Articles
Efficacy and safety of intravenous ceftriaxone at home versus intravenous flucloxacillin in hospital for children with cellulitis (CHOICE): a single-centre, open-label, randomised, controlled, non-inferiority trial

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Summary

Background

Outpatient parenteral antimicrobial therapy in children is common despite no evidence of its efficacy or safety from clinical trials. We aimed to compare the efficacy and safety of intravenous antibiotic therapy at home with that of standard treatment in hospital for children with moderate to severe cellulitis.

Methods

The Cellulitis at Home or Inpatient in Children from the Emergency Department (CHOICE) trial was a randomised, controlled, non-inferiority trial in children aged 6 months to 18 years who presented to the emergency department at The Royal Children's Hospital (Melbourne, VIC, Australia) with uncomplicated moderate to severe cellulitis. Participants were randomly assigned to receive either intravenous ceftriaxone (50 mg/kg once daily) at home or intravenous flucloxacillin (50 mg/kg every 6 h) in hospital with web-based randomisation, stratified by age and periorbital cellulitis. The primary outcome was treatment failure, which was defined as no clinical improvement or occurrence of an adverse event, resulting in a change in empiric antibiotics within 48 h of the first dose. Secondary outcomes included adverse events and acquisition of antibiotic-resistant bacteria. Outcomes were assessed in all randomised participants with outcome data (intention-to-treat population) and in all individuals who received treatment as allocated and did not have any major protocol violations (per-protocol population). For home treatment to be non-inferior to hospital treatment, the difference between groups in the proportion of children with treatment failure in the intention-to-treat population had to be less than 15%. This trial is registered with ClinicalTrials.gov, number NCT02334124.

Findings

Between Jan 9, 2015, and June 15, 2017, we screened 1135 children for eligibility, of whom 190 were randomly assigned to receive ceftriaxone at home (n=95) or flucloxacillin in hospital (n=95). The intention-to-treat analysis comprised 188 children (93 in the home group and 95 in the hospital group) because two children in the home group were found to be ineligible after randomisation and were excluded. Treatment failure occurred in two (2%) children in the home group and in seven (7%) children in the hospital group (risk difference −5·2%, 95% CI −11·3 to 0·8, p=0·088). In the per-protocol analysis, treatment failure occurred in one (1%) of 89 children in the home group and in seven (8%) of 91 children in the hospital group (−6·5%, −12·4 to −0·7). Fewer children treated at home than in hospital had an adverse event (two [2%] vs ten [11%]; p=0·048). There was no difference between groups in rates of nasal acquisition of meticillin-resistant Staphylococcus aureus or gastrointestinal acquisition of extended-spectrum β-lactamase-producing bacteria or Clostridium difficile after 3 months.

Interpretation

Home treatment with intravenous ceftriaxone is not inferior to treatment in hospital with intravenous flucloxacillin for children with cellulitis. The standard of care for the intravenous treatment of uncomplicated cellulitis in children should be home or outpatient care when feasible.

Funding

The Royal Children's Hospital Foundation and Murdoch Children's Research Institute.

Introduction

Use of intravenous antibiotics in non-inpatient settings, known as outpatient parenteral antimicrobial therapy (OPAT), has increased in children.1, 2 This change in practice is due to increased awareness among clinicians that admission to hospital can negatively affect quality of life in children, can lead to hospital-acquired infections, and is associated with greater costs than OPAT.3, 4, 5

Given the choice, children and caregivers will often choose treatment at home, an important factor as health care becomes more patient-centred.6, 7 As a result of this acceptance, OPAT has shifted rapidly from being a novel concept to an accepted model of care. However, published evidence for its use in children has not kept pace. A systematic review8 of studies published between Jan 1, 1946, and Jan 31, 2017, found only a single randomised controlled trial of OPAT in children, and its primary outcome was quality of life. The inability to mask patients and clinicians to treatment location might have discouraged trials in this field. However, most randomised controlled trials of standard in-hospital versus at-home care in adult patients have used an open-label approach,9 and this strategy could also be used in clinical trials of OPAT in children.

Research in context

Evidence before this study

We searched MEDLINE from Jan 1, 1946, to Oct 2, 2018, and Embase from Jan 1, 1974, to Oct 3, 2018, using the search terms “cellulitis/ or soft tissue infections/”, “ceftriaxone”, “outpatient”, “home care/”, and “ambulatory care/”. We limited the search to studies in children aged 18 years and younger; no language restrictions were applied. This search did not identify any randomised controlled trials investigating the efficacy or safety of home or ambulatory management of cellulitis. The only randomised controlled trial to compare home-based versus hospital-based care primarily investigated quality of life. However, several retrospective and observational studies were identified, which indicated widespread use of home or ambulatory care in children, despite the absence of robust evidence of its efficacy and safety. These studies found that some children with moderate or severe cellulitis could be successfully treated via a home or ambulatory care pathway, with readmission rates ranging from 0% to 20%.

Added value of this study

This is the first randomised controlled trial of any acute infection requiring intravenous antibiotic therapy in children to compare the efficacy and safety of home or ambulatory treatment with standard management in hospital. Findings from our study provide robust evidence that children with moderate to severe cellulitis can be effectively treated at home without the need for hospital admission. Additionally, we have shown that this management pathway is highly acceptable to families and has cost-saving benefits for the hospital. Of equal importance to clinicians, there was no sign of increased colonisation with antibiotic-resistant nasal or gastrointestinal bacteria when ceftriaxone was used for outpatient parenteral antimicrobial therapy.

Implications of all the available evidence

Our study provides the first unbiased evidence to support the existing literature and increasing practice of treating childhood infections with intravenous antibiotics outside the hospital environment. It promotes the broader uptake of home or ambulatory management of moderate to severe cellulitis so that children can avoid hospital admission. For centres without a pre-existing home-care or ambulatory service, these findings enable advocacy for resources for a similar treatment pathway. For those with existing services, this study acts as a platform to be replicated in other acute infections to increase the evidence base for home or ambulatory care.

The scarcity of evidence has not stopped clinicians from using OPAT, with an increasing number of reports of its use in institutional practice, including use of OPAT for patients directly from the emergency department, completely avoiding admission to hospital.4, 10, 11, 12, 13 The antibiotic most frequently used for OPAT in children, particularly for admission avoidance management pathways, is ceftriaxone, a broad-spectrum cephalosporin.1, 2, 13 The reasons for using ceftriaxone are that it can be administered once daily; it is given as a single dose, allowing a peripheral cannula to be inserted in the emergency department; and it is effective against many pathogens that cause common childhood infections.14 However, broad-spectrum cephalosporin use has been temporally associated with isolation of antibiotic-resistant bacteria in studies in adult inpatients.15, 16, 17 Although this finding has not been observed when ceftriaxone has been used at home, the global crisis of antibiotic resistance raises legitimate concerns, which have not been addressed for OPAT in children. It is unclear whether the benefits of OPAT outweigh the disadvantages of ceftriaxone use in this setting.

We therefore designed the first randomised controlled trial of OPAT for admission avoidance in children, using ceftriaxone to treat moderate to severe cellulitis as a paradigm. Cellulitis, a skin infection, is a common presentation to the emergency department, often but not always affecting the limbs. Although most children with cellulitis can be treated with oral antibiotic therapy, many children with moderate to severe cellulitis require intravenous antibiotic therapy; skin and soft-tissue infections in these children account for more than 74 000 hospital admissions each year in the USA.18 Cellulitis in children admitted to the hospital is usually managed with narrow-spectrum, intravenous antibiotics, such as flucloxacillin. However, flucloxacillin is administered every 6 h and so is not compatible with ambulatory use through a peripheral cannula, with ceftriaxone being the only viable alternative. For a trial of OPAT to have useful outcomes that are translatable to clinical practice, it must compare a feasible OPAT option with standard hospital treatment.

We aimed to compare the efficacy and safety of home-based treatment with intravenous ceftriaxone with that of standard treatment in hospital with intravenous flucloxacillin for children with cellulitis.

Section snippets

Study design and participants

The Cellulitis at Home or Inpatient in Children from the Emergency Department (CHOICE) trial was a single-centre, randomised, controlled, open-label, non-inferiority trial.19 Patients were enrolled from The Royal Children's Hospital, a tertiary paediatric hospital in Melbourne, VIC, Australia. The study protocol was published previously.19

Briefly, eligible participants were aged 6 months to 1 year and had presented to the emergency department at The Royal Children's Hospital with moderate to

Results

Between Jan 9, 2015, and June 15, 2017, 1135 children were screened for eligibility, of whom 190 were randomly assigned to receive treatment at home with ceftriaxone (n=95) or in hospital with flucloxacillin (n=95; figure). Two patients in the home group were found to be ineligible and were excluded post-randomisation. Thus, the intention-to-treat population comprised 188 children, including 93 in the home group and 95 in the hospital group.

Median duration of follow-up was 7 days (IQR 7–8).

Discussion

In this study, intravenous ceftriaxone at home was non-inferior to intravenous flucloxacillin in hospital for the primary outcome of treatment failure. In the per-protocol analysis, treatment failure was lower in the home group than in the hospital group. This difference was unlikely to be due to differences in the number of children who were febrile in the emergency department as, although more children in the hospital group than in the home group were febrile in the emergency department, only

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  • Cited by (25)

    • Intravenous ceftriaxone at home versus intravenous flucloxacillin in hospital for children with cellulitis: a cost-effectiveness analysis

      2019, The Lancet Infectious Diseases
      Citation Excerpt :

      A few observational studies14,15 in children have shown that moderate or severe cellulitis requiring intravenous antibiotics can be effectively and safely treated at home following discharge directly from the emergency department (instead of admitting and treating individuals as inpatients), although none have evaluated the cost-effectiveness of treatment at home. To our knowledge, the Cellulitis at Home or Inpatient in Children from the Emergency Department (CHOICE) study16 was the first randomised controlled trial (RCT) to compare the efficacy and safety of OPAT versus hospital treatment in children for the management of moderate or severe cellulitis following admission to the emergency department. Here we report the planned economic evaluation for this trial, with the aim to evaluate the cost-effectiveness of admission avoidance versus hospital treatment for moderate or severe cellulitis in children that required intravenous antibiotics.

    • OPAT for avoidance of hospitalisation in children

      2019, The Lancet Infectious Diseases
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