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

A review of the CONNECT home visitation project from the perspective of the service user

This research study was conducted on the CONNECT home visitation project which aims to alleviate loneliness among older people. The project trains volunteers to carry out a weekly one hour home visit. The volunteer talks and listens to the older people. The concept of loneliness was explored and its subjective nature outlined. Interviews were conducted with the older people to obtain their views and satisfaction with the service as well as ideas on improvements. The research indicates that the project is perceived to be a positive element to their lives. Clearer communication was the main source of recommendations made. It became evident that the older people required a better understanding of some of the elements of the project and that clearer communication would aid this

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

Chlorhexidine-alcohol versus povidone-iodine for pre-operative skin preparation: A systematic review and meta-analysis.

Background: Surgical site infection (SSI) is a dreaded postoperative complication. Although preoperative skin cleansing in order to prevent surgical site infection (SSI) is standard surgical practice, there is clinical equipoise concerning whether povidone iodine (PI) or chlorhexidine alcohol (CHA) is the antiseptic agent of choice. Objectives: To determine whether CHA or PI is the preferred preoperative skin preparation for reducing SSI in clean, clean-contaminated and contaminated surgery. Search methods: PubMed, Embase, and gray literature sources were searched for randomized controlled trials (RCTs) comparing both CHA and PI between 1980 and 2014. Comparative RCTs of preoperative CHA versus PI studying SSI in clean, clean-contaminated and contaminated surgery were included. Risk of bias was assessed using Cochrane risk of bias. Main result: We identified six eligible studies with an overall 2484 participants. The overall rate of SSI was 6.8% in the CHA group versus 11.0% in the PI group (P \u3c 0.0002). CHA was superior to PI in the prevention of SSI with a pooled RR of 0.62 (95% CI, 0.48–0.81). Conclusions: Preoperative surgical skin preparation with CHA is more effective than PI in preventing SSI across clean and clean-contaminated surgery. Further studies should evaluate the effectiveness of CHA versus PI in contaminated surgery

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