Pathway with single‐dose long‐acting intravenous antibiotic reduces emergency department hospitalizations of patients with skin infections

Abstract Objectives Emergency department (ED) patients with serious skin and soft tissue infections (SSTIs) are often hospitalized to receive intravenous (IV) antibiotics. Appropriate patients may avoid admission following a single‐dose, long‐acting IV antibiotic. Methods We conducted a preintervention versus postintervention design trial at 11 U.S. EDs comparing hospitalization rates under usual care to those using a clinical pathway that included a single IV dalbavancin dose. We enrolled adults with cellulitis, abscess, or wound infection with an infected area of ≥75 cm2 without other indications for hospitalization. Clinical pathway participants discharged from the ED received a 24‐hour follow‐up telephone call and had a 48‐ to 72‐hour in‐person visit. We hypothesized that, compared to usual care, the clinical pathway would result in a significant reduction in the initial hospitalization rate. Results Of 156 and 153 participants in usual care and clinical pathway periods, median infection areas were 255.0 (interquartile range [IQR] = 150.0 to 500.0) cm2 and 289.0 (IQR = 161.3 to 555.0) cm2, respectively. During their initial care, 60 (38.5%) usual care participants were hospitalized and 27 (17.6%) pathway participants were hospitalized (difference = 20.8 percentage points [PP], 95% confidence interval [CI] = 10.4 to 31.2 PP). Over 44 days, 70 (44.9%) usual care and 44 (28.8%) pathway participants were hospitalized (difference = 16.1 PP, 95% CI = 4.9 to 27.4 PP). Conclusions Implementation of an ED SSTI clinical pathway for patient selection and follow‐up that included use of a single‐dose, long‐acting IV antibiotic was associated with a significant reduction in hospitalization rate for stable patients with moderately severe infections. Registration: NCT02961764.


INTRODUC TI ON
Emergency department (ED) visits for skin and soft tissue infections (SSTIs) increased almost threefold between 1993 and 2005. 1 In 2009, approximately 870,000 patients were hospitalized for treatment of SSTIs in the United States, 2 with an average length of stay (LOS) of 7.3 days and total cost of $4.84 billion. 3 Several lines of evidence suggest that hospitalizations for SSTIs can be reduced. 4,5 In-hospital mortality associated with SSTIs is less than 0.5%. 4,6 Mower at al. 7 recently reported that among 2,923 patients seen in three EDs for SSTI, only 84 (2.9%) required intensive care unit (ICU) admission or operating room intervention or died. Talan et al. 8 found that among patients with SSTIs presenting to a U.S. network of 11 U.S. EDs, administration of parenteral antibiotics was the only reason for hospital admission in approximately 40% of patients, suggesting that outpatient care would be feasible in many patients if parenteral antibiotic treatment could be provided. Recently, longacting parenteral antibiotics for treatment of SSTIs have been introduced that, as a single dose, can provide definitive treatment. [9][10][11][12][13] An ED SSTI clinical pathway that could identify appropriate candidates for outpatient treatment following administration of a single-dose, long-acting intravenous (IV) antibiotic among patients who would otherwise be hospitalized could reduce hospital admissions and associated costs and improve patient satisfaction. 8,[14][15][16][17] The goal of this investigation was to determine if implementation of a clinical pathway that included use of a single-dose, longacting IV antibiotic, dalbavancin, reduced the hospitalization rate for ED patients with more advanced SSTIs. These patients had more advanced infections consistent with the definition by the U.S. Food and Drug Administration (FDA) of an acute bacterial skin and soft tissue infection (ABSSSI; e.g., an area of infection of ≥75 cm 2 ). 15,18 Therefore, we conducted a multicenter ED-based preintervention versus postintervention pragmatic clinical trial that compared the hospitalization rate associated with usual care in the preintervention period to that following implementation of a clinical pathway in the postintervention period. We hypothesized that use of a clinical pathway that incorporated dalbavancin use would be associated with a significant reduction in the initial hospitalization rate. ClinicalTrials.gov number, NCT02961764) trial at 11 U.S. academically affiliated EDs. This trial was sponsored by Allergan plc (Dublin Ireland; prior to its acquisition by AbbVie). The primary investigators (DAT, WRM, and GJM) designed the trial, had full access to the data, and vouch for the fidelity of the trial to the study protocol and statistical analysis plan and the accuracy of the results.

Design and setting
The institutional review board at each site approved the trial. Trial sites are described in the Data Supplement S1, Appendix 1 (available as supporting information in the online version of this paper, which is available at http://onlin elibr ary.wiley.com/doi/10.1111/ acem.14258/ full). Attending emergency physicians supervised care at all sites. Prior to the study, sites did not have an existing SSTI clinical pathway or dalbavancin routinely available. Each site enrolled a group of patients in the usual care period and a separate group of patients in the clinical pathway period, which allowed each site to serve as its own control. During the usual care period, we only informed providers that patients with SSTI were being studied to determine practice patterns and associated outcomes; they were not informed of the planned clinical pathway intervention or the study objective to compare between-period hospitalization rates.

Selection of patients
Patients were assessed in the ED and enrolled based on the same inclusion and exclusion criteria in both the usual care (February 2017 to January 2018) and the clinical pathway periods (March 2018 to March 2019). Enrollment criteria were created based on investigator consensus to identify patients with a moderately severe SSTI for whom parenteral therapy could be indicated due to infection severity, yet who, based on the judgment of the treating providers, could otherwise receive treatment in an outpatient setting. 15,16 SSTIs were defined as skin lesions with erythema, swelling, tenderness, and/or drainage based on physical examination and categorized as follows: abscess was defined as a closed skin lesion found to have purulent exudate upon incision and drainage, cellulitis was defined as a closed skin lesion without evidence of a wound, and wound infection was defined as an open skin lesion. We estimated lesion area by measurement of the maximal length and perpendicular width of the infection, which was outlined by a tissue marker, using the formula for an ellipse (1/4 × π × length ×width).
We enrolled patients who were ≥18 years of age with abscess, cellulitis, or wound infection of known or suspected Gram-positive etiology with an area of infection of ≥75 cm 2 . Exclusion criteria included patients with an unstable comorbidity (e.g., diabetic ketoacidosis, severe sepsis), immunosuppression, injection drug use and fever, pregnancy or breastfeeding, bilateral lower extremity involvement, severe neurological K E Y W O R D S abscess, antibacterial agents, cellulitis, critical pathways, dalbavancin, emergency department, hospital, health resources, hospitalization, skin diseases, infectious, wound infection disorder, history of allergy to glycopeptide antibiotics, suspected Gramnegative infection, infection likely to require broad-spectrum antibiotics or more intensive care (e.g., infections associated with abdominal surgery, perirectal or perineal location, diabetic foot or decubitus ulcer, or animal or human bite or requiring drainage or debridement in the operating room or intensive care), known or suspected osteomyelitis, septic arthritis, or endocarditis (Appendix 1). These enrollment criteria are consistent with the U.S. FDA's definition of an ABSSSI, 18 for which dalbavancin treatment has been FDA-approved. 19 We also required eligible patients to be willing to return for evaluation and provide informed consent. A complete description of the enrollment criteria can be found in Appendix 1.

Baseline evaluation and interventions
During both the usual care and the clinical pathway periods, we collected baseline characteristics, including demographic and clinical findings, and previous health resource utilization data. We determined comorbidities to calculate the Charlson Comorbidity Index score. 20 During the usual care period, participants were treated for SSTI  19 We informed providers (and participants later) that dalbavancin would be provided free of charge. We dosed dalbavancin at 1500 mg for participants with creatinine clearance ≥ 30 mL/min and 1,125 mg for participants with creatinine clearance < 30 mL/min not receiving regularly scheduled dialysis. 19 We also explained that participants discharged from the ED during the clinical pathway period would have a follow-up by a telephone call at about 24 hours and a scheduled visit about 48 to 72 hours after ED discharge to evaluate their clinical response. Although dalbavancin was not in routine use at any site ED during the usual care period, its use was not prohibited. During the clinical pathway period, study coordinators reminded providers of the clinical pathway at the time of patient screening for enrollment.
During both periods, the decision to admit a participant for hospital care or discharge a participant from the ED for outpatient care was at the discretion of the treating provider; neither the study hypothesis nor encouragement to discharge patients was provided during the training or postintervention phase periods. During the usual care period, follow-up care occurred but was at the discretion of the treating provider, whereas it was determined by protocol in the pathway period (see above). For participants unable to be seen back at the site, the study coordinator conducted a telephone interview. Study coordinators conducted subsequent evaluations in both time periods by telephone at 14 and 44 days after enrollment.

Outcome measures
We assessed primary and secondary outcomes by participant interview and review of the site electronic medical record for subsequent hospitalization and other health resource use. The primary outcome was hospitalization rate at the time of initial care in the population that received at least one antibiotic dose (i.e., full analysis set [FAS] population). As a secondary outcome, we assessed hospitalizations through 44 days. We chose 44 days as the follow-up period assum-  24 We administered study questionnaires including patient-related outcome surveys 14 days after enrollment; the SF-12 was also administered at baseline. Site investigators assigned hospital days and other health care events as infection-related or not and AEs as antibiotic-related or not.

Data analysis
We designed our trial as a superiority trial. Our primary hypothesis was that, compared with usual care, implementation of a SSTI clinical pathway, which included use of a single-dose of a long-acting IV antibiotic, would be associated with significant reduction in the initial hospitalization rate. We assumed an effect size of a 15-percentage-points (PP) decrease from an initial hospitalization rate of 45%. This effect size was based on estimates of the rate of hospitalization for IV antibiotics only for patients with characteristics of this study population 8 and the smallest clinically meaningful difference. With an 80% power and alpha of 0.05, we estimated the required sample size to be 322 participants (161 participants in each period), which was confirmed after a planned interim analysis once 75 participants were enrolled on usual care. The estimated final enrollment included adjustments for attrition that supported one-sided hypothesis testing (two-sample Pearson chi-square test for proportion difference with equal group weights using a normal approximation); this hypothesis assumed that the hospital admission rates comparing the preintervention and postintervention periods were 38% and 23%, respectively.
A one-sided analysis was conducted based on the assumption that introduction of a single-dose long-acting parenteral antibiotic could only decrease the hospitalization rate among patients who previously had only been admitted to receive IV antibiotics. Based on results of a planned interim analysis that was designed to check the sample size assumptions after approximately 75 usual care patients were enrolled, an adjustment was made at the time of this interim analysis (and prior to completion of the usual care period) to revise the primary outcome from total admitted hospital days to hospital admission rate at the initial episode of care at the time of the index ED visit. This change was made because a primary outcome of total admitted days was projected to require a much larger sample size and study duration than would have been feasible (interim analysis estimated over 10 times the sample size initially planned).
To test the study hypothesis, we compared hospitalization rates in the two periods using the PP difference and 95% confidence intervals (CIs) of the difference. We defined superiority to exist if the lower limit of the CI for the difference in the admission rates between usual care and the clinical pathway exceeded zero. We presented secondary outcomes in the FAS population by descriptive analyses with PP differences and 95% CIs of the differences.
We performed descriptive analyses on categorical and continuous variables. Results of these descriptive assessments are presented in terms of proportions and CIs (categorical data), and medians and interquartile ranges (IQRs; continuous data). To assess the potential for confounding factors, we conducted an adjusted multivariate logistic regression analysis predicting hospital admission using stepwise selection (threshold of p < 0.1) from a predetermined list of variables identified a priori due to clinical relevance. Our final variables for adjustment included age, race, insurance type, prior resource use (no/yes), and systemic inflammatory response syndrome (SIRS) score (<2 vs. ≥2). Finally, we conducted a time-series analysis based on the weekly proportion of patients admitted to assess the potential effects that temporal factors, including trends (assessed using the runs test) and autocorrelation (one-lag apart autocorrelation values and Durbin-Watson statistic), might play in admission rates.

Characteristics of study participants
Patient screening, enrollment, and follow-up are described in Demographic and baseline clinical characteristics among participants in the usual care and pathway periods were similar (Table 1).
Among all 309 participants in the study population, 64% were male.  F I G U R E 1 During the usual care and clinical pathway periods, patients were selected if they fulfilled eligibility requirements, i.e., adults with cellulitis, abscess, or wound infection with an infected area of ≥75 cm 2 and a known or suspected Gram-positive infection without other indications for hospitalization (e.g., unstable coorbidities, requiring the operating room or intensive care). In the usual care period, participants were treated for SSTI based on usual care. Once the usual care period was completed, over 2 to 4 weeks prior to the initiation of the clinical pathway period, each site's principal investigator and study coordinators trained physicians and other ED staff on the clinical pathway. During the clinical pathway period, all participants were administered a single IV dose of dalbavancin in the ED. For participants who did not have follow-up contact through 44 days, it was assumed that there were no additional hospitalizations beyond the last followup contact if review of their electronic medical records at the site hospital did not identify subsequent hospital admission. SSTI, skin and soft tissue infection   In addition to reduction of total hospital admissions (i.e., initial hospitalization and readmission over 44 days), the safety of this 3.0 days. 29 Although dalbavancin was not routinely available to sites during the usual care period, it could be used and was provided to two participants in this period. Thirty percent of participants receiving dalbavancin also had an oral antibiotic prescribed, which likely reflected some providers' misunderstanding about the drug's activity or duration of action, but this should not have affected outcomes for presumed Gram-positive SSTI.
In retrospect, we wish we had better tracked the specific reasons for patient exclusion. Our group previously found that about 15% of ED patients presenting with SSTI were hospitalized and by far the most common reason for admission was IV antibiotics (85%), which was the sole reason in about 40%. 8 Therefore, it is conceivable that about one-third of those intended to be hospitalized, or about 5% of SSTI patients overall, the proportion of SSTI patients we enrolled, might qualify for outpatient care following single-dose parenteral antibiotic treatment. Thus, we believe that our findings likely apply to most adults with SSTI with an area of infection of ≥75 cm 2 , but these results should not be applied to other patients who have any of the conditions described in the study's exclusion criteria.

CON CLUS IONS
Implementation of an ED skin and soft tissue infection clinical pathway for patient selection and follow-up that included use of a single-dose, long-acting IV antibiotic was associated with a significant reduction in hospitalization rate for stable patients with moderately severe infections.

ACK N OWLED G M ENTS
The

CO N FLI C T O F I NTE R E S T
DAT has received consulting fees from AbbVie Inc., GSK, and Spero.
GJM has received consulting fees from AbbVie Inc. and funding for clinical research from Cempra, Contrafect, and Nabriva. WRM, FAL, RER, and MTS received consulting fees from AbbVie Inc. KK and PG are employees of AbbVie Inc. and may have AbbVie stock. RC was an employee of ICON plc, the CRO supporting study conduct.

AUTH O R CO NTR I B UTI O N S
All authors met the ICMJE authorship criteria. All authors conceived and designed the protocol and developed the methodology. All authors played a role in the trial design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. All authors directed development of the manuscript and reviewed and commented on all manuscript drafts. All authors read and approved the final manuscript. Specific author roles in the study are described in Appendix 1.