Improving Post-discharge Antimicrobial Use: a Multicenter Stepped Wedge Trial Study
Phase: NA
Conditions: Infections
Sponsor: Iowa City Veterans Affairs Medical Center

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Improving post-discharge antimicrobial use: a multicenter stepped wedge trial 
 
Protocol date March 24, 2023 
Version 1.5 
 
Principal investigator: Daniel Livorsi, MD, MSc 
Data analyst/statistician: Amy O’Shea, PhD 
 
 

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BACKGROUND 
 
Antimicrobial stewardship programs (ASPs) often restrict their activities to inpatient 
antimicrobial-prescribing. However, at least 40% of all antimicrobial exposure associated with 
an acute-care hospital stay is prescribed at the time of hospital discharge (i.e., post-discharge).1-
3 Post-discharge antimicrobials mediate clinical outcomes after discharge and may facilitate the 
spread of antimicrobial resistance. 
 
Several studies have shown that post-discharge antimicrobial use is often inappropriate. We 
used national data to show that 61% of fluoroquinolone treatment days were prescribed at 
hospital discharge; manual chart reviews at 9 hospitals found that 40% of these post-discharge 
fluoroquinolone prescriptions were either unnecessary or sub-optimal.4 Other studies have 
found that 53-79% of all post-discharge antimicrobials are either unnecessary or sub-optimal.5-7 
 
Post-discharge antimicrobials are an important target for antimicrobial stewardship. However, 
inpatient stewardship metrics do not capture post-discharge antimicrobials and ASPs frequently 
do not evaluate these prescriptions. A 2016 Veterans Health Administration (VHA) survey found 
that less than 50% of hospitals routinely reviewed targeted antimicrobials at discharge.8 
According to a 2016 survey in Michigan, only 17% of 48 hospitals had a process for reviewing 
outpatient antimicrobial orders at discharge.9 Nearly all hospitals responding to these two 
surveys reported that they had an inpatient ASP. 
 
We currently do not know how inpatient ASP resources can be effectively leveraged to improve 
post-discharge antimicrobial use. Several randomized-controlled trials have demonstrated that 
post-prescription audit-and-review (PPR) can reduce and improve inpatient antimicrobial use, 
but these studies did not measure the effect of PPR on post-discharge antimicrobial use.10-12 
Two single-center non-randomized studies, including a study by our team of investigators, 
showed that inpatient PPR can decrease and improve post-discharge antimicrobial use.1, 13 
However, these findings may not be generalizable to other settings.  
 
If the goal is to improve post-discharge antimicrobial use, a potentially effective strategy may be 
a PPR process focused solely on prescriptions for patients who will soon be discharged. 
However, such a PPR intervention would require an innovative approach, as ASPs typically do 
not know when patients will be discharged. 
 
METHODS 
 
Trial design:  
 
We will perform a stepped-wedge cluster-randomized trial to assess the effectiveness of 
discharge- post-prescription audit-and-review (i.e. discharge-PPR) in safely reducing post-
discharge antimicrobial use.  
 
There are ten sites taking part in this study. Based on the stepped wedge study design, 
randomization will be performed at the site-level with all eligible patients having access to the 
intervention once a site has entered the intervention phase. Each facility will begin in control 
status with one facility crossing into the intervention every two weeks following a 24-week 
baseline period. A simple randomization scheme using a random number generator will be used 
a priori to determine the order of implementation. Once clinical rollout is complete, all sites will 
continue to perform the intervention for another 2.5-3 months. No site will perform the 
intervention for longer than 6 months. 

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Participants: We will enroll up to 9 antimicrobial stewardship teams and their respective 
hospital sites (n=10). Note that one stewardship team covers two hospitals.  
 
Inclusion criteria: An acute-care hospital with an antimicrobial stewardship team 
 
Exclusion criteria: A discharge-focused PPR process is already in place or will be implemented 
soon 
 
Method of recruitment: We will recruit sites through the EpiCenter’s national conference calls 
and known professional contacts of the study PI. 
 
Interventions: 
 
Pre-intervention activities: All sites must identify a site principal investigator (PI), i.e. a physician 
who preferably has experience with antimicrobial stewardship. Each site must also identify a 
study pharmacist. Ideally, the study pharmacist will already be part of stewardship activities. 
• 
Baseline survey of ASP activities: All participating hospitals will complete an electronic 
survey about their baseline ASP activities.  
• 
Process development: Before the intervention, the pharmacist and site PI will develop a 
process for identifying eligible patients for discharge-PPR audits; this process may 
include using information technology tools and collaborating with case managers or 
discharge coordinators. 
• 
Collaborative learning calls: Nine months before the intervention begins, the study 
coordinator will start organizing collaborative learning calls for the study PI (D. Livorsi) 
and the study personnel (site PI and pharmacist) at all participating sites. During these 
monthly calls, sites will share their experience developing a process to identify patients 
who will be discharged within 48 hours. In addition, participants will review the audit-and-
feedback literature and their own personal experience with stewardship to facilitate 
discussion about the optimal approach to discharge-PPR .13-15  
Intervention activities:  
During the intervention, a study team member (either a physician or pharmacist) will perform 
discharge-PPR every weekday for patients on select medical services who are receiving an 
antimicrobial and whose discharge is anticipated within the next 48 hours. The number of 
services selected for PPR will be aimed at providing approximately 200 discharges per month 
per facility. 
  
The site PI will provide physician-support for these PPR activities. Discharge-PPR audits will 
focus on optimizing antimicrobial selection, dose, and duration before discharge. The 
pharmacist will communicate all recommendations resulting from the audit to the primary 
prescribers. Site PIs and pharmacists will also participate in the collaborative learning calls 
every month during their sites’ intervention periods. 
  
All hospitals may continue their usual stewardship activities during the trial. However, hospitals 
will be strongly encouraged to not start any other new stewardship interventions targeting 
antimicrobial-prescribing at discharge. 
 
Further description of discharge-PPR process: 
• 
Content: Real-time feedback on the selection, dose, and duration of antimicrobials 
prescribed at hospital discharge 

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• 
Delivery method: Feedback will be preferably delivered in-person or by telephone. 
Electronic, asynchronous communication may also be used. 
 
• 
Unit of delivery: The feedback will be given to an inpatient provider directly caring for the 
patient who is receiving antimicrobials. 
 
• 
Deliverer: Feedback will be delivered by the participating stewardship teams or involved 
extenders. 
 
• 
Setting: The intervention will be delivered on the acute-care hospital units before 
patients receiving antimicrobials are discharged. 
 
• 
Exposure quantity and duration: Feedback will be given during weekday working hours. 
 
• 
Time span: 2-6 months, depending on when a site is randomized to the intervention 
 
• 
Activities to increase compliance or adherence: Baseline education about duration of 
antimicrobial therapy for common infections treated in hospitalized patients. 
 
Objectives: 
 
AIM 1: Evaluate whether discharge post-prescription audit-and-review (PPR) can safely reduce 
post-discharge antimicrobial use across participating hospitals. 
Hypothesis 1: The discharge audit-and-feedback intervention will reduce post-discharge 
antimicrobial use without adversely affecting patient safety. 
 
AIM 2: Through monthly collaborative learning calls with participating sites, determine barriers 
and facilitators encountered by antimicrobial stewardship teams in their implementation of the 
discharge-PPR process. 
 
Outcomes:  
 
We will use the RE-AIM framework (page 6) to assess our pilot trial. Clinical outcomes are listed 
below. Data for all clinical outcomes will be extracted from the respective data systems of each 
participating site. All data will be submitted to the project PI for final data analysis. 
 
Primary outcome 
The primary outcome will be post-discharge antimicrobial length of therapy (LOT) per 100 
admissions. This outcome will be collected every two weeks during the study period for all 
services or wards participating in the project. 
 
Secondary outcomes 
 
Additional outcomes will include inpatient antimicrobial use (inpatient LOT per 100 admissions), 
length of stay, and 30-day hospital re-admission rates. These secondary outcomes will only be 
measured for patients who were discharged from a participating service or ward.  
 

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Process measures: Each day, the study pharmacist will record the number of patients audited 
during discharge-PPR, the number of PPR recommendations communicated to providers, and 
the number of recommendations that were accepted.  
 
Implementation outcomes: We will use the RE-AIM framework to assess our intervention. 
Feasibility will be evaluated on 2 domains: 1) the development of a local process to identify 
patients who are on antimicrobials within 48 hours of hospital discharge, and 2) the initiation of 
the discharge-PPR intervention. To further understand the implementation process, the study 
coordinator will take notes during the collaborative learning calls. We will also record these calls. 
We will perform a rapid template analysis to describe each site’s implementation process, 
including barriers and facilitators to successful implementation.16 Through a weekly survey, we 
will also assess each site’s fidelity to the discharge-PPR process and the cost (i.e. time) of the 
intervention. Through a post-intervention electronic survey, we will assess the acceptability of 
discharge-PPR to frontline prescribers.  
 
Sample Size:   
We will calculate the average post-discharge LOT per 100 admissions every two weeks and will 
include 10 sites. For these power calculations, we assume: 1) an intra-cluster correlation of 
0.75; 2) an effect size of 10% from the baseline average post-discharge LOT per 100 admission 
of 135; 3) 100 discharges per site every two weeks; ; 4) a cluster-level standard deviation of 3.4; 
5) a Type I error rate of 5%, and 6) a constant treatment effect regardless of exposure time.  
Given these assumptions, under a stepped wedge study design with 1) each step lasting 2 
weeks (24 measurements/site over 48 weeks total); 2) all 10 facilities starting in control status 
and 1 facility crossing into intervention status every 2 weeks following a baseline period of 24 
weeks and ending with all facilities in intervention status in the final two-week block, we have 
more than 90% power to determine a statistical difference when discharge-PPR is used.  
 
Blinding: None 
 
Unit of Analysis: Each medical center  
 
Statistical Methods: We will evaluate the effectiveness of implementing a discharge-focused 
process for post-prescription audit-and-review (PPR) via a generalized linear mixed model with 
identity link. The primary outcome will be post-discharge length of therapy (LOT) per 100 
admissions. This model will include step and intervention indicators as fixed effects and a 
random intercept for cluster to account for facility-level factors. This model structure can provide 
proper weighting when cluster sizes vary and account for repeated measurements over time. 
Confounding variables (select covariates that may be associated with optimal antimicrobial 
prescribing) will be adjusted for statistically by inclusion in the model framework. 
 
 

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Applying the RE-AIM implementation framework to our evaluation of this pilot study’s 
findings 
Dimension 
Definition1 
Measurement 
Reach 
The absolute number, proportion and 
representativeness of individuals who are 
willing to participate in a given initiative or 
program, and reasons why they do or do not 
participate  
Who actually participates or is exposed to the 
initiative? 
Monitor the number of 
prescribers at each site 
who receive feedback. 
Effectiveness 
The effect of an intervention on important 
individual outcomes, such as clinical events, 
quality of life,  and economic outcomes 
 
See primary and 
secondary outcomes, as 
listed above 
Adoption 
The absolute number, proportion and 
representativeness of settings and agents 
who are willing to start a program and why 
they are willing to start it 
Where is the program applied and who 
applied it? 
Describe the location and 
complexity of the  
intervention sites. During 
the introductory call, ask 
the teams at the 
intervention sites why 
they want to participate.  
Implementation 
Fidelity to the key elements of an evidence-
base practice, including consistency of 
delivery as intended and the time and cost of 
the program 
 
How consistently was the program delivered? 
How was it adapted to each setting? How 
much did it cost? Why did it achieve the 
observed result? 
Measure fidelity by 
tracking the number of 
audits performed and 
recommendations made.  
 
Measure acceptability 
with a post-intervention 
survey of frontline 
prescribers. 
 
Measure implementation 
cost by having the project 
team track the time 
committed to project 
activities on a weekly 
basis.  
Maintenance 
The extent to which a program or policy 
becomes institutionalized or part of the routine 
organizational practices and policies. 
How long are the results of the program or 
policy sustained? 
Assess whether sites are 
still performing discharge 
audit-and-feedback 6 
months after the project 
ends 
1. All definitions are taken from https://www.re-aim.org 
 
 
 

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