Antimicrobial Stewardship in the Emergency Department Observation Unit: Definition of a New Indicator and Evaluation of Antimicrobial Use and Clinical Outcomes.

We aimed to define a novel indicator for monitoring antimicrobial use specifically in the Emergency Department Observation Unit (EDOU) and to assess the long-term impact of an institutional education-based antimicrobial stewardship program (ASP) on the antimicrobial prescribing pattern and clinical outcomes in this setting. A quasi-experimental interrupted time-series study was performed from 2011 to 2022. An educational ASP was implemented at the EDOU in 2015. To estimate changes in antimicrobial use, we designed an indicator adjusted for patients at risk of antimicrobial prescribing: defined daily doses (DDDs) per 100 patients transferred from the Emergency Department to the Observation Unit (TOs) per quarter. The number of bloodstream infections (BSIs) and the crude all-cause 14-day mortality were assessed as clinical outcomes. Antimicrobial use showed a sustained reduction with a trend change of -1.17 DDD per 100 TO and a relative effect of -45.6% (CI95% -64.5 to -26.7), particularly relevant for meropenem and piperacillin-tazobactam, with relative effects of -80.4% (-115.0 to -45.7) and -67.9% (-93.9 to -41.9), respectively. The incidence density of all BSIs increased significantly during the ASP period, with a relative effect of 123.2% (41.3 to 284.7). The mortality rate remained low and stable throughout the study period, with an absolute effect of -0.7% (-16.0 to 14.7). The regular monitoring of antimicrobial use in the EDOU by using this new quantitative indicator was useful to demonstrate that an institutional education-based ASP successfully achieved a long-term reduction in overall antimicrobial use, with a low and steady BSI mortality rate.

Safety of early oral ambulatory treatment of adult patients with bloodstream infections discharged from the emergency department.

This study evaluates the safety of early oral ambulatory treatment of adult patients diagnosed with bacteremia after their discharge from the emergency department. A cohort of 206 febrile ambulatory patients was assessed. Bacteremic low-risk patients were recommended an oral treatment and were compared with matched febrile non-bacteremic outpatients. Rates of 14-day mortality and unplanned re-consultations were similar and below 5% in both cohorts, highlighting the safety of oral therapy of low-risk bacteremia, even from its onset.

Assessing Tissue Transmission of Hepatitis C Virus From Viremic Donor to Seronegative Kidney Transplant Recipients: A Case Series.

The transmission of hepatitis C virus from viremic donors to seronegative recipients of kidney transplantation is well documented. Pre-transplant administration of direct-acting antivirals prevents viremia, but the seroconversion rate is high. We studied the transmission of the virus through the transplanted tissue by determining viral RNA in 15 kidneys from 8 deceased viremic donors, 5 males and 3 females aged 52.3 ± 15 years. HIV positive donors and active intravenous drugs abusers were discarded to avoid possible window periods in the virus transmission. Recipients, 9 males and 6 females aged 52.7 ± 18 years, were treated with glecaprevir/pibrentasvir for 8 weeks and received immunosuppression with thymoglobulin, tacrolimus, sirolimus and prednisone. Hepatitis C Virus was detected in 9 of the 15 histological samples analyzed but viremia was detected in no recipient at day 1 and 7 post-transplantation and 12 weeks after the treatment. However, 13 of the 15 recipients had seroconverted within 1 month. In conclusion, Hepatitis C virus was detected in a significant proportion of tissue of kidney grafts from viremic donors, but treatment with direct-acting antivirals avoids the transmission of the virus from donor to recipient. Then Donor pools should be expanded.

Study protocol for a randomized clinical trial to assess 7 versus 14-days of treatment for Pseudomonas aeruginosa bloodstream infections (SHORTEN-2 trial).

BACKGROUND: Research priorities in Antimicrobial Stewardship (AMS) have rapidly evolved in the last decade. The need for a more efficient use of antimicrobials have fueled plenty of studies to define the optimal duration for antibiotic treatments, and yet, there still are large areas of uncertainty in common clinical scenarios. Pseudomonas aeruginosa has been pointed as a priority for clinical research, but it has been unattended by most randomized trials tackling the effectiveness of short treatments. The study protocol of the SHORTEN-2 trial is presented as a practical example of new ways to approach common obstacles for clinical research in AMS. OBJECTIVE: To determine whether a 7-day course of antibiotics is superior to 14-day schemes for treating bloodstream infections by P. aeruginosa (BSI-PA). METHODS: A superiority, open-label, randomized controlled trial will be performed across 30 Spanish hospitals. Adult patients with uncomplicated BSI-PA will be randomized to receive a 7 versus 14-day course of any active antibiotic. The primary endpoint will be the probability for the 7-day group of achieving better outcomes than the control group, assessing altogether clinical effectiveness, severe adverse events, and antibiotic exposure through a DOOR/RADAR analysis. Main secondary endpoints include treatment failure, BSI-PA relapses, and mortality. A superiority design was set for the primary endpoint and non-inferiority for treatment failure, resulting in a sample size of 304 patients. CONCLUSIONS: SHORTEN-2 trial aligns with some of the priorities for clinical research in AMS. The implementation of several methodological innovations allowed overcoming common obstacles, like feasible sample sizes or measuring the clinical impact and unintended effects. TRIAL REGISTRATION: EudraCt: 2021-003847-10; ClinicalTrials.gov: NCT05210439.

Bacteraemia and quick Sepsis Related Organ Failure Assessment (qSOFA) are independent risk factors for long-term mortality in very elderly patients with suspected infection: retrospective cohort study.

BACKGROUND: In older adult patients, bloodstream infections cause significant mortality. However, data on long-term prognosis in very elderly patients are scarce. This study aims to assess 1-year mortality from bacteraemia in very elderly patients. METHODS: Retrospective cohort study in inpatients aged 80 years or older and suspected of having sepsis. Patients with (n = 336) and without (n = 336) confirmed bacteraemia were matched for age, sex, and date of culture, and their characteristics were compared. All-cause mortality and risk of death were assessed using the adjusted hazard ratio (aHR). RESULTS: Compared to controls, cases showed a higher 1-year mortality (34.8% vs. 45.2%) and mortality rate (0.46 vs. 0.69 deaths per person-year). Multivariable analysis showed significant risk of 1-year mortality in patients with bacteraemia (aHR: 1.31, 95% confidence interval [CI] 1.03-1.67), quick Sepsis Related Organ Failure Assessment (qSOFA) score of 2 or more (aHR: 2.71, 95% CI 2.05-3.57), and age of 90 years or older (aHR 1.53, 95% CI 1.17-1.99). CONCLUSIONS: In elderly patients suspected of sepsis, bacteraemia is associated with a poor prognosis and higher long-term mortality. Other factors related to excess mortality were age over 90 years and a qSOFA score of 2 or more.

Medium-term serostatus in Spanish case series recovered from SARS-CoV-2 infection.

The medium-term serologic response of SARS-CoV-2 infection recovered individuals is not well known. The aims were to quantify the incidence of seropositive failure in the medium term in a cohort of patients with different COVID-19 severity and to analyze its associated factors. Patients who had recovered from mild and severe forms of SARS-CoV-2 infection in an Academic Spanish hospital (March 12-May 2, 2020), were tested for total anti-SARS-CoV-2 antibodies by electrochemiluminescence immunoassay (Elecsys Anti-SARS-CoV-2 test; Roche Diagnostics GmbH). The non-seropositive status (seropositive failure) incidence (95% CI) was determined. Associations were tested by multiple logistic regression in a global cohort and severe pneumonia subpopulation. Of 435 patients with PCR-confirmed SARS-CoV-2, a serological test was carried out in 325: 210 (64.6%) had severe pneumonia (hospitalized patients), 51 (15.7%) non-severe pneumonia (managed as outpatients), and 64 (19.7%) mild cases without pneumonia. After a median (IQR) of 76 days (70-83) from symptom onset, antibody responses may not consistently develop or reach levels sufficient to be detectable by antibody tests (non-seropositive incidence) in 6.9% (95% CI, 4.4-10.6) and 20.3% (95% CI, 12.2-31.7) of patients with and without pneumonia, respectively. Baseline independent predictors of seropositive failure were higher leukocytes and fewer days of symptoms before admission, while low glomerular filtrate and fever seem associated with serologic response. Age, comorbidity or immunosuppressive therapies (corticosteroids, tocilizumab) did not influence antibody response. In the medium-term, SARS-CoV-2 seropositive failure is not infrequent in COVID-19 recovered patients. Age, comorbidity or immunosuppressive therapies did not influence antibody response.

The quick Sepsis-related Organ Failure Assessment (qSOFA) is a good predictor of in-hospital mortality in very elderly patients with bloodstream infections: A retrospective observational study.

People over 80 years old are now the fastest-growing age group. Bloodstream infections (BSI) in these patients may present with specific characteristics. The objective of this study was to analyze independent factors affecting in-hospital mortality (IHM) due to BSI in very elderly patients (≥80 years of age) and to compare the clinical presentation of BSI in patients aged 80-89 years versus those aged 90 or more. Retrospective, cross-sectional and observational study of BSI in patients aged 80 years or older. The study used IHM as the primary outcome. Stepwise multiple logistic regression models were used to identify associations between potential predictors and IHM. Of the 336 included patients, 76.8% (n = 258) were in the 80-89-year age group and 23.2% (n = 78) in the 90+ age group; 17.3% (n = 58) of patients died during admission. This outcome was independently associated with quick Sepsis Related Organ Failure Assessment (qSOFA) of 2 or more (adjusted odds ratio [aOR] 4.7, 95% confidence interval [CI] 2.3-9.4; p < 0.001). Other predictors included an origin of BSI outside the urinary tract (aOR 5.5, 95% CI 2.4-12.6; p < 0.001), thrombocytopenia (aOR 4.9, 95% CI 1.8-13.4; p = 0.002), hospital-acquired infection (aOR 3.0, 95% CI 1.2-7.5; p = 0.015), and inappropriate empiric antibiotics (aOR 2.0, 95% CI 1.1-3.9; p = 0.04). IHM was 23.1% in the 90+ age group and 15.5% in patients aged 80 to 89 (p = 0.012). However, the 90+ age group was more likely to have a score of at least 2 on the qSOFA (29.9% vs. 19.1%, p = 0.043) and Pitt bacteremia scales (44.9% vs. 30.2%; p = 0.02), as well as chronic kidney disease (56.4% vs. 36.0%; p = 0.001) and altered mental state (40.3% vs. 25.7%; p = 0.013). In conclusion: A qSOFA score of 2 or more and a BSI originating outside the urinary tract were independent predictors of IHM. The 90+ age group was at higher risk than the 80-89-year age group of having a qSOFA score and Pitt bacteremia score of 2 or more as well as an altered mental state.

Renal transplantation from seropositive hepatitis C virus donors to seronegative recipients in Spain: a prospective study.

Hepatitis C virus (HCV) positive donors are identified in Spain by antibody detection (HCV-Ab) techniques while a HCV nuclear acid-testing (HCV-NAT) is not mandatory. Since it has been shown that HCV-Ab positive HCV-NAT negative donors do not universally transmit the infection, we designed a protocol based on the identification of viremia in HCV-Ab positive donors to start treatment if needed. HCV-Ab-positive donors were identified and we performed HCV-NAT immediately. Donors coinfected with HIV were excluded. Recipients with a low chance to receive a transplant, with no history of liver disease and who were negative for HCV-Ab were selected after informed consent was signed. Kidney recipients from HCV-NAT-positive donors received glecaprevir and pibrentasvir from 6 h before the transplant until 8 weeks after. Recipients from HCV-NAT-negative donors were not treated. Regular monitoring by HCV-NAT was performed to initiate antiviral treatment. We included 11 recipients from six deceased donors Four recipients received grafts from HCV-NAT-positive donors and seven patients received grafts from HCV-NAT-negative donors. None of our recipients exhibited HCV-NAT positivity during the minimum follow-up period of 6 months. Recipients from HCV-NAT-positive donors exhibited sustained virologic response at 12 weeks. One recipient from an HCV-NAT-negative donor lost his graft via a process thought to be unrelated to HCV. The remaining 10 patients had a stable functioning graft at the end of the follow-up period. Our preliminary data suggest that renal transplantation from HCV-Ab- positive donors to HCV-Ab negative recipients is safe when only the recipients of organs from HCV-NAT-positive donors are treated.

Missing Cases of Herpes Simplex Virus (HSV) Infection of the Central Nervous System When the Reller Criteria Are Applied for HSV PCR Testing: a Multicenter Study.

Previous studies suggested that herpes simplex virus (HSV) PCR testing can be safely deferred in patients with normal cerebrospinal fluid (CSF) white blood cell (WBC) counts and protein levels as long as they are older than 2 years of age and are not immunocompromised, the so-called Reller criteria. In this multicenter study, we retrospectively assessed the validity of these screening criteria in our setting. A total of 4,404 CSF specimens submitted for HSV PCR testing to the respective microbiology laboratories at the participating hospitals between 2012 and 2018 were included. Six commercially available HSV PCR assays were used across the participating centers. Ninety-one of the 4,404 CSF specimens (2.1%) tested were positive for HSV DNA (75 samples for HSV-1 and 16 for HSV-2). Nine patients failed to meet the Reller criteria, of whom seven were deemed to truly have HSV encephalitis. Overall, no significant correlation between HSV PCR cycle threshold (CT ) values and WBC counts or total protein levels was found. In addition, median HSV PCR CT s were comparable between patients who met the Reller criteria and those who did not (P = 0.531). In summary, we show that HSV DNA may be detected in CSF specimens with normal WBC and protein levels collected from immunocompetent individuals older than 2 years with HSV encephalitis. Nevertheless, the data also indicate that the number of cases detected could be lowered at least by half if CSF specimens with borderline WBC counts (4 cells/mm3) as well as children of any age are systematically tested.

Evaluation of the Sepsis Flow Chip assay for the diagnosis of blood infections.

BACKGROUND: Blood infections are serious complex conditions that generally require rapid diagnosis and treatment. The big challenge is to reduce the time necessary to make a diagnosis with current clinical microbiological methods so as to improve the treatment given to patients. METHODS: In this study, we assess for the first time the Sepsis Flow Chip assay, which is a novel diagnostic assay for simultaneous rapid-detection of the vast majority of bloodstream pathogens, including Gram-positive and Gram-negative bacteria and fungi, in the same assay, and for the detection of most common antibiotic resistance genes. The SFC assay is based on multiplex PCR and low density DNA arrays. RESULTS: Positive blood cultures from 202 consecutive bacteremia patients were analyzed by SFC assay and the results were compared with the results obtained by the gold standard methodology used in clinical microbiology diagnostic laboratories (EUCAST guidelines). SFC assay overall sensitivity and specificity for bacterial identification were 93.3% and 100% respectively and sensitivity and specificity for the identification of antibiotic genetic resistance determinants were 93.6% and 100% respectively. CONCLUSIONS: This is the first evaluation of SFC assay in clinical samples. This new method appears to be very promising by combining the high number of distinct pathogens and genetic resistance determinants identified in a single assay. Further investigations should be done to evaluate the usefulness of this assay in combination with clinical multidisciplinary groups (stewardship), in order for the results to be applied appropriately to the management of patients`infectious processes.

[Epidemiological profile and sensitivity pattern of isolates causing invasive fungal infection vs. colonizing isolates in non-neutropenic critically ill patients]. / Perfil epidemiológico y patrón de sensibilidad de aislamientos causantes de infección fúngica invasora frente a aislamientos fúngicos de colonización en pacientes críticos no neutropénicos.

BACKGROUND: Patients admitted to critical care units can be infected with a large number of fungal isolates that are occasionally responsible for invasive fungal infections (IFI). AIMS: To describe the epidemiological profile and antifungal susceptibility patterns of fungal isolates in our unit, and to identify key risk factors associated with the development of IFI. METHODS: A descriptive cohort and retrospective study with patients admitted to a polyvalent Critical Care Unit of a university hospital was carried out. The isolation of at least one fungal species in a culture of biological samples, over a period of 48 months was considered. RESULTS: Twenty patients out of 232 developed IFI. Patients in the IFI group had a higher mortality and higher Candida score value 48 h prior to clinical diagnosis. Risk factors associated with the development of IFI were chronic obstructive pulmonary disease, gastrointestinal surgery, total parenteral nutrition, and prolonged systemic corticosteroid therapy. The predominant fungal species in both groups was Candida albicans, with global resistance to fluconazole and itraconazole of 1.94%. CONCLUSIONS: We found a low incidence of species of Candida non-C. albicans in our unit. The rate of resistance to azoles in C. albicans was similar to that of larger series. Gastrointestinal surgery, COPD, prolonged treatment with corticosteroids, and parenteral nutrition administration are risk factors associated with the development of IFI.

Low-level HIV viremia is associated with microbial translocation and inflammation.

BACKGROUND: Decrease in HIV viral load (VL) is accompanied by decrease in microbial translocation (MT) and chronic inflammation, but the behavior of these markers in patients with HIV-VL <20 copies per milliliter is unknown. The aim of this study was to determine whether strict control of HIV-VL is associated with MT and chronic inflammation. METHODS: Observational cross-sectional study. INCLUSION CRITERIA: HIV patients receiving antiretroviral therapy and HIV-VL <200 copies per milliliter for more than 6 months. EXCLUSION CRITERIA: chronic liver disease, active infection, or antibiotic consumption. Recruitment: patients who consecutively visited the outpatient clinic in November 2011. Primary endpoint: molecular MT as determined by detection in plasma of 16S ribosomal DNA. Secondary variables: lipopolysaccharide, soluble CD14, tumor necrosis factor α, and interleukin 6. Primary explanatory variable: HIV-VL (COBAS AmpliPrep/COBAS TaqMan HIV-1 test, version 2.0) with a detection limit of 20 copies per milliliter. RESULTS: Fifty-two patients were included: 65% men, median age 45 years, HIV acquired predominantly through sex (75%), 40% Centers for Disease Control and Prevention stage C, and median CD4 lymphocyte count 552 cells per cubic millimeter (range, 126-1640 cells/mm). Molecular MT was observed in 46% and 18% of patients with low-level (20-200 copies/mL) and negative (<20 copies/mL) HIV-VL, respectively (P < 0.05). Plasma levels of inflammatory markers (tumor necrosis factor α and interleukin 6) were higher in patients with molecular MT (P < 0.01) and were not influenced for HIV-VL. CONCLUSIONS: Patients with HIV infection receiving treatment and negative HIV-VL (<20 copies/mL) present less frequently MT than patients with low-level HIV viremias (20-200 copies/mL). MT is associated with higher levels of inflammation markers, independent of HIV-VL.

[Reproducibility of a method to quantify vaginal human immunodeficiency virus viral load]. / Estudio de consistencia de una metodología para cuantificar la carga viral vaginal del virus de la inmunodeficiencia humana.

OBJECTIVE: To assess the reproducibility of a method to collect and quantify HIV nucleic acids in vaginal secretions. METHODS: We analysed two consecutive vaginal samples collected by direct aspiration from 52 HIV infected women. Nucleic acids were extracted by QIAamp RNA-viral and quantified with a modified Cobas Amplicor HIV-1 Monitor. RESULTS: Intra-class correlation coefficient between matched samples: 0.99. Differences of pooled HIV DNA+RNa and RNA were <0.40 uLog for 95% of all samples (Bland-Altman plots). CONCLUSIONS: This method is a standard and reproducible assay to detect and measure HIV vaginal viral load.

Immunovirologic consequences and safety of short, non-structured interruptions of successful antiretroviral treatment.

OBJECTIVES: The aim was to evaluate the safety of short antiretroviral treatment interruptions and their virologic and immunologic consequences in HIV-infected adults on highly active antiretroviral treatment (HAART) with suppressed viral replication. The viral efficacy upon reintroduction was also evaluated. PATIENTS AND METHODS: All patients with undetectable viral load while on HAART were prospectively followed to detect any treatment interruption. We analysed viral and cellular kinetics, incidence of resistance mutations, clinical outcome and results after therapy resumption. RESULTS: Twenty patients were included, mean time since HIV diagnosis was 95 months and time with undetectable viral load 16 months. Treatment was interrupted because of adverse effects, cancer, tuberculosis or patient will. Treatment was reintroduced after 4 weeks using, if possible, the same combination. HIV viral load was detectable on day 28 after interruption in 18 patients (90%). Median of CD4 cell count (p25-p75) decreased from 478/mm3 (96-716) to 257/mm3 (118-663) (p=0.5). Resistance mutations were found in 9 patients (45%) after interruptions. Treatment was reintroduced in 14 patients; all of them achieved viral suppression. CONCLUSIONS: In patients receiving HAART who have undetectable viral load, an interruption, no longer than 4 weeks, due to any intercurrent problem seems to be safe. Response to resumption can usually be achieved. Due to the frequent development of resistance, a genotypic test during interruption might be helpful.

Quadruple-2 protease inhibitors (PI)-therapy does not accelerate viral decay and suppression in PI-naive HIV-1 infected patients with severe immunosuppression and high viral load as compared with standard triple therapy.

To analyse if a four-drug combination including two protease inhibitors (PIs) accelerates viral decay and suppression as compared with standard triple therapy in heavily immunosuppressed HIV-1 infected patients, an open label clinical trial was designed. PIs naive patients receiving their first highly active antiretroviral therapy were included if their CD4 cell count was lower than 200/mm3 and their HIV viral load (VL) >100,000 RNA copies/mL. Every patient received two analogues and was randomized in two groups receiving either one PI (saquinavir soft gel capsule) or two PIs (saquinavir + nelfinavir). Viral efficacy (VL <50), time to reach VL <50, viral clearance rate constant and plasmatic elimination half-life were determined. In all, 30 patients were enrolled. No viral variable was significatively improved by the four-drug combination in the short term. No clinical benefit should be expected with a four-drug (two PIs) regimen in patients with low CD4+ cell count and high VL.

Divergencias en la percepcion de la funcionalidad familiar entre padres, madres e hijos adolescentes / Differences in perception of family functioning among fathers, mothers and adolescents children

El estudio de la divergencia en la percepción de la vida familiar entre los miembros de cada familia constituye un área de especial interés para conocer los cambios evolutivos de la familia y el nivel de funcionalidad familiar. Conocer los niveles de divergencia es especialmente relevante en la etapa familiar de hijos adolescentes, dada la preocupación de éstos por clarificar su propia identidad y la preocupación de los padres por resolver adecuadamente los conflictos asociados con el desarrollo especialmente en esta etapa de adolescencia. El presente trabajo analizó la divergencia en la percepción familiar de padres, madres e hijos adolescentes en una muestra de 185 familias de la Comunidad Valenciana (España). Hemos aplicado el cuestionario FYD de dos factores, Funcionalidad y Dificultades familiares. Los análisis de varianza realizados muestran diferencias significativas en función de la variable parentesco. Las correspondientes pruebas post hoc indican que entre los progenitores no existen diferencias significativas, pero sí que las hay en las diadas madre-hijo y padre-hijo siendo los progenitores quienes perciben valores más altos en Funcionalidad familiar y más bajos en dificultades familiares

[Predictors of progression and death in patients with advanced HIV infection in the era of highly active antiretroviral therapy]. / Predictores de progresión y muerte en pacientes con infección avanzada por el VIH en la era de los tratamientos antirretrovirales de gran actividad.

INTRODUCTION: To assess the factors associated with progression of infection and death in HIV-positive patients with severe immunodepression in the era of highly active antiretroviral therapy (HAART). METHODS: We studied 146 HIV-infected patients with < 100 x 10(6)/L CD4+ lymphocytes and positive cytomegalovirus (CMV) serology enrolled between December 1997 and October 1998 and prospectively followed a median of 12.1 months. The main outcome measures were progression of HIV infection, defined as the appearance of a new AIDS-defining disease (CDC category C) or death. HIV viral load, lymphocyte count (CD4+ and CD8+), HAART administration and other clinical variables were evaluated at baseline. CMV viremia (determined by PCR) and HAART efficacy were recorded during follow-up. RESULTS: Progression was observed in 40% of patients and 17% died. Factors associated with progression or death were CD4+ lymphocyte count less than 50 x 10(6)/L, CD8+ lymphocyte count less than 500 x 10(6)/L, HIV viral load more than 300,000 copies RNA/mL, CMV viremia, and absence or inefficacy of HAART. In the multivariate model, absence of HAART and low CD4+ and CD8+ counts remained statistically associated with progression, but the only variable associated with death was CMV viremia. CONCLUSIONS: In patients with advanced HIV infection, CD4+ and CD8+ cell count and HAART were the most important factors related to progression, and CMV viremia was the strongest predictor of death.