BACKGROUND:Antibiotic overuse for acute respiratory tract infections (ARTIs) remains common in emergency departments (EDs), but national trends among older adults are not well described. METHODS:We conducted a retrospective cohort study of US ED encounters in Epic Cosmos (January 2013-December 2025) among adults aged 65 years or older with never-appropriate ARTI diagnoses. Monthly antibiotic overuse (ED administration and/or discharge prescription) was evaluated with segmented regression around Centers for Disease Control and Prevention (CDC) Core Elements (November 2016), The Joint Commission (TJC) ambulatory stewardship standard (January 2020), COVID-19 onset (March 2020), and Centers for Medicare & Medicaid Services (CMS) interpretive guidance (July 2022). RESULTS:Among 838,929 encounters, antibiotic overuse occurred in 38.5%. In the primary model, estimated 12-month changes were -5.0 percentage points (95% CI, -7.1 to -3.0; P < .001) around the CDC milestone and -15.7 percentage points (95% CI, -31.3 to -0.1; P = .049) around TJC. Estimates around COVID-19 and CMS were less stable. DISCUSSION:Declines were most consistent around the CDC milestone; later estimates were limited by closely spaced interruptions and pandemic disruption. CONCLUSIONS:ED-focused outpatient stewardship remains needed for older adults with never-appropriate ARTIs.

INTRODUCTION:Invasive fungal infections caused by Fusarium and other rare hyalohyphomycetes, such as Scopulariopsis and Paecilomyces species, can lead to devastating localized and disseminated infections in vulnerable patient populations. Currently employed antifungal agents exhibit limited effectiveness for these molds. Over the past few years, the approval of new antifungals and the ongoing development of others in clinical trials offer promising new therapeutic options for treating these infections. AREAS COVERED:In this review, utilizing PubMed literature review, we delve into selected hyalohyphomycoses and provide an overview of the pharmacokinetics and pharmacodynamics of rezafungin, ibrexafungerp, olorofim, and fosmanogepix. We examine the available in-vitro and in-vivo efficacy data for these antifungals. Rezafungin and ibrexafungerp inhibit different steps in the synthesis of (1,3) β-d-glucan, and rezafungin is a notably long-acting echinocandin; however, both have primarily been studied against candidiasis. Olorofim and fosmanogepix, in contrast, are novel antifungals in development with unique mechanisms of action with activity against hyalohyphomycoses. EXPERT OPINION:Both rezafungin and ibrexafungerp have limited efficacy and clinical experience in treating mold infections. Fosmanogepix and olorofim hold promise for treating invasive mold infections, including hyalohyphomycoses; however, given in-vitro antifungal susceptibility variability against hyalohyphomycetes, and lack of clinical trial information, future studies are needed.

Background:Older adults evaluated in emergency departments (EDs) frequently receive antibiotics, but the relationships among neighborhood deprivation, antibiotic decision concordance, and downstream outcomes remain incompletely defined. Methods:We conducted a retrospective cohort study of 1 365 957 ED encounters among adults aged ≥65 years at 119 CommonSpirit Health facilities across 15 US states (2015-2024). Census-tract Social Deprivation Index (SDI) was standardized for modeling. Indication-level concordance, overuse, and underuse were based on antibiotics administered during the index ED encounter and an encounter-level diagnosis-tier framework. Outcomes were length of stay (LOS), 30-day ED revisit, mortality, Clostridioides difficile infection (CDI), and desirability of outcome ranking (DOOR). Results:Associations between higher SDI and outcomes were statistically detectable but small in absolute magnitude. Guideline-concordant management was associated with shorter LOS, better DOOR, and lower revisit, mortality, and CDI risks; overuse was consistently associated with worse outcomes, whereas underuse showed mixed associations. Concordance mediated only a small share of SDI-associated outcome differences. Sensitivity analyses using a 4-level DOOR outcome, modified Poisson relative risks, and study-period stratification supported the principal interpretation. Conclusions:Neighborhood deprivation had small absolute associations with short-term outcomes. Indication-level concordance and avoidance of overuse were associated with more substantial outcome differences but explained little of the deprivation-associated variation.

BACKGROUND:Cefepime and piperacillin-tazobactam are commonly used broad-spectrum antibiotics used to treat patients with potential gram-negative bacterial sepsis. Piperacillin-tazobactam has been shown to be associated with acute kidney injury (AKI). However, it has not been compared with cefepime in patients with septic shock. We compared the effects of cefepime and piperacillin-tazobactam on the incidence of severe AKI in patients with septic shock. METHODS:This was a retrospective, multicenter, inverse probability-of-treatment weighted cohort study conducted in 220 geographically diverse community and teaching hospitals across the United States. Adult patients were included if they had septic shock on hospital admission and received cefepime or piperacillin-tazobactam. The proportions of patients in whom stage 3 AKI occurred during hospitalization were compared between groups. RESULTS:Of the 8427 patients included in the final cohort, 4569 received cefepime and 3858 received piperacillin-tazobactam. Patients had a mean (SD) age of 66.2 (15.2) years, and 45.3% were female; the mean (SD) estimated glomerular filtration rate was 48 (24) mL/min/1.73 m2 on the day of admission. In the weighted cohort, stage 3 AKI occurred in 9.9% receiving cefepime and 9.8% receiving piperacillin-tazobactam (odds ratio, 0.98 [95% confidence interval, .84-1.15]; P = .82). In terms of secondary outcomes, there was no significant difference between cefepime and piperacillin-tazobactam with regard to renal replacement therapy, in-hospital death, major adverse kidney events, stage 1 AKI, stage 2 AKI, maximum recorded serum creatinine, or hospital length of stay. CONCLUSIONS:Among hospitalized patients with septic shock, there was no difference between cefepime and piperacillin-tazobactam in the occurrence of severe AKI.

BACKGROUND:Posaconazole is an example of a highly protein-bound drug (>98%) in which therapeutic drug monitoring (TDM) is commonplace. Total drug concentration is typically measured, and in the setting of hypoalbuminemia, total concentrations are lower despite no anticipated change in unbound concentration. Data support that unbound posaconazole concentration is responsible for antifungal activity and, in theory, is responsible for adverse effects that are dose-related. However, the therapeutic range of posaconazole is expressed as total concentration. The objective of this study was to investigate the use of an equation to correct posaconazole concentrations for albumin concentration as a surrogate for measurement of unbound concentration. METHODS:Data on unbound and total posaconazole concentration were acquired retrospectively from a study of posaconazole pharmacokinetics in critically ill patients. The relationship between total and unbound concentration was explored with and without albumin as a covariate using linear regression. Correction equations were used to normalize total concentration to an albumin concentration of 4.4 g/dL. RESULTS:A total of 78 pairs of total and unbound concentrations were available. Total and unbound posaconazole concentrations were determined using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The median fraction unbound was 0.00645 (interquartile range of 0.00331-0.00794). Albumin concentration plays a highly significant role in the interpretation of TDM results. In a patient with hypoalbuminemia, a corrected concentration (Ccorr) = Ct/(0.01 + 0.99·Alb/4.4), where Ct is the total concentration and Alb is the albumin concentration in units of g/dL, is suggested. This equation can be further simplified to Csim = Ct·4.4/Alb, where Csim is a close approximation of Ccorr. CONCLUSIONS:Hypoalbuminemia is associated with lower total concentrations of posaconazole; however, the "active" unbound concentration is not expected to systematically change. As a result, total posaconazole concentrations in the therapeutic range for patients with hypoalbuminemia are more likely to be associated with toxicity, especially when doses are increased to achieve "therapeutic" concentrations.

Nikkomycin Z is an investigational antifungal agent that inhibits chitin synthesis. The drug shows promise against endemic fungi such as Coccidioides spp. The purpose of this study was to determine the pharmacokinetics and safety when administered as multiple, ascending doses in healthy subjects. Healthy adult volunteers received nikkomycin Z in oral doses ranging from 250 mg twice daily to 750 mg three times a day for 14 days. An intensive pharmacokinetic study was conducted after the first dose (day 1) and after the last dose (day 14). Subjects were also monitored for safety and tolerance but were not confined to the facility continuously. Doses were tracked by self-reporting and were observed prior to intensive pharmacokinetic studies. On day 14, the mean (sd) maximal concentration ranged from 3.70 (1.08) to 6.89 (1.59) mg/L, and mean time of maximal concentration ranged from 2.3 to 3.0 h. The mean area under the time curve from time 0 to end of the dosing interval (8 or 12 h) was 17.3 (5.2) mg h/L for 250 mg twice daily, 28.5 (9.5) for 500 mg twice daily, 34.5 (10.9) for 750 mg twice daily, and 35.6 (8.4) for 750 mg thrice daily. The mean half-life ranged from 1.94 to 2.18 h. Bioavailability was less than proportional to dose for the 750 mg doses. Nikkomycin Z was well tolerated, and the study was completed without any serious safety concerns. This study supports continued development of nikkomycin Z as a potential therapeutic for the treatment of coccidioidomycosis.

PURPOSE:Estimated glomerular filtration rate (eGFR) is the standard for categorizing renal function. Current creatinine-based estimates have been demonstrated to have limited accuracy, with national organizations encouraging use of cystatin C to calculate eGFR. This study aimed to describe the relationship between eGFR calculated using serum cystatin C (eGFRcysC) vs serum creatinine (eGFRcreat) using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. METHODS:A retrospective review was performed for the period from July 2018 through June 2022 that included inpatient adults with a measured serum cystatin C level and a paired serum creatinine level obtained within 24 hours of each other. eGFRcreat and eGFRcysC were calculated using the CKD-EPI equations. The primary objective was to identify factors that were significantly associated with discordance between eGFRcysC vs eGFRcreat, which was expressed as the percentage difference in eGFR (eGFRpct_diff). Differences in eGFRpct_diff by patient subgroup were assessed using a paired t test or ANOVA as appropriate. Univariate and multivariate regression analyses were performed to further identify variables associated with eGFRpct_diff. RESULTS:The study population included 226 patients. The mean (95% confidence interval) eGFRpct_diff by patient subgroup was as follows: CKD stage 4, 45.0% (25.6% to 64.4%); weight loss of greater than 10% in 1 year, -33.9% (-45.6% to -22.2%); cancer, -36.1% (-48.2% to -24.1%); and hemiplegia, -32.7% (-46.2% to -19.2%). Thirty-seven patients had at least one 24-hour urine collection for determination of creatinine clearance. Measured 24-hour creatinine clearance was better correlated with eGFRcysC (R2 = 0.754) than it was with eGFRcreat (R2 = 0.557) or creatinine clearance calculated using the Cockcroft-Gault creatinine equation (R2 = 0.288). CONCLUSION:Cautious interpretation is recommended when estimating renal function from serum creatinine alone in patients with conditions associated with loss of muscle mass, including weight loss, cancer, hemiplegia, and immobility.

Coccidioidomycosis poses a significant cost and morbidity burden in the United States. Additionally, coccidioidomycosis requires constant decision-making related to prevention, diagnosis, and management. Delays in diagnosis lead to significant consequences, including unnecessary diagnostic workup and antibacterial therapy. Antifungal stewardship considerations regarding empiric, prophylactic, and targeted management of coccidioidomycosis are also complex. In this review, the problems facing antimicrobial stewardship programs (ASPs) in the endemic region for coccidioidomycosis, consequences due to delayed or missed diagnoses of coccidioidomycosis on antibacterial prescribing, and excess antifungal prescribing for prevention and treatment of coccidioidomycosis are elucidated. Finally, our recommendations and research priorities for ASPs in the endemic region for coccidioidomycosis are outlined.

Background:Our study aimed to assess whether there was a relationship between graduating from higher-ranked medical schools and the rate of prescribing antibiotics among Medicare Part D providers in the USA. Methods:The study obtained data from the Medicare Part D Prescribers (FY2013-2021) and the Doctor and Clinicians National repositories. A regression model was fitted to assess the relationship between provider medical school ranking and the rate of antibiotic days supplied per 100 beneficiaries at the provider level. Results:A total of 197 540 providers were included. No association was found between the medical school ranking and the rate of antibiotics days supplied per 100 beneficiaries. Instead, the type of provider is associated with the prescription rates. Hospitalists and Emergency Medicine providers had fewer days supplied per 100 beneficiaries than Family Medicine providers. In contrast, students, more experienced providers (>20 years since medical school graduation) and females had more days supplied per 100 beneficiaries. Conclusion:Our study highlights the need for robust outpatient stewardship interventions and incorporating an outcome-based approach to antibiotic stewardship curricula in medical and mid-level provider schools.

Purpose: Creatinine-based estimates of glomerular filtration rate (GFR) have been the standard for classifying kidney function and guiding drug dosing for over 5 decades. There have been many efforts to compare and improve different methods to estimate GFR. The National Kidney Foundation recently updated the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations without race for creatinine (CKD-EPIcr_R) and creatinine and cystatin C (CKD-EPIcr-cys_R), and the 2012 CKD-EPI equation based on cystatin C (CKD-EPIcys) remains. The focus of this review is to highlight the importance of muscle atrophy as a cause for overestimation of GFR when using creatinine-based methods.Summary: Patients with liver disease, protein malnutrition, inactivity, de nervation, or extensive weight loss may exhibit markedly lower creatinine excretion and serum creatinine concentration, leading to overestimation of GFR or creatinine clearance when using the Cockcroft-Gault equation or CKD-EPIcr (deindexed). In some cases, estimated GFR appears to exceed the physiological normal range (eg, >150 mL/min/1.73 m2). Use of cystatin C is recommended when low muscle mass is suspected. One would expect discordance between the estimates such that CKD-EPIcys < CKDEPIcr-cys < CKD-EPIcr = Cockcroft-Gault creatinine clearance. Clinical evaluation can then occur to determine which estimate is likely accurate and should be used for drug dosing.Conclusion: In the setting of significant muscle atrophy and stable serum creatinine levels, use of cystatin C is recommended, and the resulting estimate can be used to calibrate interpretation of future serum creatinine measurements.

A novel Bayesian method was developed to interpret serum vancomycin concentrations (SVCs) following the administration of one or more vancomycin doses with potential varying doses and intervals based on superposition principles. The method was evaluated using retrospective data from 442 subjects from three hospitals.

conditions such as inflammation, high blood pressure, high cholesterol, and insulin resistance to earlier mortality.

Introduction: Resistant Gram-negative organisms complicate successful treatment of infectious diseases in critically ill patients as common antibiotic agents are ineffective. Knowledge of risk factors associated with antimicrobial resistant Gram-negative infections is necessary to select appropriate antibiotic agents as culture results are not available immediately. The primary objective was to identify risk factors associated with primary resistance of selected Gram-negative bacteria isolated from blood and establish a scoring method to predict primary resistance. Methods: A total of 378 cases from 390 isolates were analyzed within the Banner health system. Fifty susceptible cases were identified for each of the following organisms: Pseudomonas aeruginosa (Ps), Escherichia coli (EC), Klebsiella pneumoniae (KP), and Enterobacter cloacae (Ent. c). The number of nonsusceptible cases were 50 for EC and KP, 27 for Ent. c and 50 for Ps. Results: The presence of chronic kidney disease (CKD), peripheral vascular disease (PVD), connective tissue disease (CTD), hemi/paraplegia, ventilator use, central vascular access, transfer from long term care facility, admission from outpatient parenteral antibiotic therapy, receiving chemotherapy, history of cerebral vascular accident, diabetes with complication and history of infection within the previous 6 months were strongly associated with resistance. A logistic regression model was developed for predicting primary resistance. An individual with no risk factors for primary resistance would have a predicted probability of resistance of 27%. Further analysis of these factors is required to remove any correlation bias and to develop a prediction scoring system to determine primary resistance. Conclusions: To conclude, this study was able to identify certain risk factors to be statistically significant (p< 0.05) to determine primary resistance which will help develop a prediction scoring system that will aid in appropriate antibiotic selection for the treatment of selected Gram-negative bacteremia infections.

Abstract Background Invasive fungal infections carry a substantial risk of mortality and morbidity. Azole antifungals are used in the treatment of such infections; however, their extensive use can lead to the emergence of antifungal resistance and increased costs to patients and healthcare systems. The aim of this study is to evaluate trends in these antifungals use and costs. Methods The secular and regional trends of outpatient azole antifungals were analyzed using Medicare Part D Prescriber Public Use Files for the years 2013–2020. The total days supply (TDS), total drug cost (TDC) per 100 000 enrollees, and cost per day (CPD) were evaluated. Results The azole antifungal TDS for Medicare Part D enrollees increased by 12% between 2013 and 2020, and increases were noted for each azole. Southern US regions had the highest TDS, with Arizona having the highest TDS among US states in 2020. Cost analysis showed that TDC of all azoles has increased by 93% over the years, going up from $123 316 in 2013 to $238 336 per 100 000 enrollees in 2020. However, CPD showed an increase only for fluconazole and isavuconazole, with CPD of $1.62 per day and $188.30 per day, respectively. Conclusions Combined azole antifungal prescriptions TDS increased among Medicare Part D enrollees. The trend in CPD was mixed, whereas overall costs consistently increased over the same period. Such findings provide an insight into the impact of azole antifungal prescriptions, and increasing use could foreshadow more antifungal resistance. Continued studies to evaluate different prescribers’ trends are warranted.

Objective: This study aimed to examine the clinical risk factors for cephalosporin resistance in patients with Gram-negative bacteremia caused by Escherichia coli (EC), Klebsiella pneumoniae (KP), Enterobacter cloacae (ENC), and Pseudomonas aeruginosa (PS). Methods: This retrospective cohort study included 400 adults with Gram-negative bacteremia. The goal was to review 100 cases involving each species and approximately half resistant and half susceptible to first-line cephalosporins, ceftriaxone (EC or KP), or cefepime (ENC or PS). Logistic regression was used to identify factors predictive of resistance. Results: A total of 378 cases of Gram-negative bacteremia were included in the analysis. Multivariate analysis identified significant risk factors for resistance, including admission from a chronic care hospital, skilled nursing facility, or having a history of infection within the prior 6 months (OR 3.00, P < .0001), requirement for mechanical ventilation (OR 3.76, P < .0001), presence of hemiplegia (OR 3.54, P = .0304), and presence of a connective tissue disease (OR 3.77, P = .0291). Conclusions: Patients without the identified risk factors should be strongly considered for receiving ceftriaxone or cefepime rather than carbapenems and newer broad-spectrum agents.

The most appropriate vancomycin dosing regimen for adult obese patients is unclear, and recommendations concerning the most appropriate size descriptor and dosing interval for weight-based load and maintenance dosing regimens is yet to be determined.1 A recently published consensus guideline recommending 24-hour area under the curve (AUC24)–based dosing and monitoring includes recommendations for dosing obese patients.2 The issue of vancomycin dosing in patients with obesity is an important one since, according to the Centers for Disease Control and Prevention (CDC), the prevalence of obesity in the United States increased from 30.5% in 1999-2000 to 42.4% in 2017-2018, with the prevalence of severe obesity increasing from 4.7% to 9.2%.3 As noted in the consensus guideline, there is substantial interpatient variability in vancomycin exposure due to factors such as individual comorbidities and care setting (eg, critical care, noncritical care), and the risk of vancomycin nephrotoxicity may increase with inappropriate extended-interval dosing (intervals of ≥12 hours) based on total body weight (TBW), leading to supratherapeutic exposure (ie, AUC24 of >600 mg · h/L, assuming a vancomycin minimum inhibitory concentration [MIC] of 1 mg/L) in patients with obesity.2 The purpose of this commentary is to provide clinicians, particularly newer practitioners, with an overview of the seminal studies concerning vancomycin dosing in obese patients and expand on the obesity-related dosing recommendations provided in the recently published guideline. For the purposes of this article, definitions of obesity expressed as body mass index (BMI) are those of CDC, with class 1 obesity defined as a BMI of 30 to <35 kg/m2, class 2 obesity defined as a BMI of 35 to <40 kg/m2, and class 3 obesity, also referred to as severe obesity, defined as a BMI of 40 kg/m2 or higher.4 If specific studies under discussion use different definitions of obesity, these will be stated. These patients are at greatest risk for subtherapeutic and supratherapeutic vancomycin AUC24 values that could lead to clinical treatment failure or medication toxicity, respectively.

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