Role of Relebactam in the Antibiotic Resistance Acquisition in Pseudomonas aeruginosa: In Vitro Study.

BACKGROUND: Pseudomonas aeruginosa shows resistance to several antibiotics and often develops such resistance during patient treatment. OBJECTIVE: Develop an in vitro model, using clinical isolates of P. aeruginosa, to compare the ability of the imipenem and imipenem/relebactam to generate resistant mutants to imipenem and to other antibiotics. Perform a genotypic analysis to detect how the selective pressure changes their genomes. METHODS: The antibiotics resistance was studied by microdilution assays and e-test, and the genotypic study was performed by NGS. RESULTS: The isolates acquired resistance to imipenem in an average of 6 days, and to imipenem/relebactam in 12 days (p value = 0.004). After 30 days of exposure, 75% of the isolates reached a MIC > 64 mg/L for imipenem and 37.5% for imipenem/relebactam (p value = 0.077). The 37.5% and the 12.5% imipenem/relebactam mutants developed resistance to piperacillin/tazobactam and ceftazidime, respectively, while the 87.5% and 37.5% of the imipenem mutants showed resistance to these drugs (p value = 0.003, p value = 0.015). The main biological processes altered by the SNPs were the glycosylation pathway, transcriptional regulation, histidine kinase response, porins, and efflux pumps. DISCUSSION: The addition of relebactam delays the generation of resistance to imipenem and limits the cross-resistance to other beta-lactams. The clinical relevance of this phenomenon, which has the limitation that it has been performed in vitro, should be evaluated by stewardship programs in clinical practice, as it could be useful in controlling multi-drug resistance in P. aeruginosa.

A retrospective real-world study of early short-course remdesivir in non-hospitalized COVID-19 patients at high risk for progression: low rate of hospitalization or death, regardless of immunocompetence status.

Introduction: The evidence for remdesivir therapy in immunocompromised patients is scarce. To evaluate remdesivir (RDV) effectiveness and safety in COVID-19 outpatients at high risk for progression in a real-world setting, we compare the outcome in immunocompromised (IC) patients with that in non-immunocompromised patients. Methods: Two hospitals conducted a retrospective study of all adult patients with mild-to-moderate SARS-CoV-2 infection at high risk for disease progression who were treated as outpatients with a 3-day course of RDV (1st January-30th September 2022). The primary effectiveness endpoint was a composite of any cause of hospitalization or death by day 30. A multiple logistic regression model was built to explore the association between immune status and clinical outcome, estimating adjusted odds ratios [aORs (95% CI)]. Results: We have included 211 patients, of which 57% were males, with a median age of 65 years (IQR 53-77), 70.1% were vaccinated (three or four doses), and 61.1% were IC. The median duration of symptoms before RDV treatment was 3 days (IQR 2-5). During follow-up, 14 (6.6%) patients were hospitalized, of which 6 (2.8%) were hospitalized for COVID-19 progression. No patient required mechanical ventilation, and two patients died (non-COVID-19-related). After accounting for potential confounders, only anti-CD20 treatment was associated with the composed outcome [aOR 5.35 (1.02-27.5, 95% CI)], whereas the immunocompetence status was not [aOR 1.94 (0.49-7.81, 95% CI)]. Conclusion: Early COVID-19 outpatient treatment with a 3-day course of remdesivir in vaccinated patients at high risk for disease progression during the Omicron surge had a good safety profile. It was associated with a low rate of all-cause hospitalization or death, regardless of immunocompetence status.

Mild SARS-CoV-2 infection in vulnerable patients: implementation of a clinical pathway for early treatment.

INTRODUCTION: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation. METHODS: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration. OUTCOME VARIABLES: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment. RESULTS: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest 47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity. CONCLUSION: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments.

Transient Changes in the Plasma of Astrocytic and Neuronal Injury Biomarkers in COVID-19 Patients without Neurological Syndromes.

The levels of several glial and neuronal plasma biomarkers have been found to increase during the acute phase in COVID-19 patients with neurological symptoms. However, replications in patients with minor or non-neurological symptoms are needed to understand their potential as indicators of CNS injury or vulnerability. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and total Tau (T-tau) were determined by Single molecule array (Simoa) immunoassays in 45 samples from COVID-19 patients in the acute phase of infection [moderate (n = 35), or severe (n = 10)] with minor or non-neurological symptoms; in 26 samples from fully recovered patients after ~2 months of clinical follow-up [moderate (n = 23), or severe (n = 3)]; and in 14 non-infected controls. Plasma levels of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), were also determined by Western blot. Patients with COVID-19 without substantial neurological symptoms had significantly higher plasma concentrations of GFAP, a marker of astrocytic activation/injury, and of NfL and T-tau, markers of axonal damage and neuronal degeneration, compared with controls. All these biomarkers were correlated in COVID-19 patients at the acute phase. Plasma GFAP, NfL and T-tau levels were all normalized after recovery. Recovery was also observed in the return to normal values of the quotient between the ACE2 fragment and circulating full-length species, following the change noticed in the acute phase of infection. None of these biomarkers displayed differences in plasma samples at the acute phase or recovery when the COVID-19 subjects were sub-grouped according to occurrence of minor symptoms at re-evaluation 3 months after the acute episode (so called post-COVID or "long COVID"), such as asthenia, myalgia/arthralgia, anosmia/ageusia, vision impairment, headache or memory loss. Our study demonstrated altered plasma GFAP, NfL and T-tau levels in COVID-19 patients without substantial neurological manifestation at the acute phase of the disease, providing a suitable indication of CNS vulnerability; but these biomarkers fail to predict the occurrence of delayed minor neurological symptoms.

[Mild SARS-CoV-2 infection in vulnerable patients: implementation of a clinical pathway for early treatment]. / Infección leve por SARS-CoV-2 en pacientes vulnerables: implantación de una vía clínica de tratamiento precoz.

INTRODUCTION: The objective of this report is to describe the clinical pathway for early treatment of patients with acute SARS-CoV-2 infection and to evaluate the first results of its implementation. METHODS: This is a descriptive and retrospective study of the implementation of a clinical pathway of treatment in outpatients (January 1 to June 30 2022). Clinical pathway: detection and referral systems from Primary Care, Emergency services, hospital specialities and an automated detection system; clinical evaluation and treatment administration in the COVID-19 day-hospital and subsequent clinical follow-up. Explanatory variables: demographics, comorbidity, vaccination status, referral pathways and treatment administration. OUTCOME VARIABLES: hospitalization and death with 30 days, grade 2-3 toxicity related to treatment. RESULTS: Treatment was administered to 262 patients (53,4% women, median age 60 years). The treatment indication criteria were immunosupression (68,3%), and the combination of age, vaccination status and comorbidity in the rest47,3% of the patients s received remdesivir, 35,9% nirmatrelvir/ritonavir, 13,4% sotrovimab and 2,4% combined treatment with a median of 4 days after symptom onset. Hospital admission was required for 6,1% of the patients, 3,8% related to progression COVID-19. No patient died. Toxicity grade 2-3 toxicity was reported in 18,7%, 89,8% dysgeusia and metallic tasted related nirmatrelvir/ritonavir. Seven patients discontinued treatment due to toxicity. CONCLUSION: The creation and implementation of a clinical pathway for non-hospitalized patients with SARS-CoV-2 infection is effective and it allows early accessibility and equity of currently available treatments.

Early carbohydrate antigen 125 as a mortality predictor in hospitalized patients with coronavirus disease 2019.

Background: Carbohydrate antigen 125 (CA125) is an indicator of inflammation, immune response, and impaired cardiac function. The aim was to investigate whether CA125 behaves as a biomarker of severity and poor clinical outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: Serum CA125 [Elecsys CA125 II assay-(Roche Diagnostics GmbH)] was measured in stored biobank samples from COVID-19 hospitalized patients between 01 March 2020 and 17 October 2021. Multiple logistic regression models were built to explore the association between CA125 and clinical outcomes [in-hospital all-cause mortality, need for invasive mechanical ventilation (IMV), or non-invasive respiratory support (non-IRS)], estimating odds ratios (ORs; 95% CI). The gradient of risk of CA125 was evaluated by fractional polynomials. Results: A total of 691 patients were included, median age of 63 years (50-76), men (57.2%), with high comorbidity. At admission, 85.8% had pneumonia. Median CA125 was 10.33 U/ml (7.48-15.50). The in-hospital mortality rate was 7.2%. After adjusting for confounding factors, CA125 ≥ 15.5 U/ml (75th percentile) showed an increased risk of death [OR 2.85(1.21-6.71)], as age ≥ 65 years, diabetes, and immunosuppression. Furthermore, CA125 as a continuous variable was positive and significantly associated with the risk of death after multivariate adjustment. The mean hospital stay of the patients with CA125 ≥ 15.5 U/ml was longer than the rest of the study population. Conclusion: CA125 in the first 72 h of hospital admission seems a useful biomarker of mortality in hospitalized patients with moderate-severe COVID-19. If our findings are confirmed, the wide availability of this biomarker would make easy its widespread implementation in clinical practice.

Concordance of the filmarray blood culture identification panel 2 and classical microbiological methods in a bacteriemia diagnostic unit.

Our study evaluates the effectiveness of the FilmArray Blood Culture Identification Panel 2 in a rapid bacteremia diagnostic system, using bacteriological culture as a reference. A total of 2042 positive blood cultures were analyzed, the FilmArray was performed for 175. Concordance was higher in monomicrobial bacteremia (95%) than in polymicrobial bacteremia's (72.2%). For detecting bacterial resistance mechanisms, concordance was very high (100% for Gram-positive bacteria and 98.12% for Gram-negative). This methodology provides significant improvements in response time and is especially useful for the detection of monomicrobial bacteremia.

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.

Hospitalized patients with breakthrough COVID-19: Clinical features and poor outcome predictors.

OBJECTIVES: To describe breakthrough COVID-19 infection in patients who needed hospitalization and the factors associated with poor outcomes. METHODS: We conducted a retrospective study on patients hospitalized with COVID-19 between December 27, 2020, and October 17, 2021, with either a complete vaccination (CV) scheme (diagnosed 2 weeks after the second dose of the Pfizer/Moderna/AstraZeneca or first dose of the Janssen vaccine was administered) or a partial vaccination (PV) scheme. The main outcomes were all-cause mortality and the need for invasive mechanical ventilation (IMV). The baseline factors associated with the outcomes were analyzed by multiple logistic regression to estimate the odds ratios (odds ratio [OR]; 95% confidence interval [CI]). RESULTS: A total of 145 (101 CV) patients were included. The CV subgroup was mainly composed of older males with high comorbidity (Charlson Index ≥3, 72%; immunosuppression, 20%) and with bilateral pneumonia in 63.4%. Limited therapeutic effort (LTE) was agreed upon for 28% of the patients. In the CV subgroup, endotracheal intubation was required in 10.9% of patients, reaching 15.3% when excluding LTE patients; the global mortality was 22.8%, reaching 41.4% in the subgroup with LTE. Although the patients with PV were younger and had fewer comorbidities, the main outcomes did not differ significantly between the CV and PV groups. The predictors of poor outcomes were age ≥ 65 years, confusion, ferritin > 500 mg/L, extensive lung infiltrates, and a Charlson Index ≥ 3. CONCLUSIONS: Patients with CV hospitalized because of breakthrough COVID-19 infection tend to be older persons, with comorbidities, and have a high mortality.

[Valproic Acid Could Help in the Fight Against COVID-19: a case-control study]. / El ácido valproico podría ayudar en la lucha contra el COVID-19: un estudio de casos y controles.

OBJECTIVE: There is early evidence about Valproic acid (VPA) antiviral effect. Our aim was to investigate the incidence and severity of SARS-CoV-2 infection in VPA users as compared with the general population. MATERIAL AND METHODS: A case-control study nested within a cohort, carried out between March 1 and December 17, 2020. Retrospectively, we identified confirmed SARS-CoV-2 infection patients exposed to VPA in our health department (defined as case). We ascertained VPA regimen (all the time (AT)(292 days) or at least 20% of the study period (notAT)(≥58 days) and if VPA levels were in therapeutic range (ATR) (50-100 mcg/mL) in the last 24 months. We calculated the cumulative incidence of SARS-CoV-2 infection and hospital admission in the cases, comparing it with the general unexposed VPA population (controls). RESULTS: During the study period, 6183 PCR+ were detected among 281035 inhabitants, of these, 746 were hospitalized. 691 patients were on VPA notAT and 628 (90.1%) AT. The indication for VPA use was epilepsy in 54.9%. The incidence of PCR+ was 1.736 % (OR 0.785 (95%CI 0.443-1.390) and 1.910 % (OR 0.865 (95%CI 0.488-1.533), on VPA notAT and VPA AT patients, respectively vs. 2.201% in people without VPA regimen. Those patients with VPA ATR had a lower risk of PCR + (OR 0.233 (95%CI 0.057-0.951) notAT; OR 0.218 (95%CI 0.053-0.890) AT). Hospital admission incidence was lower in patient on VPA (OR was 0.543 (95% CI 0.076 to 3.871). CONCLUSION: Patients with VPA within the therapeutic range had a reduction of SARS-Cov-2 infection incidence greater than 75%. There is a downward trend in the risk of COVID-19 admission by SARS-CoV-2 in patients on VPA therapy. These findings warrant further investigation.

Nasopharyngeal Microbiota as an early severity biomarker in COVID-19 hospitalised patients.

This study aimed to analyse the diversity and taxonomic composition of the nasopharyngeal microbiota, to determine its association with COVID-19 clinical outcome. To study the microbiota, we utilized 16S rRNA sequencing of 177 samples that came from a retrospective cohort of COVID-19 hospitalized patients. Raw sequences were processed by QIIME2. The associations between microbiota, invasive mechanical ventilation (IMV), and all-cause mortality were analysed by multiple logistic regression, adjusted for age, gender, and comorbidity. The microbiota α diversity indexes were lower in patients with a fatal outcome, whereas the ß diversity analysis showed a significant clustering in these patients. After multivariate adjustment, the presence of Selenomonas spp., Filifactor spp., Actinobacillus spp., or Chroococcidiopsis spp., was associated with a reduction of more than 90% of IMV. Higher diversity and the presence of certain genera in the nasopharyngeal microbiota seem to be early biomarkers of a favourable clinical evolution in hospitalized COVID-19 patients.

Male pituitary-gonadal axis dysfunction in post-acute COVID-19 syndrome-Prevalence and associated factors: A Mediterranean case series.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 through angiotensin-converting enzyme 2 receptor can harm testes function. The objectives were to analyse the prevalence of low serum testosterone (LT) and impaired fertility potential (Leydig and Sertoli cells dysfunction, respectively) in coronavirus disease 2019 (COVID-19) male survivors and to evaluate acute infection-related associated factors. Also, we explore its association with post-acute COVID-19 syndrome (PCS) and quality of life (QOL). MATERIALS AND METHODS: Male adults recovered from polymerase chain reaction-confirmed COVID-19 were offered a structured evaluation 8-12 weeks after recovery. The main outcome measure(s) were as follows: LT, defined as total testosterone (TT) < 2 ng/ml or if TT levels 2-4 ng/ml as calculated free testosterone < 6.36 ng/dl; Sertoli cell dysfunction was defined as inhibin-B < 89 pg/ml. Secondary outcome-associated factors were analysed by multiple logistic regression (odds ratio; 95% confidence interval [CI]). QOL was evaluated by SF-36 v.2. RESULTS: One hundred and forty-three patients were evaluated at a median (interquartile range) of 77 days (72-83) after disease onset; 72% of them recovered from severe pneumonia. LT was detected in 41 patients (28.7%; 95% CI: 21.8-36.5). Low levels of inhibin-B were detected in 25 patients (18.1%; 95% CI: 12.5-25.3). After multivariate adjustment, obesity and hypokalaemia were associated with LT, whereas age more than 65 was an independent predictor of Sertoli cell dysfunction. LT or Sertoli cell dysfunction was not associated with PCS. Patients with LT had a lower score in four domains of QOL. CONCLUSIONS: Prevalence of male LT and impaired fertility potential in COVID-19 survivors is high in the medium term. Traditional risk factors and severity markers for COVID-19 could be predictive.

Latin American Origin Is Not Associated with Worse Outcomes among Hospitalized Patients with COVID-19 in a Public Healthcare System.

Exploring differences in clinical outcomes based on race and origin among patients hospitalized for COVID-19 is a controversial issue. The ALC COVID-19 Registry includes all confirmed COVID-19 patients admitted to hospital from 3 March 2020 to 17 December 2020. The data were obtained from electronic health records in order to evaluate the differences in the clinical features and outcomes among European and Latin American patients. The follow-ups occurred after 156 days. A propensity score weighting (PSW) logistic regression model was used to estimate the odds ratio (OR, 95% CI) for Latin American origin and outcome associations. Of the 696 patients included, 46.7% were women, with a median age of 65 (IQR 53-67) years, 614 (88.2%) were European, and 82 (11.8%) were Latin American. Latin American patients were younger, with fewer comorbidities, and a higher incidence of extensive pneumonia. After adjusting for residual confounders, Latin American origin was not associated with an increased risk of death (PSW OR 0.85 (0.23-3.14)) or with the need for invasive mechanical ventilation (PSW OR 0.35 (0.12-1.03)). Latin American origin was associated with a shorter hospital stay, but without differences in how long the patient remained on mechanical ventilation. In a public healthcare system, the rates of death or mechanical ventilation in severe COVID-19 cases were found to be comparable between patients of European and Latin American origins.

Isolation of Candida auris in large hospitals in the Autonomous Community of Valencia; population-based study (2013-2017).

BACKGROUND: Candida auris is an emerging multidrug-resistant and highly virulent yeast that spreads easily among patients. AIMS: To describe the characteristics of candidemia caused by C. auris in the southeast of Spain (Autonomous Community of Valencia - ACV) through a 5-year population-based study. METHODS: An analysis of all the episodes of candidemia diagnosed in the ACV, with approximately 4,500,000 inhabitants, during 2013-2017, was done. Data were obtained from the Epidemiological Surveillance Valencian Network, a network that collects all the microbiological data from the hospitals in the study region. RESULTS: Based on the records, 1.9% of the isolates recovered from the positive blood cultures (corresponding to 1789 patients) were yeasts. This implies an annual rate of 7.09 cases/100,000 inhabitants. Of the 23 yeast species isolated, Candida albicans was the most frequent (37.3%), showing a higher frequency than Candida parapsilosis (28.4%) and Candida glabrata (15.6%) (p<0.0001). It is remarkable the emergence of C. auris during 2016 and 2017, as this species became the fourth more prevalent in 2016 (9.2%), and the third in 2017 (15.7%). Fungemia was more common in hospitals with >500 beds (63.3% versus 36.7% in small hospitals) (p<0.0001), and C. auris was mostly isolated in large hospitals (8.5% versus 0.3%); its incidence was higher in autumn and among the age group of 65-84 years. CONCLUSIONS: The information about the local epidemiology of candidemia is essential in order to decide the best empirical treatment approach. This study reports the novel presence of C. auris in large hospitals. This pathogen has usually resistance to several antifungals and causes severe fungemia, so the results of this work reveal the need to monitor the presence of this species systematically.