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In 2002, Shlaes and Moellering warned that pharmaceutical companies were abandoning antibiotic research and development due to changing regulatory standards regarding noninferiority (NI) clinical trials. NI trials are subject to unique biases that may yield false-positive conclusions. The US Food and Drug Administration (FDA) developed guidance to ensure that NI results truly reflect drug efficacy. These changes, intended to reduce uncertainty in trial results, have shaped trial enrollment and conduct in ways that now require reflection.

Iron acquisition is a virulence factor for Staphylococcus aureus. We assessed the efficacy of the iron chelator, deferasirox (Def), alone or in combination with vancomycin (Van) against two methicillin-resistant S. aureus (MRSA) strains in vitro and in a murine bacteremia model. In vitro time-kill assays were carried out against MRSA or vancomycin-intermediate S. aureus (VISA) strains. The impact of Def on Van binding to the surface of S. aureus was measured by flow cytometry. Furthermore, we compared the efficacy of Def, Van, or both drugs in treating S. aureus bacteremia in a murine model. Combination therapy reduced MRSA and VISA viability in vitro versus either drug alone or untreated controls (p < 0.005); this outcome was correlated with enhanced Van surface binding to S. aureus cells. In vivo, Def + Van combination therapy significantly reduced the bacterial burden in mice kidneys (p = 0.005) and spleen (p < 0.001), and reduced the severity of infection with MRSA or VISA strains compared to placebo-treated mice. Our results show that Def enhances the in vitro and in vivo capacity of Van-mediated MRSA killing via a mechanism that appears to involve increased binding of Van to the staphylococcal surface. Iron chelation is a promising, novel adjunctive therapeutic strategy for MRSA and VISA infections.

Objectives: Host iron availability is fundamental to mucormycosis pathogenesis. The combination of liposomal amphotericin B (LAmB) and deferasirox iron chelation therapy synergistically improved survival in diabetic mice with mucormycosis. To determine the safety of combination deferasirox plus LAmB therapy for mucormycosis, a multicentred, placebo-controlled, double-blinded clinical trial was conducted.Methods: Twenty patients with proven or probable mucormycosis were randomized to receive treatment with LAmB plus deferasirox (20 mg/kg/day for 14 days) or LAmB plus placebo (NCT00419770, clinicaltrials.gov). The primary analyses were for safety and exploratory efficacy.Results: Patients in the deferasirox arm (n=11) were more likely than those in the placebo arm (n=9) to have active malignancy, neutropenia and corticosteroid therapy, and were less likely to receive concurrent non-study antifungal therapy. Reported adverse events and serious adverse events were similar between the groups. However, death was more frequent in the deferasirox than in the placebo arm at 30 days (45% versus 11%, P=0.1) and 90 days (82% versus 22%, P=0.01). Global success (alive, clinically stable, radiographically improved) for the deferasirox arm versus the placebo arm at 30 and 90 days, respectively, was 18% (2/11) versus 67% (6/9) (P=0.06) and 18% (2/11) versus 56% (5/9) (P=0.2).Conclusions: Patients with mucormycosis treated with deferasirox had a higher mortality rate at 90 days. Population imbalances in this small Phase II study make generalizable conclusions difficult. Nevertheless, these data do not support a role for initial, adjunctive deferasirox therapy for mucormycosis. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases," from the January 21, 1999 issue.

Importance: Recent evolutions in clinical care and remote monitoring suggest that some acute illnesses no longer require intravenous therapy and inpatient hospitalization., Objective: To describe outcomes of patients receiving care in a new, outpatient, virtual, home-based acute care model called Safer@Home., Design, Setting, and Participants: This retrospective cohort analysis, conducted from September 1, 2022, through August 31, 2023, included 2466 patients treated at a safety net hospital in Los Angeles County for 10 core illnesses and 24 other acute illnesses for which patients are commonly hospitalized., Exposure: Outpatient, home-based, acute care with virtual monitoring and clinic visits in lieu of inpatient or in-home care., Main Outcomes and Measures: The primary measure was hospital length of stay. Secondary measures included all-cause mortality, 30-day readmission, return urgent care visit rates, and return emergency department (ED) visit rates., Results: Safer@Home provided care to 876 patients (mean [SD] age, 54.0 [14.5] years; 541 men [61.8%]) during the study period, compared with a cohort of 1590 patients (mean [SD] age, 52.3 [19.6] years; 901 men [56.7%]) with matching diagnoses who received standard, hospital-based care. Safer@Home patients had significantly shorter mean (SD) lengths of inpatient stay than the comparison cohort (1.3 [2.0] vs 5.3 [10.4] days; P < .001), totaling 3505 bed-days avoided (mean [SD], 4.0 [10.6] bed-days saved per patient), with no significant difference in all-cause mortality at last follow-up (2.6% [23 of 876] vs 4.0% [64 of 1590]; P = .07). Safer@Home patients and control patients also had no significant difference in the proportion experiencing 30-day hospital readmission (19.9% [174 of 876] vs 16.7% [266 of 1590]; P = .06). As intended, more Safer@Home than control patients had at least one 30-day return urgent care visit (37.3% [327 of 876] vs 5.2% [82 of 1590]; P < .001). In contrast, the Safer@Home and control cohorts did not significantly differ in experiencing at least one 30-day return ED visit (15.2% [133 of 876] vs 12.5% [199 of 1590]; P = .06). Safer@Home patients had significantly fewer mean (SD) total 30-day return ED visits per patient than control patients (0.19 [0.50] vs 0.21 [0.85]; P < .001)., Conclusions and Relevance: In this cohort study, patients receiving acute, virtual, home care with remote monitoring and as-needed return urgent care visits had markedly shorter hospital stays than patients receiving standard inpatient hospital care, with no significant increase in mortality, ED revisits, or return hospitalizations. This new care model is promising for systems that cannot staff Medicare-compliant hospital-at-home visits.

Importance: Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence., Objective: To create a clinical guideline for the diagnosis and management of urinary tract infections that addresses the gap between the evidence and recommendation strength., Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In May 2023, new and existing members were solicited for questions on urinary tract infection prevention, diagnosis, and management. For each topic, literature searches were conducted up until early 2024 in any language. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were developed discussing the available literature and associated risks and benefits of various approaches., Findings: A total of 54 members representing 12 countries reviewed 914 articles and submitted information relevant to 5 sections: prophylaxis and prevention (7 questions), diagnosis and diagnostic stewardship (7 questions), empirical treatment (3 questions), definitive treatment and antimicrobial stewardship (10 questions), and special populations and genitourinary syndromes (10 questions). Of 37 unique questions, a clear recommendation could be provided for 6 questions. In 3 of the remaining questions, a clear recommendation could only be provided for certain aspects of the question. Clinical reviews were generated for the remaining questions and aspects of questions not meeting criteria for a clear recommendation., Conclusions and Relevance: In this consensus statement that applied the WikiGuidelines method for clinical guideline development, the majority of topics relating to prevention, diagnosis, and treatment of urinary tract infections lack high-quality prospective data and clear recommendations could not be made. Randomized clinical trials are underway to address some of these gaps; however further research is of utmost importance to inform true evidence-based, rather than eminence-based practice.

The emergence of plasmid-mediated resistance threatens the efficacy of polymyxins as the last line of defense against pan-drug-resistant infections. However, we have found that using Mueller-Hinton II (MHII), the standard minimum inhibitory concentration (MIC) medium, results in MIC data that are disconnected from in vivo treatment outcomes. We found that culturing putative colistin-resistant Acinetobacter baumannii clinical isolates, as defined by MICs of >2 mg/L in standard MHII testing conditions, in bicarbonate-containing media reduced MICs to the susceptible range by preventing colistin resistance-conferring lipopolysaccharide modifications from occurring. Furthermore, the lower MICs in bicarbonate-containing media accurately predicted in vivo efficacy of a human-simulated dosing strategy of colistin and polymyxin B in a lethal murine infection model for some polymyxin-resistant A. baumannii strains. Thus, current polymyxin susceptibility testing methods overestimate the contribution of polymyxin resistance-conferring mutations and incorrectly predict antibiotic activity in vivo . Polymyxins may remain a viable therapeutic option against Acinetobacter baumannii strains heretofore determined to be "pan-resistant.", Competing Interests: The authors declare no conflict of interest.

Competing Interests: The authors have no funding or conflicts of interest to disclose.

Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii . Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles., Competing Interests: The authors declare no conflict of interest.

With antimicrobial resistance (AMR) emerging as a major threat to global health, monoclonal antibodies (MAbs) have become a promising means to combat difficult-to-treat AMR infections. Unfortunately, in contrast with standard antimicrobials, for which there are well-validated clinical laboratory methodologies to determine whether an infecting pathogen is susceptible or resistant to a specific antimicrobial drug, no assays have been described that can inform clinical investigators or clinicians regarding the clinical efficacy of a MAb against a specific pathogenic strain. Using Acinetobacter baumannii as a model organism, we established and validated 2 facile clinical susceptibility assays, which used flow cytometry and latex bead agglutination, to determine susceptibility (predicting in vivo efficacy) or resistance (predicting in vivo failure) of 1 newly established and 3 previously described anti-A. baumannii MAbs. These simple assays exhibited impressive sensitivity, specificity, and reproducibility, with clear susceptibility breakpoints that predicted the in vivo outcomes in our preclinical model with excellent fidelity. These MAb susceptibility assays have the potential to enable and facilitate clinical development and deployment of MAbs that generally target the surface of microbes.

Background: Based on multiple randomized-controlled clinical trials, shorter antibiotic courses are equally effective as traditional longer courses for many types of infections. However, longer courses are still being used widely in the clinical practice., Objectives: To describe four components involved in the successful implementation of shorter antibiotic courses in our health care institutions, including an academic, public hospital and a community hospital staffed primarily by private practitioners., Sources: Clinical trials and peer-reviewed publications., Content: We provide practical advice on how to support the change in clinical practice to shorten antibiotic duration. Specifically, we list the steps that we have successfully used to develop and implement an institutional practice change regarding the duration of antibiotic therapy: (a) establishing consensus documents outlining a data-driven expected practice for using antibiotics, (b) antibiotic stewardship programme support, (c) provider education, and (d) reinforcing behaviour through psychological and other tools. The implementation of these processes has successfully led to shorter antibiotic courses and decreased antibiotic use in our diverse practice settings., Implications: Intentional improvement in decreasing the duration of antibiotic therapy can be achieved by a specific antibiotic stewardship programme strategy and tactics. The implementation of shorter antibiotic courses has effects at individual and societal levels in an era of increasing antibacterial resistance and health care costs., (Copyright © 2022 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Traditional vaccines are difficult to deploy against the diverse antimicrobial-resistant, nosocomial pathogens that cause health care-associated infections. We developed a protein-free vaccine composed of aluminum hydroxide, monophosphoryl lipid A, and fungal mannan that improved survival and reduced bacterial burden of mice with invasive blood or lung infections caused by methicillin-resistant Staphylococcus aureus , vancomycin-resistant Enterococcus faecalis , extended-spectrum beta-lactamase-expressing Escherichia coli , and carbapenem-resistant strains of Acinetobacter baumannii , Klebsiella pneumoniae , and Pseudomonas aeruginosa. The vaccine also conferred protection against the fungi Rhizopus delemar and Candida albicans . Efficacy was apparent by 24 hours and lasted for up to 28 days after a single vaccine dose, with a second dose restoring efficacy. The vaccine acted through stimulation of the innate, rather than the adaptive, immune system, as demonstrated by efficacy in the absence of lymphocytes that were abrogated by macrophage depletion. A role for macrophages was further supported by the finding that vaccination induced macrophage epigenetic alterations that modulated phagocytosis and the inflammatory response to infection. Together, these data show that this protein-free vaccine is a promising strategy to prevent deadly antimicrobial-resistant health care-associated infections.

Objectives: Physician pay-for-performance (P4P) programs frequently target inappropriate antibiotics. Yet little is known about P4P programs' effects on antibiotic prescribing among safety-net populations at risk for unintended harms from reducing care. We evaluated effects of P4P-motivated interventions to reduce antibiotic prescriptions for safety-net patients with acute respiratory tract infections (ARTIs)., Study Design: Interrupted time series., Methods: A nonrandomized intervention (5/28/2015-2/1/2018) was conducted at 2 large academic safety-net hospitals: Los Angeles County+University of Southern California (LAC+USC) and Olive View-UCLA (OV-UCLA). In response to California's 2016 P4P program to reduce antibiotics for acute bronchitis, 5 staggered Choosing Wisely-based interventions were launched in combination: audit and feedback, clinician education, suggested alternatives, procalcitonin, and public commitment. We also assessed 5 unintended effects: reductions in Healthcare Effectiveness Data and Information Set (HEDIS)-appropriate prescribing, diagnosis shifting, substituting antibiotics with steroids, increasing antibiotics for ARTIs not penalized by the P4P program, and inappropriate withholding of antibiotics., Results: Among 3583 consecutive patients with ARTIs, mean antibiotic prescribing rates for ARTIs decreased from 35.9% to 22.9% (odds ratio [OR], 0.60; 95% CI, 0.39-0.93) at LAC+USC and from 48.7% to 27.3% (OR, 0.81; 95% CI, 0.70-0.93) at OV-UCLA after the intervention. HEDIS-inappropriate prescribing rates decreased from 28.9% to 19.7% (OR, 0.69; 95% CI, 0.39-1.21) at LAC+USC and from 40.9% to 12.5% (OR, 0.72; 95% CI, 0.59-0.88) at OV-UCLA. There was no evidence of unintended consequences., Conclusions: These real-world multicomponent interventions responding to P4P incentives were associated with substantial reductions in antibiotic prescriptions for ARTIs in 2 safety-net health systems without unintended harms.

Background: We sought to compare the outcomes of patients treated with intravenous (IV)-only vs oral transitional antimicrobial therapy for infective endocarditis (IE) after implementing a new expected practice within the Los Angeles County Department of Health Services (LAC DHS)., Methods: We conducted a multicentered, retrospective cohort study of adults with definite or possible IE treated with IV-only vs oral therapy at the 3 acute care public hospitals in the LAC DHS system between December 2018 and June 2022. The primary outcome was clinical success at 90 days, defined as being alive and without recurrence of bacteremia or treatment-emergent infectious complications., Results: We identified 257 patients with IE treated with IV-only (n = 211) or oral transitional (n = 46) therapy who met study inclusion criteria. Study arms were similar for many demographics; however, the IV cohort was older, had more aortic valve involvement, were hemodialysis patients, and had central venous catheters present. In contrast, the oral cohort had a higher percentage of IE caused by methicillin-resistant Staphylococcus aureus. There was no significant difference between the groups in clinical success at 90 days or last follow-up. There was no difference in recurrence of bacteremia or readmission rates. However, patients treated with oral therapy had significantly fewer adverse events. Multivariable regression adjustments did not find significant associations between any selected variables and clinical success across treatment groups., Conclusions: These results demonstrate similar outcomes of real-world use of oral vs IV-only therapy for IE, in accord with prior randomized, controlled trials and meta-analyses., Competing Interests: Potential conflicts of interests. N. W. D. reports receipt of a speaker’s fee for IDWeek 2022, funded by a collaboration of societies that help fund IDWeek, including Infectious Diseases Society of America, The Society of Healthcare Epidemiology of America, HIV Medicine Association, Pediatric Infectious Diseases Society, and Society of Infectious Diseases Pharmacists. All remaining authors: No reported conflicts of interest. 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The belief that antibiotics must be administered intravenously (IV) to treat bacteraemia and endocarditis has its origins 70 years ago and has engrained itself in the psyche of the medical community and the public at large. This has led to hesitancy in adopting evidence-based strategies utilizing oral transitional therapy for the treatment of these infections. We aim to reframe the narrative around this debate, focusing on patient safety over vestigial psychology., Objectives: This narrative review summarizes the current state of the literature regarding the use of oral transitional therapy for the treatment of bacteraemia and infective endocarditis, focusing on studies comparing it to the traditional, IV-only approach., Sources: Relevant studies and abstracts from PubMed reviewed in April 2023., Content: Treating bacteraemia with oral transitional therapy has been studied in 9 randomized controlled trials (RCTs), totalling 625 patients, as well as numerous large, retrospective cohorts, including 3 published in the last 5 years alone, totalling 4763 patients. We identified 3 large, retrospective cohort studies; one quasi-experimental, pre-post study, and 3 RCTs of patients with endocarditis, totalling 748 patients in the retrospective cohorts and 815 patients in prospective, controlled studies. In all these studies, no worse outcomes were observed in the oral transitional therapy arm as compared with IV-only therapy. The main difference has consistently been longer durations of inpatient hospitalization and increased risk of catheter-related adverse events like venous thrombosis and line-associated blood stream infections in the IV-only groups., Implications: There are ample data showing that choosing oral therapy reduces hospital stay and has fewer adverse events for patients than IV-only therapy, all with similar or better outcomes. In selected patients, choosing IV-only therapy may serve more as an anxiolytic "placebo" for the patient and provider rather than a necessity for treating the actual infection., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Importance: Practice guidelines often provide recommendations in which the strength of the recommendation is dissociated from the quality of the evidence., Objective: To create a clinical guideline for the diagnosis and management of adult bacterial infective endocarditis (IE) that addresses the gap between the evidence and recommendation strength., Evidence Review: This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In April 2022 a call to new and existing members was released electronically (social media and email) for the next WikiGuidelines topic, and subsequently, topics and questions related to the diagnosis and management of adult bacterial IE were crowdsourced and prioritized by vote. For each topic, PubMed literature searches were conducted including all years and languages. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were crafted discussing the risks and benefits of different approaches., Findings: A total of 51 members from 10 countries reviewed 587 articles and submitted information relevant to 4 sections: establishing the diagnosis of IE (9 questions); multidisciplinary IE teams (1 question); prophylaxis (2 questions); and treatment (5 questions). Of 17 unique questions, a clear recommendation could only be provided for 1 question: 3 randomized clinical trials have established that oral transitional therapy is at least as effective as intravenous (IV)-only therapy for the treatment of IE. Clinical reviews were generated for the remaining questions., Conclusions and Relevance: In this consensus statement that applied the WikiGuideline method for clinical guideline development, oral transitional therapy was at least as effective as IV-only therapy for the treatment of IE. Several randomized clinical trials are underway to inform other areas of practice, and further research is needed.

Recently, we reported rifabutin hyper-activity against Acinetobacter baumannii. We sought to characterize if any additional rifamycins (n = 22) would also display hyper-activity when tested in iron-limited media against A. baumannii, K. pneumoniae, and E. coli. MICs were determined against representative clinical isolates using the iron-limited media RPMI-1640. Only rifabutin was hyperactive against A. baumannii., Competing Interests: Authors BL and BS are inventors on a patent for rifabutin therapy for A. baumannii infections and own equity in ExBaq, which has licensed the technology for development. The University of Southern California owns intellectual property related to these development efforts. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Lu 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.)

Polymyxin B is a "last-line-of-defense" antibiotic approved in the 1960s. However, the population pharmacokinetics (PK) of its four main components has not been reported in infected mice. We aimed to determine the PK of polymyxin B1, B1-Ile, B2, and B3 in a murine bloodstream and lung infection model of Acinetobacter baumannii and develop humanized dosage regimens. A linear 1-compartment model, plus an epithelial lining fluid (ELF) compartment for the lung model, best described the PK. Clearance and volume of distribution were similar among the four components. The bioavailability fractions were 72.6% for polymyxin B1, 12.0% for B1-Ile, 11.5% for B2, and 3.81% for B3 for the lung model and were similar for the bloodstream model. While the volume of distribution was comparable between both models (17.3 mL for the lung and ~27 mL for the bloodstream model), clearance was considerably smaller for the lung (2.85 mL/h) compared to that of the bloodstream model (5.59 mL/h). The total drug exposure (AUC) in ELF was high due to the saturable binding of polymyxin B presumably to bacterial lipopolysaccharides. However, the modeled unbound AUC in ELF was ~16.7% compared to the total drug AUC in plasma. The long elimination half-life (~4 h) of polymyxin B enabled humanized dosage regimens with every 12 h dosing in mice. Daily doses that optimally matched the range of drug concentrations observed in patients were 21 mg/kg for the bloodstream and 13 mg/kg for the lung model. These dosage regimens and population PK models support translational studies for polymyxin B at clinically relevant drug exposures., Competing Interests: The authors declare no conflict of interest.

Background: We previously reported developing 2 anticapsular monoclonal antibodies (mAbs) as a novel therapy for Acinetobacter baumannii infections. We sought to determine whether a bispecific mAb (bsAb) could improve avidity and efficacy while maximizing strain coverage in one molecule., Methods: Humanized mAb 65 was cloned into a single-chain variable fragment and attached to humanized mAb C8, combining their paratopes into a single bsAb (C73). We tested bsAb C73's strain coverage, binding affinity, ex vivo opsonic activity, and in vivo efficacy compared to each mAb alone and combined., Results: The bsAb demonstrated strain coverage, binding affinity, opsonization, and in vivo efficacy superior to either original mAb alone or combined., Conclusions: A humanized bsAb targeting distinct A. baumannii capsule moieties enabled potent and effective coverage of disparate A. baumannii clinical isolates. The bsAb enhances feasibility of development by minimizing the number of components of a promising novel therapeutic for these difficult-to-treat infections., Competing Interests: Potential conflicts of interest . T. B. N. and B. S. are inventors on patents related to monoclonal antibodies C8 and 65. T. B. N., J. Y., B. M. L., and B. S. are inventors on a patent related to bispecific monoclonal antibody C73. T. B. N. and B. S. own equity in BioAIM, which is developing the antibodies. U. S. C. has an ownership interest in BioAIM and is entitled to a share of royalties based on a licensing agreement with BioAIM. 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) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Acinetobacter baumannii is an extremely drug-resistant pathogen necessitating the development of new therapies. We seek to generate a cocktail of monoclonal antibodies (MAbs) that can target the full diversity of A. baumannii isolates. We have newly identified the antibody MAb5. Here, we demonstrate that MAb5 has broad binding against U.S. ( n  = 300) and international ( n  = 250) isolates (72.24% and 28.76%, respectively), likely targets O-antigen capsular carbohydrates, and exhibits protective efficacy in vivo .

A large community hospital sought to reduce its burden of hospital-acquired Clostridioides difficile infection (CDI). We implemented an antimicrobial stewardship program (ASP), resulting in marked reductions in unnecessary antimicrobial use, CDI rates, antimicrobial acquisition costs, with preservation of gram-negative susceptibilities. ASP programs are effective in a community setting.

Introduction: Mucormycosis is an opportunistic fungal infection with a high mortality rate. Though typically associated with diabetes and other conditions that affect innate immune function, infections can also be precipitated by conditions such as trauma and burns. Burn patients are particularly susceptible to fungal infections due to the immune dysfunction that often accompany their wounds. Indeed case series have described mucormycosis to occur in patients with burn injuries, however the factors contributing to mortality have not been well described. Thus, the purpose of our review was to identify factors contributing to morbidity and mortality in burn patients with Mucormycosis., Methods: A systematic review of the literature of mucormycosis infection in burn injury patients was performed on Pubmed and Google Scholar using the keywords: Mucor, Mucorales, Mucormycosis, Mucormycotina, Zygomycosis and burn or thermal injury. Clinical trials, observational studies, case reports, and case reviews were included if they provided information regarding mortality in adult and pediatric burn patients diagnosed with mucormycosis, review articles, non-English articles, and articles without patient information were excluded. No time limit was placed on our review. Individual patient data was stratified based on mortality. Statistical analysis was performed to investigate the relationship between patient risk factors and mortality, and the Oxford Level of Evidence was used to evaluate study quality., Results: 46 articles were included in our final review, encompassing 114 patients. On average, survivors had a total body surface area (TBSA)% of 46 (SD 19.8) while non-survivors had a TBSA of 65% (SD 16.4), and this difference was significant (p < .001). Patients with disseminated mucormycosis experienced an 80% mortality rate compared to 36% mortality rate in patients with localized disease (p < .001). We found no statistically significant difference in mean age (p > .05), diabetes (p > .05), mean delay in diagnosis (p > .05), time to antifungal therapy (p > .05), or type of therapy used (p > .05) between survivors and non-survivors. Our review was limited by the lack of prospective, controlled trials; thus, our review primarily consists of case reports., Conclusion: Disseminated infections and higher TBSA both increased the risk of mortality in burn patients with mucormycosis, while diabetes did not increase mortality risk. The severity of the initial injury and infection locations must be taken into consideration to inform patient prognosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Over the past 25 years, researchers have performed >120 randomized controlled trials (RCTs) illustrating short courses to be non-inferior to long courses of antibiotics for common bacterial infections., Objective: We sought to determine whether clinical data from RCTs affirm the mantra of 'shorter is better' for antibiotic durations in 7 common infections: pneumonia, urinary tract infection, intra-abdominal infection, bacteraemia, skin and soft tissue infection, bone and joint infections, pharyngitis and sinusitis., Sources: Published RCTs comparing short- versus long-course antibiotic durations were identified through searches of PubMed and clinical guideline documents., Content: Short-course antibiotic durations consistently result in similar treatment success rates as longer antibiotic courses among patients with community-acquired pneumonia, complicated urinary tract infections in women, gram-negative bacteraemia, and skin and soft tissue infections when the diagnosis is confirmed, appropriate antimicrobials are used, and patients show clinical signs of improvement. For patients with osteomyelitis, 6 weeks of antibiotics is adequate for the treatment of osteomyelitis in the absence of implanted foreign bodies and surgical debridement. Whether durations can be further shortened with debridement is unclear, although small studies are promising., Implications: With few exceptions, short courses were non-inferior to long courses; future research should focus on appropriately defining the patient population, ensuring the correct choice and dose of antimicrobials and developing meaningful outcomes relevant for frontline clinicians., (Published by Elsevier Ltd.)

Antimicrobial susceptibility testing (AST) in RPMI 1640, a more physiologically relevant culture medium, revealed that a substantial proportion of carbapenem-resistant Acinetobacter baumannii isolates were susceptible to azithromycin, a macrolide antibiotic not currently considered effective against A. baumannii. Experiments using Galleria mellonella validated these in vitro data. Our finding that RPMI 1640's predictive accuracy for in vivo outcomes is superior to that of Mueller-Hinton II broth also supports the use of more physiologically relevant AST culturing conditions.

Importance: Recent changes in guidelines for managing Clostridioides difficile infections (CDI) have placed fidaxomicin as a first-line treatment., Objective: To estimate the net cost of first-line fidaxomicin compared to vancomycin in the American and Canadian healthcare systems and to estimate the price points at which fidaxomicin would become cost saving for the prevention of recurrence., Data Sources and Study Selection: We identified randomized, placebo-controlled trials directly comparing fidaxomicin with vancomycin that reported on recurrence. Medication costs were obtained from the Veterans Affairs Federal Supply Schedule (US) and the Quebec drug formulary (Canada). The average cost of a CDI recurrence was established through a systematic review for each country., Data Extraction Synthesis and Outcome Measures: For efficacy, data on CDI recurrence at day 40 were pooled using a restricted maximal likelihood random effects model. For the cost review, the mean cost across identified studies was adjusted to reflect May 2022 dollars. These were used to estimate the net cost per recurrence prevented with fidaxomicin and the price point below which fidaxomicin would be cost saving., Results: The estimated mean system costs of a CDI recurrence were $15 147USD and $8806CAD, respectively. Preventing one recurrence by using first-line fidaxomicin over vancomycin would cost $38 222USD (95%CI $30 577-$57 332) and $13 760CAD (95%CI $11 008-$20 640), respectively. The probability that fidaxomicin was cost saving exceeded 95% if priced below $1140USD or $860CAD, respectively., Conclusions and Relevance: An increased drug expenditure on fidaxomicin may not be offset through recurrence prevention unless the fidaxomicin price is negotiated., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Study Objective: To describe characteristics and outcomes of coronavirus disease (COVID-19) patients with new supplemental oxygen requirements discharged from a large public urban emergency department (ED) with supplemental oxygen., Methods: This observational case series describes the characteristics and outcomes of 360 consecutive COVID-19 patients with new supplemental oxygen requirements discharged from a large urban public ED between April 2020 and March 2021 with supplemental oxygen. Primary outcomes included 30-day survival and 30-day survival without unscheduled inpatient admission. Demographic and clinical data were collected through a structured chart review., Results: Among 360 patients with COVID-19 discharged from the ED with supplemental oxygen, 30-day survival was 97.5% (95% confidence interval (CI) 95.3 to 98.9%; n=351), and 30-day survival without unscheduled admission was 81.1% (95% CI 76.7 to 85.0%; n=292). A sensitivity analysis incorporating worst-case-scenario for 12 patients without complete follow-up 30 days after index visit yields 30-day survival of 95.5% (95% CI 92.5 to 97.2%; n=343), and 30-day survival without unscheduled admission of 78.9% (95% CI 74.3 to 83.0%; n=284). Among study patients, 32.2% (n=116) had a nadir ED oxygen saturation of <90%, among these 30-day survival was 97.4% (95% CI 92.6 to 99.4%; n=113), and 30-day survival without unscheduled admission was 76.7% (95% CI 68.8 to 84.1%; n=89)., Conclusion: COVID-19 patients with new supplemental oxygen requirements discharged from the ED had survival comparable to COVID-19 ED patients with mild exertional hypoxia treated with supplemental oxygen in other settings, and this held true when the analysis was restricted to patients with nadir ED index visit oxygen saturations <90%. Discharge of select COVID-19 patients with supplemental oxygen from the ED may provide a viable alternative to hospitalization, particularly when inpatient capacity is limited., (Copyright © 2022 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Like all fields of medicine, Infectious Diseases is rife with dogma that underpins much clinical practice. In this study, we discuss 2 specific examples of historical practice that have been overturned recently by numerous prospective studies: traditional durations of antimicrobial therapy and the necessity of intravenous (IV)-only therapy for specific infectious syndromes. These dogmas are based on uncontrolled case series from >50 years ago, amplified by the opinions of eminent experts. In contrast, more than 120 modern, randomized controlled trials have established that shorter durations of therapy are equally effective for many infections. Furthermore, 21 concordant randomized controlled trials have demonstrated that oral antibiotic therapy is at least as effective as IV-only therapy for osteomyelitis, bacteremia, and endocarditis. Nevertheless, practitioners in many clinical settings remain refractory to adopting these changes. It is time for Infectious Diseases to move beyond its history of eminent opinion-based medicine and truly into the era of evidenced-based medicine., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Prolonged antibiotics are associated with toxicity, selection for resistant organisms, and secondary infections such as Clostridioides difficile colitis. Emerging clinical data suggest that short courses of antibiotics can be used for common bacterial infections among immune competent patients, but for many randomized controlled trials (RCTs), immunocompromised patients, including solid organ transplant recipients (SOTRs), have been excluded., Methods: Peer-reviewed publications were identified through PubMed and Embase searches., Results: We review data examining shorter antibiotic courses among immunocompetent and immunocompromised patients and the rationale for use of short antibiotic courses in SOTRs., Conclusion: There are known harms associated with antibiotics and, when studied, existing data do not demonstrate harm associated with shorter courses of antibiotics among SOTRs. Furthermore, several RCTs did include some immune compromised patients and found shorter therapy to result in similar clinical efficacy with diminished adverse effects. Shorter antibiotic durations should be considered in SOTRs, and questions of antibiotic duration among SOTRs should be prioritized for study in clinical trials., (© 2022 Wiley Periodicals LLC.)

Novel approaches to combating antibiotic resistance are needed given the ever-continuing rise of antibiotic resistance and the scarce discovery of new antibiotics. Little is known about the colonization dynamics and the role of intrinsic plant-food characteristics in this process. We sought to determine whether plant fiber could alter colonization dynamics by antibiotic-resistant bacteria in the gut. We determined that ingestion of antibiotics in mice markedly enhanced gut colonization by a pathogenic extended-spectrum beta-lactamase-producing Escherichia coli strain of human origin, E. coli JJ1886 (ST131- H 30Rx). Furthermore, ingestion of soluble acacia fiber before and after antibiotic exposure significantly reduced pathogenic E. coli colonization. 16S rRNA analysis and ex vivo cocultures demonstrated that fiber protected the microbiome by serving as a prebiotic, which induced native gut E. coli to inhibit pathogenic E. coli via colicin M. Fiber may be a useful prebiotic with which to administer antibiotics to protect human and livestock gut microbiomes against colonization from antibiotic-resistant, pathogenic bacteria. IMPORTANCE A One Health-based strategy-the concept that human health and animal health are interconnected with the environment-is necessary to determine the drivers of antibiotic resistance from food to the clinic. Moreover, humans can ingest antibiotic-resistant bacteria on food and asymptomatically, or "silently," carry such bacteria in the gut long before they develop an opportunistic extraintestinal infection. Here, we determined that fiber-rich foods, in particular acacia fiber, may be a new, promising, and inexpensive prebiotic to administer with antibiotics to protect the mammalian (i.e., human and livestock) gut against such colonization by antibiotic-resistant, pathogenic bacteria.