Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19.

Background: An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Method: Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results: In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions: These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167.

Spanish adaptation of the Start Smart-Then Focus tool for optimizing the use of antimicrobials.

OBJECTIVE: The Start Smart-Then Focus tool of the United Kingdom's National Health System is a tool to be implemented in antimicrobial stewardship programs. The objective of this work is the adaptation of Start Smart-Then Focus tool to the Spanish health system. METHOD: Delphi methodology was used. Two rounds were conducted by  email. In the first, a questionnaire was sent out that included the criteria of the tool. These criteria were independently assessed by 16 experts. They rated the suitability and applicability of each criterion on a scale from 1 to 9 and made free comments on each one. The tool was modified and sent out again to all the experts. They re-scored the questionnaire individually, while aware of the anonymized results of the first round. RESULTS: The first questionnaire was made up of 19 indicators. Of these, 16 indicators had a median of more than 7 in suitability and applicability. However, regarding applicability, 3 indicators had a median of less than 7 and 10 had a minimum of less than 5. From the initial 19 indicators, we obtained 8 final indicators and 8 options were added to the sixth indicator. CONCLUSIONS: It would be very useful to implement the Spanish adaptation of the Start Smart-Then Focus tool in antimicrobial stewardship programs at a national level. It would also contribute to improving the use of antimicrobials.

Objetivo: La herramienta Start Smart-Then Focus del Sistema Nacional de Salud de Reino Unido es una herramienta de ayuda de los programas de optimización de antibióticos. El objetivo de este trabajo es la adaptación de la herramienta Start Smart-Then Focus al sistema de salud  español.Método: Se utilizó la metodología Delphi, mediante dos rondas de evaluación por correo electrónico. En la primera se envió un cuestionario con los criterios de la herramienta, estos fueron evaluados de  forma independiente por 16 expertos. Puntuaron de 1-9 la idoneidad y  aplicabilidad de cada criterio, y realizaron comentarios libres. La  herramienta fue modificada y enviada de nuevo a todos los expertos, volvieron a puntuar individualmente, pero conociendo los resultados de la primera ronda.Resultados: El primer cuestionario estaba constituido por 19 indicadores; 16 indicadores obtuvieron una mediana mayor de 7 en idoneidad y aplicabilidad, 3 indicadores obtuvieron mediana menor de 7 y  10 indicadores con mínimos menores de 5 en aplicabilidad. De 19 indicadores iniciales pasamos a 8; con 8 opciones dentro del sexto  indicador.Conclusiones: La adaptación de la herramienta Start Smart-Then Focus a nivel nacional puede ser de utilidad para implantarla en los programas de optimización de antibióticos y contribuir a la mejora del uso de los antimicrobianos.

[Clinical approach to imported eosinophilia]. / Aproximación clínica a la eosinofilia importada.

Eosinophilia is a common finding in international travelers and immigrants, being an helmintic infection its main etiology. The positive predictive value of eosinophilia for an helmintosis is low in travellers. Eosinophilia may be an incidental finding, or symptomatic, and it represents a clinical challenge due to the low sensitivity and specificity of direct and indirect parasitological diagnostic tests, respectively. It requires a structured approach based on geographical areas, environmental exposures and behavioral risks, and associated symptoms. The initial assessment should include a comprehensive and tailored anamnesis and physical examination, basic laboratory tests, a complete parasitological examination of stool samples and a Strongyloides stercoralis serology, supplemented with other explorations guided by epidemiological and clinical suspicion. Empiric treatment with albendazole and/or ivermectin (plus praziquantel if risk of schistosomiasis) is an option for unidentified persistent eosinophilia after study, and in persons in whom a proper assessment or follow-up can not be assured. In patients at risk for estrongiloidosis who are candidates for immunosuppressive therapies, it is indicated a prior screening and treatment to prevent a future hyperinfestation syndrome.

Acinetobacter baumannii in critically ill patients: Molecular epidemiology, clinical features and predictors of mortality.

INTRODUCTION: The main aim of this study was to assess changes in the epidemiology and clinical presentation of Acinetobacter baumannii over a 10-year period, as well as risk factors of mortality in infected patients. METHOD: Prospective, multicentre, hospital-based cohort studies including critically ill patients with A. baumannii isolated from any clinical sample were included. These were divided into a first period ("2000 study") (one month), and a second period ("2010 study") (two months). Molecular typing was performed by REP-PCR, PFGE and MSLT. The primary endpoint was 30-day mortality. RESULTS: In 2000 and 2010, 103 and 108 patients were included, and the incidence of A. baumannii colonization/infection in the ICU decreased in 2010 (1.23 vs. 4.35 cases/1000 patient-days; p<0.0001). No differences were found in the colonization rates (44.3 vs. 38.6%) or infected patients (55.7 vs. 61.4%) in both periods. Overall, 30-day mortality was similar in both periods (29.1 vs. 27.8%). The rate of pneumonia increased from 46.2 in 2000 to 64.8% in 2010 (p<0.001). Performing MSLT, 18 different sequence types (ST) were identified (18 in 2000, 8 in 2010), but ST2 and ST79 were the predominant clones. ST2 isolates in the ICU increased from 53.4% in the year 2000 to 73.8% in 2010 (p=0.002). In patients with A. baumannii infection, the multivariate analysis identified appropriate antimicrobial therapy and ST79 clonal group as protective factors for mortality. CONCLUSIONS: At 10 years of the first analysis, some variations have been observed in the epidemiology of A. baumannii in the ICU, with no changes in mortality. Epidemic ST79 clone seems to be associated with a better prognosis and adequate treatment is crucial in terms of survival.

[Candidemias: multicentre analysis in 16 hospitals in Andalusia (Spain)]. / Candidemias: análisis multicéntrico en 16 hospitales andaluces.

INTRODUCTION: Candidemia is a nosocomial infection with high associated mortality. There have been changes in microbiology, epidemiology and treatment over the last few years, which has led us to analyse our own situation. MATERIAL AND METHODS: Prospective, multicentre and observational study. All episodes of candidemia in adult patients seen in 17 Andalusian hospitals from 1 October 2005 to 30 September 2006 were included. RESULTS: Were detected 220 cases, the incidence was 0.58 cases/1,000 hospital discharges. Candida albicans was the most frecuent species (53% of cases). The majority of isolates (89%) was susceptibility to fluconazole. Sepsis was the most frequent clinical manifestation (65.7%). The treatment was inadequate in 38.7% of cases. Overall mortality was 40%. On univarite analysis death was found to be significantly associated with: aged > 60 years, unknown candidemia focus, Pitt score ≥ 2, APACHE II, shock at onset, persistents positive second blood cultures, non-removal of the central venous catheter and Candida species different of C. parasilopsis, among others. In the multivariate analysis death was found to be significantly associated with: aged > 60 years, Pitt score ≥ 2, Candida species different of C.parasilopsis and inadequate treatment. CONCLUSIONS: The candidemia clinical epidemiology in our region is similar to other areas and receiving inadequate treatment is the only modifiable risk factor associated with higher odds of mortality. Therefore, this modifiable factor needs to be improved to reduce the mortality.

[Guidelines for the diagnosis and treatment of patients with bacteriemia. Guidelines of the Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica]. / Guía para el diagnóstico y tratamiento del paciente con bacteriemia. Guías de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC).

Bacteremia is a complex clinical syndrome in constant transformation that is an important, growing cause of morbidity and mortality. Even though there is a great deal of specific information about bacteremia, few comprehensive reviews integrate this information with a practical AIM. The main objective of these Guidelines, which target hospital physicians, is to improve the clinical care provided to patients with bacteremia by integrating blood culture results with clinical data, and optimizing the use of diagnostic procedures and antimicrobial testing. The document is structured into sections that cover the epidemiology and etiology of bacteremia, stratified according to the various patient populations, and the diagnostic work-up, therapy, and follow-up of patients with bacteremia. Diagnostic and therapeutic decisions are presented as recommendations based on the grade of available scientific evidence.

[Blood cultures in the emergency department]. / Hemocultivos en el servicio de urgencias.

INTRODUCTION: Culture of emergency room blood samples is common practice, but open to controversy. As compared to other emergency tests, blood collection requires twice as much time and needs a refined technique to avoid contamination, and the study has no immediate diagnostic utility. METHODS: This prospective study includes consecutive adult patients with positive emergency room blood cultures. We analyzed the diagnostic sensitivity and contamination rate of the cultures and the etiology, clinical features and prognosis of the bacteremias encountered. RESULTS: During the study period, 5.2 blood cultures were indicated per 1000 patients attended in the emergency room. The diagnostic yield (positive blood cultures/total cultures) was 20% and the contamination rate (contaminated blood cultures/total cultures) was 1%. The incidence of bacteriemia was 0.99 episodes per 1000 patients attended in the emergency room and 10.3 episode per 1000 hospitalized patients. Gram-negative bacteria predominated (57%). Sepsis was the most frequent clinical manifestation (50%), followed by severe sepsis (40%) and septic shock (10%). Mortality was 22%. Diabetes mellitus and severe sepsis/septic shock were independent factors associated with mortality. CONCLUSIONS: Diagnostic performance and quality of emergency room blood cultures was high. The predominant etiology was gram-negative bacteria. Patients had a severe clinical presentation. Diabetes mellitus and severe sepsis and/or septic shock were independent prognostic factors of mortality.

[Nosocomial pneumonia due to Acinetobacter baumannii]. / Neumonía nosocomial por Acinetobacter baumannii.

Acinetobacter baumannii is a significant cause of nosocomial pneumonia, especially late ventilator-associated pneumonia. In Spain, A. baumannii is the third leading pathogen after Pseudomonas aeruginosa and Staphylococcus aureus. Risk factors for pneumonia due to A. baumannii are head injury, neurosurgery, acute respiratory distress syndrome, aspiration, and previous antibiotic therapy. Definitive diagnosis requires respiratory samples and invasive techniques with quantitative cultures to differentiate true infections from simple colonizations. The crude mortality of patients with ventilator-associated A. baumannii pneumonia is high, although the attributable mortality is controversial. Adequate empirical antimicrobial therapy of A. baumannii pneumonia is a protective factor, even though the therapeutic options are often limited. The treatment of choice is imipenem and sulbactam may be considered an acceptable alternative. Nowadays, colistin is the treatment of choice in A. baumannii pneumonia caused by panresistant strains. The associations of imipenem and rifampin or imipenem and sulbactam may be acceptable alternatives to colistin in infections caused by these strains. Surveillance measures are essential to eradicate this multidrug-resistant pathogen in outbreaks and reduce the number of episodes in endemic situations. Although these measures are important throughout the hospital, intensive care units are especially high-risk areas.

[Infectious disease assessment in solid organ transplant candidates]. / Evaluación de las enfermedades infecciosas en el candidato a un trasplante de órgano sólido.

BACKGROUND: Infections are one of the leading causes of morbidity and mortality in solid organ transplant recipients. Many of these infections can be prevented or their effects reduced by accurate preoperative evaluation of risk in the transplantation candidate. The elaboration of guidelines using a multidisciplinary approach can help to establish more rational diagnostic, therapeutic, and preventive measures in this setting. OBJECTIVE: To elaborate guidelines for the assessment of infectious diseases in transplant candidates, based on consensus among professionals in this field and under the auspices of Spanish scientific societies. MATERIAL AND METHODS: The Infections in Transplant Patients Group (GESITRA), within the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), appointed a panel of four microbiologists and infectious disease specialists to elaborate a draft of the guidelines, which was subsequently approved by all the members of this Group. With the support of the National Transplant Organization, the GESITRA document was then presented to various professionals in this field so they could provide their comments and suggestions. RESULTS: The final document, after incorporation of all appropriate modifications and suggestions, is presented herein. The guidelines focus on the following: a) diagnosis of active and latent infections, and identification of risk factors in the candidate; b) recommended approach for infections diagnosed during the evaluation process and their corresponding treatment; c) definition of infections contraindicating transplantation; and d) prevention of post-transplantation infectious complications by systematic vaccination and instruction on preventive measures provided to patients, their relatives, and persons living with them. DISCUSSION: Using a multidisciplinary approach that included the efforts of experts in the field and the collaboration of scientific societies, a comprehensive document containing specific recommendations was elaborated. Systematic review of the guidelines in the future is considered worthwhile by both the authors and supporters of this document.