Quantifying aminoglycoside resistance in extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales clinical isolates: a retrospective cohort study.

AIMS: Aminoglycoside resistance is frequently detected in extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales (ESBL-PE), questioning the appropriateness of aminoglycosides as empiric therapy in patients with suspected ESBL-PE infections. Therefore, we aimed to evaluate the frequency of aminoglycoside resistance in patients harbouring ESBL-PE and identify patient-related risk factors associated with aminoglycoside resistance to facilitate early detection of at-risk patients. METHODS: This retrospective single-centre cohort study included hospitalised patients aged ≥18 years with an ESBL-PE-positive sample between January 2016 and December 2018. Aminoglycoside resistance was defined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoints for Enterobacterales for the current year of testing. RESULTS: Five hundred forty-four patients met the eligibility criteria, of which 240 (44.1%) harboured aminoglycoside-resistant ESBL strains. Identification of ESBL-Klebsiella pneumoniae was significantly associated with aminoglycoside resistance (odds ratio [OR] = 2.64, 95% confidence interval [CI] = 1.65-4.21, p <0.001) and an international travel history within the past 12 months was marginally associated with aminoglycoside resistance (OR = 1.51, 95% CI = 0.95-2.42, p = 0.084). CONCLUSIONS: In a low ESBL endemicity setting, aminoglycoside resistance in patients harbouring ESBL-PE is common, especially ESBL-K. pneumoniae, and needs to be considered in clinicians' decision-making regarding empiric therapy regimens.

Differential frequency of persister cells in clinically derived isolates of Pseudomonas aeruginosa after exposure to cefiderocol and ceftolozane/tazobactam.

BACKGROUND: Bacterial persistence is a phenomenon whereby a subpopulation of bacteria survive high concentrations of an active antibiotic in the absence of phenotypic alterations. Persisters are associated with chronic and recurrent infections for pathogens including Pseudomonas aeruginosa. Understanding persister profiles of newer antibiotics such as cefiderocol and ceftolozane/tazobactam against P. aeruginosa is warranted as these agents generally target difficult-to-treat infections. METHODS: Persister formation was assessed using in vitro assays against nine clinical P. aeruginosa isolates exposed to cefiderocol or ceftolozane/tazobactam. Quantitative persister assays were performed using a stationary phase of bacteria challenged with 10-fold MIC drug concentrations. Persisters were quantitated as the percent persisters at 24 h and the log ratio (LR) difference in AUC for cfu for each antibiotic alone compared with growth control. The tolerance disc test (TDtest) was used to qualitatively detect persisters. RESULTS: Percent persisters at 24 h was lower with cefiderocol compared with ceftolozane/tazobactam for six of the nine tested isolates. Eight of the nine isolates had higher reduction in LR for cefiderocol groups, suggesting an overall higher and more rapid bacterial reduction in cefiderocol groups. For cefiderocol, five of the nine tested isolates lacked regrowth after replacement with glucose disc, suggesting no persistence via the TDtest. For ceftolozane/tazobactam, three isolates lacked persister formation. CONCLUSIONS: Cefiderocol resulted in less bacterial persistence relative to ceftolozane/tazobactam against nine clinical P. aeruginosa isolates. Cefiderocol's siderophore mechanism may be advantageous over ceftolozane/tazobactam through enhanced anti-persister effects. Clinical correlation of these findings is warranted as persisters can lead to antibiotic resistance and treatment failure.

Clinical outcomes and emergence of resistance of Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam.

Few studies compare outcomes of patients with difficult-to-treat resistance (DTR) Pseudomonas aeruginosa infections treated with ceftolozane-tazobactam versus ceftazidime-avibactam. A multicenter prospective study was conducted of unique patients with DTR P. aeruginosa infections from 2018 to 2023 receiving >72 h of ceftolozane-tazobactam or ceftazidime-avibactam, with confirmation that the P. aeruginosa isolate was susceptible to the agent administered by broth microdilution. Inverse probability weighting (IPW) incorporating propensity scores was utilized to ensure balanced baseline characteristics. Regression performed on the post-IPW group determined 30-day mortality and subsequent emergence of resistance (i.e., ≥4-fold increase in MIC) to the initial treatment (i.e., ceftolozane-tazobactam or ceftazidime-avibactam). Among 186 eligible patients, 102 (55%) received ceftolozane-tazobactam and 84 (45%) received ceftazidime-avibactam. In the post-IPW cohort, balance was achieved across all variables [e.g., demographics, severity of illness, severe immunocompromise, Charlson Comorbidity Index ≥5, continuous renal replacement therapy (CRRT), source of infection, combination therapy]. Thirty-day mortality was similar between the ceftolozane-tazobactam and ceftazidime-avibactam groups [21% vs 17%; adjusted odds ratio (aOR): 1.01 (95% confidence interval, CI: 0.90-1.14)]. Emergence of resistance was higher in the ceftolozane-tazobactam group [38% vs 25%; aOR: 1.89 (95% CI: 0.98-4.88)], but did not achieve statistical significance. Prolonged treatment durations and use of CRRT were associated with increased emergence of resistance (both P = 0.04). Although the survival of patients with DTR P. aeruginosa infections appears similar regardless of whether ceftolozane-tazobactam or ceftazidime-avibactam is prescribed, the emergence of resistance may be more concerning with the former. Plausible mechanistic explanations support these findings. Modifiable risk factors were identified that may mitigate this risk.

Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections.

BACKGROUND: The Infectious Diseases Society of America (IDSA) is committed to providing up-to-date guidance on the treatment of antimicrobial-resistant (AMR) infections. This guidance document focuses on infections caused by extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E), AmpC ß- lactamase-producing Enterobacterales (AmpC-E), carbapenem-resistant Enterobacterales (CRE), Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa), carbapenem-resistant Acinetobacter baumannii (CRAB), and Stenotrophomonas maltophilia. This updated document replaces previous versions of the guidance document. METHODS: A panel of six infectious diseases specialists with expertise in managing antimicrobial- resistant infections formulated questions about the treatment of infections caused by ESBL-E, AmpC-E, CRE, DTR P. aeruginosa, CRAB, and S. maltophilia. Because of differences in the epidemiology of AMR and availability of specific anti-infectives internationally, this document focuses on the treatment of AMR infections in the United States. RESULTS: Preferred and alternative suggested treatment approaches are provided with accompanying rationales, assuming the causative organism has been identified and antibiotic susceptibility results are known. Approaches to empiric treatment, transitioning to oral therapy, duration of therapy, and other management considerations are discussed briefly. Suggested approaches apply for both adult and pediatric populations, although suggested antibiotic dosages are provided only for adults. CONCLUSIONS: The field of AMR is highly dynamic. Consultation with an infectious diseases specialist is recommended for the treatment of AMR infections. This document is current as of December 31, 2023 and will be updated periodically. The most current version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance/.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Diverticulitis in Adults and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for diagnostic imaging of suspected acute diverticulitis. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment in Adults and Children.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides a recommendation for risk stratification according to severity of illness score. The panel's recommendation is based on evidence derived from systematic literature reviews and adheres to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Intra-abdominal Abscess in Adults, Children, and Pregnant People.

This article is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this article, the panel provides recommendations for diagnostic imaging of suspected acute intra-abdominal abscess. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Utility of Intra-abdominal Fluid Cultures in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this paper, the panel provides recommendations for obtaining cultures of intra-abdominal fluid in patients with known or suspected intra-abdominal infection. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Utility of Blood Cultures in Adults, Children, and Pregnant People.

This article is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this guideline, the panel provides recommendations for obtaining blood cultures in patients with known or suspected intra-abdominal infection. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Diagnostic Imaging of Suspected Acute Appendicitis in Adults, Children, and Pregnant People.

This paper is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America (IDSA). In this paper, the panel provides recommendations for diagnostic imaging of suspected acute appendicitis. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intraabdominal Infections: Diagnostic Imaging of Suspected Acute Cholecystitis and Acute Cholangitis in Adults, Children, and Pregnant People.

This article is part of a clinical practice guideline update on the risk assessment, diagnostic imaging, and microbiological evaluation of complicated intraabdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America. In this article, the panel provides recommendations for diagnostic imaging of suspected acute cholecystitis and acute cholangitis. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.

2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on Complicated Intra-abdominal Infections: Risk Assessment, Diagnostic Imaging, and Microbiological Evaluation in Adults, Children, and Pregnant People.

As the first part of an update to the clinical practice guideline on the diagnosis and management of complicated intra-abdominal infections in adults, children, and pregnant people, developed by the Infectious Diseases Society of America, the panel presents 21 updated recommendations. These recommendations span risk assessment, diagnostic imaging, and microbiological evaluation. The panel's recommendations are based on evidence derived from systematic literature reviews and adhere to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach.

Extended-Infusion ß-Lactam Therapy, Mortality, and Subsequent Antibiotic Resistance Among Hospitalized Adults With Gram-Negative Bloodstream Infections.

Importance: Current evidence is conflicting for associations of extended-infusion ß-lactam (EI-BL) therapy with clinical outcomes. Objective: To investigate the association of EI-BL therapy with survival, adverse events, and emergence of antibiotic resistance in adults with gram-negative bloodstream infections (GN-BSI). Design, Setting, and Participants: This cohort study of consecutive adults with GN-BSI admitted to 24 United States hospitals between January 1, 2019, and December 31, 2019, receiving EI-BL were compared with adults with GN-BSI receiving the same agents as intermittent infusion ß-lactam (II-BL; ≤1-hour infusions). Statistical analysis was performed from January to October 2023. Exposures: EI-BL (ie, ≥3-hour infusion). Main Outcomes and Measures: EI-BL and II-BL groups underwent 1:3 nearest-neighbor propensity score matching (PSM) without replacement. Multivariable regression was applied to the PSM cohort to investigate outcomes, all censored at day 90. The primary outcome was mortality; secondary outcomes included antibiotic adverse events and emergence of resistance (≥4-fold increase in the minimum inhibitory concentration of the ß-lactam used to treat the index GN-BSI). Results: Among the 4861 patients included, 2547 (52.4%) were male; and the median (IQR) age was 67 (55-77) years. There were 352 patients in the EI-BL 1:3 PSM group, and 1056 patients in the II-BL 1:3 PSM group. Among 1408 PSM patients, 373 (26.5%) died by day 90. The odds of mortality were lower in the EI-BL group (adjusted odds ratio [aOR], 0.71 [95% CI, 0.52-0.97]). In a stratified analysis, a survival benefit was only identified in patients with severe illness or elevated minimum inhibitory concentrations (ie, in the intermediate range for the antibiotic administered). There were increased odds of catheter complications (aOR, 3.14 [95% CI, 1.66-5.96]) and antibiotic discontinuation because of adverse events (eg, acute kidney injury, cytopenias, seizures) in the EI-BL group (aOR, 3.66 [95% CI, 1.68-7.95]). Emergence of resistance was similar in the EI-BL and II-BL groups at 2.9% vs 7.2%, respectively (P = .35). Conclusions and Relevance: In this cohort study of patients with GN-BSI, EI-BL therapy was associated with reduced mortality for patients with severe illness or those infected with nonsusceptible organisms; potential advantages in other groups remain unclear and need to be balanced with potential adverse events. The subsequent emergence of resistance warrants investigation in a larger cohort.

Diagnosing and Managing Urinary Tract Infections in Kidney Transplant Recipients.

In the article, the authors review antibiotic treatment options for both acute uncomplicated UTI and complicated UTI. In addition, they review alternative regimens which are needed in the setting of drug-resistant pathogens including vancomycin-resistant Enterococcus, -extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales, and carbapenem-resistant Pseudomonas, which are encountered with more frequency.

Lessons Learned from a National Hospital Antibiotic Stewardship Implementation Project.

BACKGROUND: The goal of antibiotic stewardship programs (ASPs) is to ensure that patients receive effective therapy while minimizing adverse events. To overcome barriers commonly faced in implementing successful ASPs, the Agency for Healthcare Research and Quality (AHRQ) established a multifaceted, nationwide Safety Program for Improving Antibiotic Use in 2018. This report summarizes the lessons learned from the implementation of this initiative based on structured interviews of personnel from participating sites. METHODS: At the completion of the one-year initiative, semistructured exit interviews were conducted with site leaders at 151 of the 402 hospitals that participated. These interviews consisted of open-ended questions about the perceived effectiveness of components of the Safety Program. Qualitative analyses incorporated both deductive coding themes (based on existing literature) and an iteratively developed inductive coding framework (based on salient themes that emerged from a subset of interviews). RESULTS: Several components of the Safety Program were identified as effective in expanding local stewardship activities, including techniques and strategies to implement sustainable ASPs, access to Implementation Advisors to keep sites engaged, provision of local benchmarked antibiotic use data to compare to similar hospitals, and Safety Program materials such as the antibiotic time-out tool to integrate stewardship techniques into daily work flows. The biggest challenges to greater effectiveness were suboptimal frontline staff engagement and difficulty changing antibiotic prescribing culture. Some approaches used to overcome these barriers (peer-to-peer communication and education through team huddles, identifying physician champions, informal rounds to enhance collegiality and buy-in, and engagement of hospital leadership) were identified. CONCLUSION: Lessons learned from the Safety Program can be applied by other teams looking to promote an effective ASP at their hospital or system. The themes that emerged in this study likely also have relevance across a wide range of large-scale quality improvement initiatives.

Assessing the impact of meropenem exposure on ceftolozane/tazobactam-resistance development in Pseudomonas aeruginosa using in vitro serial passage.

BACKGROUND: Patients infected with difficult-to-treat Pseudomonas aeruginosa are likely to receive meropenem (MEM) empirically before escalation to ceftolozane/tazobactam (C/T). We assessed whether pre-exposure to MEM affected C/T resistance development on C/T exposure. MATERIALS AND METHODS: Nine clinical P. aeruginosa isolates were exposed to MEM 16 mg/L for 72 h. Then, isolates were serially passaged in the presence of C/T (concentration of 10 mg/L) for 72 h as two groups: an MEM-exposed group inoculated with MEM pre-exposed isolates and a non-MEM control group. At 24 h intervals, samples were plated on drug-free and drug-containing agar (C/T concentration 16/8 mg/L) and incubated to quantify bacterial densities (log10 cfu/mL). Growth on C/T agar indicated resistance development, and resistant population was calculated by dividing the cfu/mL on C/T plates by the cfu/mL on drug-free agar. RESULTS: At 72 h, resistant populations were detected in 6/9 isolates. In five isolates, MEM exposure significantly increased the prevalence of ceftolozane/tazobactam-resistance development; the percentages of resistance population were 100%, 100%, 53.5%, 31% and 3% for the MEM-exposed versus 0%, 0%, 2%, 0.35% and ≤0.0003% in the unexposed groups. One isolate had a similar resistant population at 72 h between the two groups. The remaining isolates showed no development of resistance, regardless of previous MEM exposure. CONCLUSIONS: MEM exposure may pre-dispose to C/T resistance development and thus limit the therapeutic utility of this ß-lactam/ß-lactamase inhibitor. Resistance may be a result of stress exposure or molecular-level mutations conferring cross-resistance. Further in vivo studies are needed to assess clinical implications of these findings.

Successful Treatment of Carbapenem-Resistant Acinetobacter baumannii Meningitis With Sulbactam-Durlobactam.

BACKGROUND: The treatment of carbapenem-resistant Acinetobacter baumannii/calcoaceticus complex (CRAB) presents significant treatment challenges. METHODS: We report the case of a 42-year-old woman with CRAB meningitis who experienced persistently positive cerebrospinal fluid (CSF) cultures for 13 days despite treatment with high-dose ampicillin-sulbactam and cefiderocol. On day 13, she was transitioned to sulbactam-durlobactam and meropenem; 4 subsequent CSF cultures remained negative. After 14 days of sulbactam-durlobactam, she was cured of infection. Whole genome sequencing investigations identified putative mechanisms that contributed to the reduced cefiderocol susceptibility observed during cefiderocol therapy. Blood and CSF samples were collected pre-dose and 3-hours post initiation of a sulbactam-durlobactam infusion. RESULTS: The CRAB isolate belonged to sequence type 2. An acquired blaOXA-23 and an intrinsic blaOXA-51-like (ie, blaOXA-66) carbapenemase gene were identified. The paradoxical effect (ie, no growth at lower cefiderocol dilutions but growth at higher dilutions) was observed by broth microdilution after 8 days of cefiderocol exposure but not by disk diffusion. Potential markers of resistance to cefiderocol included mutations in the start codon of piuA and piuC iron transport genes and an A515V substitution in PBP3, the primary target of cefiderocol. Sulbactam and durlobactam were detected in CSF at both timepoints, indicating CSF penetration. CONCLUSIONS: This case describes successful treatment of refractory CRAB meningitis with the administration of sulbactam-durlobactam and meropenem and highlights the need to be cognizant of the paradoxical effect that can be observed with broth microdilution testing of CRAB isolates with cefiderocol.

A multi-center validation of the electronic health record admission source and discharge location fields against the clinical notes for identifying inpatients with long-term care facility exposure.

Identifying long-term care facility (LTCF)-exposed inpatients is important for infection control research and practice, but ascertaining LTCF exposure is challenging. Across a large validation study, electronic health record data fields identified 76% of LTCF-exposed patients compared to manual chart review. OBJECTIVE: Residence or recent stay in a long-term care facility (LTCF) is an important risk factor for antibiotic-resistant bacterial colonization. However, absent dedicated intake questionnaires or resource-intensive chart review, ascertaining LTCF exposure in inpatients is challenging. We aimed to validate the electronic health record (EHR) admission and discharge location fields against the clinical notes for identifying LTCF-exposed inpatients. METHODS: We conducted a retrospective study of 1020 randomly sampled adult admissions between 2016 and 2021 across 12 University of Maryland Medical System hospitals. Using study-developed guidelines, we categorized the following data for LTCF exposure: each admission's history & physical (H&P) note, each admission's EHR-extracted "Admission Source," and (3) the EHR-extracted admission and discharge locations for previous admissions (≤90 days). We estimated sensitivities, with 95% CIs, of H&P notes and of EHR admission/discharge location fields for detecting "current" and "any recent" (≤90 days, including current) LTCF exposure. RESULTS: For detecting current LTCF exposure, the sensitivity of the index admission's EHR-extracted "Admission Source" was 46% (95% CI: 35%­58%) and of the H&P note was 92% (83%­97%). For detecting any recent LTCF exposure, the sensitivity of "Admission Source" across the index and previous admissions was 32% (24%­41%), "Discharge Location" across previous admission(s) was 57% (47%­66%), and of the H&P note was 68% (59%­76%). The combined sensitivity of admission source and discharge location for detecting any recent LTCF exposure was 76% (67%­83%). CONCLUSIONS: The EHR-obtained admission source and discharge location fields identified 76% of LTCF-exposed patients compared to chart review but disproportionately missed currently exposed patients.

Understanding the role of antibiotic-associated adverse events in influencing antibiotic decision-making.

Objective: To (1) understand the role of antibiotic-associated adverse events (ABX-AEs) on antibiotic decision-making, (2) understand clinician preferences for ABX-AE feedback, and (3) identify ABX-AEs of greatest clinical concern. Design: Focus groups. Setting: Academic medical center. Participants: Medical and surgical house staff, attending physicians, and advanced practice practitioners. Methods: Focus groups were conducted from May 2022 to December 2022. Participants discussed the role of ABX-AEs in antibiotic decision-making and feedback preferences and evaluated the prespecified categorization of ABX-AEs based on degree of clinical concern. Thematic analysis was conducted using inductive coding. Results: Four focus groups were conducted (n = 15). Six themes were identified. (1) ABX-AE risks during initial prescribing influence the antibiotic prescribed rather than the decision of whether to prescribe. (2) The occurrence of an ABX-AE leads to reassessment of the clinical indication for antibiotic therapy. (3) The impact of an ABX-AE on other management decisions is as important as the direct harm of the ABX-AE. (4) ABX-AEs may be overlooked because of limited feedback regarding the occurrence of ABX-AEs. (5) Clinicians are receptive to feedback regarding ABX-AEs but are concerned about it being punitive. (6) Feedback must be curated to prevent clinicians from being overwhelmed with data. Clinicians generally agreed with the prespecified categorizations of ABX-AEs by degree of clinical concern. Conclusions: The themes identified and assessment of ABX-AEs of greatest clinical concern may inform antibiotic stewardship initiatives that incorporate reporting of ABX-AEs as a strategy to reduce unnecessary antibiotic use.