Best Practice Proposal to Enhance Application of the Standardized Antimicrobial Administration Ratio (SAAR).

Description A core element of hospital antibiotic stewardship programs is the tracking of outcomes. It is recommended that hospitals do this by reporting to the National Healthcare Safety Network (NHSN) Antimicrobial Use (AU) Option. With this, hospitals can access the Standardized Antimicrobial Administration Ratio (SAAR) for various antibiotic groupings and locations. While there are benefits to the SAAR, several limitations reduce the interpretation and utility of SAAR values. In particular, the SAAR cannot inform users of antimicrobial appropriateness. This article describes an antimicrobial days of therapy (DOT) report that was developed by a tele-stewardship infectious diseases pharmacist. This article proposes that a DOT report, such as the one described, is used in combination with SAAR values to better assess where improvements in antimicrobial prescribing are needed and track the progress of interventions. If not reporting to the NHSN AU Option, this type of report can help meet antimicrobial stewardship standards from The Joint Commission.

Effect of Reduced Fluoroquinolone Use on Cephalosporin Use, Susceptibilities and Clostridioides difficile Infections.

Background: Overuse of fluoroquinolones has led to concerning rates of resistance, particularly among Gram-negative organisms. They are also highly implicated as a risk factor for Clostridioides difficile infection, and reports of other serious adverse events led to recommendations to restrict their use. Our health system began targeting the reduction in unnecessary fluoroquinolone prescribing in 2018, aiming to promote their safe and effective use. Broad-spectrum cephalosporins are often used as an alternative to fluoroquinolones. We sought to evaluate whether decreased fluoroquinolone use was associated with increased third- and fourth-generation cephalosporin use and whether these changes in utilization impacted other outcomes, including C. difficile infection (CDI) rates and susceptibilities among Gram-negative organisms. Methods: This retrospective descriptive analysis included adult patients who received a fluoroquinolone or broad-spectrum cephalosporin in a three-year time period across a large healthcare system. The primary objective was to evaluate the change in days of therapy (DOT) of fluoroquinolones and third- and fourth-generation cephalosporins. Secondary objectives included rates of resistance among common Gram-negative organisms, CDI, and analyses stratified by antibiotic indication. Results: Cephalosporin use increased by an average of 1.70 DOT/1000 PD per month (p < 0.001). Additionally, fluoroquinolone use decreased by an average of 1.18 DOT/1000 PD per month (p < 0.001). C. difficile infections decreased by 0.37 infections/10,000 patient-days per month (p < 0.001). Resistance to fluoroquinolones remained stable from 2018 to 2020, and a declining trend was observed in 2021. Conclusion: This study demonstrated that reduced fluoroquinolone use in a large healthcare system was associated with increased usage of broad-spectrum cephalosporins, decreased CDI and improvements in resistance patterns.

A Pharmacokinetic-Pharmacodynamic Analysis to Dose Optimize Daptomycin in Vancomycin-Resistant Enterococcus faecium: Is the Answer Fixed Dosing or Lowering Breakpoints?

BACKGROUND: The optimal daptomycin dose for vancomycin-resistant Enterococcus faecium remains unclear. Dosing of 8 to 12 mg/kg/d has been recommended to improve outcomes, but literature suggests fixed dosing may improve methicillin-resistant Staphylococcus aureus bacteremia pharmacodynamic (PD) targets. OBJECTIVE: This study sought to evaluate weight-based versus fixed dosing of daptomycin based on pharmacokinetic and PD (PK-PD) targets in vancomycin-resistant E faecium bacteremia. METHODS: PK-PD analyses were conducted using previously published PK models for daptomycin. Probability of target attainment (PTA) was assessed for 8 to 12 mg/kg/d and various fixed doses. The percentage of simulated participants who achieved a free area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration ratio (fAUC0-24/MIC) >27.43 for susceptible dose-dependent (SDD) MICs and the probability of a minimum concentration (Cmin) > 24.3 mg/L were calculated. RESULTS: At MICs ≤2 mg/L, fixed doses had the best overall PTA. At the SDD breakpoint of 4 mg/L, all weight-based doses had <60% PTA. A fixed dose of 1500 mg/d was necessary for >/= 90% PTA at higher MICs considered SDD; however, this dose had elevated risks of Cmin ≥24.3 mg/L. CONCLUSION AND RELEVANCE: Fixed doses were more likely to achieve a fAUC/MIC of 27.43 than weight-based doses up to 12 mg/kg/d. However, fixed doses necessary for 90% PTA against SDD isolates with higher MICs were associated with elevated risks of toxicity. A reevaluation of Clinical Laboratory Standards Institute breakpoints may need to be considered, with an emphasis on lowering the SDD breakpoint to 1 mg/L.

A Fixed versus Weight-Based Dosing Strategy of Daptomycin May Improve Safety in Obese Adults.

OBJECTIVES: To compare daptomycin exposures and predicted safety outcomes with a simulated weight-based and fixed dose in morbidly obese and nonobese subjects. METHODS: We performed a nonparametric population pharmacokinetic analysis of daptomycin concentration-time data from a prior obese and nonobese kidney function-matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (Cmax ), minimum concentrations (Cmin ), and area under the curve (AUC) with the standard daptomycin 6 mg/kg/day dose or a 500-mg daily fixed dose in obese and nonobese subjects. The probability of exceeding a daptomycin Cmin target (24.3 mg/L or higher) associated with creatine phosphokinase (CPK) elevations was computed with the two regimens. RESULTS: No significant differences were observed in clearance, volume of distribution at steady state, or terminal half-life between the morbidly obese and nonobese PK models. Daptomycin 6 mg/kg/day resulted in AUC, Cmax , and Cmin values that were ~2-fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a Cmin target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage. CONCLUSIONS: Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety.

Effects of i.v. push administration on ß-lactam pharmacodynamics.

PURPOSE: The effects of i.v. push administration on the pharmacodynamic exposures of meropenem, cefepime, and aztreonam were evaluated. METHODS: Pharmacokinetic and pharmacodynamic analyses were conducted using previously published pharmacokinetic data for meropenem, cefepime, and aztreonam. The probability of target attainment (PTA) was assessed using Monte Carlo simulations for 30-minute and 5-minute infusions of approved dosing regimens and alternative dosing schemes often used in clinical practice, including 500 mg every 6 hours and 1 g every 8 hours for meropenem, 1 g every 6 hours and 2 g every 8 hours for cefepime, and 2 g every 8 hours for aztreonam. For each regimen examined, means and standard deviations for the percentage of the dosing interval that the free drug concentration remained above the minimum inhibitory concentration (MIC) were calculated and reported. RESULTS: No or only minor differences were noted between 30-minute and 5-minute infusions. The largest differences were observed at an MIC of 4 mg/L for meropenem and an MIC of 16 mg/L for aztreonam. At an MIC of 4 mg/L, meropenem 500 mg every 6 hours as a 30-minute infusion had an 8% greater PTA compared with the 5-minute infusion. At an MIC of 16 mg/L, a 30-minute infusion of aztreonam 2 g every 8 hours had a 12% greater PTA compared with the 5-minute infusion. CONCLUSION: Simulations of meropenem, cefepime, and aztreonam by i.v. push over 5 minutes indicated that there would be minimal or no effect on pharmacodynamic exposures compared with the effect when administered by 30-minute infusions.