Pseudomonas stutzeri bloodstream infection is a prevailing community-onset disease with important mortality rates: results from a retrospective observational study in Australia.

BACKGROUND: The recognition of Pseudomonas stutzeri as a cause of infections in humans has been increasing. However, only case reports and small series of P. stutzeri bloodstream infections have been published. Epidemiological data on these infections are extremely scarce. Our objective was to describe the incidence, epidemiology, antimicrobial resistance rates, and outcomes of P. stutzeri bloodstream infections in a large population-based cohort in Australia. METHODS: Retrospective, laboratory-based surveillance study conducted in Queensland, Australia (population ≈ 5 million) during 2000-2019. Clinical information was obtained from public hospital admissions and vital statistics databases. RESULTS: In total, 228 episodes of P. stutzeri bloodstream infections were identified. Increased incidence was observed in the later years, especially in older men, and was higher during the rainy months of the year and in the warmest and more humid regions of the state. The majority of bloodstream infections were community-onset with 120 (52.6%) community-associated and 59 (25.9%) ambulatory healthcare-associated episodes. Only 49 cases (21.5%) were nosocomial. The most common foci of infection were skin and soft tissue, lower respiratory tract, and intra-abdominal. No isolate showed antimicrobial resistance. Thirty-one patients (13.6%) died. The mortality rate in patients with a respiratory infectious source was higher (21%). CONCLUSIONS: P. stutzeri bloodstream infection was predominantly a community-onset condition including ambulatory healthcare related cases, with increasing incidence, especially in older males. No antimicrobial resistance was observed. Mortality was high in patients with respiratory infectious source. This new observational data have implications when considering the epidemiology of these infections and for patient management.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Safety and efficacy of favipiravir in COVID-19 patients with pneumonia. A randomized, double-blind, placebo-controlled study (FAVID).

PURPOSE: To design a randomized clinical trial to assess the efficacy and safety of favipiravir in patients with COVID-19 disease with pneumonia. METHODS: A randomized, double blind, placebo-controlled clinical trial of favipiravir in patients with COVID-19 pneumonia was conducted in three Spanish sites. Randomization 1:1 to favipiravir or placebo (in both groups added to the Standard of Care) was performed to treat the patients with COVID-19 pneumonia. The primary endpoint was "time to clinical improvement," measured as an improvement for ≥ two categories on a 7-point WHO ordinal scale in an up to 28 days' time frame. RESULTS: Forty-four patients were randomized (23 in the favipiravir group and 21 in the placebo group). The median time to clinical improvement was not different between the favipiravir and the placebo arms (10 days for both groups) and none of the secondary endpoints showed significant differences between arms. The proportion of adverse events (both serious and non-serious) was statistically different between the favipiravir group (68.29%) and the placebo group (31.7%) (p = 0.019), but there was insufficient statistical evidence to correlate the degree of severity of the events with the treatment group. CONCLUSIONS: Favipiravir administered for ten days to patients with COVID-19 and pneumonia did not improve outcomes compared with placebo. Although this is an underpowered negative study, efficacy results align with other randomized trials. However, in the present study, the non-serious adverse events were more frequent in the favipiravir group.

Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials.

BACKGROUND: Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. FINDINGS: ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups. INTERPRETATION: Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. FUNDING: Melinta Therapeutics and Cidara Therapeutics.

Executive summary: Guidelines for the diagnosis and treatment of septic arthritis in adults and children, developed by the GEIO (SEIMC), SEIP and SECOT.

Infection of a native joint, commonly referred to as septic arthritis, is a medical emergency because of the risk of joint destruction and subsequent sequelae. Its diagnosis requires a high level of suspicion. These guidelines for the diagnosis and treatment of septic arthritis in children and adults are intended for use by any physician caring for patients with suspected or confirmed septic arthritis. They have been developed by a multidisciplinary panel with representatives from the Bone and Joint Infections Study Group (GEIO) belonging to the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Paediatric Infections (SEIP) and the Spanish Society of Orthopaedic Surgery and Traumatology (SECOT), and two rheumatologists. The recommendations are based on evidence derived from a systematic literature review and, failing that, on the opinion of the experts who prepared these guidelines. A detailed description of the background, methods, summary of evidence, the rationale supporting each recommendation, and gaps in knowledge can be found online in the complete document.

Clinical, Microbiological and Treatment Characteristics of Severe Postoperative Respiratory Infections: An Observational Cohort Study.

Respiratory infections are frequent and life-threatening complications of surgery. This study aimed to evaluate the clinical, microbiological and treatment characteristics of severe postoperative pneumonia (POP) and tracheobronchitis (POT) in a large series of patients. This single-center, prospective observational cohort study included patients with POP or POT requiring intensive care unit admission in the past 10 years. We recorded demographic, clinical, microbiological and therapeutic data. A total of 207 patients were included, and 152 (73%) were men. The mean (SD) age was 70 (13) years and the mean (SD) ARISCAT score was 46 (19). Ventilator-associated pneumonia was reported in 21 patients (10%), hospital-acquired pneumonia was reported in 132 (64%) and tracheobronchitis was reported in 54 (26%). The mean (SD) number of days from surgery to POP/POT diagnosis was 6 (4). The mean (SD) SOFA score was 5 (3). Respiratory microbiological sampling was performed in 201 patients (97%). A total of 177 organisms were cultured in 130 (63%) patients, with a high proportion of Gram-negative and multi-drug resistant (MDR) bacteria (20%). The most common empirical antibiotic therapy was a triple-drug regimen covering MDR Gram-negative bacteria and MRSA. In conclusion, surgical patients are a high-risk population with a high proportion of early onset severe POP/POT and nosocomial bacteria isolation.

Real-world experience of therapeutic drug monitoring and PK/PD achievement of ceftaroline administered by different infusion regimens in patients with confirmed infections caused by Gram-positive bacteria.

BACKGROUND: Ceftaroline is a novel cephalosporin active against MDR Gram-positive (GP) bacteria. For ß-lactam antibiotics, such as ceftaroline, prolonged infusions and therapeutic drug monitoring (TDM) are used for dosage optimization based on their pharmacokinetics/pharmacodynamics (PK/PD). OBJECTIVES: To describe our experience with TDM and PK/PD target attainment of ceftaroline administered by intermittent and prolonged infusion in a cohort of patients with MDR-GP bacterial infections. METHODS: Patients treated with ceftaroline administered by continuous (24 h), extended (3 h/6 h) and intermittent infusion (1 h) and undergoing TDM of plasma concentrations were included. A 100%fT>4×MIC was the pre-specified PK/PD target and 100%fT>10×MIC was considered overexposure. Dose recommendations were made based on TDM results and each patient's clinical condition. RESULTS: Twelve patients [83.3% male, median age of 73 (38-83) years] were included. Nine patients (75%) achieved 100%fT>4×MIC, all under prolonged infusions. In one patient, the 100%fT was >10×MIC but no toxicity was observed. Based on TDM results, initial doses were recommended to be maintained in eight patients, decreased in three and increased in one. CONCLUSIONS: The administration of ceftaroline by prolonged infusion together with TDM may be a useful strategy for achieving the desired PK/PD target in these patients. However, more studies evaluating the relationship between PK/PD attainment and clinical outcomes are needed.

Staphylococcus aureus surgical site infection rates in 5 European countries.

OBJECTIVE: To determine the overall and procedure-specific incidence of surgical site infections (SSI) caused by Staphylococcus aureus (S. aureus) as well as risk factors for such across all surgical disciplines in Europe. METHODS: This is a retrospective cohort of patients with surgical procedures performed at 14 European centres in 2016, with a nested case-control analysis. S. aureus SSI were identified by a semi-automated crossmatching bacteriological and electronic health record data. Within each surgical procedure, cases and controls were matched using optimal propensity score matching. RESULTS: A total of 764 of 178 902 patients had S. aureus SSI (0.4%), with 86.0% of these caused by methicillin susceptible and 14% by resistant pathogens. Mean S. aureus SSI incidence was similar for all surgical specialties, while varying by procedure. CONCLUSIONS: This large procedure-independent study of S. aureus SSI proves a low overall infection rate of 0.4% in this cohort. It provides proof of principle for a semi-automated approach to utilize big data in epidemiological studies of healthcare-associated infections. Trials registration The study was registered at clinicaltrials.gov under NCT03353532 (11/2017).

Reducing the duration of antibiotic therapy in surgical patients through a specific nationwide antimicrobial stewardship program. A prospective, interventional cohort study.

BACKGROUND: Guidelines recommend 5-7 days of antibiotic treatment in patients with surgical infection and adequate source control. This nationwide stewardship intervention aimed to reduce the duration of treatments in surgical patients to <7 days. METHODS: Prospective cohort study evaluating surgical patients receiving antibiotics ≥7 days in 32 hospitals. Indication for treatment, quality of source control, type of recommendations issued, and adherence to the recommendations were analysed. Temporal trends in the percentages of patients with treatment >7 days were evaluated using a linear regression model and Pearson's correlation coefficients. RESULTS: A total of 32 499 patients were included. Of these, 13.7% had treatments ≥7 days. In all, 3912 stewardship interventions were performed, primarily in general surgery (90.7%) and urology (8.1%). The main types of infection were intra-abdominal (73.4%), skin/soft tissues (9.8%) and urinary (9.2%). The septic focus was considered controlled in 59.9% of cases. Out of 5458 antibiotic prescriptions, the most frequently analysed drugs were piperacillin/tazobactam (21.7%), metronidazole (11.2%), amoxicillin/clavulanate (10.3%), meropenem (10.7%), ceftriaxone (9.3%) and ciprofloxacin (6.7%). The main recommendations issued were: treatment discontinuation (35.0%), maintenance (40.0%) or de-escalation (15.5%), and the overall adherence rate was 91.5%. With adequate source control, the most frequent recommendation was to terminate treatment (51.2%). Throughout the study period, a significant decrease in the percentage of prolonged treatments was observed (Pc=-0.69;P < 0.001). CONCLUSIONS: This stewardship programme reduced the duration of treatments in surgical departments. Preference was given to general surgery services, intra-abdominal infection, and beta-lactam antibiotics, including carbapenems. Adherence to the issued recommendations was high.

Treatment of COVID-19 during the Acute Phase in Hospitalized Patients Decreases Post-Acute Sequelae of COVID-19.

BACKGROUND: The post-acute sequelae of SARS-CoV-2 (PASC) infection have caused a significant impact on our health system, but there is limited evidence of approved drugs focused on its prevention. Our objective was to identify risk factors that can determine the presence of PASC, with special attention to the treatment received in the acute phase, and to describe the profile of persistent symptoms in a multidisciplinary Post-Coronavirus Disease-19 (COVID-19) Unit. METHODS: This one-year prospective observational study included patients following an acute COVID-19 infection, irrespective of whether they required hospital admission. A standardized symptom questionnaire and blood sampling were performed at the first follow-up visit, and demographic and clinical electronic data were collected. We compared subjects with PASC with those who had fully recovered. Multivariate logistic regression was performed to identify factors associated with PASC in hospitalized patients, and Kaplan-Meier curves were used to assess duration of symptoms according to disease severity and treatments received in the acute phase. RESULTS: 1966 patients were evaluated; 1081 had mild disease, 542 moderate and 343 severe; around one third of the subjects had PASC, and were more frequently female, with obesity, asthma, and eosinophilia during acute COVID-19 disease. Patients who received treatment with dexamethasone and remdesivir during the course of the acute illness showed a lower median duration of symptoms, compared with those who received none of these treatments. CONCLUSION: Treatment with dexamethasone and/or remdesivir may be useful to reduce the impact of PASC secondary to SARS-CoV-2 infection. In addition, we identified female gender, obesity, asthma, and disease severity as risk factors for having PASC.

Suboptimal Concentrations of Ceftazidime/Avibactam (CAZ-AVI) May Select for CAZ-AVI Resistance in Extensively Drug-Resistant Pseudomonas aeruginosa: In Vivo and In Vitro Evidence.

This study correlates in vivo findings in a patient with an extensively drug-resistant (XDR) P. aeruginosa infection who developed resistance to ceftazidime-avibactam (CAZ-AVI) with in vitro results of a 7-day hollow-fiber infection model (HFIM) testing the same bacterial strain. The patient was critically ill with ventilator-associated pneumonia caused by XDR P. aeruginosa ST175 with CAZ-AVI MIC of 6 mg/L and was treated with CAZ-AVI in continuous infusion at doses adjusted for renal function. Plasma concentrations of CAZ-AVI were analyzed on days 3, 7, and 10. In the HIFM, the efficacy of different steady-state concentrations (Css) of CAZ-AVI (12, 18, 30 and 48 mg/L) was evaluated. In both models, a correlation was observed between the decreasing plasma levels of CAZ-AVI and the emergence of resistance. In the HIFM, a Css of 30 and 48 mg/L (corresponding to 5× and 8× MIC) had a bactericidal effect without selecting resistant mutants, whereas a Css of 12 and 18 mg/L (corresponding to 2× and 3× MIC) failed to prevent the emergence of resistance. CAZ/AVI resistance development was caused by the selection of a single ampC mutation in both patient and HFIM. Until further data are available, strategies to achieve plasma CAZ-AVI levels at least 4× MIC could be of interest, particularly in severe and high-inoculum infections caused by XDR P. aeruginosa with high CAZ-AVI MICs.

ATP Bioluminescence Assay To Evaluate Antibiotic Combinations against Extensively Drug-Resistant (XDR) Pseudomonas aeruginosa.

Time-kill curves are used to study antibiotic combinations, but the colony count method to obtain the results is time-consuming. The aim of the study was to validate an ATP assay as an alternative to the conventional colony count method in studies of antibiotic combinations. The cutoff point for synergy and bactericidal effect to categorize the results using this alternative method were determined in Pseudomonas aeruginosa. The ATP assay was performed using the GloMax 96 microplate luminometer (Promega), which measures bioluminescence in relative light units (RLU). To standardize this assay, background, linearity, and the detection limit were determined with one strain each of multidrug-resistant P. aeruginosa and Klebsiella pneumoniae. Twenty-four-hour time-kill curves were performed in parallel by both methods with 12 strains of P. aeruginosa. The conventional method was used as a "gold" standard to establish the pharmacodynamic cutoff points in the ATP method. Normal saline solution was established as washing/dilution medium. RLU signal correlated with CFU when the assay was performed within the linear range. The categorization of the pharmacodynamic parameters using the ATP assay was equivalent to that of the colony count method. The bactericidal effect and synergy cutoff points were 1.348 (93% sensitivity, 81% specificity) and 1.065 (95% sensitivity, 89% specificity) log RLU/mL, respectively. The ATP assay was useful to determine the effectiveness of antibiotic combinations in time-kill curves. This method, less laborious and faster than the colony count method, could be implemented in the clinical laboratory workflow. IMPORTANCE Combining antibiotics is one of the few strategies available to overcome infections caused by multidrug-resistant bacteria. Time-kill curves are usually performed to evaluate antibiotic combinations, but obtaining results is too laborious to be routinely performed in a clinical laboratory. Our results support the utility of an ATP measurement assay using bioluminescence to determine the effectiveness of antibiotic combinations in time-kill curves. This method may be implemented in the clinical laboratory workflow as it is less laborious and faster than the conventional colony count method. Shortening the obtention of results to 24 h would also allow an earlier guided combined antibiotic treatment.

A profile of delafloxacin in the treatment of adults with community-acquired bacterial pneumonia.

INTRODUCTION: Community-acquired bacterial pneumonia (CABP) is the most common infectious cause of hospital admission in adults, and poses a significant clinical and economic burden. At the same time, antimicrobial resistance is increasing worldwide with only a few new antibiotics developed in recent years. Delafloxacin is an anionic fluoroquinolone available in intravenous and oral formulations and with a broad spectrum of activity targeting Gram-positives, including methicillin-resistant Staphylococcus aureus (MRSA), gram-negative organisms, and atypical and anaerobic organisms. It also has a better adverse event profile compared to other fluoroquinolones. AREAS COVERED: This article reviews the current epidemiology of CABP, etiologic agents and current resistance rates, current treatment guidelines, characteristics of delafloxacin (chemistry, microbiology, PK/PD), clinical efficacy and safety in pneumonia and other indications, and regulatory affairs. EXPERT OPINION: Delafloxacin's susceptibility profile against respiratory pathogens, bioequivalent intravenous and oral formulations and favorable safety profile, support its use for the treatment of CABP. It could be useful as empirical treatment in countries with high rates of penicillin-resistant S. pneumoniae and in patients with suspected or documented pneumonia due to MRSA. In post-influenza staphylococcal bacterial pneumonia, MRSA could be also considered an important pathogen.

Comparison of Ceftolozane/Tazobactam Infusion Regimens in a Hollow-Fiber Infection Model against Extensively Drug-Resistant Pseudomonas aeruginosa Isolates.

The aim of this study was to compare the efficacy of intermittent (1-h), extended (4-h), and continuous ceftolozane-tazobactam (C/T) infusion against three extensively drug-resistant (XDR) sequence type (ST) 175 P. aeruginosa isolates with different susceptibilities to C/T (MIC = 2 to 16 mg/L) in a 7-day hollow-fiber infection model (HFIM). C/T in continuous infusion achieved the largest reduction in total number of bacterial colonies in the overall treatment arms for both C/T-susceptible and -resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. These data suggest that continuous C/T infusion should be considered a potential treatment for infections caused by XDR P. aeruginosa isolates, including nonsusceptible ones. Proper use of C/T dosing regimens may lead to better clinical management of XDR P. aeruginosa infections. IMPORTANCE Ceftolozane-tazobactam (C/T) is an antipseudomonal antibiotic with a high clinical impact in treating infection caused by extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates, but resistance is emerging. Given its time-dependent behavior, C/T continuous infusion can improve exposure and therefore the pharmacokinetic/pharmacodynamic target attainment. We compared the efficacy of intermittent, extended, and continuous C/T infusion against three XDR ST175 P. aeruginosa isolates with different C/T MICs by means of an in vitro dynamic hollow-fiber model. We demonstrated that C/T in continuous infusion achieved the largest reduction in bacterial density in the overall treatment arms for both susceptible and resistant isolates. It was also the only regimen with bactericidal activity against all three isolates. Through this study, we want to demonstrate that developing individually tailored antimicrobial treatments is becoming essential. Our results support the role of C/T level monitoring and of dose adjustments for better clinical management and outcomes.

Unraveling COVID-19: A Large-Scale Characterization of 4.5 Million COVID-19 Cases Using CHARYBDIS.

Purpose: Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) Characterizing Health Associated Risks and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD. Patients and Methods: We conducted a descriptive retrospective database study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11th June 2020 and are iteratively updated via GitHub. We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19, and 113,627 hospitalized with COVID-19 requiring intensive services. Results: We aggregated over 22,000 unique characteristics describing patients with COVID-19. All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts and are readily available online. Globally, we observed similarities in the USA and Europe: more women diagnosed than men but more men hospitalized than women, most diagnosed cases between 25 and 60 years of age versus most hospitalized cases between 60 and 80 years of age. South Korea differed with more women than men hospitalized. Common comorbidities included type 2 diabetes, hypertension, chronic kidney disease and heart disease. Common presenting symptoms were dyspnea, cough and fever. Symptom data availability was more common in hospitalized cohorts than diagnosed. Conclusion: We constructed a global, multi-centre view to describe trends in COVID-19 progression, management and evolution over time. By characterising baseline variability in patients and geography, our work provides critical context that may otherwise be misconstrued as data quality issues. This is important as we perform studies on adverse events of special interest in COVID-19 vaccine surveillance.

A Descriptive Analysis of Urinary ESBL-Producing-Escherichia coli in Cerdanya Hospital.

Urinary tract infections caused by extended-spectrum ß-lactamase Escherichia coli (ESBL-EC) are increasing worldwide and are a current concern because treatment options are often limited. This study investigated antimicrobial susceptibility, antimicrobial resistance genes (ARGs), and the biological diversity of urinary ESBL-EC isolates at Cerdanya Hospital, a European cross-border hospital that combines French and Spanish healthcare models. Bacterial identification and susceptibility were determined using the Microscan WalkAway® system and ESBL production was examined by the double-disk synergy method. Isolates were sequenced using the Ion S5™ next-generation sequencing system, with the whole-genome sequences then assembled using SPADEs software and analyzed using PubMLST, ResFinder, FimTyper, PlasmidFinder, and VirulenceFinder. A phylogenetic analysis was performed by constructing an assembly-based core-SNV alignment, followed by a phylogenetic tree constructed using Parsnp from the Harvest suite. All isolates studied were multidrug-resistant and could be classified into 19 different sequence types characterized by a high genetic diversity. The most prevalent ESBL-enzymes were CTX-M-14 and CTX-M-15. High-risk international clones (ST131, ST10, and ST405) were also identified. The results demonstrated the absence of a single predominant clone of ESBL-MDR-EC at Cerdanya Hospital.

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of the Monoclonal Antibody MHAA4549A in Patients With Acute Uncomplicated Influenza A Infection.

BACKGROUND: MHAA4549A, a human monoclonal antibody targeting the influenza A hemagglutinin stalk, neutralizes influenza A virus in animal and human volunteer challenge studies. We investigated the safety and tolerability, efficacy, and pharmacokinetics of MHAA4549A in outpatients with acute, uncomplicated influenza A infection. METHODS: This was a phase 2, randomized, double-blind, placebo-controlled trial of single intravenous (IV) doses of 3600 mg or 8400 mg of MHAA4549A or IV placebo in adult outpatients testing positive for influenza A. Patients were enrolled across 35 sites in 6 countries. Randomization and dosing occurred within ≤72 hours of symptom onset; the study duration was 14 weeks. The primary end point was the nature and frequency of adverse events (AEs). Secondary end points included median time to alleviation of all influenza symptoms, effects on nasopharyngeal viral load and duration of viral shedding, and MHAA4549A serum pharmacokinetics. RESULTS: Of 125 randomized patients, 124 received study treatment, with 99 confirmed positive for influenza A by central testing. The frequency of AEs between the MHAA4549A and placebo groups was similar; nausea was most common (8 patients; 6.5%). MHAA4549A serum exposure was confirmed in all MHAA4549A-treated patients and was dose-proportional. No hospitalizations or deaths occurred. Between the MHAA4549A and placebo groups, no statistically significant differences occurred in the median time to alleviation of all symptoms, nasopharyngeal viral load, or duration of viral shedding. CONCLUSIONS: While MHAA4549A was safe and well tolerated with confirmed exposure, the antibody did not improve clinical outcomes in patients with acute uncomplicated influenza A infection.

Comparative Analysis of Dalbavancin versus Other Antimicrobial Options for Gram-Positive Cocci Infections: Effectiveness, Hospital Stay and Mortality.

Dalbavancin is a new antibiotic that is effective against Gram-positive microorganisms, including methicillin-resistant Staphylococci, and offers the possibility of administering intravenous therapy once weekly in an ambulatory setting. We conducted a multicenter observational case-control study, comparing all patients who received dalbavancin (cases) with hospitalized patients who were treated instead with daptomycin, linezolid or vancomycin (controls), based on clinical diagnosis, main microorganism involved, and age. The primary outcome was the length of hospital stay after starting the study antimicrobial. Secondary outcomes were 7-day and 30-day efficacy, 30-day mortality, 90-day recurrence, 90-day and 6-month hospitalization, presence of adverse events and healthcare-associated infections; 161 patients (44 cases and 117 controls) were included. Bivariate analysis showed that dalbavancin reduced the total length of hospital stay (p < 0.001), with fewer 90-day recurrences (p = 0.005), 6-month hospitalizations related to the same infection (p = 0.004) and non-related hospitalizations (p = 0.035). Multivariate analyses showed that length of hospital stay was significantly shorter in patients treated with dalbavancin (-12.05 days 95% CI [-17.00, -7.11], p < 0.001), and 30-day efficacy was higher in the dalbavancin group (OR 2.62 95% CI [1.07, 6.37], p = 0.034). Although sample size of the study may be a limitation, we can conclude that Dalbavancin is a useful antimicrobial drug against Gram-positive infections, including multidrug-resistant pathogens, and allows for a remarkable reduction in length of hospital stay with greater 30-day efficacy.