the basis of 2 years of follow-up for each participant, and safety as solicited vaccine-related adverse events reported up to day 21 after injection. Key secondary objectives were to assess vaccine efficacy among participants according to dengue serostatus at baseline and according to the dengue viral serotype; efficacy according to age was also assessed. RESULTS: Over a 3-year enrollment period, 16,235 participants received either Butantan-DV (10,259 participants) or placebo (5976 participants). The overall 2-year vaccine efficacy was 79.6% (95% confidence interval [CI], 70.0 to 86.3) - 73.6% (95% CI, 57.6 to 83.7) among participants with no evidence of previous dengue exposure and 89.2% (95% CI, 77.6 to 95.6) among those with a history of exposure. Vaccine efficacy was 80.1% (95% CI, 66.0 to 88.4) among participants 2 to 6 years of age, 77.8% (95% CI, 55.6 to 89.6) among those 7 to 17 years of age, and 90.0% (95% CI, 68.2 to 97.5) among those 18 to 59 years of age. Efficacy against DENV-1 was 89.5% (95% CI, 78.7 to 95.0) and against DENV-2 was 69.6% (95% CI, 50.8 to 81.5). DENV-3 and DENV-4 were not detected during the follow-up period. Solicited systemic vaccine- or placebo-related adverse events within 21 days after injection were more common with Butantan-DV than with placebo (58.3% of participants, vs. 45.6%). CONCLUSIONS: A single dose of Butantan-DV prevented symptomatic DENV-1 and DENV-2, regardless of dengue serostatus at baseline, through 2 years of follow-up. (Funded by Instituto Butantan and others; DEN-03-IB ClinicalTrials.gov number, NCT02406729, and WHO ICTRP number, U1111-1168-8679.).

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.

Efficacy and safety of Butantan-DV in participants aged 2-59 years through an extended follow-up: results from a double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil.

BACKGROUND: A single-dose dengue vaccine that protects individuals across a wide age range and regardless of dengue serostatus is an unmet need. We assessed the safety and efficacy of the live, attenuated, tetravalent Butantan-dengue vaccine (Butantan-DV) in adults, adolescents, and children. We previously reported the primary and secondary efficacy and safety endpoints in the initial 2 years of follow-up. Here we report the results through an extended follow-up period, with an average of 3·7 years of follow-up. METHODS: In this double-blind, randomised, placebo-controlled, phase 3, multicentre trial in Brazil, healthy participants (aged 2-59 years) who had not previously received a dengue vaccine were enrolled and randomly assigned 2:1 (stratified by age 18-59 years, 7-17 years, and 2-6 years) using a central electronic randomisation system to receive 0·5 mL of Butantan-DV (containing approximately 103 plaque-forming units of each of the four vaccine virus strains) or placebo, administered subcutaneously. Syringes containing vaccine or placebo were prepared by an unmasked trial pharmacist who was not involved in any subsequent participant assessments; other site staff and the participants remained unaware of the group allocations. Vaccine efficacy was calculated with the accrual of virologically confirmed dengue (VCD) cases (by RT-PCR) at least 28 days after vaccination up until the cutoff (at least 2 years of follow-up from the last participant enrolled). The primary endpoint was vaccine efficacy against VCD after day 28 by any dengue virus (DENV) serotype regardless of dengue serostatus at baseline in the per-protocol population. The primary and secondary safety endpoints up until day 21 were previously reported; secondary safety endpoints include the frequency of unsolicited vaccine-related adverse events after day 22. Safety analyses were done on all participants as treated. This trial is registered with ClinicalTrials.gov (NCT02406729) and is ongoing. FINDINGS: Of 16 363 participants assessed for eligibility, 16 235 were randomly assigned between Feb 22, 2016, and July 5, 2019, and received single-dose Butantan-DV (10 259 participants) or placebo (5976 participants). 16 162 participants (Butantan-DV n=10 215; placebo n=5947) were included in the per-protocol population and 16 235 (Butantan-DV n=10 259; placebo n=5976) in the safety population. At the data cutoff (July 13, 2021), participants had 2-5 years of follow-up (mean 3·7 years [SD 1·0], median 4·0 years [IQR 3·2-4·5]). 356 VCD cases were captured through the follow-up (128 in the vaccine group and 228 in the placebo group). Vaccine efficacy against VCD caused by any DENV serotype was 67·3% (95% CI 59·4-73·9); cases caused by DENV-3 or DENV-4 were not observed. The proportions of participants who had serious adverse events were similar between treatment groups (637 [6·2%] in the vaccine group and 395 [6·6%] in the placebo group) up until the cutoff. INTERPRETATION: A single dose of Butantan-DV was generally well tolerated and efficacious against symptomatic VCD (caused by DENV-1 and DENV-2) for a mean of 3·7 years. These findings support the continued development of Butantan-DV to prevent dengue disease in children, adolescents, and adults regardless of dengue serostatus. FUNDING: Instituto Butantan and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. TRANSLATIONS: For the Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Efficacy of oral 20-hydroxyecdysone (BIO101), a MAS receptor activator, in adults with severe COVID-19 (COVA): a randomized, placebo-controlled, phase 2/3 trial.

Background: SARS-CoV-2 binding to ACE2 is potentially associated with severe pneumonia due to COVID-19. The aim of the study was to test whether Mas-receptor activation by 20-hydroxyecdysone (BIO101) could restore the Renin-Angiotensin System equilibrium and limit the frequency of respiratory failure and mortality in adults hospitalized with severe COVID-19. Methods: Double-blind, randomized, placebo-controlled phase 2/3 trial. Randomization: 1:1 oral BIO101 (350 mg BID) or placebo, up to 28 days or until an endpoint was reached. Primary endpoint: mortality or respiratory failure requiring high-flow oxygen, mechanical ventilation, or extra-corporeal membrane oxygenation. Key secondary endpoint: hospital discharge following recovery (ClinicalTrials.gov Number, NCT04472728). Findings: Due to low recruitment the planned sample size of 310 was not reached and 238 patients were randomized between August 26, 2020 and March 8, 2022. In the modified ITT population (233 patients; 126 BIO101 and 107 placebo), respiratory failure or early death by day 28 was 11.4% lower in the BIO101 (13.5%) than in the placebo (24.3%) group, (p = 0.0426). At day 28, proportions of patients discharged following recovery were 80.1%, and 70.9% in the BIO101 and placebo group respectively, (adjusted difference 11.0%, 95% CI [-0.4%, 22.4%], p = 0.0586). Hazard Ratio for time to death over 90 days: 0.554 (95% CI [0.285, 1.077]), a 44.6% mortality reduction in the BIO101 group (not statistically significant). Treatment emergent adverse events of respiratory failure were more frequent in the placebo group. Interpretation: BIO101 significantly reduced the risk of death or respiratory failure supporting its use in adults hospitalized with severe respiratory symptoms due to COVID-19. Funding: Biophytis.

Copper-coated hospital surfaces: reduction of total bacterial loads and resistant Acinetobacter spp.

Healthcare-associated infections (HAIs) represent a global challenge and an even more staggering concern when related to microorganisms capable of resisting and surviving for long periods in the environment, such as Acinetobacter spp. Strategies that allow a reduction of pathogens from hospital environments represent an additional barrier in infection control protocols, minimizing transmission to hospitalized patients. Considering the antimicrobial properties of copper, here, the bacterial load and the presence of Acinetobacter spp. were monitored on high handling surfaces covered by 99.9% copper films on intensive and non-intensive care unit bedrooms in a tertiary care hospital. Firstly, copper-coated films were able to inhibit the adhesion and biofilm formation of A. baumannii strains in in vitro assays. On the other hand, Acinetobacter spp. were isolated from both copper-coated and uncoated surfaces in the hospital, although the majority was detected on surfaces without copper. All carbapenem-resistant A. baumannii isolates identified harbored the blaoxa-23 gene, while the A. nosocomialis isolates were susceptible to most antimicrobials tested. All isolates were susceptible to polymyxin B. Regarding the total aerobic bacteria, surfaces with copper-coated films presented lower total loads than those detected for controls. Copper coating films may be a workable strategy to mitigate HAIs, given their potential in reducing bacterial loads in nosocomial environments, including threatening pathogens like A. baumannii.

Consequences of a Delayed Diagnosis of Kaposi's Sarcoma: A Case Report of Disseminated Infection.

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A Cohort Study of the Impact of Carbapenem-Resistant Enterobacteriaceae Infections on Mortality of Patients Presenting with Sepsis.

The objective of this study is to evaluate the impact of carbapenem-resistant Enterobacteriaceae (CRE) infection on sepsis 30-day mortality. A retrospective cohort of patients >18 years old with sepsis and organ dysfunction or septic shock was conducted. Univariate analysis was done for variables potentially related to 30-day mortality, and the ones with P values of <0.05 were included in a backward stepwise hierarchic Cox regression model. Variables that remained with P values of <0.05 were retained in the model. A total of 1,190 sepsis episodes were analyzed. Gram-negative bacterial infections occurred in 391 (68.5%) of 571 patients with positive cultures, of which 69 (17.7%) were caused by a CRE organism. Patients with CRE infections had significantly higher 30-day mortality: 63.8% versus 33.4% (P < 0.01). CRE infection was also associated with a lower rate of appropriate empirical therapy (P < 0.01) and with the presence of septic shock (P < 0.01). In the hierarchic multivariate model, CRE remained significant when controlling for demographic variables, comorbidities, and infection site but lost significance when controlling for septic shock and appropriate empirical therapy. Older age (P < 0.01), HIV-positive status (P < 0.01), cirrhosis (P < 0.01), septic shock (P < 0.01), higher quick sepsis-related organ failure assessment (quick-SOFA) (P < 0.01), and appropriate empirical therapy (P = 0.01) remained in the final model. CRE infections were associated with higher crude mortality rates. A lower rate of appropriate empirical therapy and late diagnosis were more frequent in this group, and improvement of stewardship programs is needed.IMPORTANCE The importance of this work relies on exploring the impact of multidrug-resistant bacterial infections such as those with carbapenem-resistant Enterobacteriaceae (CRE) on sepsis mortality. These infections are growing at alarming rates worldwide and are now among the most frequent and difficult-to-treat bacteria due to the very few options for susceptible antimicrobials available. This study examined 1,190 sepsis episodes, and the main findings were as follows: (i) the prevalence of CRE infections significantly increased over time, (ii) CRE infection was associated with higher 30-day mortality than that of patients with other infections (63.8% versus 33.4%), and (iii) the effect of CRE on mortality was probably influenced by the fact that those patients received lower rates of empirical therapy with active antibiotics and were also diagnosed in more advanced stages of sepsis (septic shock). Those findings point to the need for rapid diagnostic methods to identify these bacteria and the need to adjust therapeutic guidelines to this worrisome epidemiological scenario.

Pharmacokinetics of intravenous polymyxin B in critically ill patients.

BACKGROUND: Although not much pharmacokinetic knowledge is available, polymyxin B is increasingly used for treatment of infections caused by gram-negative bacteria that are resistant to all other antibiotics. METHODS: This study involved 8 patients who received intensive care after intravenous administration of a 60-min infusion of polymyxin B at currently recommended doses. Blood and urine samples were collected, and plasma protein binding of polymyxin B was determined. Concentrations of polymyxin B in plasma and urine samples were measured by a specific high-performance liquid chromatographic method. RESULTS: Polymyxin B was well tolerated. The peak plasma concentrations at the end of the infusion varied from 2.38 to 13.9 mg/L. For 4 patients from whom it was possible to collect urine samples over a dosing interval, only 0.04%-0.86% of the dose was recovered in the urine in unchanged form. Plasma protein binding of polymyxin B was higher in samples from patients (range, 78.5%-92.4%) than in plasma samples from healthy human subjects (mean +/- standard deviation, 55.9% +/- 4.7%). Unbound plasma concentrations of polymyxin B were in the vicinity of or lower than the minimum inhibitory concentration of the pathogen. CONCLUSION: To our knowledge, this is the first study to report plasma concentrations over time and urinary recovery of polymyxin B in critically ill patients after intravenous administration. Polymyxin B is eliminated mainly by nonrenal pathways, and the total body clearance appears to be relatively insensitive to renal function. Additional investigations are required to assess the appropriateness of currently recommended doses of this drug for the treatment of severe infections in critically ill persons.

Immune reconstitution inflammatory syndrome in treatment-experienced HIV-infected patients

We described two cases of treatment-experienced HIV-infected patients who presented with cytomegalovirus uveitis and Cryptococcus neoformans adenitis as a manifestation of immune reconstitution inflammatory syndrome (IRIS) during salvage treatment. Little is known about IRIS in highly experienced patients, and this report suggests that IRIS should be considered in this setting if there is a favorable response to salvage therapy

Vancomycin resistant Enterococcus spp (VRE): follow up during 9 years in a tertiary teaching hospital in southern Brazil

Introduction: Infection with vancomycin-resistant Enterococcus spp (VRE) has been a worldwide problem since mid 1980’s and, in Brazil, since 1996. This study was conducted to evaluate the experience with VRE in our institution. Methods: A prospective cohort study from 2000 to 2009 was conducted at Hospital São Lucas da PUCRS. All hospitalized patients with VRE positive culture were included and followed from their diagnosis until they were negative for VRE or their discharge. Only the first admission for each VRE positive patient was included. Pulsed field gel electrophoresis (PFGE) was performed to determine how VRE had spread. Results: A total of 315 cases of VRE were identified, 224 of which were isolated from rectal swabs. Vancomycin-resistant/ampicilin susceptible Enterococcus faecalis were identified in 312 isolates. PFGE was performed in 47 VRE isolates that presented an indistinguishable migratory profile. The median length of hospital stay and length of stay before VRE isolation were 46 days and 21 days, respectively; 52% of the patients were aged 60 and above. The annual distribution of the new VRE cases showed a clear decrease from 2000 to 2009. Discussion: This study shows a substantial VRE colonization (71%) with a homogenous pattern that emphasizes its transversal spread. Predominance of E. faecalis differs from the literature which largely describes a higher prevalence of vancomycin-resistant Enterococcus faecium. The follow up of VRE during 9 years in our institution highlighted the importance of continuous surveillance to prevent outbreaks in our hospital.

The influence of metallo-beta-lactamase production on mortality in nosocomial Pseudomonas aeruginosa infections.

OBJECTIVES: To assess the effect of metallo-beta-lactamase (MBL) production on Pseudomonas aeruginosa nosocomial infection mortality and to identify the determinants of such effect. METHODS: A cohort study of patients with P. aeruginosa nosocomial infections was conducted at two teaching hospitals. MBL was detected by ceftazidime/2-mercaptopropionic disc approximation test and selected isolates were submitted to PCR using bla(SPM-1) primer. Molecular typing was performed by DNA macrorestriction. To evaluate the influence of MBL on mortality a Cox proportional hazards model was performed using a hierarchized framework of the variables. RESULTS: A total of 298 patients with P. aeruginosa infections were included. Infections by MBL-carrying Pseudomonas aeruginosa (MBL-PA) resulted in higher in-hospital mortality than those by non-MBL-PA (51.2% versus 32.1%, respectively; relative risk 1.60, 95% CI 1.20-2.12) and higher mortality rates [17.3 per 1000 versus 11.8 per 1000 patient-days, respectively; hazard ratio (HR) 1.55, 95% CI 1.06-2.27]. In the final multivariate model, severe sepsis or septic shock [adjusted HR (AHR) 3.62, 95% CI 2.41-5.43], age (AHR 1.02, 95% CI 1.01-1.03) and use of appropriate therapy

Prevalência de sintomas depressivos em uma amostra de prostitutas de Porto Alegre / Prevalence of depressive symptoms in a sample of prostitutes in Porto Alegre

INTRODUÇÃO: a prevalência de transtornos depressivos na população feminina de Porto Alegre é estimada em 14,5 por cento. Não existem relatos sobre a prevalência de sintomas ou transtornos depressivos entre as prostitutas, população de risco para transtornos mentais. OBJETIVOS: quantificar a prevalência de sintomas depressivos em amostra de prostitutas de Porto Alegre e fatores associados. MATERIAL E MÉTODOS: uma amostra consecutiva e não aleatória de 97 mulheres entre 18 e 60 anos, cadastradas na Organização Não Governamental Núcleo de Estudos da Prostituição (NEP), de Porto Alegre, foi estudada. Após consentimento informado, as entrevistadas foram investigadas através do Inventário para depressão de Beck (BDI). O ponto de corte igual ou maior que 13 foi utilizado para detecção de sintomas depressivos. RESULTADOS: na amostra estudada, a idade média foi de 29,6 anos (dp 8,5 anos); 67 por cento apresentaram sintomas depressivos (ponto de corte³ 13) com escore médio no BDI de 19,1 (dp 10,9); 24,7 por cento da amostra apresentava sintomas leves; 40,2 por cento sintomas moderados e 7,2 por cento sintomas graves. Houve associação estatisticamente significativa entre a presença de sintomas depressivos e uso de álcool, história de doenças sexualmente transmissíveis e ausência de prática religiosa (p<0,05). CONCLUSÃO: além de alta taxa de prevalência de sintomas depressivos (67 por cento), 47,4 por cento das mulheres avaliadas apresentaram níveis moderado e grave de sintomatologia. O uso de álcool, história de doenças sexualmente transmissíveis e ausência de prática religiosa surgiram como fatores associados à presença de sintomas depressivos na amostra estudada.

Perfil das gestantes atendidas na Sala de Admissão do Centro Obstétrico do Hospital São Lucas da PUCRS / Profile of pregnants admited at the Obstetric Center of Hospital São Lucas da PUCRS

O objetivo deste artigo é determinar o perfil da paciente atendida na Sala de Admissão do Hospital São Lucas da PUCRS (HSL). Sugerir rotinas de atendimento em nosso serviço a fim de dinamizar a atuação dos profissionais envolvidos no mesmo. O método utilizado foi o estudo de casos, retrospectivo, de 1065 pacientes atendidas na Sala de Admissão do Centro Obstétrico (CO) do HSL, entre os meses de Setembro e Outubro do ano 2001. Entre as 1065 pacientes estudadas, 86 eram gestantes. No total, 25,4 eram procedentes de Viamão, 69,8 de POA e 4,9 de outras procedências. A raça predominantes foi a branca, com 73,1 dos atendimentos. A média de idade foi de 24,82 anos. Da amostra estudada 82,1 mão apresentaram indicações para internação hospitalar, e 9,9 internaram por trabalho de parto, 3 por ruptura prematura das membranas, 0,5 para indução eletiva do parto, 1,2 por patologia materna, 0,3 por morte fetal e 3,1 por outras causas. O perfil desenhado acima nos fornece uma visão da realidade do nosso serviço, porém é preciso uma continuidade na coleta e armazenamento computadorizado dos dados e na sua análise, a fim de que rotinas elaboradas com maior precisão possam ser sugeridas para melhorar a dinâmica dos profissionais envolvidos no atendimento das gestantes.