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Background: Antimicrobial resistance is a critical global health issue, significantly contributing to patient mortality. Recent antibiotic developments have aimed to counteract carbapenemase-producing Enterobacterales; however, the impact of their use on the emergence of antibiotic resistance is unknown. This study investigates the first case of a non-carbapenemase-producing, pan-β-lactam-resistant Escherichia coli strain from a patient previously treated with ceftolozane-tazobactam and cefiderocol., Methods: This study describes the clinical progression of a 39-year-old ICU patient who developed multiple infections, culminating in the isolation of a pan-β-lactam-resistant E. coli strain (EC554). The resistance profile was characterised through MIC determination, whole-genome sequencing, the use of the β-lactam inactivation method, RT-qPCR, efflux pump inhibition assays, outer membrane protein analysis, and bla TEM transformation., Findings: The EC554 isolate displayed resistance to all tested β-lactams and β-lactam-β-lactamase inhibitor combinations. Whole-genome sequencing revealed four plasmids in EC554, with the only β-lactamase gene being blaTEM-252 on the pEC554-PBR-X1-X1 plasmid. We found that the extremely resistant phenotype was attributable to a combination of different mechanisms: a high expression of TEM-252, efflux pump activity, porin loss, and PBP3 mutations., Interpretation: The findings illustrate the complex interplay of multiple resistance mechanisms in E. coli, highlighting the potential for high-level resistance even without carbapenemase production. This study underscores the importance of comprehensively characterising resistance mechanisms in order to inform effective treatment strategies and mitigate the spread of resistant strains., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine whether the β-lactam allergy delabeling was safe and cost-saving in Primary Care (PC) patients., Design: We have conducted a retrospective chart review of PC patients with β-lactam allergy label evaluated in our Allergy Unit between 2017 and 2022. SITE: Allergy Department. Hospital Virgen del Rocio (Sevilla)., Participants: A total of 391 patients labeled for β-lactam allergy in PC were studied., Main Measurements: (a) Outcome evaluation of a β-lactam allergy delabeling procedure. (b) A ratio between the total e-prescribed antibiotic cost and the number of treatment days (the experimental daily antibiotic cost or EDAC) before and after delabeling was analyzed in delabeled and truly allergic patients., Results: The results of skin testing were positive in 9.2% of the reported cases (36 of 391 patients). The reactions to oral provocation challenge (OPC) occurred in 2.14% of the patients who underwent negative skin testing to offending β-lactam (in 15 of 699 OPC). A total of 307 patients (78.5%) were delabeled; 70 (17.9%) had a β-lactam selective response and 14 (3.59%) reacted to both penicillin and cephalosporin. The EDAC before and after the procedure in delabeled patients was significantly lower (0.88 € vs 0.62 €, p<10 -3 ), than that observed in truly allergic group (0.87 € vs. 0.76 €, p=not significant)., Conclusion: To delabel β-lactam allergy in Primary Care patients is safe in most patients, cost-saving in antibioticotherapy, and allows identify the main clinical β-lactam allergy phenotypes that benefit from this procedure., (Copyright © 2024 The Author(s). Publicado por Elsevier España S.L.U. All rights reserved.)

Background: Bacterial infections frequently occur in haematological patients, especially during prolonged neutropenia after intensive chemotherapy, often leading to bloodstream infections and pneumonia., Objective: Routine antimicrobial prophylaxis (AMP) for high-risk haematology patients is still debated while prevalence of multi-drug resistant (MDR) Gram-negative bacteria (GNB) is rising globally. We aimed to assess the current practice of AMP in this population., Design: Cross-sectional observational survey study., Methods: Haematologists and infectious diseases physicians Europewide were invited to an online survey including questions on routine screening for GNB, incidence of MDR-GNB colonization, antimicrobial prophylaxis practices, rates of bloodstream infections (BSI), ICU admission and mortality differentiated by infections due to GNB versus MDR-GNB., Results: 120 haematology centres from 28 countries participated. Screening for MDR-GNB is performed in 86.7% of centres, mostly via rectal swabs (58.3%). In 39.2% of routine AMP is used, mostly with fluoroquinolones. Estimates of GNB-BSI yielded higher rates in patients not receiving anti-GNB prophylaxis than in those who do for E. coli (10% vs 7%) Klebsiella spp. (10% vs 5%), and Pseudomonas spp. (5% vs 4%). Rates for MDR-GNB infection were estimated lower in centres that administer AMP for MDR E. coli (5% vs 3%) Klebsiella spp. (5% vs 3%), and Pseudomonas spp. (2% vs 1%). In an exploratory analysis, Southern and Eastern European countries expected higher rates of MDR-GNB infections with lower ICU admission and mortality rates which may be subject to estimation bias., Conclusion: Screening for MDR-GNB is frequently performed. AMP against GNB infections is still often implemented. Estimated BSI rates are rather low, while the rate of MDR-GNB infections rises. Tailored prophylaxis including antimicrobial stewardship becomes more important., (© The Author(s), 2024.)

Background: Plitidepsin has shown potent preclinical activity against severe acute respiratory syndrome coronavirus 2 and was generally well tolerated in a phase I trial of hospitalized patients with coronavirus disease 2019 (COVID-19). NEPTUNO, a phase III, multicenter, randomized, controlled trial, was designed to evaluate the efficacy and safety of plitidepsin in the management of moderate COVID-19 in hospitalized adult patients., Methods: Included patients had documented severe acute respiratory syndrome coronavirus 2 infection, required oxygen therapy, and had adequate organ function. The planned sample size was 609 patients. Patients were randomized 1:1:1 to at least 3 days of dexamethasone plus either plitidepsin (1.5 mg/day or 2.5 mg/day, for 3 days) or standard of care (control). The primary endpoint was the time to sustained withdrawal of supplemental oxygen. Secondary endpoints included time to sustained hospital discharge, clinical status, duration of oxygen support, percentage of patients requiring admission to the intensive care unit, and safety., Results: After randomizing 205 patients, NEPTUNO was discontinued due to a notable drop in COVID-19-related hospitalizations. Available data suggest a 2-day improvement in the median time to sustained oxygen therapy discontinuation (5 vs 7 days) favoring both plitidepsin arms (hazard ratio, 1.37; 95% confidence interval, .96-1.96; P = .08 for plitidepsin 1.5 mg vs control; hazard ratio, 1.06; 95% confidence interval, .73-1.53; P = .78 for plitidepsin 2.5 mg vs control). Plitidepsin was generally well tolerated., Conclusions: Despite the trial limitations, these results suggest that plitidepsin may have a positive benefit-risk ratio in the management of patients requiring oxygen therapy. Further studies with plitidepsin, including those in immunosuppressed patients, are warranted.Results from this phase III trial suggest that plitidepsin, a first-in-class antiviral, may have a positive benefit-risk ratio in the management of hospitalized patients requiring oxygen therapy for moderate COVID-19., Competing Interests: Potential conflicts of interest. V. E. has received economic support for educational talks and advisory boards from Gilead Sciences and PharmaMar SA. M. M-M. has received grants and fees for scientific advice not related with this work; received in the past 36 months from Boehringer Ing, Roche, Ferrer, Chiesi. P. V. has received provision of study materials, travel support travel from PharmaMar SA, and payments from PharmaMar SA and GlaxoSmithKline (GSK). P. G-V. received speaker fees from FLS Science, PharmaMar SA (Madrid, Spain), Pfizer (Spain), and GSK (Spain); consulting fees from Angelini Pharma and PharmaMar SA; served as an advisory board member for Berlin Cures GmbH and PharmaMar SA; and received meeting grants from GSK and PharmaMar SA. A. L. has received occasional training fees from Gilead, is a member of a Data Monitoring Committee for a randomized controlled trial for Biophytis Biopharma. R. P. has received grants or contracts from MSD, ViiV Healthcare; consulting fees Pfizer, Gilead, AstraZeneca, PharmaMar SA, GSK, Atea. G. P. has received fees, as member advisory panels and consultancy, from Pfizer, MSD, Menarini, and Gilead. M. M. has received fees from Boehringer as scientific advisor and payments for lectures and educational events from GSK. J. F. has received grants and payments from Gilead, Pfizer, Shionogy, Astellas, and MSD, as well as travel support. P. R. has received fees and travel support from Gilead, Merck, VIV, and Gesida. D. L-M., E-M. S-L, F. M., J. G., and N. T. are a full-time employees of PharmaMar. J. J. holds stocks of Pangaea Oncology, has a nonremunerated role in the Scientific Advisory Board, and holds stocks of Promontory Therapeutics; is a full-time employee and shareholder of PharmaMar, S.A. (Madrid, Spain), and a co-inventor of 2 patents for Plitidepsin (WO99-42125). J. A. L.-M. is a full-time employee and shareholder of PharmaMar, S.A (Madrid, Spain), and a co-inventor of a patent for plitidepsin (WO2008135793A1). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: There is a need for additional therapeutic options for serious infections caused by Gram-negative pathogens. In the phase 3, descriptive REVISIT study, we investigated the safety and efficacy of aztreonam-avibactam in the treatment of complicated intra-abdominal infections or hospital-acquired pneumonia or ventilator-associated pneumonia (HAP-VAP) caused, or suspected to be caused, by Gram-negative bacteria., Methods: This prospective, multinational, open-label, central assessor-masked study enrolled adults who were hospitalised with a complicated intra-abdominal infection or HAP-VAP. Patients were randomly allocated via block randomisation using interactive response technology stratified by infection type in a 2:1 ratio to aztreonam-avibactam (with metronidazole for complicated intra-abdominal infection) or meropenem with or without colistin for 5-14 days for complicated intra-abdominal infection or 7-14 days for HAP-VAP. The primary endpoint was clinical cure at the test-of-cure visit (within 3 days before or after day 28) in the intention-to-treat (ITT) population. Secondary endpoints included 28-day mortality in the ITT population and safety in patients in the ITT population who received study drug (safety analysis set). No formal hypothesis testing was planned. The study was registered with ClinicalTrials.gov (NCT03329092) and EudraCT (2017-002742-68) and is complete., Findings: Between April 5, 2018, and Feb 23, 2023, we screened 461 patients. 422 patients were enrolled and randomly allocated (282 in the aztreonam-avibactam group and 140 in the meropenem group, forming the ITT analysis set), of whom ten patients (seven in the aztreonam-avibactam group and three in the meropenem group) were randomly allocated but did not receive study treatment. 271 (64%) of 422 patients had at least one Gram-negative pathogen from an adequate specimen identified at baseline. The most frequent baseline pathogens were Enterobacterales (252 [93%] of 271). Overall, 19 (24%) of 80 isolates tested for carbapenemases were carbapenemase-positive (serine, metallo-β-lactamase, or both). 193 (68·4%) of 282 patients in the aztreonam-avibactam group and 92 (65·7%) of 140 in the meropenem group had clinical cure at the test-of-cure visit (treatment difference 2·7% [95% CI -6·6 to 12·4]). For patients with complicated intra-abdominal infection, the adjudicated clinical cure rate was 76·4% (159 of 208) for the aztreonam-avibactam group and 74·0% (77 of 104) for the meropenem group. Cure rates in patients with HAP-VAP were 45·9% (34 of 74) for aztreonam-avibactam and 41·7% (15 of 36) for meropenem. 28-day all-cause mortality rates were 4% (12 of 282) for aztreonam-avibactam and 7% (ten of 140) for meropenem; in patients with complicated intra-abdominal infection, mortality was 2% (four of 208) and 3% (three of 104) for aztreonam-avibactam and meropenem, respectively, and in patients with HAP-VAP, mortality was 11% (eight of 74) and 19% (seven of 36), respectively. Aztreonam-avibactam was generally well tolerated, and safety findings were consistent with the known safety profile of aztreonam monotherapy. There were no treatment-related serious adverse events in the aztreonam-avibactam group., Interpretation: These phase 3 efficacy and safety data provide support for aztreonam-avibactam as a potential therapeutic option for complicated intra-abdominal infection or HAP-VAP caused by Gram-negative bacteria., Funding: Pfizer., Competing Interests: Declaration of interests HR, MWi, and JLL are employees of, and shareholders in, Pfizer. FFA, JWC, RP, and AL are former employees of Pfizer. YC is an advisor for, and has received grant support and honoraria from, Pfizer, Qpex, Roche, and Merck. MP received grant support from Pfizer through Innovative Medicines Initiative. GLD is an advisor and consultant for, and has received honoraria from, Pfizer, and has received honoraria from MSD and Viatris. R-MJ-R has received honoraria from Abex, JnJ, and Braun. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We evaluated the efficacy of the adoptive transfer of memory B, CD4+, and CD8+ T lymphocytes compared with sulbactam and tigecycline in an experimental murine pneumonia model by two multidrug-resistant Acinetobacter baumannii strains, colistin-susceptible AbCS01 and colistin-resistant AbCR17. Pharmacodynamically optimized antimicrobial dosages were administered for 72 h, and intravenous administration of 2 × 10 6 of each of the memory cells in a single dose 30 min post-infection. Bacterial lung and blood counts and mortality rates were analyzed. Results showed that a single dose of memory B or CD4+ T cells was as effective as sulbactam in terms of bacterial clearance from the lungs and blood compared with the untreated mice or the tigecycline-treated mice inoculated with the AbCS01 strain. In the pneumonia model by AbCR17, a single dose of memory B or CD4+ T cells also reduced the bacterial load in the lungs compared with both antibiotic groups and was more efficacious than tigecycline in terms of blood clearance. Regarding survival, the adoptive transfer of memory B or CD4+ T cells was as effective as three days of sulbactam treatment for both strains. These data suggest that adoptive memory cell transfer could be a new effective treatment of multidrug-resistant A. baumannii infections.

Background: The COVID-19 pandemic has resulted in great incertitude and overwhelming changes in healthcare that have had a direct impact on antibiotic prescription. However, the influence of this pandemic on antibiotic consumption in patients undergoing surgery has not yet been analysed. The goal of this study was to analyse antimicrobial consumption and prescription in the same period of 2019 (pre-COVID-19), 2020 (beginning of the COVID-19 pandemic) and 2021 (established COVID-19) according to the DDD system in surgical patients at a tertiary-level hospital., Methods: A prospectively maintained database was analysed. All patients who underwent elective or emergency gastrointestinal surgery during the same period (2019, 2020 and 2021) were included. Those who received at least 1 of the 10 most frequently prescribed antimicrobials during those periods were analysed., Results: A total of 2975 patients were included in this study. In 2020, the number of procedures performed decreased significantly (653 versus 1154 and 1168 in 2020 versus 2019 and 2021, respectively; P = 0.005). Of all patients who underwent surgery during these periods, 45.08% received at least one of the antimicrobials studied (45.8% in 2020 versus 22.9% and 22.97% in 2019 and 2021, respectively; P = 0.005). Of these, 22.97% of the patients received a combination of these antimicrobials, with ceftriaxone/metronidazole being the most frequent. Hepato-Pancreato-Biliary and Liver Transplant, Emergency Surgery and Colorectal Surgery units had higher antibiotic consumption., Conclusions: The COVID-19 pandemic has resulted in a significant decrease in surgical activity and higher post-operative antimicrobial prescription compared with previous and subsequent years., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Patients with haematologic malignancies (HM) COVID-19 have more severe disease, with increased risk of mortality. Therefore, this study aimed to evaluate the effect of SARS-CoV-2 RNAemia and the specific humoral immune responses on the clinical outcomes of patients with HM and COVID-19., Methods: Interferon-α/γ (IFN-α/IFN-γ) serum levels, neutralizing antibodies and RNAemia at COVID-19 diagnosis, and persistent RNAemia during the follow-up were evaluated., Results: Overall, 63 (58.9%) out of 107 patients had RNAemia, which was persistent in 26 (41.3%) patients. RNAemia at diagnosis and persistent RNAemia were associated with the need for high-flow nasal oxygen therapy during admission. Persistent RNAemia, age >70 years, and CURB-65 score ≥2 in patients with pneumonia were associated with increased 90-day mortality (P = 0.009, P = 0.030 and P = 0.001, respectively). The 90-day overall survival was lower (P = 0.006) in patients with persistent RNAemia. In addition, dexamethasone administration was associated with a COVID-19 episode with persistent RNAemia., Conclusion: Our results suggest that in patients with HM, RNAemia at the time of COVID-19 diagnosis and during the follow-up can be used to stratify patients with HM according to their clinical evolution and to guide clinical decisions tailored to the specific needs of each patient., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The combination of several therapeutic strategies is often seen as a good way to decrease resistance rates, since bacteria can more easily overcome single-drug treatments than multi-drug ones. This strategy is especially attractive when several targets and subpopulations are affected, as it is the case of Klebsiella pneumoniae persister cells, a subpopulation of bacteria able to transiently survive antibiotic exposures. This work aims to evaluate the potential of a repurposed anticancer drug, mitomycin C, combined with the K. pneumoniae lytic phage vB&#95;KpnM-VAC13 in vitro and its safety in an in vivo murine model against two clinical isolates of this pathogen, one of them exhibiting an imipenem-persister phenotype. At the same time, we verified the absence of toxicity of mitomycin C at the concentration using the human chondrocyte cell line T/C28a2. The viability of these human cells was checked using both cytotoxicity assays and flow cytometry.

Water contamination with pesticides is one of the major pollution problems in northwestern Mexico, and this is due to the extensive use of pesticides in agriculture. In this research, water samples of ten sampling sites (fishing grounds, beaches, and both) were analyzed in the search for 28 pesticides (organochlorines, organophosphates, pyrethroids, carbamates, among other chemical classes), supplemented with a calculation of the resulting potential environmental risk. Pesticides were separated from the matrix by liquid-liquid extraction and quantified by gas chromatography coupled to electron micro-capture (organohalogenated) and pulsed flame photometric detectors (organophosphates). In addition, the ecotoxicological risk of pesticides in algae, invertebrates, and fish was assessed, based on seawater pesticide concentrations using the Risk Quotient (RQ) and Toxic Units (TU) approach. The results showed 18 pesticides identified in the analyzed samples, where cypermethrin and chlorpyrifos were identified with the maximum concentrations of 1.223 and 0.994 μg L -1 , respectively. In addition, these two pesticides have been associated with acute toxic effects on algae, invertebrates, and fish. It is important to pay particular attention to the search for long-term alternatives to the use of chlorpyrifos and cypermethrin due to their high detection rates and the risks associated with their toxic properties. However, the adoption of alternative measures to synthetic pesticide control should be a priority, moving towards sustainable practices such as the use of biopesticides, crop rotation and polycultures., Competing Interests: The authors declare no conflict of interest.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Staphylococcus aureus bloodstream infection is treated with at least 14 days of intravenous antimicrobials. We assessed the efficacy and safety of an early switch to oral therapy in patients at low risk for complications related to S aureus bloodstream infection., Methods: In this international, open-label, randomised, controlled, non-inferiority trial done in 31 tertiary care hospitals in Germany, France, the Netherlands, and Spain, adult patients with low-risk S aureus bloodstream infection were randomly assigned after 5-7 days of intravenous antimicrobial therapy to oral antimicrobial therapy or to continue intravenous standard therapy. Randomisation was done via a central web-based system, using permuted blocks of varying length, and stratified by study centre. The main exclusion criteria were signs and symptoms of complicated S aureus bloodstream infection, non-removable foreign devices, and severe comorbidity. The composite primary endpoint was the occurrence of any complication related to S aureus bloodstream infection (relapsing S aureus bloodstream infection, deep-seated infection, and mortality attributable to infection) within 90 days, assessed in the intention-to-treat population by clinical assessors who were masked to treatment assignment. Adverse events were assessed in all participants who received at least one dose of study medication (safety population). Due to slow recruitment, the scientific advisory committee decided on Jan 15, 2018, to stop the trial after 215 participants were randomly assigned (planned sample size was 430 participants) and to convert the planned interim analysis into the final analysis. The decision was taken without knowledge of outcome data, at a time when 126 participants were enrolled. The new sample size accommodated a non-inferiority margin of 10%; to claim non-inferiority, the upper bound of the 95% CI for the treatment difference (stratified by centre) had to be below 10 percentage points. The trial is closed to recruitment and is registered with ClinicalTrials.gov (NCT01792804), the German Clinical trials register (DRKS00004741), and EudraCT (2013-000577-77)., Findings: Of 5063 patients with S aureus bloodstream infection assessed for eligibility, 213 were randomly assigned to switch to oral therapy (n=108) or to continue intravenous therapy (n=105). Mean age was 63·5 (SD 17·2) years and 148 (69%) participants were male and 65 (31%) were female. In the oral switch group, 14 (13%) participants met the primary endpoint versus 13 (12%) in the intravenous group, with a treatment difference of 0·7 percentage points (95% CI -7·8 to 9·1; p=0·013). In the oral switch group, 36 (34%) of 107 participants in the safety population had at least one serious adverse event compared with 27 (26%) of 103 participants in the intravenous group (p=0·29)., Interpretation: Oral switch antimicrobial therapy was non-inferior to intravenous standard therapy in participants with low-risk S aureus bloodstream infection. However, it is necessary to carefully assess patients for signs and symptoms of complicated S aureus bloodstream infection at the time of presentation and thereafter before considering early oral switch therapy., Funding: Deutsche Forschungsgemeinschaft., Translations: For the German, Spanish, French and Dutch translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AJK received funding for this study from the Deutsche Forschungsgemeinschaft and is Chairperson of the German Sepsis Society. HSe received grants or research support from the Bundesministerium für Bildung und Forschung (BMBF) Germany and the German Center for Infection Research, and has been a consultant for Debiopharm, Gilead, MSD, and Shionogi. AS has received grants from Gilead Sciences (IN-ES-540–6089) and Pfizer, consulting fees and lecture honoraria from Pfizer, MSD, Angelini, Shionogi, Gilead, and Menarini, and travel support from Pfizer. JR-B has received grants or research support from the Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/00001) and Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC, CB21/13/00012), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, which are co-financed by the European Development Regional Fund. SH received honoraria and travel support from Shionogi, Pfizer, Infectopharm, and AdvanzPharma. NJ reports receiving honoraria for lectures from AbbVie, Bayer, Infectopharm, and Medacta, travel support from Gilead, Pfizer, and Correvio, participation in paid advisory board meetings for MSD, and membership in the steering committee of the German Society of Internal Medicine. SRi received honoraria for lectures from Falk Foundation, Pfizer, bioMérieux, Akademie für Infektionsmedizin, Med Update, streamedup!, and Deutscher Apotheker-Verlag. TW reports receiving honoraria for presentations from AstraZeneca, Advanz, MSD, Pfizer, and Shionogi, grants or research support from BMBF Germany, and travel support from Pfizer. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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.

Infective endocarditis (IE) caused by Enterococcus spp. represents the third most common cause of IE, with high rates of relapse compared with other bacteria. Interestingly, late relapses (>6 months) have only been described in Enterococcus faecalis, but here we describe the first reported IE relapse with Enterococcus faecium more than a year (17 months) after the initial endocarditis episode. Firstly, by multi locus sequence typing (MLST), we demonstrated that both isolates (EF646 and EF641) belong to the same sequence type (ST117). Considering that EF641 was able to overcome starvation and antibiotic treatment conditions surviving for a long period of time, we performed bioinformatic analysis in identifying potential genes involved in virulence and stringent response. Our results showed a 13-nucleotide duplication (positions 1638-1650) in the gene relA , resulting in a premature stop codon, with a loss of 167 amino acids from the C-terminal domains of the RelA enzyme. RelA mediates the stringent response in bacteria, modulating levels of the alarmone guanosine tetraphosphate (ppGpp). The relA mutant (EF641) was associated with lower growth capacity, the presence of small colony variants, and higher capacity to produce biofilms (compared with the strain EF646), but without differences in antimicrobial susceptibility patterns according to standard procedures during planktonic growth. Instead, EF641 demonstrated tolerance to high doses of teicoplanin when growing in a biofilm. We conclude that all these events would be closely related to the long-term survival of the E. faecium and the late relapse of the IE. These data represent the first clinical evidence of mutations in the stringent response ( relA gene) related with E. faecium IE relapse., Competing Interests: The authors declare no conflict of interest.

Objective: Human monkeypox (mpox) is usually self-limited infection; however, rising data show a worse outcome in patients with impaired immune status, particularly those co-infected with HIV [Mitjà O, Alemany A, Marks M, Lezama Mora JI, Rodríguez-Aldama JC, Torres Silva MS et al. Mpox in people with advanced HIV infection: A global case series. Lancet. 2023; 401:939-49. DOI:https://doi.org/10.1016/S0140-6736(23)00273-8] [Govind A, Lazarte SM, Kitchell E, Chow JY, Estelle CD, Fixsen E et al. Severe mpox infections in people with uncontrolled human immunodeficiency virus (HIV). Clin Infect Dis. 2023; 76:1843-6. DOI:https://doi.org/10.1093/cid/ciad052]., Methods: We report the clinical, pathological, and molecular study of a patient with mpox infection and a late HIV diagnosis, with fatal outcome., Results: Necropsy revealed visceral spread of mpox. Mpox virus was sequenced twice during the admission, uncovering an emerging mutation near a genomic region where mutations associated with tecovirimat resistance have been documented., Discussion: Monkeypox can manifest as an opportunistic infection in individuals with advanced HIV-associated immunosuppression., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Antimicrobial stewardship programmes (ASPs) have resulted in antimicrobial consumption (AMC) reduction and quality of prescription (QOP) improvement. However, evidence of ASP impact in paediatrics is still limited. This study aims to assess a paediatric ASP long-term outcomes., Methods: A quality improvement study assessed by a interrupted time series analysis was conducted in a paediatric tertiary hospital. QOP expressed as proportion of adequate prescriptions, AMC measured by defined daily dose incidence per 1000 occupied bed days, incidence density of bloodstream infections (BSIs) and its related all-cause crude death rate (CDR) were compared between pre (from January 2013 to December 2015) and post (from January 2016 to December 2019) ASP activities intensification, which included a dedicated paediatric infectious diseases physician to actively perform educational interviews with prescribers., Results: Inappropriate prescribing showed a significant downward shift associated to the intervention with a -51.4% (-61.2% to -41.8%) reduction with respect to the expected values. Overall AMC showed no trend change after the intervention. For neonatology a28.8% (-36.8% to -20.9%) reduction was observed. Overall anti-pseudomonal cephalosporin use showed a -51.2% (-57.0% to -45.4%) reduction. Decreasing trends were observed for carbapenem use, with a quarterly per cent change (QPC) of -2.4% (-4.3% to -0.4%) and BSI-related CDR (QPC=-3.6%; -5.4% to -1.7%) through the study period. Healthcare-associated multi-drug-resistant BSI remained stable (QPC=2.1; -0.6 to 4.9)., Conclusions: Intensification of counselling educational activities within an ASP suggests to improve QOP and to partially reduce AMC in paediatric patients. The decreasing trends in mortality remained unchanged., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: RB has received personal honoraria from AbbVie and Eli Lilly unrelated to the topic of this Comment. All other authors declare no competing interests.

Objectives: To evaluate the clinical and epidemiological impact of a new molecular surveillance strategy based on qPCR to control an outbreak by Serratia marcescens in a Neonatal Intensive Care Unit (NICU)., Methods: We design a specific qPCR for the detection of S. marcescens in rectal swabs of patients admitted to a NICU. We divided the surveillance study into two periods: (a) the pre-PCR, from the outbreak declaration to the qPCR introduction, and (b) the PCR period, from the introduction of the qPCR until the outbreak was solved. In all cases, S. marcescens isolates were recovered and their clonal relationship was analysed by PFGE. Control measures were implemented during the outbreak. Finally, the number of bloodstream infections (BSI) was investigated in order to evaluate the clinical impact of this molecular strategy., Results: Nineteen patients colonized/infected by S. marcescens were detected in the pre-PCR period (October 2020-April 2021). On the contrary, after the PCR implementation, 16 new patients were detected. The PFGE revealed 24 different pulsotypes belonging to 7 different clonal groups, that were not overlapping at the same time. Regarding the clinical impact, 18 months after the qPCR implementation, no more outbreaks by S. marcescens have been declared in the NICU of our hospital, and only 1 episode of BSI has occurred, compared with 11 BSI episodes declared previously to the outbreak control., Conclusions: The implementation of this qPCR strategy has proved to be a useful tool to control the nosocomial spread of S. marcescens in the NICU., (© 2023. The Author(s).)

Nursing homes (NH) conceptually should look as much like a home as possible. However NH have unquestionable similarities with a nosocomium as they are places where many patients with underlying diseases and comorbidities accumulate. There is evidence of transmission of microorganisms between residents and between residents and caregivers. We have not found any recommendations specifically aimed at the prevention of nosocomial infections in NH by the major Public Health Agencies and, therefore, the Health Sciences Foundation (Fundación de Ciencias de la Salud) has convened a series of experts and 14 Spanish scientific societies to discuss recommendations that could guide NH personnel in establishing written programs for the control and reduction of these infections. The present document is the result of these deliberations and contains suggestions for establishing such control programs on a voluntary and flexible basis in NH. We also hope that the document can help the health authorities to encourage this control activity in the different territorial areas of Spain. In our opinion, it is necessary to draw up a written plan and establish the figure of a coordinator or person responsible for implementing these projects. The document includes measures to be implemented and ways of quantifying the reality of different problems and of monitoring the impact of the measures established., (©The Author 2023. Published by Sociedad Española de Quimioterapia. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).)

West Nile virus (WNV) is a neurotropic flavivirus transmitted by the bites of infected mosquitoes. Severe forms of West Nile disease (WND) can curse with meningitis, encephalitis or acute flaccid paralysis. A better understanding of the physiopathology associated with disease progression is mandatory to find biomarkers and effective therapies. In this scenario, blood derivatives (plasma and serum) constitute the more commonly used biofluids due to its ease of collection and high value for diagnostic purposes. Therefore, the potential impact of this virus in the circulating lipidome was addressed combining the analysis of samples from experimentally infected mice and naturally WND patients. Our results unveil dynamic alterations in the lipidome that define specific metabolic fingerprints of different infection stages. Concomitant with neuroinvasion in mice, the lipid landscape was dominated by a metabolic reprograming that resulted in significant elevations of circulating sphingolipids (ceramides, dihydroceramides, and dihydrosphingomyelins), phosphatidylethanolamines and triacylglycerols. Remarkably, patients suffering from WND also displayed an elevation of ceramides, dihydroceramides, lactosylceramides, and monoacylglycerols in their sera. The dysregulation of sphingolipid metabolism by WNV may provide new therapeutic opportunities and supports the potential of certain lipids as novel peripheral biomarkers of WND progression.

Continued human population growth has resulted in increased demand for products, including those derived from aquaculture. The main challenge in aquaculture is producing more every year. In recent years, environmentally friendly supplements that provide the necessary pathways for optimal production have been emphasized. One of them is prebiotics, selectively utilized substrates by host microorganisms conferring a health benefit. Interest in applying prebiotics in global fish farming has increased in recent years as it has been shown to improve growth, boost the immune system, resist stress conditions, and cause the modulation of digestive enzymes. These effects reflect reduced production and disease costs. However, in Latin American countries such as Mexico, large-scale use of these food supplements is needed as a sustainable alternative to improve fish production. This paper gives a review of the current advances obtained with the application of prebiotics in commercially farmed fish worldwide, mentions the prebiotics to use in the aquaculture industry, and updates the status of studies about the used prebiotics in global commercial fish cultivated in Mexico, as well as freshwater and marine endemic fish in this country. Also, the limitations of prebiotics application in terms of their use and legislation are analyzed.

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., Competing Interests: The authors declare no conflict of interest.

Objectives: The BIChromET selective medium for detecting piperacillin-tazobactam (TZP) and cefepime (FEP) resistant Pseudomonas aeruginosa was developed., Methods: The performance of this medium was first evaluated using a collection of 100 P. aeruginosa clinical strains (70 TZP-susceptible, 30 TZP-resistant, 58 FEP-susceptible, and 42 FEP-resistant). Then, we performed clinical validation by testing 173 respiratory clinical samples., Results: The BIChromET medium showed excellent sensitivity (TZP (avg. 96.7%); FEP (avg. 92.7%)) and specificity (TZP (avg. 98.9%); FEP (avg. 98%)) in distinguishing the detection limit ranging from 10 4 to 10 8 CFU/mL. Then, testing the bronchoalveolar lavage (BAL) and tracheobronchial aspirate (TBA) clinical specimens (N = 173) revealed the excellent performance of the medium with P. aeruginosa , showing 100% and 92.6% of categorical agreements with the results obtained via the broth microdilution methods (BMD) for TZP and FEP, respectively., Conclusion: This medium allows for easy and accurate detection of TZP/FEP-resistant isolates regardless of their resistance mechanisms.

Surgical antibiotic prophylaxis is one of the most useful measures to prevent surgical wound infection., Objective: The aim of this project is to evaluate the appropriateness of the use of antibiotic prophylaxis in surgical procedures performed in Spanish hospitals, both globally and according to the type of surgery performed., Method: For this purpose, an observational, retrospective, cross-sectional and multicenter study has been designed to collect all the variables that allow the evaluation of the appropriateness of surgical antibiotic prophylaxis by comparing the prescribed treatment, the recommendations included in the local guidelines and the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology and the Spanish Association of Surgeons. Indication, choice of antimicrobial, dose, route and duration of administration, timing, re-dosing and duration of the prophylaxis will be taken into account. The sample will consist of patients who underwent scheduled or emergency surgery, either as inpatients or outpatients, in hospitals in Spain. A sample size of 2,335 patients has been established to estimate, with 95% confidence and 80% power, a percentage of appropriateness that is expected to be around 70%. Differences between variables will be analyzed using Student's t-test, Mann-Whitney U test, Chi-square test, or Fisher's test, as appropriate. The degree of agreement between the antibiotic prophylaxis recommended by the guidelines of the different hospitals and that recommended in the literature will be analyzed by calculating the Cohen's kappa indicator. Binary logistic regression analysis using generalized linear mixed models will be performed to identify possible factors associated with differences in the appropriateness of antibiotic prophylaxis., Discussion: The results of this clinical study will allow us to focus on specific surgical areas with higher rates of inappropriateness, identify key points of action and guide future strategies for antimicrobial stewardship programs in the area of antibiotic prophylaxis., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Piperacillin-tazobactam resistance (P/T-R) is increasingly reported among Escherichia coli isolates. Although in vitro experiments have suggested that bla TEM gene plays a key role in the P/T-R acquisition, no clinical in vivo study has yet confirmed the role of bla TEM or other genes. Therefore, we aimed to identify the mechanisms underlying P/T-R by following up patients with E. coli complicated intra-abdominal infections (cIAI) who experienced P/T treatment failure. Four pairs of strains, clonally related from four patients, were isolated both before and after treatment with P/T dosed at 4 g/0.5 g intravenously. The P/T MIC was tested using broth microdilution, and β-lactamase activity was determined in these isolates. Whole-genome sequencing (WGS) was performed to decipher the role of bla TEM and other genes associated with P/T-R. Changes in the outer membrane protein (OMP) profile were analyzed using SDS-PAGE, and bla TEM and ompC transcription levels were measured by RT-qPCR. In addition, in vitro competition fitness was performed between each pairs of strains (P/T-susceptible vs. P/T-resistant). We found a higher copy number of bla TEM gene in P/T-R isolates, generated by three different genetic events: (1) IS26-mediated duplication of the bla TEM gene, (2) generation of a small multicopy plasmid (ColE-like) carrying bla TEM , and (3) adaptive evolution via reduction of plasmid size, leading to a higher plasmid copy number. Moreover, two P/T-R strains showed reduced expression of OmpC. This study describes the mechanisms involved in the acquisition of P/T-R by E. coli in patients with cIAI. The understanding of P/T-R evolution is crucial for effectively treating infected patients and preventing the spread of resistant microorganisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Surgical antibiotic prophylaxis is one of the most useful measures to prevent surgical wound infection., Objective: The aim of this project is to evaluate the appropriateness of the use of antibiotic prophylaxis in surgical procedures performed in Spanish hospitals, both globally and according to the type of surgery performed., Method: For this purpose, an observational, retrospective, cross-sectional, and multicentre study has been designed to collect all the variables that allow the evaluation of the appropriateness of surgical antibiotic prophylaxis by comparing the prescribed treatment, the recommendations included in the local guidelines, and the consensus document of the Spanish Society of Infectious Diseases and Clinical Microbiology and the Spanish Association of Surgeons. Indication, choice of antimicrobial, dose, route and duration of administration, timing, re-dosing, and duration of the prophylaxis will be taken into account. The sample will consist of patients who underwent scheduled or emergency surgery, either as inpatients or outpatients, in hospitals in Spain. A sample size of 2335 patients has been established to estimate, with 95% confidence and 80% power, a percentage of appropriateness that is expected to be around 70%. Differences between variables will be analysed using Student's t-test, Mann-Whitney U test, Chi-square test, or Fisher's test, as appropriate. The degree of agreement between the antibiotic prophylaxis recommended by the guidelines of the different hospitals and that recommended in the literature will be analysed by calculating the Cohen's kappa indicator. Binary logistic regression analysis using generalised linear mixed models will be performed to identify possible factors associated with differences in the appropriateness of antibiotic prophylaxis., Discussion: The results of this clinical study will allow us to focus on specific surgical areas with higher rates of inappropriateness, identify key points of action and guide future strategies for antimicrobial stewardship programs in the area of antibiotic prophylaxis., Competing Interests: Conflicts of interest None declared., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

This study explored the feasibility of a bundle of indicators aimed at assessing the quality of antimicrobial use in intensive care units (ICUs) through an observational prospective study spanning 12 quarters (January 2019-December 2021) in a 1290-bed teaching hospital in Spain. Members of the antimicrobial stewardship programme team selected the indicators to analyse the quality of antimicrobial use based on consumption data from a list proposed in a previous study. Antimicrobial use in the ICU was measured as defined daily dose (DDD) per 100 occupied bed-days. Trends and points of change were analysed with segmented regression. The intravenous macrolides/intravenous respiratory fluoroquinolones ratio in the ICU increased progressively, although not significantly, by 11.14% per quarter, likely related to prioritization of the use of macrolides in serious community-acquired pneumonia and the coronavirus disease 2019 pandemic. A remarkable upward trend of 2.5% per quarter was detected in the anti-methicillin-susceptible Staphylococcus aureus/anti-methicillin-resistant S. aureus agents ratio in the ICU, which could be explained by the low prevalence of methicillin-resistant S. aureus at the study centre. Patterns of amoxicillin-clavulanic acid/piperacillin-tazobactam ratio and diversification of anti-pseudomonal beta-lactams showed an increment in use over the study. The use of these novel indicators provides additional information for the current analysis of DDD. Implementation is feasible, and led to the detection of patterns that agree with local guidelines and cumulative antibiogram reports, and foster targeted improvement actions within antimicrobial stewardship programmes., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The objective of this study was to evaluate the accuracy of the MDR Direct Flow Chip Kit for the detection of antimicrobial resistance (AMR) determinants from bacterial colonies. Ninety-two clinical isolates with known AMR determinants genotypically characterized were used. The MDR Direct Flow Chip Kit is a microarray-based assay that included 55 AMR determinants for beta-lactams (23), quinolones (13), aminoglycosides (5), macrolides (5), sulfonamides (3), colistin (2), vancomycin (2), chloramphenicol (1), and linezolid (1). The MDR Direct Flow Chip Kit correctly detects 52 of 53 AMR determinants tested. The cfr gene (linezolid resistance) was not detected. The global sensibility, specificity, positive predictive value, and the negative predictive value calculated were 98%, 100%, 100%, and 97%. The Cohen's Kappa coefficient calculated was 0.97 [95% Confidence Interval (0.90-1.03)]. In conclusion, the MDR Direct Flow Chip is an accurate assay for the detection of multiple AMR determinants in one simple reaction.

Introduction: Whole-body autopsies may be crucial to understand coronavirus disease 2019 (COVID-19) pathophysiology. We aimed to analyze pathological findings in a large series of full-body autopsies, with a special focus on superinfections., Methods: This was a prospective multicenter study that included 70 COVID-19 autopsies performed between April 2020 and February 2021. Epidemiological, clinical and pathological information was collected using a standardized case report form., Results: Median (IQR) age was 70 (range 63.75-74.25) years and 76% of cases were males. Most patients (90%,) had at least one comorbidity prior to COVID-19 diagnosis, with vascular risk factors being the most frequent. Infectious complications were developed by 65.71% of the patients during their follow-up. Mechanical ventilation was required in most patients (75.71%) and was mainly invasive. In multivariate analyses, length of hospital stay and invasive mechanical ventilation were significantly associated with infections ( p  = 0.036 and p  = 0.013, respectively). Necropsy findings revealed diffuse alveolar damage in the lungs, left ventricular hypertrophy in the heart, liver steatosis and pre-infection arteriosclerosis in the heart and kidneys., Conclusion: Our study confirms the main necropsy histopathological findings attributed to COVID-19 in a large patient series, while underlining the importance of both comorbid conditions and superinfections in the pathology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ruiz-Cáceres, Hermida Romero, Guerra Merino, Portu Zapirain, Pérez-Mies, Sánchez-Conde, Riaño, Rubio, Fortés Alen, Vidal González, Salas Antón, Múñez, Sánchez Sánchez, Corona-Mata, Aldecoa Ansorregui, Miró, Beloqui Pérez de Obanos, Ibero, Gómez-Román, Fariñas, Tabuyo Bello, de Alava, Cisneros, Matías-Guiu and Rivero.)

Delafloxacin is a new fluoroquinolone indicated for the treatment of complicated bacterial skin infections caused by Staphylococcus aureus. Despite its recent approval by the US Food and Drug Administration, the emergence of S. aureus-resistant strains has been reported. As such, this study aimed to investigate the activity of delafloxacin against a collection of S. aureus, and to determine the mechanisms of resistance. The activity of delafloxacin was measured in 59 S. aureus clinical isolates [40 methicillin-resistant S. aureus (MRSA) and 19 methicillin-susceptible S. aureus (MSSA)]. Whole-genome sequencing (WGS) was performed in the isolates resistant to delafloxacin. The minimum inhibitory concentrations required to inactivate 50% and 90% of the isolates (MIC 50 and MIC 90, respectively) were higher in MRSA (0.19 mg/L and 0.75 mg/L, respectively) than in MSSA (0.008 mg/L and 0.25 mg/L, respectively). Furthermore, 10 S. aureus clinical isolates (16.9%) were categorized as resistant to delafloxacin. Regarding the WGS data, several mutations were found in the quinolone resistance-determining region. Nevertheless, a mutation in the same position (E84K and E84V) of topoisomerase IV (ParC) was found exclusively in the four high-level delafloxacin-resistant isolates. Interestingly, a plasmid-encoded qacC gene (efflux pump) was found to be harboured by the isolate with the highest delafloxacin MIC value (32 mg/L). The use of a wide-spectrum efflux pump inhibitor revealed an important contribution of this system to the acquisition of delafloxacin resistance. In conclusion, delafloxacin has activity against S. aureus, including MRSA. However, this study showed that mutations in position 84 of ParC and the acquisition of a QacC efflux pump are key factors for the development of delafloxacin resistance in S. aureus., (Copyright © 2023 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Objectives: To analyse the adherence and impact of quality-of-care indicators (QCIs) in the management of Staphylococcus aureus bloodstream infection in a prospective and multicentre cohort., Methods: Analysis of the prospective, multicentre international S. Aureus Collaboration cohort of S. Aureus bloodstream infection cases observed between January 2013 and April 2015. Multivariable analysis was performed to evaluate the impact of adherence to QCIs on 90-day mortality., Results: A total of 1784 cases were included. Overall, 90-day mortality was 29.9% and mean follow-up period was 118 days. Adherence was 67% (n = 1180/1762) for follow-up blood cultures, 31% (n = 416/1342) for early focus control, 77.6% (n = 546/704) for performance of echocardiography, 75.5% (n = 1348/1784) for adequacy of targeted antimicrobial therapy, 88.6% (n = 851/960) for adequacy of treatment duration in non-complicated bloodstream infections and 61.2% (n = 366/598) in complicated bloodstream infections. Full bundle adherence was 18.4% (n = 328/1784). After controlling for immortal time bias and potential confounders, focus control (adjusted hazard ratio = 0.76; 95% CI, 0.59-0.99; p 0.038) and adequate targeted antimicrobial therapy (adjusted hazard ratio = 0.75; 95% CI, 0.61-0.91; p 0.004) were associated with low 90-day mortality., Discussion: Adherence to QCIs in S. Aureus bloodstream infection did not reach expected rates. Apart from the benefits of application as a bundle, focus control and adequate targeted therapy were independently associated with low mortality., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Antimicrobial stewardship programs (ASPs) are recommended in nursing homes (NHs), although data are limited. We aimed to determine the clinical and ecological impact of an ASP for NHs., Methods: We performed a cluster, randomized, controlled trial and a before-after study with interrupted time-series analyses in 14 NHs for 30 consecutive months from July 2018 to December 2020 in Andalusia, Spain. Seven facilities implemented an ASP with a bundle of 5 educational measures (general ASP) and 7 added 1-to-1 educational interviews (experimental ASP). The primary outcome was the overall use of antimicrobials, calculated monthly as defined daily doses (DDD) per 1000 resident days (DRD)., Results: The total mean antimicrobial consumption decreased by 31.2% (-16.72 DRD; P = .045) with respect to the preintervention period; the overall use of quinolones and amoxicillin-clavulanic acid dropped by 52.2% (P = .001) and 42.5% (P = .006), respectively; and the overall prevalence of multidrug-resistant organisms (MDROs) decreased from 24.7% to 17.4% (P = .012). During the intervention period, 12.5 educational interviews per doctor were performed in the experimental ASP group; no differences were found in the total mean antimicrobial use between groups (-14.62 DRD; P = .25). Two unexpected coronavirus disease 2019 waves affected the centers increasing the overall mean use of antimicrobials by 40% (51.56 DRD; P < .0001)., Conclusions: This study suggests that an ASP for NHs appears to be associated with a decrease in total consumption of antimicrobials and prevalence of MDROs. This trial did not find benefits associated with educational interviews, probably due to the coronavirus disease 2019 pandemic. Clinical Trials Registration. NCT03543605., Competing Interests: Potential conflicts of interest. J. M. C. has received travel grants and honoraria as a speaker from Novartis, Astellas Pharma, Pfizer, MSD, Janssen Pharmaceuticals, and AstraZeneca outside the submitted work. A. R. V. has received honoraria as a speaker from Pfizer outside the submitted work. J. M. C. reports funding from Centro de Investigación Biomédica en Red de Enfermedades Infecciosas, Madrid, Spain. J. M. C., G. P., and J. C. C.-R. report grants from the Instituto de Salud Carlos III, Spanish Government, cofinanced by the European Development Regional Fund (A Way to Achieve Europe), and from the Spanish Network for Research in Infectious Diseases during the conduct of the study. A. B. G.-G. reports funding from the Subprograma Río Hortega and Juan Rodés, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spanish Government. L. H.-H. reports funding from the Subprograma Río Hortega. M. E. P.-I. is a researcher funded by the program Nicolás Monardes, Servicio Andaluz de Salud, Junta de Andalucía, Spain. A. R. V. is supported by the Subprograma Juan Rodés, Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spain. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Rapid determination of susceptibility to piperacillin-tazobactam (TZP) is very important since the development of antibiotic resistance and inadequate treatment could increase the risk of clinical failure in infected patients, especially if such resistance is unknown to the clinician. Therefore, based on color change from orange to yellow of phenol red due to glucose metabolism (bacterial growth) in the presence of an adequate concentration of TZP (10 mg/L piperacillin and 5 mg/L tazobactam), the RapidTZP test has been developed to detect TZP resistance in Escherichia coli and Klebsiella pneumoniae isolates in a maximum of 3 h. A total of 140 isolates, 43 of E. coli and 97 of K. pneumoniae, were used to evaluate the performance of the test, 60 being resistant to TZP. The sensitivity and specificity of the test were 98.24% and 100%, respectively. Additionally, the RapidTZP test was validated by a pellet obtained directly from blood culture bottles. A total of 37 positive blood cultures for E. coli and 43 for K. pneumoniae were used for validation, 8 of them resistant to TZP. The sensitivity and specificity shown in the evaluation were 100% for both parameters. This new test is easy, fast, and accurate, providing results in 3 h. IMPORTANCE TZP is an antibiotic widely used for the empirical treatment of severe infections such as bloodstream infections. However, resistance to TZP in K. pneumoniae and E. coli has been increasing in the last few years. Thus, rapid detection of TZP resistance is critical to optimize the empirical treatment of patients with severe infections. In this study, we developed and evaluated a rapid test (RapidTZP) for the detection of TZP resistance in K. pneumoniae and E. coli directly from positive hemocultures in just 3 h. This rapid test has been validated on 138 K. pneumoniae and E. coli clinical isolates directly from agar plates and 80 K. pneumoniae and E. coli isolates causing bloodstream infections. The results demonstrate that the RapidTZP test has great clinical potential to optimize the empirical treatment of patients with bloodstream infections.

In 2019, the biggest listeriosis outbreak by Listeria monocytogenes (Lm) in the South of Spain was reported, resulting in the death of three patients from 207 confirmed cases. One strain, belonging to clonal complex 388 (Lm CC388), has been isolated. We aimed to determine the Lm CC388 virulence in comparison with other highly virulent clones such as Lm CC1 and Lm CC4, in vitro and in vivo. Four L. monocytogenes strains (Lm CC388, Lm CC1, Lm CC4 and ATCC 19115) were used. Attachment to human lung epithelial cells (A549 cells) by these strains was characterized by adherence and invasion assays. Their cytotoxicities to A549 cells were evaluated by determining the cells viability. Their hemolysis activity was determined also. A murine intravenous infection model using these was performed to determine the concentration of bacteria in tissues and blood. Lm CC388 interaction with A549 cells is non-significantly higher than that of ATCC 19115 and Lm CC1, and lower than that of Lm CC4. Lm CC388 cytotoxicity is higher than that of ATCC 19115 and Lm CC1, and lower than that of Lm CC4. Moreover, Lm CC388 hemolysis activity is lower than that of the Lm CC4 strain, and higher than that of Lm CC1. Finally, in the murine intravenous infection model by Lm CC388, higher bacterial loads in tissues and at similar levels of Lm CC4 were observed. Although a lower rate of mortality of patients during the listeriosis outbreak in Spain in 2019 has been reported, the Lm CC388 strain has shown a greater or similar pathogenicity level in vitro and in an animal model, like Lm CC1 and Lm CC4.

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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Molina et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Garrido-Torres, Cerrillos, García Cerro, Pérez Gómez, Canal-Rivero, de Felipe, Alameda, Marqués Rodríguez, Anillo, Praena, Duque Sánchez, Roca, Paniagua, López Díaz, Romero-García, Olbrich, Puertas Albarracín, Reguera Pozuelo, Sosa, Moreno Dueñas, Pineda Cachero, Zamudio Juan, García Rumi, Guerrero Benitez, Figueroa, Martín Rendón, Partida, Rodríguez Cocho, Gallardo Trujillo, Gallego Jiménez, García Spencer, Gómez Verdugo, Bermejo Fernández, Pérez Benito, Castillo Reina, Cejudo López, Sánchez Tomás, Chacón Gamero María Ángeles, Rubio, Moreno Mellado, Ramos Herrero, Starr, González Fernández de Palacios, García Victori, Pavón Delgado, Fernández Cuervo, Arias Ruiz, Menéndez Gil, Domínguez Gómez, Coca Mendoza, Ayesa-Arriola, Fañanas, Leza, Cisneros, Sánchez Céspedes, Ruiz-Mateos, Crespo-Facorro and Ruiz-Veguilla.)

Background: We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups., Methods: Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence.Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment., Findings: Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73-1.58; 30-day mortality: 1.08, 0.62-1.91). Relapse (1.00, 0.50-1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80-1.22); and infection complications (local: 1.62 0.76-3.47; distant: 2.00, 0.18-22.08), were without significant difference, and so were adverse events or resistance emergence.No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection., Interpretation: For patients hemodynamically stable and afebrile at 48 h prior to discontinuation, seven days of antibiotic therapy for enterobacterales bacteremia result in similar outcomes as 14 days, in terms of mortality, relapse, length of hospital stay, complications of infection, resistance emergence, and adverse events. These results apply for any adult age group, gender, source of infection, immune status, and hemodynamic status on presentation., Funding: There was no funding source for this study., Competing Interests: We declare no competing interests., (© 2022 The Authors.)