Treatment outcome measures for randomized controlled trials of antibiotic treatment for acute bacterial skin and skin structure infections in the emergency department setting

Acute bacterial skin and skin structure infections (ABSSSIs), which include cellulitis, abscesses, and wound infections, are among the most commonly encountered conditions in emergency departments (EDs) internationally. Primarily, as a result of the recent epidemic of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) in North America, ED attendances and hospital admissions secondary to ABSSSIs have increased significantly. First-line antibiotic drug therapies for ABSSSIs have therefore changed to take account of CA-MRSA and the threat of evolving antibiotic resistance. Prior to 2010, randomized controlled trials (RCTs) of antibiotic therapy for ABSSSI used broad trial inclusion criteria and utilized investigator-determined clinical resolution, 7 to 14 days after the end of therapy, as the primary outcome measure. In order to produce more objective, reproducible, and quantifiable primary outcome measures, the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research and a multidisciplinary consortium convened by the Foundation for the National Institutes of Health (FNIH) issued significantly changed trial guidance criteria. The currently recommended primary outcome measure is an assessment of greater than 20% reduction in the area of erythema, edema, or induration from baseline, measured at 48 to 72 h after randomization and initiation of drug treatment. In contrast, the European Medicines Agency (EMA) still recommends measurement of clinical resolution at a later time period. We discuss the evolution of changes to trial guidance criteria issued by the FDA since 1998 and the potential difficulties of implementing the recommended primary outcome measured at an earlier time point in RCTs of outpatient antibiotic treatment performed in the ED setting

Oral flucloxacillin and phenoxymethylpenicillin versus flucloxacillin alone for the emergency department outpatient treatment of cellulitis: study protocol for a randomised controlled trial

BACKGROUND: Oral flucloxacillin, either alone or in combination with phenoxymethylpenicillin, is a commonly prescribed antibiotic for the treatment of cellulitis, particularly in Ireland and the United Kingdom. This study aims to establish the non-inferiority of oral monotherapy (flucloxacillin alone) to dual therapy (flucloxacillin and phenoxymethylpenicillin) for the outpatient treatment of cellulitis in adults. METHODS/DESIGN: This study is a multicentre, randomised, double-blind, placebo-controlled trial of adults who present to the emergency department (ED) with cellulitis that is deemed treatable on an outpatient basis with oral antibiotics. After fulfilling specified inclusion and exclusion criteria, informed consent will be taken. Patients will be given a treatment pack containing 7 days of treatment with flucloxacillin 500 mg four times daily and placebo or flucloxacillin 500 mg four times daily and phenoxymethylpenicillin 500 mg four times daily. The primary outcome measure under study is the proportion of patients in each group in which there is greater than or equal to a 50% reduction in the area of diameter of infection from the area measured at enrolment at the end-of-treatment visit (7 to 10 days). Secondary endpoints include a health-related quality of life measurement as rated by the SF-36 score and the Extremity Soft Tissue Infection Score (not validated), compliance and adverse events. Patients will be followed up by telephone call at 3 days, end-of-treatment visit (EOT) at 7 to 10 days and test-of-cure (TOC) visit at 30 days. To achieve 90% power, a sample size of 172 patients per treatment arm is needed. This assumes a treatment success rate of 85% with oral flucloxacillin and phenoxymethylpenicillin, an equivalence threshold Δ = 12.5% and an α = 0.025. Non-inferiority will be assessed using a one-sided confidence interval on the difference of proportions between the two groups. Standard analysis including per-protocol and intention-to-treat will be performed. DISCUSSION: This trial aims to establish the non-inferiority of flucloxacillin monotherapy to dual therapy in the treatment of uncomplicated cellulitis among ED patients. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. TRIAL REGISTRATION: EudraCT Number 2008-006151-4

A systematic review of the cost of data collection for performance monitoring in hospitals.

Background: Key performance indicators (KPIs) are used to identify where organisational performance is meeting desired standards and where performance requires improvement. Valid and reliable KPIs depend on the availability of high-quality data, specifically the relevant minimum data set ((MDS) the core data identified as the minimum required to measure performance for a KPI) elements. However, the feasibility of collecting the relevant MDS elements is always a limitation of performance monitoring using KPIs. Preferably, data should be integrated into service delivery, and, where additional data are required that are not currently collected as part of routine service delivery, there should be an economic evaluation to determine the cost of data collection. The aim of this systematic review was to synthesise the evidence base concerning the costs of data collection in hospitals for performance monitoring using KPI, and to identify hospital data collection systems that have proven to be cost minimising. Methods: We searched MEDLINE (1946 to May week 4 2014), Embase (1974 to May week 2 2014), and CINAHL (1937 to date). The database searches were supplemented by searching for grey literature through the OpenGrey database. Data was extracted, tabulated, and summarised as part of a narrative synthesis. Results: The searches yielded a total of 1,135 publications. After assessing each identified study against specific inclusion exclusion criteria only eight studies were deemed as relevant for this review. The studies attempt to evaluate different types of data collection interventions including the installation of information communication technology (ICT), improvements to current ICT systems, and how different analysis techniques may be used to monitor performance. The evaluation methods used to measure the costs and benefits of data collection interventions are inconsistent across the identified literature. Overall, the results weakly indicate that collection of hospital data and improvements in data recording can be cost-saving. Conclusions: Given the limitations of this systematic review, it is difficult to conclude whether improvements in data collection systems can save money, increase quality of care, and assist performance monitoring of hospitals. With that said, the results are positive and suggest that data collection improvements may lead to cost savings and aid quality of care

The prevalence of severe sepsis or septic shock in an Irish emergency department

Severe sepsis and septic shock are among the leading causes of death globally. Despite the central role the emergency department (ED) plays in the early identification of patients presenting to hospital with sepsis, the prevalence of severe sepsis and septic shock in the Irish ED setting has not been described. The primary aim of this study was to measure the prevalence of severe sepsis or septic shock in an Irish adult ED setting. The clinical records of patients presenting to the ED over a four-week period were retrospectively reviewed to determine if they met the current Health Service Executive (HSE) criteria for severe sepsis or septic shock. Overall, 3,585 adult patients attended the ED during the study period, with 42 patients meeting the criteria for severe sepsis or septic shock. The ED prevalence of severe sepsis or septic shock was 11.7 patients (95% CI 8.1 – 15.4%) per 1000 ED attendances

What Proportion of Patients Meet the Criteria for Uncomplicated Sepsis in an Irish Emergency Department?

Emergency medicine plays a central role in the early recognition of patients presenting to hospital with sepsis. However, the epidemiology of sepsis in the Irish Emergency Department (ED) setting has not been described. The primary aim of this study was to determine the proportion of adult ED patients who meet the current criteria for uncomplicated sepsis. This cross-sectional study was performed in the ED of Beaumont Hospital, Dublin. The clinical records of all patients presenting to the ED over a four-week period were retrospectively screened to determine if they met the current Health Service Executive (HSE) criteria for uncomplicated sepsis. Overall, 3,585 adult patients attended the ED during the study period, with 152 patients meeting the criteria for uncomplicated sepsis. The proportion of ED patients who met the criteria for uncomplicated sepsis was 4.24% (95% CI 3.57-4.91%)

A pilot cross-sectional study of patients presenting with cellulitis to emergency departments.

To characterise the Emergency Department (ED) prevalence of cellulitis, factors predicting oral antibiotic therapy and the utility of the Clinical Resource Efficiency Support Team (CREST) guideline in predicting patient management in the ED setting, a prospective, cross-sectional study of consecutive adult patients presenting to 3 Irish EDs was performed. The overall prevalence of cellulitis was 12 per 1,000 ED visits. Of 59 patients enrolled, 45.8% were discharged. Predictors of treatment with oral antibiotics were: CREST, Class 1 allocation (odds ratio (OR) 6.81, 95% Cl =1.5-30.1, p=0.012), patient self-referral (OR= 6.2, 95% Cl 1.9- 20.0, p=0.03) and symptom duration longer than 48 hours (OR 1.2, 95% Cl = 1.0-1.5,p=0.049). In conflict with guideline recommendation, 43% of patients in CREST Class 1 received IV therapy. Treatment with oral antibiotics was predicted by CREST Class 1 allocation, self-referral, symptom duration of more than 48 hours and absence of pre-EO antibiotic therapy

Prevalence and predictors of initial oral antibiotic treatment failure in adult emergency department patients with cellulitis: a pilot study.

INTRODUCTION: Assessment of cellulitis severity in the emergency department (ED) setting is problematic. Given the lack of research performed to describe the epidemiology and management of cellulitis, it is unsurprising that heterogeneous antibiotic prescribing and poor adherence to guidelines is common. It has been shown that up to 20.5% of ED patients with cellulitis require either a change in route or dose of the initially prescribed antibiotic regimen. The current treatment failure rate for empirically prescribed oral antibiotic therapy in Irish EDs is unknown. The association of patient risk factors with treatment failure has not been described in our setting. Lower prevalence of community-acquired methicillin-resistant Staphylococcus aureus-associated infection, differing antibiotic prescribing preferences and varying availability of outpatient intravenous therapy programmes may result in different rates of empiric antibiotic treatment failure from those previously described. METHODS AND ANALYSIS: Consecutive ED patients with cellulitis will be enrolled on a 24/7 basis from 3 Irish EDs. A prespecified set of clinical variables will be measured on each patient discharged on empiric oral antibiotic therapy. A second independent study recruiter will assess at least 10% of cases for each of the predictor variables. Follow-up by telephone call will occur at 14 days for all discharged patients where measurement of the primary outcome will occur. Our primary outcome is treatment failure, defined as a change in route of antibiotic administration from oral to intravenous antibiotic. Our secondary outcome is change in dose or type of prescribed antibiotic. A cohort of approximately 152 patients is required to estimate the proportion of patients failing oral antibiotic treatment with a margin of error of 0.05 around the estimate. ETHICS AND DISSEMINATION: Full ethics approval has been granted. An integrated dissemination plan, involving diverse clinical specialties and enrolled patients, is described. TRIAL REGISTRATION NUMBER: NCT 02230813

The Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial: update to the study protocol and detailed statistical analysis plan (SAP)

Background: Cellulitis is a painful, potentially serious, infectious process of the dermal and subdermal tissues and represents a significant disease burden. The statistical analysis plan (SAP) for the Penicillin for the Emergency Department Outpatient treatment of CELLulitis (PEDOCELL) trial is described here. The PEDOCELL trial is a multicentre, randomised, parallel-arm, double-blinded, non-inferiority clinical trial comparing the efficacy of flucloxacillin (monotherapy) with combination flucloxacillin/phenoxymethylpenicillin (dual therapy) for the outpatient treatment of cellulitis in the emergency department (ED) setting. To prevent outcome reporting bias, selective reporting and data-driven results, the a priori-defined, detailed SAP is presented here. Methods/design: Patients will be randomised to either orally administered flucloxacillin 500 mg four times daily and placebo or orally administered 500 mg of flucloxacillin four times daily and phenoxymethylpenicillin 500 mg four times daily. The trial consists of a 7-day intervention period and a 2-week follow-up period. Study measurements will be taken at four specific time points: at patient enrolment, day 2-3 after enrolment and commencing treatment (early clinical response (ECR) visit), day 8-10 after enrolment (end-of-treatment (EOT) visit) and day 14-21 after enrolment (test-of-cure (TOC) visit). The primary outcome measure is investigator-determined clinical response measured at the TOC visit. The secondary outcomes are as follows: lesion size at ECR, clinical treatment failure at each follow-up visit, adherence and persistence of trial patients with orally administered antibiotic therapy at EOT, health-related quality of life (HRQoL) and pharmacoeconomic assessments. The plan for the presentation and comparison of baseline characteristics and outcomes is described in this paper. Discussion: This trial aims to establish the non-inferiority of orally administered flucloxacillin monotherapy with orally administered flucloxacillin/phenoxymethylpenicillin dual therapy for the ED-directed outpatient treatment of cellulitis. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. The SAP for the PEDOCELL trial was developed a priori in order to minimise analysis bias

Single dose oral dexamethasone versus multi-dose prednisolone in the treatment of acute exacerbations of asthma in children who attend the emergency department: study protocol for a randomized controlled trial.

BACKGROUND: Asthma is a major cause of pediatric morbidity and mortality. In acute exacerbations of asthma, corticosteroids reduce relapses, subsequent hospital admission and the need for ß2-agonist therapy. Prednisolone is relatively short-acting with a half-life of 12 to 36 hours, thereby requiring daily dosing. Prolonged treatment course, vomiting and a bitter taste may reduce patient compliance with prednisolone. Dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72 hours. It is used frequently in children with croup and bacterial meningitis, and is well absorbed orally. The purpose of this trial is to examine whether a single dose of oral dexamethasone (0.3 mg/kg) is clinically non-inferior to prednisolone (1 mg/kg/day for three days) in the treatment of exacerbations of asthma in children who attend the Emergency Department. METHODS/DESIGN: This is a randomized, non-inferiority, open-label clinical trial. After informed consent with or without assent, patients will be randomized to either oral dexamethasone 0.3 mg/kg stat or prednisolone 1 mg/kg/day for three days. The primary outcome measure is the comparison between the Pediatric Respiratory Assessment Measure (PRAM) across both groups on Day 4. The PRAM score, a validated, responsive and reliable tool to determine asthma severity in children aged 2 to 16 years, will be performed by a clinician blinded to treatment allocation. Secondary outcomes include relapse, hospital admission and requirement for further steroid therapy. Data will be analyzed on an intention-to-treat and a per protocol basis. With a sample size of 232 subjects (105 in each group with an estimated 10% loss to follow-up), we will be able to reject the null hypothesis - that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The Type I error probability associated with this test (of the null hypothesis) is 0.05. DISCUSSION: This clinical trial may provide evidence that a shorter steroid course using dexamethasone can be used in the treatment of acute pediatric asthma, thus eliminating the issue of compliance to treatment. REGISTRATION: ISRCTN26944158 and EudraCT Number 2010-022001-18