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Background: Despite the burden of pyelonephritis after kidney transplantation, there is no consensus on initial empirical antibiotic management., Methods: We surveyed clinicians throughout the world on their practice and opinions about the initial empirical therapy of post-transplant pyelonephritis, using clinical vignettes. A panel of experts from 19 countries on six continents designed this survey, and invited 2145 clinicians to participate., Results: A total of 721 clinicians completed the survey (response rate: 34%). In the hypothetical case of a kidney transplant recipient admitted with pyelonephritis but not requiring intensive care, most respondents reported initiating either a 3rd-generation cephalosporin (37%) or piperacillin-tazobactam (21%) monotherapy. Several patient-level factors dictated the selection of broader-spectrum antibiotics, including having a recent urine culture showing growth of a resistant organism (85% for extended-spectrum ß-lactamase-producing organisms, 90% for carbapenemase-producing organisms, and 94% for Pseudomonas aeruginosa). Respondents attributed high importance to the appropriateness of empirical therapy, which 87% judged important to prevent mortality. Significant practice and opinion variations were observed between and within countries., Conclusion: High-quality studies are needed to guide the empirical management of post-transplant pyelonephritis. In particular, whether prior urine culture results should systematically be reviewed and considered remains to be determined. Studies are also needed to clarify the relationship between the appropriateness of initial empirical therapy and outcomes of post-transplant pyelonephritis., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

Objectives: We aimed to evaluate the prevalence and perception of scientific misconduct in infectious diseases (ID) and clinical microbiology (CM), as reported by the ID/CM community., Methods: An anonymous online European Society of Clinical Microbiology and Infectious Diseases survey circulated among society members from October 2023 to June 2024; the questionnaire included data on participants' views on their own and their colleagues' scientific misconduct in the last 5 years., Results: The survey received 220 responses. Responders were 73% ID physicians, 52% men, 56% aged 35-54 years, and represented 48 countries, mainly European (126 participants). The vast majority of participants (78%) reported that they did not personally commit scientific misconduct, whereas 54% reported witnessing misconduct by colleagues in their field. The most commonly committed misconduct by both responders and their colleagues was misconduct of authorship rules, 14% and 41%, respectively. Overall, 18% reported witnessing misleading reporting and 14% reported witnessing nonaccurate reporting of conflict of interest. Nevertheless, the majority (>60%) of responders reported high confidence in the integrity of published work in the field of ID/CM. Approximately one-third of responders were not aware of the European Society of Clinical Microbiology and Infectious Diseases ethics advisory committee as an authority to which members can report misconduct., Discussion: Scientific misconduct, mostly related to violation of authorship rules, seems to be common in ID/CM. Efforts to improve scientific integrity should be made to keep trust in the scientific process., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Carbapenem-resistant Acinetobacter baumannii (CRAB) has emerged as a significant health care-associated infection carrying substantial mortality. We assessed the clinical impact of active screening cultures for CRAB., Methods: A systematic review and meta-analysis, aiming to answer 2 questions: (1) Does screening versus no screening improve clinical outcomes? (2) Does positive screening ("CRAB carrier") predict CRAB infections? We searched the literature until January 2024 for comparative studies reporting clinical outcomes (mortality, invasive CRAB infections)., Results: Of 5,407 screened publications, 9 studies (10,865 individuals) were included. Invasive CRAB infection rate was significantly higher among CRAB carriers (OR 11.14, 95% CI 4.95-25.05, with substantial heterogeneity stemming from size rather than direction of the effect). Negative predictive value of noncarriage for invasive infection was 97%. CRAB bloodstream infection rate was significantly higher among carriers (odds ratio 16.23, 95% confidence interval 2.9-110.08). No difference was demonstrated between the groups for CRAB ventilator-associated pneumonia, length of stay, and mortality. Only 1 study reported outcomes for study question #1., Conclusions: Data to support active CRAB screening are scarce regarding its clinical benefit for patients. Positively screened patients are at significantly higher risk for invasive CRAB infections, with high negative predictive value for noncarriage. This did not translate to reduced mortality., (Copyright © 2024 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: Older adults admitted to the intensive care unit (ICU) usually have fair baseline functional capacity, yet their age and frailty may compromise their management. We compared the characteristics and management of older (≥ 75 years) versus younger adults hospitalized in ICU with hospital-acquired bloodstream infection (HA-BSI)., Methods: Nested cohort study within the EUROBACT-2 database, a multinational prospective cohort study including adults (≥ 18 years) hospitalized in the ICU during 2019-2021. We compared older versus younger adults in terms of infection characteristics (clinical signs and symptoms, source, and microbiological data), management (imaging, source control, antimicrobial therapy), and outcomes (28-day mortality and hospital discharge)., Results: Among 2111 individuals hospitalized in 219 ICUs with HA-BSI, 563 (27%) were ≥ 75 years old. Compared to younger patients, these individuals had higher comorbidity score and lower functional capacity; presented more often with a pulmonary, urinary, or unknown HA-BSI source; and had lower heart rate, blood pressure and temperature at presentation. Pathogens and resistance rates were similar in both groups. Differences in management included mainly lower rates of effective source control achievement among aged individuals. Older adults also had significantly higher day-28 mortality (50% versus 34%, p < 0.001), and lower rates of discharge from hospital (12% versus 20%, p < 0.001) by this time., Conclusions: Older adults with HA-BSI hospitalized in ICU have different baseline characteristics and source of infection compared to younger patients. Management of older adults differs mainly by lower probability to achieve source control. This should be targeted to improve outcomes among older ICU patients., (© 2024. The Author(s).)

Older adults hospitalized in internal medicine wards or long-term care facilities (LTCF) are progressively increasing. Older adults with multimorbidity are more susceptible to infections, as well as to more vulnerable to adverse effects (and interactions) of antibiotics, resulting in a need for effective and safer strategies for antimicrobial stewardship (ASM), both in hospitalization wards and long-term care facilities. Studies on antimicrobial stewardship in older patients are scarce and guidelines are required. Given the peculiarities of the optimization of antimicrobial prescription in individual older adults for common infections, tactics to overcome barriers need an update. The use of rapid diagnosis tests, biomarkers, de-escalation and switching from intravenous to oral/subcutaneous therapy strategies are examples of successful AMS interventions. AMS interventions are associated with reduced side effects, lower mortality, shorter hospital stays, and reduced costs. The proposed AMS framework in LTCF should focus on five domains: strategic vision, team, interventions, patient-centred care and awareness. Internists can partner with geriatrists, pharmacists and infectious disease specialists to address barriers and to improve patient care., Competing Interests: Declaration of competing interest Authors disclose no conflicts of interest regarding this manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: While Open Access (OA) journals provide free access to articles, they entail high article processing charges (APC), limiting opportunities for young researchers and those from low-middle income countries to publish OA., Methods: Cross-sectional study, evaluating APC and academic impact of full OA (FOA) journals in infectious diseases (ID) and clinical microbiology (CM) compared to hybrid journals. Data were collected from Journal Citation Reports and journals' websites., Results: Among 255 journals, median APC was 2850 (interquartile range [IQR] 1325-3654$). Median APC for 120 FOA journals was significantly lower than for 119 hybrid journals (2000, IQR 648-2767$ versus 3550, IQR 2948-4120$, p < 0.001). FOA journals had lower citation numbers and impact metrics compared to hybrid journals., Conclusion: While FOA ID/CM journals have lower APCs, they also lower academic impact compared to hybrid journals. These findings highlight the need for reforms in the publication process in view of achieving equitable data dissemination., 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 Elsevier Masson SAS. All rights reserved.)

Background: Early reports described an increased risk of herpes zoster following receipt of mRNA-based COVID-19 vaccines. The objective was to assess whether COVID-19 vaccine is associated with varicella-zoster virus-induced neurologic disease (VZV-ND)., Methods: This multicenter retrospective case-control study with a test-negative design was conducted at 12 hospitals in Israel. We included all patients admitted with VZV-ND between January 2020 and December 2021 and matched controls with a negative polymerase chain reaction result for VZV in cerebrospinal fluid., Results: We identified 188 patients meeting the case definition of VZV-ND who were admitted during the study period. Cases were matched with 376 controls. There was no significant variation in the incidence of VZV-ND between 1 year preceding and 1 year following the deployment of BNT162b2 in Israel. Analysis of persons who had received at least 1 dose of COVID-19 vaccine (n = 259) showed similar proportions of VZV-ND and non-VZV-ND in 4 intervals (30, 42, 50, 60 days) following the last vaccine dose. The median time from the last vaccine dose to hospitalization with a neurologic syndrome was 53 days (IQR, 25-128) and 82 days (IQR, 36-132) for VZV-ND and non-VZV-ND, respectively, not reaching statistical significance ( P = .056). The rate of VZV-ND in vaccinated patients was no different from the rate in the unvaccinated group (30.9% vs 35.4%, P = .2)., Conclusions: We did not find an association between COVID-19 vaccine and VZV-ND. Since COVID-19 vaccine is now recommended yearly, every fall and winter, establishing the safety of the vaccine is of great importance., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Left ventricular assist devices (LVAD) are increasingly used for management of heart failure; infection remains a frequent complication. Phage therapy has been successful in a variety of antibiotic refractory infections and is of interest in treating LVAD infections. We performed a retrospective review of four patients that underwent five separate courses of intravenous (IV) phage therapy with concomitant antibiotic for treatment of endovascular Pseudomonas aeruginosa LVAD infection. We assessed phage susceptibility, bacterial strain sequencing, serum neutralization, biofilm activity, and shelf-life of phage preparations. Five treatments of one to four wild-type virulent phage(s) were administered for 14-51 days after informed consent and regulatory approval. There was no successful outcome. Breakthrough bacteremia occurred in four of five treatments. Two patients died from the underlying infection. We noted a variable decline in phage susceptibility following three of five treatments, four of four tested developed serum neutralization, and prophage presence was confirmed in isolates of two tested patients. Two phage preparations showed an initial titer drop. Phage biofilm activity was confirmed in two. Phage susceptibility alone was not predictive of clinical efficacy in P. aeruginosa endovascular LVAD infection. IV phage was associated with serum neutralization in most cases though lack of clinical effect may be multifactorial including presence of multiple bacterial isolates with varying phage susceptibility, presence of prophages, decline in phage titers, and possible lack of biofilm activity. Breakthrough bacteremia occurred frequently (while the organism remained susceptible to administered phage) and is an important safety consideration., Competing Interests: Saima Aslam: Research funding support from the Cystic Fibrosis Foundation, Armata Pharmaceuticals, Adaptive Phage Therapeutics, and Contrafect Inc. Consultant for BiomX and Phico Therapeutics. Medical advisory board for Pherecydes Pharma and Phiogen. Dwayne Roach: none. Mikeljon P. Nikolich: Royalty-bearing Biological Material License Agreement with Adaptive Phage Therapeutics exists now but work presented in this manuscript predated it. Patent PCT/US22/73852, METHOD OF TREATING DRUG RESISTANT ESKAPE PATHOGENS USING THERAPEUTIC BACTERIOPHAGES was filed, but work reported in this manuscript predated the filing. Biswajit Biswas: Navy Work Unit # A1417. Dr. Biswas has a patent "Bacteriophage compositions and methods of selection of components against specific bacteria" US patent #10357522, which was licensed before. Robert T Schooley: Consulting fees from GSK, LyseNtech. Kimberley A. Lilly-Bishop: none. Gregory K. Rice: none. Regina Z. Cer: none. Theron Hamilton: none. Mathew Henry: Mr. Henry has a patent 10357522 licensed. Tiffany Luong: none. Ann-Charlott Salabarria: none. Laura Sisk-Hackworth: none. Andrey A. Filippov: Pending Patent PCT/US22/73852, METHOD OF TREATING DRUG RESISTANT ESKAPE PATHOGENS USING THERAPEUTIC BACTERIOPHAGES Francois Lebreton: none. Lindsey Hall: none. Ran Nir-Paz: Consultant for BiomX; and has participated and served as a PI and on Data Safety Monitoring Board for a clinical trial by Technophage. Hadil Onalla: none. Gilat Livni: none. Eran Shostak: none. Anat Weider-Feinsod: none. Dafna Yahav: none. Ortal Yerushalmy: none. Sivan Alkalay-Oren: none. Leron Khalifa: none. Amit Rimon: none. Daniel Gelman: none. Ronen Hazan: none.

Decreased diffusion capacity for carbon monoxide (DLCO) is the most prevalent pulmonary testing abnormality among COVID-19 recoverees. We prospectively followed 51 individuals with impaired DLCO at an average of ∼3 months following COVID-19 and re-examined them at one year. At follow-up, mean DLCO increased from 68.0 % to 72.6 % (p = 0.002); while 33 % of the cohort experienced a clinically significant rise (>10 points) in DLCO, only 29 % normalized their values. While DLCO change did not correlate with symptoms, lack of improvement was more prevalent among individuals with obesity. Regardless of COVID-19 severity, a substantial proportion continued to exhibit DLCO impairment at 1-year., 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 Elsevier Masson SAS. All rights reserved.)

Background: Prophylaxis with fluoroquinolones (FQ) is commonly used in patients with acute leukemia (AL) during neutropenia. This practice is supported by an older meta-analysis reporting reduced mortality using FQ prophylaxis. Later meta-analyses have failed to reproduce this finding, presumably due to higher background FQ resistance rates limiting their effectiveness., Summary: This article reviews the pros and cons of FQ prophylaxis mainly in patients with AL. Most current guidelines do not support universal prophylaxis but rather recommend a selective approach, weighing the benefits against the risks. This recommendation is based on the lack of mortality benefit reported in more recent meta-analyses. FQ prophylaxis was demonstrated to reduce bacteremia and febrile neutropenia episodes, although mostly in trials performed in low-resistance settings (&lt;20%), whereas current FQ resistance rates may reach 30-60%. Other disadvantages of FQ include potential adverse events, antibiotic resistance development, cost, increase in Gram-positive infections and resistant Gram-negative infections following prophylaxis, Clostridioides difficile infection, and an effect on gut microbiota., Key Messages: Taking the above into consideration, alternative approaches other than universal FQ prophylaxis should be considered. Centers with high FQ resistance rates may consider either withholding prophylaxis or providing selective prophylaxis for high-risk patients screened negative for FQ-resistant bacteria., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: It is unclear how soon after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection it is safe to resume systemic anti-neoplastic treatment in patients with cancer. We assessed the risk of admissions or postponed treatment cycle in vaccinated patients with breast cancer receiving early systemic anti-neoplastic treatment following SARS-CoV-2 infection., Methods: This was a retrospective cohort study conducted during Omicron SARS-CoV-2 outbreak in Israel, January-July 2022. SARS-CoV-2 cohort included 30 vaccinated patients with breast cancer with SARS-CoV-2 infection 7-14 days prior to systemic treatment. All patients had resolved symptoms and a negative antigen detection test on the day of treatment. The pre-coronavirus disease 2019 (COVID-19) pandemic cohort consisted of 49 matched patients with breast cancer treated with systemic anti-neoplastic agents during 2019., Results: In 30 vaccinated patients with breast cancer who received systemic anti-neoplastic treatment 7-14 days following SARS-CoV-2 infection, compared with 49 matched patients treated in 2019, the rates of emergency department (ED) visits (13% versus 6%, respectively), hospitalizations (3% versus 4%), next cycle of treatment given per protocol (90% versus 88%), and death (0% versus 0%) were similar., Conclusion: In a cohort of vaccinated patients with breast cancer who received systemic anti-neoplastic treatment 7-14 days after SARS-CoV-2 infection, we did not observe substantially higher rates of ED visits, hospitalizations, or deaths compared with a similar cohort of pre-COVID-19 patients with breast cancer. Most patients received the next planned cycle on time. Early resumption of systemic anti-neoplastic treatment following SARS-CoV-2 infection in vaccinated patients with breast cancer with a negative antigen test at the day of treatment appeared to be safe. Additional data on larger cohorts and other malignancies are needed to support clinical guidelines., (© 2023. The Author(s).)

Long-term risk for malignancy is higher among solid organ transplant (SOT) recipients compared to the general population. Four non-hepatitis viruses have been recognized as oncogenic in SOT recipients-EBV, cause of EBV-associated lymphoproliferative diseases; human herpes virus 8 (HHV8), cause of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease; human papilloma virus, cause of squamous cell skin cancers, and Merkel cell polyomavirus, cause of Merkel cell carcinoma. Two of these viruses (EBV and HHV8) belong to the human herpes virus family. In this review, we will discuss key aspects regarding the clinical presentation, diagnosis, treatment, and prevention of diseases in SOT recipients associated with the two herpesviruses., 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 Atamna, Yahav and Hirzel.)

Objectives: We aimed to examine the rate and characteristics of retracted articles in infectious diseases and clinical microbiology., Methods: Using the Retraction Watch Database, we conducted a cross-sectional study for retracted publications categorized as 'Infectious Disease' or 'Microbiology' until June 30 2022. We included publications for which citation information was available through the Web of Science database. Study characteristics, retraction trends and number of citations before and after the retraction year were analysed., Results: Overall, 1004 retracted publications were included, retracted between August 1968 and June 2022. The number of retractions climbed through the years, peaking in 2020-2021. A total of 614 retractions originated from USA, China, and India, of total 183 736 PubMed publications from these countries. Overall, 378 (38%) were retracted because of errors; 182 (18%) because of plagiarism; and 142 (14%) because of falsification/fabrication. Specific reasons included 'concerns/issues about data' (158, 16%); 'duplication of image' (127, 13%); and 'unreliable results' (116, 12%). Of the 347 retractions during 2020 to June 2022, 91 (26%) were COVID-19 related. Fifty of 895 (5.6%) first authors had two retracted papers, and 14 (1.6%) had ≥2 retractions. Of 824 publications cited at least once, 466 (57%) were cited more often after retraction., Discussion: Retractions of infectious diseases and clinical microbiology publications are increasing. Concerning reasons such as plagiarism, falsification/fabrication and errors are not uncommon. Nonetheless, these publications continue to be commonly cited after being retracted., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Staphylococcus aureus bloodstream infection (bacteraemia) is traditionally treated with at least two weeks of IV antibiotics in adults, 3-7 days in children, and often longer for those with complicated disease. The current practice of treating S. aureus bacteraemia (SAB) with prolonged IV antibiotics (rather than oral antibiotics) is based on historical observational research and expert opinion. Prolonged IV antibiotic therapy has significant disadvantages for patients and healthcare systems, and there is growing interest in whether a switch to oral antibiotics following an initial period of IV therapy is a safe alternative for clinically stable patients., Protocol: The early oral switch (EOS) domain of the S. aureus Network Adaptive Platform (SNAP) trial will assess early switch to oral antibiotics compared with continued IV treatment in clinically stable patients with SAB. The primary endpoint is 90-day all-cause mortality. Hospitalised SAB patients are assessed at platform day 7 +/- 2 (uncomplicated SAB) and day 14 +/-2 (complicated SAB) to determine their eligibility for randomisation to EOS (intervention) or continued IV treatment (current standard of care)., Discussion: Recruitment is occurring to the EOS domain of the SNAP trial. As of August 2023, 21% of all SNAP participants had been randomised to the EOS domain, a total of 264 participants across 77 centres, with an aim to recruit at least 1000 participants. We describe challenges and facilitators to enrolment in this domain to aid those planning similar trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Central nervous system (CNS) infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacterales and difficult-to-treat resistant (DTR) Pseudomonas aeruginosa represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections., Methods: Therapeutic drug monitoring (TDM) was performed in 3 patients with health care-associated ventriculitis and meningitis (HAVM) using CAZ-AVI 2.5 g infused intravenously every 8 hours as standard and extended infusion. Simultaneous CSF and plasma samples were obtained throughout the dosing interval in each patient. Concentrations of CAZ and AVI were determined by liquid chromatography/mass spectrometry., Results: Bacterial identification revealed KPC-producing Klebsiella pneumoniae (KPC- Kp ), DTR Pseudomonas aeruginosa, and KPC-producing Enterobacter cloacae (KPC- Ent.c ). All isolates were resistant to carbapenems. The minimum inhibitory concentrations (MICs) of CAZ-AVI were 0.25/4, 4/4, and 0.25/4 μg/mL, respectively. CAZ and AVI concentrations were determined in CSF samples ranging from 29.0 to 15.0 µg/mL (CAZ component) and 4.20 to 0.92 µg/mL (AVI component), respectively. AVI achieved concentrations ≥1 µg/mL in 11 out of 12 CSF samples collected throughout the dosing interval. Clinical and microbiologic cure were attained in all patients., Conclusions: Postinfusion concentrations of CAZ-AVI were measured in plasma and CSF samples obtained from 3 patients with complicated CNS infections caused by antimicrobial-resistant isolates. The measured concentrations revealed that standard CAZ and AVI exposures sufficiently attained values correlating to 50% f T > MIC, which are associated with efficient bacterial killing., Competing Interests: Potential conflicts of interest. No potential conflicts of interest exist for each contributing author as they pertain to this work. Robert A. Bonomo receives funding from VenatoRx, Shionogi, Merck, and Entasis outside the scope of the submitted work. All other authors report no potential conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections., Methods: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections., Findings: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen., Conclusions: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials., Funding: The study was funded in part by The Israeli Science Foundation IPMP (ISF&#95;1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program., Competing Interests: Declaration of interests R.N.P. has been a scientific consultant for BiomX and has participated and served as a PI and on Data Safety Monitoring Boards for a clinical trial by Technophage. N.B. is currently an employee of Pfizer, Israel. M.J.B., J.R.F., B.H., R.H., and S.B. were or are APT (manufacturer of the i.v. PASA16 formulation) employees. K.L.U. is a recipient of NIH grant NIAMS R01 AR082167; he also declares consulting fees from APT not related to the cases described here. R.H. is a recipient of MTEC Foundation Fund MTEC #2019-432. R.H., J.F., and B.H. declare owning stocks or stock options at APT. J.R.F. declares a contract with the United States Defense Health Agency (DHA) to support advancing phage therapy. R.M.L.H. serves on the Takeda advisory board. M.M. was a consultant for Karius, Inc. and Cidara Therapeutics. J.R.I. has been a scientific consultant for Vectura Fertin Pharma. R.C.Y.L., S.L., and A.K. are recipients of the Australia Medical Research Future Fund, Frontiers Stage 1 RFRHPI000017, 2021–2022. R.C.Y.L. and S.L. are recipients of the Australian National Health and Medical Research Council grant Gnt1197534. A.K. is a recipient of the Australian National Health and Medical Research Council grant GNT2008024 and has participated on DSMB for the FluBub Study. R.C.Y.L. had participated on DSMB for Phage Australia as a part of the leadership team, as a chair on the Genomics Scientific Advisory Committee, and as a committee member on the Biobanking Scientific Advisory Committee. S.L. serves as an organizer in Phage Bite, Phage Directory, and as a committee member on Australia Society for Microbiology, Special Interest Group, Phage. P.N.B. received funding from the Royal Australasian College of Physicians for a Cottrell Research Establishment Fellowship. R.B.-A. is a recipient of Israeli Science Foundation grant 442/18, Ministry of Science and Technology grant 88555, and National Health and Medical Research Council (NHMRC) Ideas grant APP2002520. He also received honoraria from Gilead Sciences, Inc. and Teva Pharmaceuticals and has participated on DSMB for Merck and Pfizer., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clostridioides difficile infection (CDI) has become the most common healthcare-associated infection in the United States, with considerable morbidity, mortality, and healthcare costs. Assessing new preventive strategies is vital. We present a literature review of studies evaluating a strategy of screening and isolation of asymptomatic carriers in hospital settings. Asymptomatic detection of C. difficile is reported in ~ 10-20% of admitted patients. Risk factors for carriage include recent hospitalization, previous antibiotics, older age, lower functional capacity, immunosuppression, and others. Asymptomatic C. difficile carriers of toxigenic strains are at higher risk for progression to CDI. They are also shedders of C. difficile spores and may contribute to the persistence and transmission of this bacterium. Screening for asymptomatic carriers at hospital admission can theoretically reduce CDI by isolating carriers to reduce transmission, and implementing antibiotic stewardship measures targeting carriers to prevent progression to clinical illness. Several observational studies, summarized in this review, have reported implementing screening and isolation strategies, and found a reduction in CDI rates. Nevertheless, the data are still limited to a few observational studies, and this strategy is not commonly practiced. Studies supporting screening were performed in North America, coinciding with the period of dominance of the 027/BI/NAP1 strain. Additional studies evaluating screening, followed by infection control and antibiotic stewardship measures, are needed., (© 2023. The Author(s).)

Prevention of mpox has become an important public health interest. We aimed to evaluate the safety and immunogenicity of the Modified Vaccinia Ankara (MVA) vaccine. We conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) comparing MVA versus no intervention, placebo, or another vaccine. Outcomes included safety and immunogenicity outcomes. We also performed a systematic review of RCTs evaluating various MVA regimens. Fifteen publications were included in the quantitative meta-analysis. All but one (ACAM2000) compared MVA with placebo. We found that cardiovascular adverse events following two MVA doses were significantly more common compared to placebo (relative risk [RR] 4.07, 95% confidence interval [CI] 1.10-15.10), though serious adverse events (SAEs) were not significantly different. Following a single MVA dose, no difference was demonstrated in any adverse event outcomes. Seroconversion rates were significantly higher compared with placebo after a single or two doses. None of the RCTs evaluated clinical effectiveness in preventing mpox. This meta-analysis provides reassuring results concerning the immunogenicity and safety of MVA. Further studies are needed to confirm the immunogenicity of a single dose and its clinical effectiveness. A single vaccine dose may be considered according to vaccine availability, with preference for two doses.

Background: P. aeruginosa bacteremia is a common and severe infection carrying high mortality in older adults. We aimed to evaluate outcomes of P. aeruginosa bacteremia among old adults (≥ 80 years)., Methods: We included the 464/2394 (19%) older adults from a retrospective multinational (9 countries, 25 centers) cohort study of individuals hospitalized with P. aeruginosa bacteremia. Bivariate and multivariable logistic regression models were used to evaluate risk factors for 30-day mortality among older adults., Results: Among 464 adults aged ≥ 80 years, the mean age was 84.61 (SD 3.98) years, and 274 (59%) were men. Compared to younger patients, ≥ 80 years adults had lower Charlson score; were less likely to have nosocomial acquisition; and more likely to have urinary source. Thirty-day mortality was 30%, versus 27% among patients 65-79 years (n = 894) and 25% among patients < 65 years (n = 1036). Multivariate analysis for predictors of mortality among patients ≥ 80 years, demonstrated higher SOFA score (odds ratio [OR] 1.36, 95% confidence interval [CI] 1.23-1.51, p < 0.001), corticosteroid therapy (OR 3.15, 95% CI: 1.24-8.01, p = 0.016) and hospital acquired P. aeruginosa bacteremia (OR 2.30, 95% CI: 1.33-3.98, p = 0.003) as predictors. Appropriate empirical therapy within 24 h, type of definitive anti-pseudomonal drug, and type of regimen (monotherapy or combination) were not associated with 30-day mortality., Conclusions: In older adults with P. aeruginosa bacteremia, background conditions, place of acquisition, and disease severity are associated with mortality, rather than the antimicrobial regimen. In this regard, preventive efforts and early diagnosis before organ failure develops might be beneficial for improving outcomes., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: This is a systematic review and meta-analysis of diagnostic test accuracy studies to assess the predictive value of both tuberculin skin test (TST) and interferon-gamma release assays (IGRA) for active tuberculosis (TB) among solid organ transplantation (SOT) recipients., Methods: Medline, Embase, and the CENTRAL databases were searched from 1946 until June 30, 2022. Two independent assessors extracted data from studies. Sensitivity analyses were performed to investigate the effect of studies with high or low risk of bias. Methodological quality of each publication was assessed using QUADAS-2., Results: A total of 43 studies (36 403 patients) with patients who were screened for latent TB infection (LTBI) and who underwent SOT were included: 18 were comparative and 25 noncomparative (19 TST, 6 QuantiFERON-TB Gold In-Tube [QFT-GIT]). For IGRA tests taken together, positive predictive value (PPV) and negative predictive value (NPV) were 1.2% and 99.6%, respectively. For TST, PPV was 2.13% and NPV was 95.5%. Overall, PPV is higher when TB burden is higher, regardless of test type, although still low in absolute terms. Incidence of active TB was similar between studies using LTBI prophylaxis (mean incidence 1.22%; 95% confidence interval [CI], .2179-2.221) and those not using prophylaxis (mean incidence 1.045%; 95% CI, 0.2731-1.817; P = .7717). Strengths of this study include the large number of studies available from multiple different countries; limitations include absence of gold standard for diagnosis of latent TB and low incidence of active TB., Conclusions: We found both TST and IGRA had a low PPV and high NPV for the development of active TB posttransplant. Further studies are needed to better understand how to prevent active TB in the SOT population., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI., Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m 2 ). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model., Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88)., Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Previous studies demonstrated a 'weekend effect' and a 'night effect' of increased mortality among patients admitted during weekends or night shifts, presumably due to understaffing., Aims: To examine whether death during hospitalisation follows a similar effect regardless of admission time., Methods: A retrospective cohort study among deceased patients hospitalised in the internal medicine wing of a tertiary medical centre in Israel, between 2019 and 2020. Demographic and medical data were retrieved from electronic medical charts. Causes of death were specifically categorised. We applied statistical models to test for differences in mortality using incidence rate ratio (IRR) according to the day, time and cause of death., Results: One thousand, two hundred and seventy-eight deceased patients were included. All-cause mortality was similar between weekends and weekdays. When sepsis was the cause of death, higher IRR were demonstrated on Fridays in comparison with weekdays (IRR 1.4; 95% confidence interval (CI) 1.1-1.9; P < 0.05). Other causes of death were not consistent with a 'weekend effect'. Mortality during night shifts was higher in comparison with the afternoon (IRR 1.5; 95% CI 1.3-4.7) and similar to the morning (IRR 1; 95% CI 0.9-1.2)., Conclusion: Our study did not find a pattern of 'weekend effect' or 'night effect' on all-cause mortality among hospitalised patients in internal medicine wards. Our findings suggest that perhaps specifically death from sepsis, and not all-cause mortality, can be used as a surrogate for the measurement of understaffing or quality of care in the internal ward., (© 2022 Royal Australasian College of Physicians.)

We report an outbreak of Candida auris across multiple healthcare facilities in Israel. For the period of May 2014-May 2022, a total of 209 patients with C. auris infection or colonization were identified. The C. auris incidence rate increased 30-fold in 2021 (p = 0.00015), corresponding in time with surges of COVID-19-related hospitalization. Multilocus sequence typing revealed hospital-level outbreaks with distinct clones. A clade III clone, imported into Israel in 2016, accounted for 48.8% of typed isolates after January 2021 and was more frequently resistant to fluconazole (100% vs. 63%; p = 0.00017) and voriconazole (74% vs. 5.2%; p<0.0001) than were non-clade III isolates. A total of 23% of patients had COVID-19, and 78% received mechanical ventilation. At the hospital level, outbreaks initially involved mechanically ventilated patients in specialized COVID-19 units and then spread sequentially to ventilated non-COVID-19 patients and nonventilated patients.

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings., Competing Interests: The authors declare a conflict of interest. E.D.M. reports grants and/or personal fees from Pfizer, M.S.D., Rosh, Anglini, Nordic Pharma, and Sanofi-Aventis. G.L.D. reports grants and/or personal fees from Pfizer, Menarini, and M.S.D. K.S.K. reports grants and/or personal fees from Spero Therapeutics, Q.P.E.X., and MicuRx. M.P. reports grants and/or personal fees from Shionogi and Pfizer. Y.C. reports grants and/or personal fees from Allecra Therapeutics, Genentech, Nabriva Therapeutics, Pfizer, PPD, Q.P.E.X. Biopharma, Roche Pharmaceuticals, Spero Therapeutics, VenatoRX Pharmaceuticals. All other authors have no interests to declare.

Introduction: The effect of remdesivir on COVID-19 mortality remains conflicting. Elderly individuals are at risk for poor COVID-19 outcomes. We aimed to assess the effect of remdesivir on COVID-19 mortality among elderly individuals, using real-world data., Methods: Retrospective multinational cohort of individuals aged ≥65 years, hospitalized with COVID-19 in six medical centres between January 2020 and May 2021. Associations with in-hospital mortality were evaluated using a multivariable logistic regression model with propensity score adjustment for remdesivir therapy and while implementing generalized estimating equations to control for centre effect. Sensitivity analysis was performed by stratification according to the degree of respiratory support., Results: Of 3010 individuals included, 2788 individuals required either oxygen supplementation or non-invasive/invasive mechanical ventilation, 489 (16%) were treated with remdesivir, and 836 (28%) died. Median age was 77 (IQR 70-84) years and 42% were women. Remdesivir was the only therapeutic intervention associated with decreased mortality [adjusted OR (aOR) 0.49, 95% CI 0.37-0.66, P < 0.001]. This protective effect was shown for individuals requiring oxygen support and non-invasive mechanical ventilation, while no association was found among individuals necessitating invasive mechanical ventilation.Risk factors for mortality included invasive ventilation (aOR 5.18, 95% CI 2.46-10.91, P < 0.001), higher serum creatinine (aOR 1.25, 95% CI 1.09-1.43, P = 0.001) and dyspnoea (aOR 1.40, 95% CI 1.07-1.84, P = 0.015) on presentation, and other non-modifiable factors, such as comorbidities., Conclusions: Among elderly individuals hospitalized with COVID-19, remdesivir carries survival benefit for those with moderate to severe disease. Its role among individuals with critical illness should be further assessed., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Microbiological diagnosis is central for adequate treatment of bone and joint infections. Culture-based methods have a limited diagnostic sensitivity and a long turnaround time (TAT). The objective of this study was to compare the diagnostic performance of BioFire Joint Infection Panel Investigational Use Only version (hereafter BioFire)-a sample-to-result multiplex PCR panel-with culture-based methods and 16S ribosomal RNA (rRNA) PCR and sequencing, when available., Methods: This study presents a retrospective analysis of a prospective validation study of the BioFire panel. Specimens were obtained from consecutive patients evaluated for suspected bone and joint infections and processed using culture, BioFire, and 16S rRNA PCR and sequencing. Final clinical diagnosis was used as the reference for definition of infection., Results: Samples, including synovial fluid, bone and periarticular tissue, were obtained from 57 patients, 39 of whom were finally diagnosed with a bone or joint infection. Cultures were positive in 27/39 infected patients and in 3/18 uninfected patients (sensitivity 69%, specificity 83%). BioFire was positive in 22/39 infected patients and in none of the uninfected patients (sensitivity 56%, specificity 100%). Sensitivity for PCR panel organisms was 92% (22/24) and sensitivity for organisms identified by any microbiological modality was 69% (22/32). Gram stain results were positive in 13/39 infected patients and in none of the uninfected patients (sensitivity 33%, specificity 100%). 16S rRNA was positive in 20/28 infected patients and in 0/12 uninfected patients (sensitivity 71%, specificity 100%). Net machine time for BioFire-1 h-was shorter than the mean TAT for Gram stain results, which was 4 h., Conclusion: BioFire offered equivalent diagnostic performance with superior TAT for bone and joint infections, compared with conventional methods., (© 2023. The Author(s).)

Background: Older adults and immunocompromised individulas are often excluded from vaccine trials., Aim: We hypothesised that during the coronavirus disease 2019 (COVID-19) pandemic, the proportion of trials excluding these patients decreased., Methods: Using the US Food and Drug Administration and and European Medicines Agency search engines, we identified all vaccines approved against pneumococcal disease, influenza (quadrivalent vaccines), and COVID-19 from 2011 to 2021. Study protocols were screened for direct and indirect age exclusion criteria and exclusion of immunocompromised individuals. In addition, we reviewed the studies with no explicit exclusion criteria and investigated the actual inclusion of those individuals., Results: We identified 2024 trial records; 1702 were excluded (e.g., use of other vaccine or risk group); and 322 studies were eligible for our review. Among the pneumococcal and influenza vaccine trials (n = 193), 81 (42%) had an explicit direct age exclusion, and 150 (78%) had an indirect age-related exclusion. In total, 163 trials (84%) trials were likely to exclude older adults. Among the COVID-19 vaccine trials (n = 129), 33 (26%) had direct age exclusion and 82 (64%) had indirect age exclusion; in total, 85 (66%) trials were likely to exclude older adults. Therefore was a 18% decrease in the proportion of trials with age-related exclusion between 2011 and 2021 (only influenza and pneumococcal vaccine trials) and 2020-2021 (only COVID-19 vaccine trials) (p = 0.014). In a sub-analysis assessing observational and randomised trials, the decrease was 25% and 9%, respectively. Immunocompromised individuals were included in 87 (45%) of the pneumococcal and influenza vaccine trials compared with 54 (42%) of the COVID-19 vaccine trials (p = 0.058)., Conclusions: During the COVID-19 pandemic, we found a decrease in the exclusion of older adults from vaccine trials but no significant change in the inclusion of immunocompromised individulas., (© 2023. The Author(s).)

Background: Management of infections due to carbapenemase-resistant Enterobacterales (CRE) in solid organ transplant (SOT) recipients remains a difficult challenge. The INCREMENT-SOT-CPE score has been specifically developed from SOT recipients to stratify mortality risk, but an external validation is lacking., Methods: Multicenter retrospective cohort study of liver transplant (LT) recipients colonized with CRE infection who developed infection after transplant over 7-year period. Primary endpoint was all-cause 30-day mortality from infection onset. A comparison between INCREMENT-SOT-CPE and other selected scores was performed. A two-level mixed effects logistic regression model with random effects for the center was fitted. Performance characteristics at optimal cut-point were calculated. Multivariable Cox regression analysis of risk factors for all-cause 30-day mortality was carried out., Results: Overall, 250 CRE carriers developed infection after LT and were analyzed. The median age was 55 years (interquartile range [IQR]: 46-62) and 157 were males (62.8%). All-cause 30-day mortality was 35.6%. A sequential organ failure assessment (SOFA) score ≥ 11 showed a sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 69.7%, 76.4%, 62.0%, 82.0%, and 74.0%, respectively. An INCREMENT-SOT-CPE ≥ 11 reported a sensitivity, specificity, PPV, NPV, and accuracy of 73.0%, 62.1%, 51.6%, 80.6% and 66.0%, respectively. At multivariable analysis acute renal failure, prolonged mechanical ventilation, INCREMENT-SOT-CPE score ≥ 11 and SOFA score ≥ 11 were independently associated with all-cause 30-day mortality, while a tigecycline-based targeted regimen was found to be protective., Conclusions: Both INCREMENT-SOT-CPE ≥ 11 and SOFA ≥ 11 were identified as strong predictors of all-cause 30-day mortality in a large cohort of CRE carriers developing infection after LT., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

Objective: To identify predictors of 30-day survival in elderly patients with coronavirus disease 2019 (COVID-19)., Methods: Retrospective cohort study including patients with COVID-19 aged ≥65 years hospitalized in six European sites (January 2020 to May 2021). Data on demographics, comorbidities, clinical characteristics, and outcomes were collected. A predictive score (FLAMINCOV) was developed using logistic regression. Regression coefficients were used to calculate the score. External validation was performed in a cohort including elderly patients from a major COVID-19 centre in Israel. Discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in the derivation and validation cohorts. Survival risk groups based on the score were derived and applied to the validation cohort., Results: Among 3010 patients included in the derivation cohort, 30-day survival was 74.5% (2242/3010). The intensive care unit admission rate was 7.6% (228/3010). The model predicting survival included independent functional status (OR, 4.87; 95% CI, 3.93-6.03), a oxygen saturation to fraction of inspired oxygen (SpO 2 /FiO 2 ) ratio of >235 (OR, 3.75; 95% CI, 3.04-4.63), a C-reactive protein level of <14 mg/dL (OR, 2.41; 95% CI, 1.91-3.04), a creatinine level of <1.3 (OR, 2.02; 95% CI, 1.62-2.52) mg/dL, and absence of fever (OR, 1.34; 95% CI, 1.09-1.66). The score was validated in 1174 patients. The FLAMINCOV score ranges from 0 to 15 and showed good discrimination in the derivation (AUC, 0.79; 95% CI, 0.77-0.81; p < 0.001) and validation cohorts (AUC, 0.79; 95% CI, 0.76-0.81; p < 0.001). Thirty-day survival ranged from 39.4% (203/515) to 95.3% (634/665) across four risk groups according to score quartiles in the derivation cohort. Similar proportions were observed in the validation set., Discussion: The FLAMINCOV score identifying elderly with higher or lower chances of survival may allow better triage and management, including intensive care unit admission/exclusion., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to characterize overlooked cases of patients with monkeypox infection in the 2022 outbreak., Methods: Clinical characteristics of 26 patients who were misdiagnosed with other diseases were described., Results: Of the 26 patients who were misdiagnosed, six (23%) were given a diagnosis of bacterial tonsillitis, six (23%) were diagnosed with primary syphilis, five (19.2%) with oral or genital herpes, and four (15.3%) with bacterial proctitis or anal abscess. The average time interval between missed and right diagnosis was 4.4 days. There was no difference in the missed cases between the early and the later month of the outbreak., Conclusion: Monkeypox might still be commonly overlooked, especially in patients presenting with fever and sore throat or solitary ulcer as sole manifestations., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Clinical investigations of long-term effects of coronavirus disease 2019 (COVID-19) are rarely translated to objective findings., Objectives: To assess the functional capacity of individuals reported on deconditioning that hampered their return to their pre-COVID routine., Methods: Assessment included the 6-minute walk test (6MWT) and the 30-second sit-to-stand test (30-STST). We compared the expected and observed scores using the Wilcoxon signed-rank test. Predictors of test scores were identified using linear regression models., Results: We included 49 individuals, of whom 38 (77.6%) were recovering from mild COVID-19. Twenty-seven (55.1%) individuals had a 6MWT score lower than 80% of expected. The average 6MWT scores were 129.5 ± 121.2 meters and 12.2 ± 5.0 repeats lower than expected scores, respectively (P < 0.001 for both). The 6MWT score was 107.3 meters lower for individuals with severe COVID-19 (P = 0.013) and rose by 2.7 meters per each 1% increase in the diffusing capacity of carbon monoxide (P = 0.007). The 30-STST score was 3.0 repeats lower for individuals who reported moderate to severe myalgia (P = 0.038)., Conclusions: Individuals with long COVID who report on deconditioning exhibit significantly decreased physical capacity, even following mild acute illness. Risk factors include severe COVID-19 and impaired diffusing capacity or myalgia during recovery.

Viridans group streptococci (VGS) bloodstream infection (BSI) in neutropenic patients can be a severe complication. A higher prevalence of vancomycin use has been reported due to reduced susceptibility to penicillin. We aimed to assess the impact on mortality of both penicillin minimal inhibitory concentration (MIC) and the use of vancomycin. We conducted a retrospective multicenter study including consecutive neutropenic patients with VGS BSI between 2007 and 2019. Univariable and multivariable analyses were conducted to evaluate risk factors for mortality, including penicillin susceptibility as an independent variable. Non-susceptibility to penicillin was defined as MIC ≥ 0.25. We included 125 neutropenic patients with VGS BSI. Mean age was 53 years and ~ 50% were women. Overall, 30-day mortality rate was 25/125 (20%), and 41 patients (33%) had a VGS isolate non-susceptible to penicillin. In univariable analysis, no significant association was demonstrated between penicillin non-susceptibility and mortality (9/25, 26% vs. 32/100, 32%, p = 0.81). Among patients with a non-susceptible strain, the use of vancomycin was not significantly associated with mortality (empirical, p = 0.103, or definitive therapy, p = 0.491). Factors significantly associated with increased mortality in multivariable analysis included functional status (ECOG > 1, adjusted odds ratio [aOR] 12.53, 95% CI 3.64-43.14; p < 0.0001); allogeneic transplantation (aOR 6.33, 95% CI 1.96-20.46; p = 0.002); and co-pathogen in blood cultures (aOR 3.99, 95% CI 1.34-11.89; p = 0.013). Among neutropenic hemato-oncological patients with VGS BSI, penicillin non-susceptibility and the use of vancomycin were not associated with mortality. Thus, vancomycin should not be used routinely as empirical therapy in neutropenic patients with suspected VGS BSI., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recruitment of patients with critical priority antimicrobial-resistant (AMR) bacteria into drug approval randomized controlled trials (RCTs) has not been successful to date. Approaching from the viewpoint of clinician-investigators and learning from the experience of AMR-focused investigator-initiated trials, we present suggestions to improve feasibility and efficiency of RCTs evaluating patients with severe infections caused by carbapenem-resistant Gram-negative or other AMR bacteria. Considerations address the trials' eligibility criteria, whether the focus of the trial is pathogen- or syndrome-targeted, trials' case report forms and monitoring, informed consent strategies for the recruitment of extremely ill patients, team dedication and incentives to run the trial and alternative trial designs. Evidence on the effects of new drugs against the AMR that these drugs target is weak and needs to be improved through better industry-academic collaboration, taking advantage of the different strengths of industry-led and investigator-initiated research., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Introduction: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial., Methods: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment., Results: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality., Conclusions: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking., (© 2022 S. Karger AG, Basel.)

Background: Although regulatory changes towards correcting the underrepresentation of women in randomized controlled trials (RCTs) occurred (National Institutes of Health 1994), concerns exist about whether an improvement is taking place. In this systematic review and meta-analysis, we aimed to assess the inclusion rates of women in recent RCTs and to explore the potential barriers for the enrollment of women., Methods: RCTs published in 2017 examining any type of intervention in adults were searched in PubMed and Cochrane Library. The following predefined medical fields were included: cardiovascular diseases, neoplasms, endocrine system diseases, respiratory tract diseases, bacterial and fungal infections, viral diseases, digestive system diseases, and immune system diseases. Studies were screened independently by two reviewers, and an equal number of studies was randomly selected per calendric month. The primary outcome was the enrollment rate of women, calculated as the number of randomized women patients divided by the total number of randomized patients. Rates were weighted by their inverse variance; statistical significance was tested using general linear models (GLM)., Results: Out of 398 RCTs assessed for eligibility, 300 RCTs were included. The enrollment rate of women in all the examined fields was lower than 50%, except for immune system diseases [median enrollment rate of 68% (IQR 46 to 81)]. The overall median enrollment rate of women was 41% (IQR 27 to 54). The median enrollment rate of women decreased with older age of the trials' participants [mean age of trials' participants ≤ 45 years: 47% (IQR 30-64), 46-55 years: 46% (IQR 33-58), 56-62 years: 38% (IQR 27-50), ≥ 63 years: 33% (IQR 20-46), p < 0.001]. Methodological quality characteristics showed no significant association with the enrollment rates of women. Out of the 300 included RCTs, eleven did not report on the number of included women. There was no significant difference between these studies and the studies included in the analysis., Conclusions: Women are being inadequately represented, in the selected medical fields analyzed in our study, in recent RCTs. Older age is a potential barrier for the enrollment of women in clinical trials. Low inclusion rates of elderly women might create a lack of crucial knowledge in the adverse effects and the benefit/risk profile of any given treatment. Factors that might hinder the participation of women should be sought and addressed in the design of the study., (© 2022. The Author(s).)

Objectives: To describe long-COVID symptoms among older adults and to assess the risk factors for two common long-COVID symptoms: fatigue and dyspnea., Methods: This is a multicenter, prospective cohort study conducted in Israel, Switzerland, Spain, and Italy. Individuals were included at least 30 days after their COVID-19 diagnosis. We compared long-COVID symptoms between elderly (aged >65 years) and younger individuals (aged 18-65 years) and conducted univariate and multivariable analyses for the predictors of long-COVID fatigue and dyspnea., Results: A total of 2333 individuals were evaluated at an average of 5 months (146 days [95% confidence interval 142-150]) after COVID-19 onset. The mean age was 51 years, and 20.5% were aged >65 years. Older adults were more likely to be symptomatic, with the most common symptoms being fatigue (38%) and dyspnea (30%); they were more likely to complain of cough and arthralgia and have abnormal chest imaging and pulmonary function tests. Independent risk factors for long-COVID fatigue and dyspnea included female gender, obesity, and closer proximity to COVID-19 diagnosis; older age was not an independent predictor., Conclusion: Older individuals with long-COVID have different persisting symptoms, with more pronounced pulmonary impairment. Women and individuals with obesity are at risk. Further research is warranted to investigate the natural history of long-COVID among the elderly population and to assess possible interventions aimed at promoting rehabilitation and well-being., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2022. Published by Elsevier Ltd.)

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.)

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes., Competing Interests: Potential conflicts of interest. A. M. is an employee of Berry Consultants LLC, in which capacity she is contracted as a consultant to numerous pharmaceutical and device companies on topics of statistical modeling and trial design, and reports grants and contracts unrelated to this work and consulting fees from Berry Consultants LLC. A. C. B. reports participation as a member of the CAMERA-2 data and safety monitoring board (DSMB) and as chair of the Skin Trial DSMB; a role as Vice President of the World Society of Pediatric Infectious Diseases and as Co-Chair, Australian and New Zealand Paediatric Infectious Diseases group of the Australasian Society of Infectious Diseases (ASID). D. L. P. reports grants or contracts made to institution and unrelated to this work from Shionogi, Merck, and Pfizer; consulting fees to author from Antimicrobial Resistance Action Fund and Spero Therapeutics; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events to author from Pfizer and Merck; support for attending meetings and/or travel to author from Pfizer; and an unpaid leadership or fiduciary role with ASID. J. A. R. reports contracts or grants paid to institution and unrelated to this work from the British Society of Antimicrobial Chemotherapy, bioMérieux, Pfizer, and QPEX; consulting fees paid to author from Gilead, Pfizer, Sandoz, Wolters Kluwer, Summit Pharma, and MSD; payment to author for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from MSD, Pfizer, and Cipla; an unpaid leadership or fiduciary role with Sepsis Clinical Care Standard, Australian Commission on Safety and Quality in Health Care, Consensus Guidelines on Prolonged Infusion of Beta-Lactam Antibiotics, American College of Clinical Pharmacy, Disease Modifying Treatment and Chemoprophylaxis, Australian National COVID-19 Clinical Evidence Taskforce, and Surviving Sepsis Guidelines. M. P. C. reports research support from the McGill Interdisciplinary Initiative in Infection and Immunity; research contracts from Cidara Therapeutics, Scynexis, and Amplyx; consulting fees as a scientific consultant for AstraZeneca; 3 pending patents (Methods for detecting tissue damage, graft-versus-host disease, and infections using cell-free DNA profiling; Methods for assessing the severity and progression of SARS-CoV-2 infections using cell-free DNA; and rapid identification of antimicrobial resistance and other microbial phenotypes using highly-multiplexed fluorescence in situ hybridization); stock options as a member of the scientific advisory board for GEn1E Lifesciences and Nomic Bio; and equity as co-founder of Kanvas Biosciences. R. J. L. is an employee of Berry Consultants, LLC, a statistical consulting firm that specializes in the design of adaptive and platform clinical trials. Berry Consultants received compensation for work included in the content of the submission. S. A. W. reports personal consulting fees from ClinicIQ pharma and Roche; an unpaid role as chair of Australian Clinical Trials Alliance; and stock and options with ClinicIQ. S. Y. C. T. reports a contract as a paid consultant for advice on clinical trial design, and consulting fees from Roivant Sciences as a paid consultant for advice on clinical trial design. T. C. L. reports research salary support from Fonds de Recherche Quebec–Sante, operating funds for other studies including CATCO from the CIHR; and operating funds for other studies from the McGill Interdisciplinary Institute Infection and Immunity. S. C. M. reports grants or contracts unrelated to this work from the HRC, and a nonremunerated role as the Chair of the New Zealand Microbiology Network. 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.)

Background: Fatigue is the most prevalent and debilitating long-COVID (coronavirus disease) symptom; however, risk factors and pathophysiology of this condition remain unknown. We assessed risk factors for long-COVID fatigue and explored its possible pathophysiology., Methods: This was a nested case-control study in a COVID recovery clinic. Individuals with (cases) and without (controls) significant fatigue were included. We performed a multidimensional assessment evaluating various parameters, including pulmonary function tests and cardiopulmonary exercise testing, and implemented multivariable logistic regression to assess risk factors for significant long-COVID fatigue., Results: A total of 141 individuals were included. The mean age was 47 (SD: 13) years; 115 (82%) were recovering from mild coronavirus disease 2019 (COVID-19). Mean time for evaluation was 8 months following COVID-19. Sixty-six (47%) individuals were classified with significant long-COVID fatigue. They had a significantly higher number of children, lower proportion of hypothyroidism, higher proportion of sore throat during acute illness, higher proportions of long-COVID symptoms, and of physical limitation in daily activities. Individuals with long-COVID fatigue also had poorer sleep quality and higher degree of depression. They had significantly lower heart rate [153.52 (22.64) vs 163.52 (18.53); P = .038] and oxygen consumption per kilogram [27.69 (7.52) vs 30.71 (7.52); P = .036] at peak exercise. The 2 independent risk factors for fatigue identified in multivariable analysis were peak exercise heart rate (OR: .79 per 10 beats/minute; 95% CI: .65-.96; P = .019) and long-COVID memory impairment (OR: 3.76; 95% CI: 1.57-9.01; P = .003)., Conclusions: Long-COVID fatigue may be related to autonomic dysfunction, impaired cognition, and decreased mood. This may suggest a limbic-vagal pathophysiology., Clinical Trials Registration: NCT04851561., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: We aimed to review the current state, challenges, and needs of antimicrobial stewardship programs (ASPs) in adult solid organ transplantation (SOT) centers in Israel., Methods: We conducted a survey using electronic questionnaires sent during February 2022 to infectious disease (ID) consultants of SOT centers, encompassing general and organ-specific ASP issues., Results: All six centers performing adult SOTs in Israel participated. The institutional ASPs in all centers included SOT recipients, and five centers had specific stewardship activities targeting SOT recipients. ASP activities were performed by ID consultants in all centers, with clinical pharmacists in most. ASP protocols and activity scope were highly variable. Formulary restriction with pre-authorization was used in all centers. Antibiotic allergy was addressed in ASP guidelines in half of the centers. Peri-transplantation antibiotic, antifungal, and antiviral prophylactic regimens varied based on center, transplanted organ, and patient risk group. Approaches to surveillance cultures, diagnosis and treatment of various graft infections were also variable. ASP outcome measurement was not performed in all centers. The main challenges and barriers to successful ASP implementation were difficulty in defining appropriate durations of therapy for certain infections, high rates of antimicrobial resistance (AMR), and lack of dedicated ASP teams., Conclusion: Antimicrobial stewardship in SOT centers in Israel is performed by ID consultants and practices vary. Challenges are related to high AMR rates, insufficient evidence to support practices, lack of dedicated ASP teams, and lack of outcome measurement. There is an urgent need to establish a national collaborative program including all SOT centers., (© 2022 Wiley Periodicals LLC.)

Introduction: There is no consensus regarding optimal duration of antibiotic therapy for Pseudomonas aeruginosa bacteremia. We aimed to evaluate the impact of short antibiotic course., Methods: We present a retrospective multicenter study including patients with P. aeruginosa bacteremia during 2009-2015. We evaluated outcomes of patients treated with short (6-10 days) versus long (11-15 days) antibiotic courses. The primary outcome was a composite of 30-day mortality or bacteremia recurrence and/or persistence. Univariate and inverse probability treatment-weighted (IPTW) adjusted multivariate analysis for the primary outcome was performed. To avoid immortal time bias, the landmark method was used., Results: We included 657 patients; 273 received a short antibiotic course and 384 a long course. There was no significant difference in baseline characteristics of patients. The composite primary outcome occurred in 61/384 patients in the long-treatment group (16%) versus 32/273 in the short-treatment group (12%) (p = 0.131). Mortality accounted for 41/384 (11%) versus 25/273 (9%) of cases, respectively. Length of hospital stay was significantly shorter in the short group [median 13 days, interquartile range (IQR) 9-21 days, versus median 15 days, IQR 11-26 days, p = 0.002]. Ten patients in the long group discontinued antibiotic therapy owing to adverse events, compared with none in the short group. On univariate and multivariate analyses, duration of therapy was not associated with the primary outcome., Conclusions: In this retrospective study, 6-10 days of antibiotic course for P. aeruginosa bacteremia were as effective as longer courses in terms of survival and recurrence. Shorter therapy was associated with reduced length of stay and less drug discontinuation., (© 2022. The Author(s).)