The deleterious impact of inappropriate and/or excessive antimicrobial usage is well recognized. In the United States, the Centers for Disease Control and Prevention (CDC) estimates that at least 2 million people become infected with antimicrobial-resistant bacteria with 23,000 subsequent deaths and at least $1 billion in excess medical costs per year.1
In response, many healthcare organizations have developed antimicrobial stewardship programs (ASPs). Guidelines co-sponsored by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America, as well as recent statements from the CDC and the Transatlantic Taskforce on Antimicrobial Resistance, all recommend core ASP elements.2-5 The guidelines provide general recommendations on ASP structure, strategies, and activities. The recommended ASP structure is a team of physicians and pharmacists that collaborates with facility governing committees and other stakeholders to optimize antimicrobial use. While personnel with expertise in infectious diseases (ID) often lead ASPs, hospitalists are also recognized as key contributors, especially in quality improvement.6,7 Recommended strategies include prospective audit of antimicrobial use with intervention and feedback and formulary restriction with preauthorization. Recommended activities include education, creation of guidelines, clinical pathways, and order forms, and programs to promote de-escalation and conversion from parenteral (IV) to oral (PO) antimicrobial therapy. However, limited evidence exists regarding the effectiveness of these ASP core elements.8,9 While Cochrane reviews found clear evidence that particular stewardship strategies (eg, audit and feedback, formulary restriction, guidelines implemented with or without feedback, protocols, computerized decision support) can be effective in reducing antimicrobial usage and improving clinical outcomes over the long term, little evidence exists favoring 1 strategy over another.8 Furthermore, most individual studies of ASPs are single-center, making their conclusions less generalizable.
In 2012, the VA National Antimicrobial Stewardship Task Force (ASTF), in conjunction with the VA Healthcare Analysis and Information Group (HAIG) administered a survey on the characteristics of ASPs at all 130 acute care VA facilities (Appendix A). We used these survey results to build an implementation model and then assess associations between facility-level variables and 4 antimicrobial utilization measures.
Survey and Data
In 2011, the ASTF was chartered to develop, deploy, and monitor a strategic plan for optimizing antimicrobial therapy management. Monthly educational webinars and sample policies were offered to all facilities, including a sample business plan for stewardship and policies to encourage de-escalation from broad-spectrum antimicrobials, promote conversion from parenteral to oral antimicrobial therapy, avoid unnecessary double anaerobic coverage, and mitigate unnecessary antimicrobial usage in the context of Clostridium difficile infection.10
At the time that ASTF was chartered, the understanding of how ASP structures across VA facilities operated was limited. Hence, to capture baseline institutional characteristics and stewardship activities, ASTF and HAIG developed an inventory assessment of ASPs that was distributed online in November 2012. All 130 VA facilities providing inpatient acute care services responded.
We derived 57 facility characteristics relevant to antimicrobial utilization and conducted a series of factor analyses to simplify the complex dataset, and identify underlying latent constructs. We categorized resulting factors into domains of evidence, context, or facilitation as guided by the Promoting Action on Research Implementation in Health Services framework.11 Briefly, the evidence domain describes how the facility uses codified and noncodified sources of knowledge (eg, research evidence, clinical experience). Organizational context comprises a facility’s characteristics that ensure a more conducive environment to put evidence into practice (eg, supportive leadership, organizational structure, evaluative systems). Facilitation emphasizes a facility personnel’s “state of preparedness” and receptivity to implementation.
Using factor analysis to identify facility factors as correlates of the outcomes, we first examined polychoric correlations among facility characteristics to assess multicollinearity. We performed independent component analysis to create latent constructs of variables that were defined by factor loadings (that indicated the proportion of variance accounted for by the construct) and uniqueness factors (that determined how well the variables were interpreted by the construct). Factors retained included variables that had uniqueness values of less than 0.7 and factor loadings greater than 0.3. Those associated with uniqueness values greater than 0.7 were left as single items, as were characteristics deemed a priori to be particularly important to antimicrobial stewardship. Factor scales that had only 2 items were converted into indices, while factor scores were generated for those factors that contained 3 or more items.12-15
Data for facility-level antimicrobial utilization measures were obtained from the VA Corporate Data Warehouse from calendar year 2012. The analysis was conducted within the VA Informatics and Computing Infrastructure. All study procedures were approved by the VA Central Institutional Review Board.
Four utilization measures were defined as dependent measures: overall antimicrobial use; antimicrobial use in patients with non-infectious discharge diagnoses; missed opportunities to convert from parenteral to oral antimicrobial therapy; and missed opportunities to avoid double anaerobic coverage with metronidazole.
Overall antimicrobial use was defined as total acute care (ie, medical/surgical/intensive care) antibacterial use for each facility aggregated as per CDC National Healthcare Safety Network Antimicrobial Use Option guidelines (antimicrobial days per 1000 patient days present). A subanalysis of overall antimicrobial use was restricted to antimicrobial use among patients without an infection-related discharge diagnosis, as we surmised that this measure may capture a greater proportion of potentially unnecessary antimicrobial use. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)16 codes for infectious processes were identified by a combination of those classified previously in the literature,17 and those identified by finding the descendants of all infections named in the Systematized Nomenclature of Medicine--Clinical Terms.18 Next, all remaining codes for principal discharge diagnoses for which antimicrobials were administered were reviewed for potential indications for systemic antibacterial use. Discharges were considered noninfectious if no codes were identified when systemic antimicrobials were or could be indicated. For this measure, antimicrobial days were not counted if administered on or 1 day after the calendar day of surgery warranting antimicrobial prophylaxis.
Missed opportunities for conversion from parenteral to oral (IV to PO) formulations of highly bioavailable oral antimicrobials (ciprofloxacin, levofloxacin, moxifloxacin, azithromycin, clindamycin, linezolid, metronidazole, and fluconazole) were defined as the percentage of days of unnecessary IV therapy that were given when PO therapy could have been used among patients who were not in intensive care units at the time of antimicrobial administration who were receiving other oral medications, using previously described methodology.19 Missed opportunities for avoiding redundant anaerobic coverage with metronidazole were defined as the percentage of days in which patients receiving metronidazole also received antibiotics with activity against anaerobic bacteria, specifically beta-lactam/beta-lactamase inhibitors, carbapenems, cefotetan/cefoxitin, clindamycin, moxifloxacin, or tigecycline), using previously described methodology.20 Patients for whom C. difficile testing was either ordered or positive within the prior 28 days (indicating potential clinical concern for C. difficile infection) were excluded from this endpoint.
The variables derived above were entered into a multivariable model for each of the 4 antimicrobial utilization measures. The least absolute shrinkage and selection operator (LASSO) regression was used to determine significant associations between variables and individual utilization measures.21 LASSO was chosen because it offers advantages over traditional subset selection approaches in large multivariable analyses by assessing covariates simultaneously rather than sequentially, supporting prediction rather than estimation of effect.22P values were not reported as they are not useful in determining statistical significance in this methodology. A tuning parameter of 0.025 was determined for the model based on a cross-validation approach. Significant variables remaining in the model were reported with the percent change in each utilization measure per unit change in the variable of interest. For binary factors, percent change was reported according to whether the variable was present or not. For ordinal variables, percent change was reported according to incremental increase in ordinal score. For continuous variables or variables represented by factor or index scores, percent change was reported per each 25% increase in the range of the score.
Inpatient Facility Antimicrobial Stewardship Characteristics and Antimicrobial Utilization
Frequencies of key facility characteristics that contributed to variable development are included in Table 1. Full survey results across all facilities are included in Appendix B. Factor analysis reduced the total number of variables to 32; however, we also included hospital size and VA complexity score. Thus, 34 variables were evaluated for association with antimicrobial utilization measures: 4 in the evidence domain, 23 in the context domain, and 7 in the facilitation domain (Table 2).
Median facility antimicrobial use was 619 antimicrobial days per 1000 days present (interquartile range [IQR], 554-700; overall range, 346-974). Median facility noninfectious antimicrobial use was 236 per 1000 days present (IQR, 200-286). Missed opportunities for conversion from IV to PO antimicrobial therapy were common, with a median facility value of 40.4% (391/969) of potentially eligible days of therapy (IQR, 32.2-47.8%). Missed opportunities to avoid double anaerobic coverage were less common (median 15.3% (186/1214) of potentially eligible days of therapy (IQR, 11.8%-20.2%; Figure).
Overall Antimicrobial Use
Four variables were associated with decreased overall antimicrobial use, although with small magnitude of change: presence of postgraduate physician/pharmacy training programs (0.03% decrease per quarter increase in factor score; on the order of 0.2 antimicrobial days per 1000 patient days present), presence of pharmacists and/or ID attendings on general medicine ward teams (0.02% decrease per quarter increase in index score), frequency of systematic de-escalation review (0.01% decrease per ordinal increase in score), and degree of involvement of ID physicians and/or fellows in antimicrobial approvals (0.007% decrease per quarter increase in index score). No variables were associated with increased overall antimicrobial use.
Antimicrobial Use among Discharges without Infectious Diagnoses
Six variables were associated with decreased antimicrobial use in patients without infectious discharge diagnoses, while 4 variables were associated with increased use. Variables associated with the greatest magnitude of decreased use included facility educational programs for prudent antimicrobial use (1.8% on the order of 4 antimicrobial days per 1000 patient days present), frequency of systematic de-escalation review (1.5% per incremental increase in score), and whether a facility’s lead antimicrobial stewardship pharmacist had ID training (1.3%). Also significantly associated with decreased use was a factor summarizing the presence of 4 condition-specific stewardship processes (de-escalation policies, policies for addressing antimicrobial use in the context of C. difficile infection, blood culture review, and automatic ID consults for certain conditions) (0.6% per quarter increase in factor score range), the extent to which postgraduate physician/pharmacy training programs were present (0.6% per quarter increase in factor score range), and the number of electronic antimicrobial-specific order sets present (0.4% per order set). The variables associated with increased use of antimicrobials included the presence of antimicrobial stop orders (4.6%), the degree to which non-ID physicians were involved in antimicrobial approvals (0.7% per increase in ordinal score), the level engagement with ASTF online resources (0.6% per quarter increase in factor score range), and hospital size (0.6% per 50-bed increase).
Missed Opportunities for Parenteral to Oral Antimicrobial Conversion
Missed opportunities for IV to PO antimicrobial conversion had the largest number of significant associations with organizational variables: 14 variables were associated with fewer missed opportunities, while 5 were associated with greater missed opportunities. Variables associated with the largest reductions in missed opportunities for IV to PO conversion included having guidelines for antimicrobial duration (12.8%), participating in regional stewardship collaboratives (8.1%), number of antimicrobial-specific order sets (6.0% per order set), ID training of the ASP pharmacist (4.9%), and VA facility complexity designation (4.2% per quarter increase in score indicating greater complexity).23 Variables associated with more missed opportunities included stop orders (11.7%), overall perceived receptiveness to antimicrobial stewardship among clinical services (9.4%), the degree of engagement with ASTF online resources (6.9% per quarter increase in factor score range), educational programs for prudent antimicrobial use (4.1%), and hospital size (1.0% per 50-bed increase).
Missed Opportunities for Avoidance of Double Anaerobic Coverage
Four variables were associated with more avoidance of double anaerobic coverage: ID training of the lead ASP pharmacist (8.8%), presence of pharmacists and/or ID attendings on acute care ward teams (6.2% per quarter increase in index score), degree of ID pharmacist involvement in antimicrobial approvals, ranging from not at all (score=0) to both weekdays and nights/weekends (score=2; 4.3% per ordinal increase), and the number of antimicrobial-specific order sets (1.5% per order set). No variables were associated with less avoidance of double anaerobic coverage.
Variables Associated with Multiple Favorable or Unfavorable Antimicrobial Utilization Measures
To better assess the consistency of the relationship between organizational variables and measures of antimicrobial use, we tabulated variables that were associated with at least 3 potentially favorable (ie, reduced overall or noninfectious antimicrobial use or fewer missed opportunities) measures. Altogether, 5 variables satisfied this criterion: the presence of postgraduate physician/pharmacy training programs, the number of antimicrobial-specific order sets, frequency of systematic de-escalation review, the presence of pharmacists and/or ID attendings on acute care ward teams, and formal ID training of the lead ASP pharmacist (Table 3). Three other variables were associated with at least 2 unfavorable measures: hospital size, the degree to which the facility engaged with ASTF online resources, and presence of antimicrobial stop orders.
Variability in ASP implementation across VA allowed us to assess the relationship between ASP and facility elements and baseline patterns of antimicrobial utilization. Hospitalists and hospital policy-makers are becoming more and more engaged in inpatient antimicrobial stewardship. While our results suggest that having pharmacists and/or physicians with formal ID training participate in everyday inpatient activities can favorably improve antimicrobial utilization, considerable input into stewardship can be made by hospitalists and policy makers. In particular, based on this work, the highest yield from an organizational standpoint may be in working to develop order sets within the electronic medical record and systematic efforts to promote de-escalation of broad-spectrum therapy, as well as encouraging hospital administration to devote specific physician and pharmacy salary support to stewardship efforts.
While we noted that finding the ASTF online resources helpful was associated with potentially unfavorable antimicrobial utilization, we speculate that this may represent reverse causality due to facilities recognizing that their antimicrobial usage is suboptimal and thus seeking out sample ASTF policies to implement. The association between the presence of automatic stop orders and potentially unfavorable antimicrobial utilization is less clear since the timeframe was not specified in the survey; it may be that setting stop orders too far in advance may promote an environment in which critical thinking about antimicrobial de-escalation is not encouraged or timely. The larger magnitude of association between ASP characteristics and antimicrobial usage among patients without infectious discharge diagnoses versus overall antimicrobial usage also suggests that clinical situations where infection was of low enough suspicion to not even have the providers eventually list an infectious diagnosis on their discharge summaries may be particularly malleable to ASP interventions, though further exploration is needed in determining how useful this utilization measure may be as a marker for inappropriate antimicrobial use.
Our results complement those of Pakyz et al.24 who surveyed 44 academic medical facilities in March 2013 to develop an ASP intensity score and correlate this score and its specific components to overall and targeted antimicrobial use. This study found that the overall ASP intensity score was not significantly associated with total or targeted antimicrobial use. However, ASP strategies were more associated with decreased total and targeted antimicrobial use than were specific ASP resources. In particular, the presence of a preauthorization strategy was associated with decreased targeted antimicrobial use. Our particular findings that order set establishment and de-escalation efforts are associated with multiple antibiotic outcomes also line up with the findings of Schuts et al, who performed a meta-analysis of the effects of meeting antimicrobial stewardship objectives and found that achieving guideline concordance (such as through establishment of order sets) and successfully de-escalating antimicrobial therapy was associated with reduced mortality.25,26 This meta-analysis, however, was limited by low rigor of its studies and potential for reverse causality. While our study has the advantages of capturing an entire national network of 130 acute care facilities with a 100% response rate, it, too, is limited by a number of issues, most notably by the fact that the survey was not specifically designed for the analysis of antimicrobial utilization measures, patient-level risk stratification was not available, the VA population does not reflect the U.S. population at-large, recall bias, and that antimicrobial prescribing and stewardship practices have evolved in VA since 2012. Furthermore, all of the antimicrobial utilization measures studied are imperfect at capturing inappropriate antibiotic use; in particular, our reliance on principal ICD-9 codes for noninfectious outcomes requires prospective validation. Many survey questions were subjective and subject to misinterpretation; other unmeasured confounders may also be present. Causality cannot be inferred from association. Nevertheless, our findings support many core indicators for hospital ASP recommended by the CDC and the Transatlantic Taskforce on Antimicrobial Resistance,3,4 most notably, having personnel with ID training involved in stewardship and establishing a formal procedure for ASP review for the appropriateness of an antimicrobial at or after 48 hours from the initial order.
In summary, the VA has made efforts to advance the practice of antimicrobial stewardship system-wide, including a 2014 directive that all VA facilities have an ASP,27 since the 2012 HAIG assessment reported considerable variability in antimicrobial utilization and antimicrobial stewardship activities. Our study identifies areas of stewardship that may correlate with, positively or negatively, antimicrobial utilization measures that will require further investigation. A repeat and more detailed antimicrobial stewardship survey was recently completed and will help VA gauge ongoing effects of ASTF activities. We hope to re-evaluate our model with newer data when available.
The authors wish to thank Michael Fletcher, Jaime Lopez, and Catherine Loc-Carrillo for their administrative and organizational support of the project and Allison Kelly, MD, for her pivotal role in survey development and distribution. This work was supported by the VA Health Services Research and Development Service Collaborative Research to Enhance and Advance Transformation and Excellence (CREATE) Initiative; Cognitive Support Informatics for Antimicrobial Stewardship project (CRE 12-313).
The authors report no financial conflicts of interest.