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

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.

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

Assessing the predictive performance of population pharmacokinetic models for intravenous polymyxin B in critically ill patients

Polymyxin B (PMB) has reemerged as a last-line therapy for infections caused by multidrug-resistant gram-negative pathogens, but dosing is challenging because of its narrow therapeutic window and pharmacokinetic (PK) variability. Population PK (POPPK) models based on suitably powered clinical studies with appropriate sampling strategies that take variability into consideration can inform PMB dosing to maximize efficacy and minimize toxicity and resistance. Here we reviewed published PMB POPPK models and evaluated them using an external validation data set (EVD) of patients who are critically ill and enrolled in an ongoing clinical study to assess their utility. Seven published POPPK models were employed using the reported model equations, parameter values, covariate relationships, interpatient variability, parameter covariance, and unexplained residual variability in NONMEM (Version 7.4.3). The predictive ability of the models was assessed using prediction-based and simulation-based diagnostics. Patient characteristics and treatment information were comparable across studies and with the EVD (n = 40), but the sampling strategy was a main source of PK variability across studies. All models visually and statistically underpredicted EVD plasma concentrations, but the two-compartment models more accurately described the external data set. As current POPPK models were inadequately predictive of the EVD, creation of a new POPPK model based on an appropriately powered clinical study with an informed PK sampling strategy would be expected to improve characterization of PMB PK and identify covariates to explain interpatient variability. Such a model would support model-informed precision dosing frameworks, which are urgently needed to improve PMB treatment efficacy, limit resistance, and reduce toxicity in patients who are critically ill

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Farmacocinetica da polimixina B intravenosa em pacientes em Unidade de Terapia Intensiva

Foi realizado um estudo de farmacocinética da polimixina B em pacientes críticos com desenvolvimento de um modelo populacional. Os critérios de inclusão foram pacientes internados em Unidade de Terapia Intensiva, com idade igual ou superior a 18 anos e em uso de polimixina B intravenosa por um período mínimo de 48 horas. Amostras de sangue, urina e dialisato foram coletadas durante um intervalo de doses no estado de equilíbrio. A concentração de polimixina B no plasma foi medida por meio de cromatografia líquida de alta performance associada à espectrometria de massas acoplada à espectrometria de massas, sua ligação às proteínas plasmáticas foi determinada por meio de diálise de equilíbrio rápido e a fração livre foi calculada. Foram realizadas análise farmacocinética populacional e Simulações de Monte Carlo. Foram incluídos 24 pacientes, dos quais dois estavam em hemodiálise contínua; 54,2% eram do sexo masculino e as medianas da idade, do escore APACHE e do peso corporal total foram de 61,5 anos, 21,5 e 62,5kg, respectivamente. As doses de polimixina B, conforme prescrição do médico assistente, variaram entre 0,45-3,38mg/kg/dia. O clearance estimado da creatinina nos 22 pacientes sem hemodiálise variou entre 10-143mL/min. A mediana da fração livre plasmática da polimixina B foi de 0,42 e a média (± desvio padrão) da fração livre da área sob a curva ao longo de um dia (fAUC0-24h) da polimixina B foi de 29,2±12,0mg•h/L, incluindo os pacientes em hemodiálise. A polimixina B foi excretada predominantemente por vias não renais e as medianas de sua recuperação urinária de forma inalterada foi de 4,04% e do seu clearance renal foi de 0,061L/hora. Nos pacientes 1 e 2 em hemodiálise foram identificados, respectivamente, clearance corporal total de 0,043 e 0,027L/h/kg, clearance da hemodiálise de 0,0052 e 0,0015L/h/kg; no dialisato foram recuperados 12,2% e 5,62% da dose como polimixina B não modificada. O clearance corporal total da polimixina B não mostrou nenhuma relação com o clearance da creatinina, escore APACHE II ou idade. A disposição da polimixina B no tempo foi adequadamente descrita pelo modelo de dois compartimentos com eliminação linear. O modelo farmacocinético populacional proporcionou ajustes excelentes para os perfis observados de concentração-tempo para pacientes individuais e as concentrações individuais e populacionais ajustadas foram precisas. O ajuste dos clearances e dos volumes de distribuição para o peso corporal total reduziu a variabilidade intersujeitos em 3,4% para o clearance e 41,7% para o volume de distribuição central; nos pacientes em diálise, após esse ajuste, os parâmetros estimados se assemelharam aos dos demais pacientes. As Simulações de Monte Carlo foram feitas com seis diferentes regimes de doses clinicamente relevantes escalonados pelo peso corporal total. O regime de doses de 1,5mg/kg 12/12h forneceu uma AUC0-24h de polimixina B no dia 4 de 90.4mg•hora/L para 50% dos pacientes, adequada para erradicação bacteriana em infecções graves por Pseudomonas aeruginosa ou Acinetobacter baumannii com concentração inibitória mínima para a polimixina B ≤2mg/L. Nas Simulações de Monte Carlo também foi possível identificar que uma melhor área sob a curva só foi atingida no dia 4 de tratamento. Este estudo mostrou que a dose de polimixina B intravenosa deve ser ajustada ao peso corporal total, que o melhor regime de doses é o de 1,5mg/kg 12/12h precedido de dose de ataque de 2,5mg/kg e que não há indicação de ajuste para a função renal, mesmo em pacientes em hemodiálise contínua.A polymyxin B pharmacokinetics study in critically ill patients was conducted with the development of a population modeling. The inclusion criteria were patients from Intensive Care Unit, aged ≥18 years who received intravenous polymyxin B for ≥ 48 hours. Blood, urine and dialysate samples were collected over a dosing interval at steady state. Polymyxin B concentrations was measured by liquid chromatography- tandem mass spectrometry, its plasma protein binding was determined by rapid equilibrium dialysis and unbound fraction was calculated. Population pharmacokinetic analysis and Monte Carlo Simulations were conducted. Twenty four patients were enrolled, two of whom on continuous hemodialysis; 54.2% were male; the median of age, APACHE II score and total body weight were 61.5years, 21.5 and 62.5kg, respectively. The physician-selected dose of polymyxin B was 0.45- 3.38mg/kg/day. The creatinine clearance of the 22 patients without hemodialysis ranged from 10 to 143mL/min. The median unbound fraction in plasma of polymyxin B was 0.42 and the mean (± standard deviation) of the area under the curve over a day for unbound (fAUC0-24h) polymyxin B was 29.2±12.0mg•hour/L, including hemodialysis patients. Polymyxin B was predominantly nonrenally cleared with median unchanged urinary recovered of 4.04%; the median renal clearance was 0.061L/hour. Patients 1 and 2 in hemodialysis presented, respectively, total body clearance of 0.043 and 0.027L/h/kg, hemodialysis clearance of 0.0052 and 0.0015L/h/kg; 12.2% and 5.62% of the polymyxin dose were recovered intact in the dialysate. Polymyxin B total body clearance did not show any relationship with creatinine clearance, APACHE II score, or age. The time course of polymyxin B concentrations was well described by a 2-compartment disposition model with linear elimination. The population pharmacokinetics model provided excellent fits to the observed concentration-time profiles for individual patients and the individual-fitted and population-fitted concentrations were adequately precise. Linear scaling of clearances and volumes of distribution by total body weight reduced the between subject variability in 3.4% for clearance and 41.7% for the central volume of distribution; after this scaling, the estimated parameters in hemodialysis patients were within the range of estimates from the other patients. The population mean of the total body clearance of polymyxin B when scaled by total body weight (0.0276L/hour/kg) showed remarkably low interindividual variability. The Monte Carlo Simulations were performed for six different clinically relevant dosage regimens scaled by total body weight. The regimen of 1.5mg/kg/12 hours provided an AUC0- 24h of polymyxin B of 90.4 mg•h/L in day 4 for 50% of patients which is appropriate considering severe infections by Pseudomonas aeruginosa or Acinetobacter baumannii with minimal inhibitory concentration for polymyxin B ≤2mg/L. In Monte Carlo Simulations we also identified that the best area under the curve was attained only in the day 4 of the treatment. This study showed that doses of intravenous polymyxin B are best scaled by total body weight, that the best regimen of doses is 3mg/kg/day with a loading dose of 2.5mg/kg and that its dosage selection should not be based on renal function, even in patients in continuous hemodialysis

Enterococcus SPP resistente à vancomicina : tipagem molecular, caracterização clínica e associação com mortalidade

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