Respiratory illness is the most common reason for unnecessary antibiotic therapy in hospitalized adults. Although procalcitonin and respiratory virus testing help differentiate between viral and bacterial illness, they tend not to influence antibiotic decision-making.Figure 1.Testing Wisely Disease Risk Calculator for Bacterial PneumoniaFigure 2.Example of Templated Note for a Patient with Low Post-test Probability of Bacterial Pneumonia We conducted a pragmatic randomized-controlled trial comparing antimicrobial stewardship-guided test interpretation versus usual care among hospitalized adults receiving antibiotics for suspected respiratory infection with either low serum procalcitonin or positive respiratory virus testing at 2 hospitals (NCT05976581). The intervention involved chart review to estimate post-test probability of bacterial pneumonia based on either the low procalcitonin or positive respiratory viral panel and available imaging using an online calculator (Figure 1). Post-test probability was then documented in a note in the patient’s chart along with templated recommendations (Figure 2). When post-test probability was low, antibiotics were recommended to be discontinued. When post-test probability was medium or high, recommendations focused on tailoring antibiotics and setting an appropriate duration of therapy. An electronic message referring to the note and summarizing recommendations was also sent to the clinical team. Between 11/1/2023 and 1/10/2025, 107 adult inpatients were randomized, including 54 to the intervention and 53 to usual care (Table 1). Thirty percent of enrolled patients had a low serum procalcitonin, and 70% had a positive respiratory virus panel. The intervention significantly decreased antibiotic use (median hospital days of antibiotic therapy 7.5 versus 11, p = 0.005, Table 2) and increased discontinuation of all respiratory antibiotics within 5 days of initiation (76% versus 49%, p = 0.004). Clinical outcomes, including length of stay (5.5d with intervention versus 6.6d with usual care, p = 0.16) and 30-day readmission (7% with intervention versus 19% with usual care, p = 0.079), were equivalent between groups. Guided interpretation of standard diagnostic tests for viral infection substantially reduced unnecessary antibiotic use for hospitalized adults with community-acquired respiratory illness. Anthony Harris, MD, MPH, UpToDate Wolters Kluwer Health: Infection control section editor Emily L. Heil, PharmD, MS, Wolters-Kluwer: Advisor/Consultant

BACKGROUND:The Infectious Diseases Society of America (IDSA) is committed to delivering timely, evidence-informed guidance on the management of antimicrobial-resistant (AMR) infections. This updated IDSA AMR Guidance document provides treatment suggestions for infections caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E), AmpC β-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 update replaces earlier versions of the IDSA AMR Treatment Guidance. METHODS:A panel of six infectious diseases specialists with expertise in AMR convened to address important questions regarding the treatment of infections due to ESBL-E, AmpC-E, CRE, DTR P. aeruginosa, CRAB, and S. maltophilia. Given geographic variability in AMR epidemiology and antibiotic availability, the IDSA AMR Guidance focuses on clinical practice in the United States. RESULTS:Preferred and alternative treatment strategies are outlined with accompanying rationales, based on pathogen identification and in vitro susceptibility data. Suggestions addressing empiric therapy, transition to oral therapy, duration of treatment, and other management considerations are briefly discussed. While applicable to both adult and pediatric populations, specific dosing guidance is only provided for adults. CONCLUSION:The field of AMR is highly dynamic. This document is current as of March 1, 2026 and will be updated periodically. The most up-to-date version of this document, including date of publication, is available at www.idsociety.org/practice-guideline/amr-guidance/.

Sepsis remains a leading cause of morbidity and mortality in US hospitals despite extensive efforts to improve early recognition and treatment, particularly through implementation of the Centers for Medicare & Medicaid Services (CMS) SEP-1 quality measure. Recognizing the need for broader approaches to sepsis improvement, CMS and the Centers for Disease Control and Prevention are advancing new sepsis quality measures focused on outcomes and hospital programmatic capacity, while the Surviving Sepsis Campaign guidelines continue to provide evidence-based recommendations for bedside clinical management. However, there remains a need for practical, actionable guidance that complements existing guidelines and quality frameworks by addressing hospital-based strategies across the continuum of sepsis care. To address this gap, the Infectious Diseases Society of America convened a multidisciplinary, multisociety expert panel to develop a consensus-based position paper outlining evidence-informed recommendations for hospital-based sepsis improvement. The recommendations focus on infection-related aspects of sepsis management and span 6 domains: diagnostic testing and pathogen detection, antimicrobial management and delivery, surveillance and performance metrics, adjunctive therapy, program infrastructure and organizational support, and infection prevention. Examples include implementing multiplex nucleic acid amplification tests for positive blood cultures paired with active stewardship support; optimizing workflows for timely antibiotic delivery in septic shock; using clinical decision support to prioritize β-lactam administration before vancomycin when both are ordered; defaulting antipseudomonal β-lactams to prolonged infusion in critically ill patients; adopting EHR-based sepsis surveillance; tracking rates of inadequate empiric therapy, unnecessarily broad empiric therapy, antibiotic de-escalation, and timeliness of source control; establishing protocols for appropriate corticosteroid use in severe community-acquired pneumonia; and standardizing daily tooth brushing to prevent hospital-acquired pneumonia. The panel also highlights emerging approaches, particularly novel diagnostic strategies, that show promise but require further validation before widespread adoption. Collectively, these recommendations provide a pragmatic framework for hospitals to strengthen infection-related sepsis management and improve patient outcomes.

We recalibrated a risk score to identify difficult-to-treat resistant Pseudomonas aeruginosa among 197 intensive care unit patients with bloodstream or respiratory infection. Prevalence was 6%. Models showed moderate discrimination (c-statistic 0.71-0.74), low sensitivity (18%), and high specificity (94%-96%), highlighting the need for local validation and consideration of performance tradeoffs.

Molnupiravir (MOV) is a prodrug of N-hydroxycytidine (NHC), an analog of the endogenous ribonucleoside cytidine that can be administered orally. MOV is used for treating patients infected by SARS-CoV-2, the coronavirus responsible for COVID-19. MOV and NHC are mutagenic in bacterial and in mammalian cell cultures, yet both chemicals have been negative or equivocal in nonclinical in vivo models of mutagenesis. We designed and validated a novel error-corrected sequencing (ECS) method for detecting single basepair substitutions in tissue samples obtained from genetically heterogeneous humans. The software used for this ECS method is available for free from a public on-line repository and it is suitable for analysis of in vivo and in vitro derived samples collected in various experimental scenarios. We recruited two groups of patients having COVID-19 one to three years ago, one group that received a full course of MOV therapy and the other group (matched for age and COVID-19 diagnosis date) that did not receive MOV. Using the ECS method, we determined the frequencies of basepair substitutions in nucleated cells isolated from peripheral blood of the patients. There was no observed difference in the frequency of mutations, the types of mutations, or mutational spectra between the MOV and the control groups. Also, the spectra of mutations in the MOV group did not show any evidence of the mutational signature expected from exposures to MOV or NHC based on data from mammalian cell culture models. Within the limits of this study, the dose of MOV authorized for the treatment of COVID-19 under emergency use authorization appears to have no mutational consequences for treated patients.

We hypothesize that short durations (≤10 days) of antibiotics for uncomplicated gram-negative bacteremia (GNB) would have similar clinical outcomes compared to long durations ( >10 days) in solid organ transplant (SOT) patients. DOOR Probability Forest PlotFigure 1.Forest plot demonstrating the desirability of outcome ranking (DOOR) probabilities for each individual DOOR component (survival without adverse events, microbiologic failure, isolation of an MDR gram-negative in the blood, C. difficile infection or death) as well as the overall DOOR probability of having a more desirable outcome with < 10 days versus ≥10 days of antimicrobial treatment. A retrospective cohort review was conducted on patients admitted to University of Maryland Medical System hospitals from 1/1/2019 to 6/30/2024. Included patients were ≥18 years old with an uncomplicated GNB defined as a confirmed Enterobacterales bacteremia, source control, and clinical stability at 72 hours. The primary outcome was a Desirability of Outcome Ranking (DOOR) comparison between < 10 days versus ≥10 days of treatment. Each patient was assigned a DOOR rank from 1 (survival without adverse events) to 5 (death). Ranks 2-4 included patients who survived but had 1, 2, or 3 undesirable events occur during the 30-day follow-up period, respectively. Undesirable events included microbiologic failure, isolation of an MDR gram-negative in the blood, or C. difficile infection. Confidence intervals for the DOOR probability were calculated using the Halperin et al. (1989) method with a 95% confidence level, with a statistically significant two-sided p-value of < 0.05. A total of 105 patients were included in this study, with 27 patients in < 10 day cohort and 78 patients in the ≥10 day cohort. The source of GNB was significantly different between groups (p=0.007), with the < 10 day cohort having more intrabdominal infections (48.2% vs 19.2%) and the ≥ 10 cohort having more urinary sources of infection (67.9% vs 37.0%). There were more patients with an oral switch in the ≥10 day treatment cohort (66.7% vs 33.3%, p=0.003). The overall DOOR probability of having a more favorable outcome with a treatment duration of < 10 days compared to ≥10 day treatment was not statistically different (44.7%, 95% CI: 36.8%, 52.9%; p = 0.1235), highlighting that longer durations of therapy were not associated with improved outcomes. In patients with a solid organ transplant and uncomplicated GNB, there was no significant difference in outcomes when treated for < 10 days or ≥ 10 days. Further studies with larger sample sizes are needed to highlight the efficacy and safety of shorter antibiotic durations for uncomplicated GNB in solid organ transplantation. Emily L. Heil, PharmD, MS, Wolters-Kluwer: Advisor/Consultant

Multidrug-resistant Pseudomonas aeruginosa (MDR PSA) is an exigent threat due to antibiotic resistance, lack of suitable rapid diagnostics, and delays in initiating active therapy. Locally, Zou et al. (2023) built a simplified risk scoring tool to predict MDR PSA and guide empiric antibiotic therapy. Our goal was to assess the accuracy and calibration of this tool in an updated patient population using the Infectious Diseases Society of America’s standardized definition of difficult-to-treat (DTR) PSA. Retrospective cohort study of adult ICU patients with PSA-positive blood or respiratory cultures from 2021-2024. The developed Zou et al. (2023) risk scoring tool included: previous MDR PSA within 6 months of admission, not present on admission (POA), ongoing hemodialysis, and > 4 anti-pseudomonal antibiotics within 30 days of isolation. For model development, dataset was divided into a training cohort and a test cohort. Further, beta coefficients were estimated using Firth’s method and transformed into a risk score by normalizing coefficients. The logistic regression models were trained using different sets of predictors from above. Among 197 patients, 27 (14%) had MDR PSA and 11 (6%) had DTR PSA. DTR PSA patients were more likely than non-DTR PSA patients to have previous MDR PSA (9% vs 5%, p = 0.4), not have infection POA (9% vs 26%, p = 0.3), hemodialysis (64% vs 28%, p = 0.08), and > 4 previous anti-pseudomonal antibiotics (72% vs 35%, p = 0.02). Three models were developed with combinations of different risk factors. All had low sensitivity (18%), but Model 2 has the highest accuracy (c-statistics = 0.7, 95% CI: 0.6–0.9) while Model 3 had highest specificity (96%). Model 3 correctly classifies the highest true positive and negative cases (91.9%), followed by Model 2 (91.4%). Calibration curves (Figure 1) were created for all models and Model 2 had the best overall alignment between predicted and observed event rates. Model 2 was the best model, especially to screen high-risk patients for urgent targeted antibiotic therapy with minimal false positives. However, additional analysis is required before clinical implementation. Validation with larger patient datasets that contain more positive cases is needed to develop a higher sensitive model. Emily L. Heil, PharmD, MS, Wolters Kluwer: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria

Abstract Pharmacist services demonstrate a positive impact on healthcare delivery, patient outcomes, and cost of care. Translating this evidence into sustainable funding models demands significant change in healthcare policy and payment that accounts for institutional constraints, payment structures, and scalability requirements. Meanwhile, the gap grows between the positive impact of pharmacist services and reimbursement limited to narrowly defined services or drug product costs. Lack of federally designated provider status and payer-imposed cost containment strategies threaten the financial sustainability of pharmacist services. Future solutions include innovative value-based payment with quality driven reimbursement, comprehensive medication and care management, and shared financial savings linked to outcomes. Priority funding areas using a shared-savings model include acute and chronic care service lines that cater to high-acuity patients who require high-cost medications and experience frequent care transitions. This model is based on reductions in medication costs, adverse drug-related outcomes, length of stay, and readmissions. A call to action is proposed, focused on policy changes in provider status, adequate payer reimbursement, improving current fee-for-service models and shifting payment models to value-based payment, and removing misaligned financial strategies.

There is hesitance to use linezolid for durations past 14 days due to adverse drug events (ADEs), such as myelosuppression and neuropathy. This study evaluated the incidence of and patient characteristics associated with ADEs. This was a single-center, retrospective, observational cohort study. Adult patients prescribed linezolid for greater than 14 consecutive days at the time of discharge from 1/1/2020 to 7/31/2024 were included. Patients with outpatient laboratory results for hemoglobin, white blood cell, and platelet count were assessed for myelosuppression. Development of neuropathies were assessed via documentation in the medical record. Patient demographics, such as age, weight, creatinine clearance (CrCl) and treatment-related information were evaluated. The primary outcome was assessed using descriptive statistics to describe incidence of ADEs. Secondary outcomes were assessed using multivariate logistic regression analysis to determine patient characteristics associated with ADEs and rates of therapy discontinuation due to ADEs. Of 311 screened patients, 159 met inclusion criteria. A total of 143 (89.9%) patients completed prescribed therapy while 16 (10.1%) discontinued early. Patients with older age, lower baseline platelet count, lower baseline CrCl, and myelosuppression were more likely to stop treatment early. Neuropathy was documented in 6 patients (3.8%). Of 118 patients assessed for myelosuppression, 26 cases occurred in 23 patients (19.5%). Thrombocytopenia occurred in 9 patients (7.6%). Patients who developed myelosuppression were more likely to be older, have a lower baseline creatinine clearance, and discontinue therapy early. After multivariate regression, only lower baseline CrCl was significantly associated with increased myelosuppression risk. Overall, the use of linezolid for durations greater than 14 days was well tolerated as evident by the treatment completion rate of nearly 90% despite a myelosuppression incidence of 19.5%. Our findings suggest an increased risk of myelosuppression in patients with reduced renal function. When considering patients for prolonged durations of therapy with linezolid, caution should be taken in patients with reduced renal function and increased age. Emily L. Heil, PharmD, MS, Wolters Kluwer: Advisor/Consultant

Addressing antimicrobial resistance requires multi-disciplinary action, including from the clinical laboratory. Cascade reporting of the antimicrobial susceptibility test (AST) is a strategy used by some laboratories to nudge clinicians toward the use of more narrow-spectrum antimicrobials. Cascade reporting involves suppression of broader-spectrum antimicrobials if the narrower-spectrum first-line antimicrobials show in-vitro susceptibility. Studies have shown that cascade reporting can reduce use of broad-spectrum antimicrobials and reduce antimicrobial resistance rates. However, implementing cascade reporting can be complex, and some question the effectiveness on impacting long-term prescribing behaviors. Furthermore, there are concerns surrounding compliance and the possible negative impact on public health surveillance for antimicrobial resistance. In this article, experts weigh in on the benefits and risks associated with implementing AST cascade reporting. General consensus is that cascade reporting is a benefit to antimicrobial stewardship, but protocols need careful implementation to minimize risk to patients and public health.

Oral β-lactams are frequently referred to as low bioavailability agents that are inferior in the treatment of systemic gram-negative infections. This notion limits their utility beyond their use. The pharmacokinetic/pharmacodynamic profiles of oral β-lactams differ among agents, and each agent must be considered individually in the context of the patient. In this review, we describe 3 scenarios where oral β-lactams may play a role in the treatment of systemic gram-negative infections and the decision process to select or avoid these agents. Each case represents a risk-vs-benefit scenario in which the degree of confidence in using an oral β-lactam varies.

The treatment of gram-negative bacterial infections exhibiting resistance to all traditional β-lactam and fluoroquinolone agents (ie, difficult-to-treat resistance [DTR]) poses challenges due to the limited number of active antibiotic agents. Managing DTR gram-negative infections becomes even more complex when present in the central nervous system due to concerns for insufficient concentrations of agents in the cerebrospinal fluid and brain parenchyma. Several newer β-lactam agents with activity against DTR gram-negatives are available, including cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-cilastatin-relebactam, meropenem-vaborbactam, and sulbactam-durlobactam. This article examines host and drug factors that influence an antibiotic's effectiveness for the treatment of bacterial meningitis. The preclinical and clinical data in support of or against each of the aforementioned agents for the treatment of bacterial meningitis are also reviewed.

Abstract Background CACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for the treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We previously demonstrated that treatment with C/T resulted in higher rates of clinical success compared to CZA. The objective of this analysis is to compare the day 30 Desirability of Outcome Ranking (DOOR) between matched patient pairs. Methods C/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The DOOR scale applied is described in Figure 1. Each matched pair was compared for a better ranking. The frequency of an improved DOOR for C/T compared to CZA was determined for the entire cohort (n = 210 pairs) and pneumonia subgroup (n = 175 pairs) where a DOOR of 50% would represent no difference. In addition, we measured the magnitude of DOOR differences within matched pairs. Results C/T was not associated with an improved DOOR relative to CZA in the overall cohort (53.3% (95% CI 47.2 – 59.4)) or pneumonia subgroup (54.6% (95% CI 47.9 – 61.2); Figure 1). Specifically, 37% of pairs had the same DOOR, 33% had a lower (better) DOOR with C/T, and 30% had a lower DOOR with CZA. Figure 2 shows the magnitude of DOOR differences for patient pairs. The magnitude was greater for pairs when C/T was associated with a better outcome as compared to the magnitude for pairs when CZA was associated with a better outcome. This difference was more pronounced among patients with pneumonia (Figure 3). A summary of major comparisons is shown in Figure 4. For the entire cohort, an improved DOOR by ≥2 categories within matched pairs occurred more commonly with C/T vs. CZA (p=0.03). In the subgroup of patients with pneumonia, a greater proportion of pairs showed the greatest possible difference (success without complications (DOOR=1) versus death (DOOR=5)) in favor of C/T compared to pairs in favor of CZA; 14% vs. 7%; p = 0.06. Conclusion These data demonstrate the power of matched data for analyzing DOOR endpoints. While there was no difference in the overall DOOR, the magnitude of improved outcomes consistently favored C/T over CZA and suggests clinically important differences in these agents for patients with MDR P. aeruginosa pneumonia or bacteremia. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support

Abstract Background Respiratory infections are among the most common reasons antibiotics are prescribed. However, 30-50% of patients started on antibiotics for CAP do not have bacterial infections. Methods We implemented clinical decision support (CDS) in the electronic health record of two hospitals to support diagnosis of viral vs. bacterial CAP. The CDS (1) estimates the probability of bacterial CAP using logic from a publicly available calculator and (2) provides probability-based options for diagnostic testing. The CDS is triggered by an order for respiratory virus testing and can be dismissed if bacterial CAP is not suspected or the patient is not being admitted. Design of the CDS was refined iteratively in usability testing with frontline clinicians (Fig. 1). The final design was an order panel embedded within other order sets (Fig. 2). The CDS was activated on 11/1/2023. Impact of the CDS was assessed in a quasi-experiment comparing antibiotic use (AU) during the post-intervention respiratory virus season (10/2023 – 3/2024) to corresponding months in 2021-2022 and 2022-2023. AU was defined as days of therapy / 1000 patient bed-days (DOT/1000 BD) for antibiotics started on hospital day 0-7 for respiratory infection, regardless of whether the CDS triggered. AU categories, including extended-spectrum AU, were defined by pharmacy. Average quarterly AU was compared between the post-intervention respiratory virus season and preceding seasons using Student’s t-test. Results CDS guided test ordering in 890 of 3,201 eligible CAP patients (28% of appearances, Fig. 3) through 3/31/2024, with usage declining in February and March. Feedback from clinicians noted that the CDS is unobtrusive, but it does not apply to all patients, and recommended tests sometimes have longer turnaround times than alternatives. Overall AU for respiratory infections did not change in the post-intervention respiratory season (129.1 vs. 129.6 DOT/1000 BD, p = 0.94), but extended-spectrum AU decreased significantly (46.6 vs. 40.6 DOT/1kBD, p = 0.046, Fig. 4). Conclusion This project demonstrates use of CDS to guide diagnostic testing based on pre-test probability of bacterial CAP. An associated antimicrobial stewardship intervention is under investigation (NCT05976581). Disclosures Anthony Harris, MD, MPH, Innoviva: Advisor/Consultant|UpToDate: Infection Control Editor Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria R. Gentry Wilkerson, MD, Beckton Dickinson: Grant/Research Support|CalciMedica: Grant/Research Support|CoapTech: Grant/Research Support|Eldon: Grant/Research Support|EndPoint Health, Inc: Grant/Research Support|Global Blood Therapeutics: Grant/Research Support|Novartis: Grant/Research Support|Pfizer: Grant/Research Support|Tonix: Grant/Research Support|Vapotherm: Grant/Research Support

BACKGROUND AND OBJECTIVES:The relative contribution of vancomycin exposure versus clinical factors to acute kidney injury (AKI) development in pediatric patients remains unclear. This study examined risk factors for AKI in pediatric patients receiving intravenous vancomycin therapy, with particular focus on elucidating the role of vancomycin concentrations and evaluating the safety implications of recent dosing guideline changes published in 2020. METHODS:For this retrospective cohort study, Texas Children's Hospital database was queried between 2011 and 2019 for demographics, concomitant medications, vancomycin dosing and levels, serum creatinine, and mortality. AKI was defined using modified KDIGO criteria. Empirical Bayesian forecasting with a published population pharmacokinetic (PK) model generated rich PK profiles from sparse sampling data. Multivariate logistic regression was used to identify risk factors, and simulations were performed to evaluate 2020 guideline recommendations. RESULTS:The final analysis dataset included 2318 vancomycin courses in 1714 unique patients. The typical dosing regimen in our dataset was 45 mg/kg/day every 8 h. AKI occurred in 18.9% of patients. Independent risk factors included lower age, ICU residence, vasopressor administration, concurrent piperacillin/tazobactam, and amphotericin B use. While vancomycin 24-h area under the curve (AUC0-24) showed statistically significant association with AKI, the relationship was modest with minimal improvement in model performance compared to clinical factors alone. Simulations of 2020 guideline recommendations (60-80 mg/kg/day) predicted modest increases in AKI incidence from 19% to 21% when AUC was capped at 600 mg·h/L. However, given low mortality rate (1.9%) in our dataset despite only 43% of patients achieving the recommended AUC target of 400 mg·h/L, the clinical necessity for increased dosing remains questionable. CONCLUSIONS:Clinical factors are substantially more predictive of AKI than vancomycin exposure in pediatric patients. Given the questionable clinical necessity for increased dosing based on low mortality rates, prospective studies incorporating clinical efficacy endpoints are needed to establish optimal dosing strategies that balance therapeutic benefit with nephrotoxicity risk.

INTRODUCTION:Little is known about the epidemiology and management of gram-negative bloodstream infections (GN-BSIs) in patients after solid organ transplant (SOT). We describe epidemiology, treatment approaches, and outcomes in a subset of patients with SOT from a larger cohort with GN-BSI. METHODS:This was a multicenter, retrospective cohort study that enrolled unique, consecutive adults with GN-BSI hospitalized at any of 24 participating hospitals between January and December 2019. RESULTS:Of 4581 adults in the overall cohort, 298 (6.5%) were SOT recipients, including kidney (177, 59%), liver (67, 22%), heart (23, 8%), lung (12, 4%), and multiorgan (19, 6%) recipients. The most common organisms were Escherichia coli (45%), Klebsiella pneumoniae (20%), and Pseudomonas aeruginosa (15%). Twenty-two percent of E. coli, Klebsiella spp., or Proteus spp. isolates had extended-spectrum beta-lactamase phenotype. Sixty-six (22%) subjects did not receive active empirical therapy within the first 48 h. Median treatment duration was 15 days (IQR 12-18 days). Transition to oral therapy occurred in 161 (54%) patients at a median of 4 days (IQR 3-7 days). Thirty-one patients (10%) had recurrent bacteremia, and 10% of the cohort died within 90 days. DISCUSSION:In this large cohort of SOT patients with GN-BSI, durations exceeded 14 days in most patients, while more than half transitioned to oral antibiotics. Approximately 1 in 5 did not receive active empirical antibiotics, highlighting the impact of drug resistance and the importance of access to rapid diagnostic tools in this patient population. Mortality aligned with published estimates from other studies.

Abstract Background Prospective audit and feedback (PAF) remains the backbone of antimicrobial stewardship (AS) action. However, PAF is time consuming and does not always result in intervention. A prioritization scoring tool is a proposed solution to improve AS efficiency. We sought to assess the impact of a scoring tool (‘score’) on the efficiency of our AS program.Figure 1.Interrupted Time Series Analysis of Intervention Rate Pre-Post Score Implementation Methods A pre-post evaluation of AS PAF at an academic medical center was performed. The pre-score period (November 2022 – June 2023) consisted of standard PAF (largely 48-hour review). The post-score period (July 2023 – March 2024) included standard PAF in addition to the score. The scoring tool is embedded within the AS surveillance system in the electronic medical record and is used to readily identify patients with opportunities for antimicrobial optimization. It consists of pre-defined “points” for each programmed alert (e.g. bug-drug mismatch=10) which are reported in real-time as a prioritized list (higher score = higher priority). An interrupted time series was conducted to compare the intervention rate pre- and post-score implementation. A subgroup analysis was conducted on the post-score period comparing the reviews triggered by the score versus the 48-hour review. A univariate logistic regression was carried out to determine the association of the score with AS intervention.Table 1.Comparison of Score Interventions vs 48-hour Review during the Post-Period Results There were 5801 AS reviews in total, 2927 pre-score and 2874 post-score (92 missing outcome data). The mean intervention rate pre- and post-score was 46.2% and 52.3%, respectively (p< 0.001), with a +2.2% difference per month (p=0.036) as illustrated by Figure 1. The change was gradual without any significant, immediate level change. The score subgroup consisted of 312 reviews and were compared to 1180 48-hour reviews during the same period. Table 1 compares the two groups demonstrating overall high intervention rate in the score group (52.6% vs 40.9%, p < 0.0001); however, notable characteristics were different. An AS intervention was 1.6 times more likely when using the score approach (OR 1.6, 95% CI 1.3 – 2.0). Conclusion Implementation of an antimicrobial scoring tool may improve PAF efficiency by better predicting patients for antimicrobial optimization than standard 48-hour review. The scoring tool can be an impactful method when performing PAF. Disclosures Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria

Abstract Background CACTUS is a retrospective, matched, multicenter study comparing the efficacy of C/T and CZA for treatment of bacteremia or pneumonia due to MDR P. aeruginosa. We found that treatment with C/T resulted in higher rates of clinical success compared to CZA after controlling for baseline differences between cohorts. The objective of this study is to determine the impact of patient subgroups on the overall findings. Methods C/T and CZA patients were matched 1:1 within each study site based on severity of illness, infection type, and time to treatment initiation. The primary outcome was clinical success at day 30, defined as survival, resolution of signs/symptoms of infection with the intended treatment course, and absence of recurrent infection. For subgroups of interest, the proportion with clinical success in each group was compared using an unadjusted odds ratio (OR) and 95% confidence interval. Results Among 420 cases from 28 sites, 60.95% (128/210) of C/T- and 51.9% (109/210) of CZA-treated patients experienced clinical success. Groups were overall well-balanced by matching; however, CT-treated patients were older, more likely to have immunocompromising conditions, and to receive suboptimal dosing (Table 1). After conditional logistic regression, the adjusted OR for clinical success with C/T treatment was 1.97 (95% CI: 1.11 – 3.49; P=0.02). Unadjusted OR for patient subgroups are listed in Table 2. Overall, the effect size was consistent across all subgroups. Key factors are highlighted in Figure 1. Significantly higher rates of clinical success were found for treatment with C/T compared to CZA for patients with pneumonia, SOFA ≤7, mechanical ventilation, and optimal dosing. Table 3 displays comparative 30-day mortality rates. Higher mortality rates were identified in both C/T- and CZA-treated patients who were critically-ill, received suboptimal dosing, and were treated within 72 hours of index culture (Table 3); rates did not vary by treatment. Conclusion The consistency of the results in this subgroup analysis of CACTUS reinforces the primary finding of higher rates of clinical success for patients with MDR P. aeruginosa pneumonia or bacteremia treated with C/T compared to CZA. Disclosures jason M. Pogue, PharmD, Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Venatorx: Advisor/Consultant Samuel L. Aitken, PharmD, MPH, Basilea: Advisor/Consultant|bioMerieux: Advisor/Consultant|Melinta: Advisor/Consultant|Shionogi: Advisor/Consultant Ahmed Babiker, MBBS, Beckman Coulter Inc.: Advisor/Consultant Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria Kate DeSear, PharmD, BCIDP, AAHIVP, FIDSA, AbbVie Inc: Advisor/Consultant|Basilea Pharmaceutica: Advisor/Consultant|GSK: Advisor/Consultant|La Jolla (Entasis): Advisor/Consultant|Melinta Therapuetics: Advisor/Consultant Alan E. Gross, PharmD, Becton Dickinson Co: Advisor/Consultant Keith S. Kaye, MD, MPH, Allecra: Advisor/Consultant|CARB-X: Advisor/Consultant|GSK: Advisor/Consultant|Merck: Advisor/Consultant|Shionogi: Advisor/Consultant|Spero: Advisor/Consultant Wesley D. Kufel, Pharm.D., BCPS, BCIDP, Merck & Co.: Grant/Research Support|Shionogi, Inc: Grant/Research Support Conan MacDougall, PharmD, MAS, Merck: Grant/Research Support Erin K. McCreary, PharmD, Abbvie: Advisor/Consultant|Basilea: Advisor/Consultant|Ciadara: Advisor/Consultant|Entasis: Advisor/Consultant|Ferring: Advisor/Consultant|GSK: Advisor/Consultant|GSK: Honoraria|Melinta: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria William R. Miller, M.D., Merck: Grant/Research Support|UptoDate: Royalties Jeffrey C. Pearson, PharmD, inflarx: Advisor/Consultant Michael J. Satlin, MD, AbbVie: DSMB participant|bioMerieux: Grant/Research Support|Merck: Grant/Research Support|Selux Diagnostics: Grant/Research Support|SNIPRBiome: Grant/Research Support David van Duin, MD, PhD, Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Qpex: Advisor/Consultant|Roche: Advisor/Consultant|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support Ryan K. Shields, PharmD, MS, Allergan: Advisor/Consultant|Cidara: Advisor/Consultant|Entasis: Advisor/Consultant|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|Melinta: Grant/Research Support|Menarini: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Pfizer: Advisor/Consultant|Roche: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Grant/Research Support|Utility: Advisor/Consultant|Venatorx: Advisor/Consultant|Venatorx: Grant/Research Support

Abstract Background Newer broad-spectrum beta-lactam antibiotics (cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam) have been introduced. Ceftazidime-avibactam and ceftolozane-tazobactam predominated newer antibiotic use through 2021; however, less is known about current use patterns and for what clinical indications, in inpatient settings. The aim of this study was to describe the use of these newer antibiotics across a large national cohort. Methods We performed a retrospective cohort study of adults discharged from June 2022 through May 2023 among hospitals in the Premier Healthcare Database. Antibiotic utilization was ascertained from daily charge data, and clinical indication(s) were inferred from ICD-10 diagnosis codes. A stratified analysis was performed among patients receiving >3 days of antibiotic therapy to understand when these antibiotics are being used as definitive therapy. Results Across 832 hospitals, 3,890,557 admissions (61.9% of all admissions) included receipt of antibiotics. In 8,655 admissions (0.2% of antibiotic-prescribing admissions), newer antibiotics were prescribed (see Table 1 for patient demographic distribution). Ceftolozane-tazobactam was prescribed in 4157 (48%), 3660 (42.3%) ceftazidime-avibactam, 1060 (12.2%) cefiderocol, 456 (5.3%) meropenem-vaborbactam, and 99 (1.1%) imipenem-relebactam. Most patients who received newer antibiotics (69%, n=5,998) received them for greater than 3 days. Of these, ceftolozane-tazobactam was prescribed in 2607 admissions (43.5%), 2505 (41.7%) ceftazidime-avibactam, 832 (13.9%) cefiderocol, 332 (5.5%)meropenem-vaborbactam, and 68 (1.1%) imipenem-relebactam for greater than 3 days. Sepsis was the most common clinical indication for receipt of newer agents, followed by urinary tract infection (Table 2). Conclusion Ceftazidime-avibactam and ceftolozane-tazobactam remain the most frequently prescribed new antibiotics, with uptake of subsequently approved agents trailing. Most of the prescribing of these antibiotics are for sepsis. Disclosures Anthony Harris, MD, MPH, Innoviva: Advisor/Consultant|UpToDate: Infection Control Editor Kimberly C. Claeys, PharmD, PhD, bioMérieux: Advisor/Consultant|bioMérieux: Honoraria

Background:In recent years, new broad-spectrum antibiotics targeting Gram-negative organisms have been introduced, including cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, eravacycline, imipenem-relebactam, omadacycline, and meropenem-vaborbactam. This study aimed to describe new antibiotic use across a large national cohort. Methods:We performed a retrospective cohort study of hospital discharges from June 2022 to May 2023 using the Premier Healthcare Database. Antibiotic utilization was ascertained from daily charges. Clinical indication(s) were inferred from International Classification of Diseases, 10th revision, diagnosis codes. Antibiotic therapy was considered definitive if continued >3 days. Piperacillin-tazobactam was used as a comparator. Results:Across 832 hospitals, 3 890 557 admissions (61.9% of all admissions) included an antibiotic prescription. New antibiotics were prescribed in 9768 admissions (0.25% of antibiotic-prescribing admissions) across 537 hospitals. Ceftolozane-tazobactam was prescribed in 4157 admissions (42.6% of 9768), ceftazidime-avibactam in 3660 (37.5%), eravacycline in 1213 (12.4%), cefiderocol in 1060 (10.9%), meropenem-vaborbactam in 456 (4.7%), omadacycline in 104 (1.1%), and imipenem-relebactam in 99 (1.0%). In contrast, piperacillin-tazobactam was prescribed in 731 719 (18.8%) and colistin in 570 (0.01%) admissions. Forty-six percent (n = 4647/9768) of new antibiotics were started in the first 3 days of hospital admission, and 70% (n = 6799/9768) were used as definitive therapy. Sepsis (76%), pneumonia (46%), and urinary tract infection (39%) were the most common clinical indications. On average, patients treated with new antibiotics had 8 more comorbid conditions than patients receiving piperacillin-tazobactam. Conclusions:Ceftazidime-avibactam and ceftolozane-tazobactam remain the most frequently prescribed new antibiotics, with uptake of subsequently approved agents trailing. New antibiotics are most commonly used as treatment for sepsis among patients with multiple comorbidities.