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Who Can Have Parenteral Antibiotics at Home?

A Prospective Observational Study in Children with Moderate/Severe Cellulitis

Ibrahim, Laila F. MB BCh, BAO; Hopper, Sandy M. MB BS; Babl, Franz E. MD; Bryant, Penelope A. PhD

Author Information
The Pediatric Infectious Disease Journal: March 2016 - Volume 35 - Issue 3 - p 269-274
doi: 10.1097/INF.0000000000000992
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Abstract

Cellulitis is a common infection in children, but while adults who require intravenous (IV) antibiotics for moderate or severe cellulitis commonly receive it under an outpatient parenteral antimicrobial treatment (OPAT) model, children are usually admitted to hospital.1,2 In comparison with hospital admission, children treated at home do better psychologically and physically, have fewer investigations, are at decreased risk of hospital-acquired infections and have subsequent decreased use of healthcare resources.3–6 It is also cheaper and psychologically better for their families.6,7 Previous randomized trials in adults with cellulitis show OPAT is a safe and efficient model of care.8,9 OPAT may be delivered as an outpatient returning daily to the hospital, or via a hospital-in-the-home (HITH) program whereby nurses visit the patient’s home daily to administer IV antibiotics. Although OPAT has been used in children since the 1970s for those requiring long-term antibiotics, it is less commonly used for acute infections requiring short-term antibiotics.10,11

When IV treatment is required for cellulitis, a semisynthetic penicillin or first-generation cephalosporin are the usual choices because they are effective against Staphylococcus aureus and group A streptococci (Streptococcus pyogenes), the main pathogens causing cellulitis.12 However, they are not suitable for OPAT because of their frequent dosing with the majority of OPAT services only able to deliver once daily interventions. Although probenecid can overcome this problem for adults on cefazolin, there are no pharmacokinetic studies of its use children, and the side effect of vomiting may prevent probenecid use.9 Ceftriaxone has anti-staphylococcal activity and can be administered once daily.13 There are only a few studies in children in which ceftriaxone has been used to treat cellulitis either in hospital or OPAT, and although promising, none have compared outcomes to children treated with the standard-of-care inpatient therapy.11,13–16

Increasingly hospitals are developing programs where patients who have traditionally been treated as inpatients are treated at home under the care of hospital doctors and nurses in HITH programs. The Royal Children’s Hospital (RCH) Melbourne has the largest pediatric HITH program in Australia. As an alternative to hospital admission for IV flucloxacillin, RCH HITH recently developed a direct-from-the Emergency Department (ED) pathway for moderate/severe cellulitis, using once daily ceftriaxone and medical review at home. However, currently, there are no guidelines about which patients can be transferred to HITH to receive treatment at home. Therefore, the decision between hospital-based and home-based treatment is made variably by ED clinicians. A new pathway should be as safe and as effective as the current standard of care, so evaluating clinical features and outcomes provides evidence to inform guidelines.17

The aim of this study was to describe the demographics, clinical and microbiological features, outcomes and cost of a cohort of patients with moderate/severe cellulitis who were treated with IV ceftriaxone at home. Additionally, we aimed to compare these with patients concurrently admitted to hospital with the same diagnosis, to determine the differences between these 2 groups at presentation and whether treatment via HITH affected outcomes unfavorably. Based on our findings, we aimed to propose a guideline for which patients with cellulitis can safely receive IV antibiotics at home.

METHODS

Setting

This was a prospective observational study of children presenting to the ED at the RCH Melbourne over a 17-month period from September 1, 2012 to January 31, 2014 with uncomplicated moderate/severe cellulitis and treated at home. As there is no validated or objective score for distinguishing moderate/severe from mild cellulitis, this was defined in the study as those assessed by ED physicians as requiring IV antibiotics because of any of the following clinical features: rapidly spreading redness (from history), significant swelling/redness/pain, systemic symptoms/signs (eg, fever, lethargy) or failed oral therapy (not improving despite at least 24 hours oral antibiotics).

Inclusion Criteria

Patients aged 3 months to 18 years with moderate/severe cellulitis who were referred by ED clinicians directly to the HITH program for IV ceftriaxone were included.

Exclusion Criteria

Children younger than 3 months, those with mild or complicated cellulitis and those where the initial antibiotic choice within HITH was not ceftriaxone were excluded. Complicated cellulitis included cellulitis associated with abscess requiring surgical drainage, lymphadenitis, underlying soft-tissue malformation, bite or penetrating injury, foreign body, fracture, lymphedema, orbital cellulitis, medical comorbidities or immunosuppression.

Study Procedure

Children with moderate/severe cellulitis were identified by ED clinicians and assessed for HITH suitability at presentation. They were referred to the HITH program directly from ED. This involved the ED clinician filling an online referral form and calling the admitting HITH nurse to hand over the patient. After receiving the first dose of ceftriaxone 50 mg/kg once daily in the ED, the patient went home with the peripheral cannula in situ. The HITH nurse visited the child the following day and administered IV ceftriaxone at home. This was followed by daily nursing review and daily ceftriaxone until the child was deemed suitable for oral therapy. The HITH doctor reviewed the child at least once during the course of treatment in person, via teleconferencing or by reviewing digital photographs taken by nursing staff. The decision to cease IV antibiotics was made by the HITH doctor. The HITH nurse removed the cannula upon cessation of IV therapy in the patient’s home.

Hospitalized Group

The standard of care for moderate/severe cellulitis at RCH is hospitalization with at least daily medical review and IV flucloxacillin 50 mg/kg every 6 hours. Patients who received the standard-of-care therapy were identified retrospectively from the ED electronic database (Emergency Department Information System for Oracle Version EDISAPAC 12.1 1B5). The same inclusion and exclusion criteria were applied when identifying these patients retrospectively, except for the decision to refer to HITH. Patients who did not receive IV flucloxacillin as their empiric antibiotic were excluded to enable comparison with standard recommended management.

Data Collection

Data for HITH patients were collected prospectively including demographic data and clinical information: age, sex, systemic symptoms at presentation (reported or documented fever >38°C, vomiting, tachycardia or hypotension), prior use of oral antibiotics, results from skin swab and/or blood culture if taken and timing of IV ceftriaxone administration. For all patients who were hospitalized, case notes and microbiology results were reviewed retrospectively.

Outcome Measures

The primary outcome was treatment failure, defined as admission from HITH back to hospital because of inadequate improvement at home as determined by the treating clinician.

Secondary outcomes were change of antibiotic because of poor clinical improvement, septic complications or recurrence during use or within 48 hours of ceasing empiric IV antibiotics, adverse events and readmission to hospital for the same diagnosis or death within 28 days of discharge, length of stay, duration of IV antibiotics and subsequent oral antibiotic duration. A cost analysis was also done which included the average costs of beds, consumables and overhead costs, such as administrative time, information technology, and use of hospital cars. Antibiotic costs were included but were low. A vial of ceftriaxone costs Australian Dollar (AUD) 0.60 [United States Dollar (USD) 0.46], whereas a vial of flucloxacillin costs AUD 0.94 (USD 0.72).

Data Analysis

Student t test was used to compare continuous data between the 2 groups and χ2-square test for categorical data, with a P value of <0.05 considered statistically significant.

Ethics

This study received approval from the RCH Human Research Ethics Committee (32291A).

RESULTS

Over the 17 months of the study, 700 children presented to the ED with cellulitis, of which 396 (57%) were discharged home on oral antibiotics. Of the 304 children treated with IV antibiotics, 120 were excluded from the analysis because of being younger than 3 months or having complicated cellulitis, and 40 patients were excluded for being treated with nonstandard antibiotics (Fig. 1). One hundred and forty-four children were treated for uncomplicated moderate/severe cellulitis. Forty-one were treated at home via HITH, and 103 were hospitalized, receiving the RCH standard of care. In terms of the primary outcome, none of the 41 HITH patients had treatment failure at home necessitating admission to hospital. Demographic, clinical and microbiological data were compared with those from the hospitalized patients to determine differences that might explain their different treatment location choices. Secondary outcomes were compared with determine whether treatment under HITH affected outcomes unfavorably.

F1-8
FIGURE 1:
Disposition of patients presenting to the ED with cellulitis.

Demographics and Clinical Features

Patients had similar sex distribution, but HITH patients were older than hospitalized patients (9.0 vs. 5.9 years; P < 0.01; Table 1). Of patients younger than 5 years, 58 (83%) were hospitalized. Patients treated under HITH had a higher rate of prior oral antibiotic treatment than hospitalized patients (59% vs. 40%; P = 0.04) and a lower rate of systemic symptoms, in particular fever (22% vs. 37%; P = 0.04). Only 1 patient received a fluid bolus, and no patient in either group was hypotensive. Fewer HITH patients than hospitalized patients had a blood culture taken (27% vs. 41%; P < 0.01), but no cultures were truly positive for a pathogen in either group. Patients with periorbital cellulitis were less likely to be treated under HITH than hospitalized (10% vs. 30%; P = 0.01), whereas a higher proportion of HITH patients than hospitalized patients had lower limb cellulitis (56% vs. 37%; P = 0.03). A total of 59 skin swabs were taken. The 2 most common pathogens isolated were S. aureus in 31 (22%) children and S. pyogenes in 9 (6%) children. Methicillin-resistant S. aureus (MRSA) was identified in 6 children, accounting for 10% of pathogens where a skin swab was taken.

T1-8
TABLE 1:
Comparison of Characteristics of HITH Patients and Hospitalized Patients for Uncomplicated Moderate/Severe Cellulitis

Secondary Outcomes

Two HITH patients had empirical antibiotic treatment changed because of poor clinical improvement and both cultured MRSA (Table 2). Of the hospitalized patients, 6 had empirical antibiotic treatment changed because of poor clinical improvement and 1 changed because of rapid progression (5% vs. 7%, P = 0.67). There were no complications while on IV antibiotics or within 48 hours of switching to oral antibiotics or severe adverse reactions in either group. There were no readmissions for HITH patients after discharge from the HITH program. There were 3 readmissions for hospitalized patients who had been on more than 48 hours oral antibiotics following discharge after clinical improvement on IV flucloxacillin (2 with abscesses and 1 with recurrence of cellulitis). The length of stay under medical care was 2.7 days in both groups, although this equated to inpatient bed days for hospitalized patients and days at home for HITH patients. The duration of IV antibiotic treatment was similar for both groups (HITH, 2.3 vs. hospitalized 2.5 days; P = 0.23), although subsequent oral antibiotic durations were shorter for HITH patients (HITH, 5.6 vs. hospitalized 6.9 days; P < 0.01).

T2-8
TABLE 2:
Outcomes of HITH Patients and Hospitalized Patients for Uncomplicated Moderate/Severe Cellulitis

Cost Analysis

The 41 patients treated at home were under HITH for a combined total of 110 days. The difference in antibiotic costs was small with the total number of vials of ceftriaxone for all patients costing AUD 93 (USD 72), whereas the same patients receiving flucloxacillin would have cost AUD 496 (USD 383). The bed cost differences were larger: the cost of being under HITH for 1 day for the treatment of cellulitis is AUD 530 (USD 409), compared with an inpatient medical bed for the same condition which costs AUD 1297 (USD 1001) at our hospital. Based on these costs, these 41 HITH patients cost AUD 17,600 (USD 13,589) compared with AUD 46,200 (USD 35, 674) if they had been treated in hospital, a real cost saving AUD 28,600 (USD 22,083). If all of the hospitalized patients had been treated under HITH (combined total of 275 days), the estimated cost saving would have been AUD 210,925 (USD 163,072).

DISCUSSION

This is the first study describing demographics, clinical and microbiological characteristics and outcomes of children with uncomplicated moderate/severe cellulitis treated at home. Home treatment of cellulitis under HITH appears both feasible and efficacious, particularly for older children with limb cellulitis without systemic symptoms.

The reason to compare HITH patients with inpatients is not to suggest that the 2 groups are necessarily equivalent, but to identify features associated with safe treatment under HITH and to evaluate whether the benefits of treatment at home come at a cost in any outcome measures. The measured outcomes, duration of IV antibiotics and length of stay were the same in the 2 groups analyzed. Given that the outcomes were not inferior, referral of these patients to HITH resulted in significant cost savings. As this was a new pathway, it is likely that there were other patients who could have been treated via HITH with additional cost savings. This would need to be evaluated in a prospective study.

There were differences between HITH patients and hospitalized patients. First, HITH patients were older, possibly because of concern about higher likelihood of bacteremia in younger children. This is also reflected in a higher proportion of blood cultures taken in the hospitalized group. Another difference was that hospitalized patients had more systemic symptoms (almost exclusively fever), although this did not reflect bacteremia or risk of progression to sepsis. A higher proportion of HITH patients received prior oral antibiotics, which may indicate that they had more indolent presentations rather than rapidly progressive cellulitis. Children with periorbital cellulitis were more likely to be hospitalized (only 11% were admitted under HITH). The most likely reason is uncertainty in distinguishing periorbital from orbital cellulitis at presentation especially in an uncooperative young child. One previous study of periorbital cellulitis described 42 children treated on an ambulatory basis with low rates of complications.16 However, the clinical characteristics of these patients were not specified. Other previous studies using outpatient ceftriaxone in children have either excluded or not reported on periorbital cellulitis.11,14,18

Ceftriaxone is the antibiotic of choice for home-based treatment of cellulitis because it can be administered once daily via a peripheral cannula. Use of peripheral cannula is usual practice for patients on HITH receiving short-term OPAT because these are the easiest IV access devices to insert, do not require general anesthesia and have low complication rates. Flucloxacillin at home would need to be infused over 24 hours via a central venous catheter (CVC). As the mean duration of IV antibiotics in our patient population was only 2.5 days, CVC insertion would not be justified. The only adverse event in either group in our study was a single patient with a rash secondary to cannula fixation tape. No patients needed their cannula resiting, but even if they had, the benefits still outweigh the disadvantages of a CVC.

As a novel intervention, it is important to consider whether ceftriaxone is an appropriate antibiotic regarding its effectiveness for the treatment of S. aureus infection and the potential for adverse ecological effects due its broad spectrum. Regarding effectiveness, the literature suggests a rate of <3% ceftriaxone resistance in methicillin-sensitive S. aureus.19 The few studies in children, in which ceftriaxone has been used to treat cellulitis (in hospital or as an outpatient), have not used home-based treatment, and there is a lack of comparative outcome data.11,13–16 However, treatment failure rates have been reportedly low. The rate of positive blood culture in our study was extremely low, reflected in other studies in children with cellulitis.11,20 Skin swabs were positive on 68% of occasions when they were taken and showed MRSA in 10%. Interestingly, 5 of the 6 patients with MRSA had clinical improvement with flucloxacillin or ceftriaxone. This phenomenon has been noted previously.21 Highly bioavailable oral antibiotics such as clindamycin could also be considered, although each has disadvantages, such as bad taste or side effects, and relies on the drug being orally tolerated, which is frequently not the case in young children. Our data indicate that ceftriaxone can be used to treat cellulitis successfully.

Regarding the broader effects of ceftriaxone, although likely multifactorial, in adult inpatients ceftriaxone has been associated with an increased rate of Clostridium difficile infections.22–24 Children have significantly lower rates of C. difficile disease than adults, and this has not been identified as an issue in OPAT for adults or children. Although not studied in pediatrics for the short-term treatment of cellulitis, the use of ceftriaxone has the potential to increase the selection of resistant Gram-negative organisms. Its use to treat Gram-positive pathogens should be weighed against this potential risk, although resistance is less likely to emerge with short-term use. This study was not designed to investigate this, and no other studies of the treatment of children with cellulitis have investigated subsequent other infections with resistant bacteria or changes in gut flora. This is an important area of future research.

A thorough review of the literature on cellulitis did not identify any guidelines for treating children at home. The lack of guidelines for ED clinicians regarding who can be safely treated at home is reflected in the fact that only 28% of patients in this study were treated under HITH. We propose a guideline based on the findings of this study to be evaluated prospectively (Fig. 2).

F2-8
FIGURE 2:
Proposed guideline for the referral of children with uncomplicated moderate/severe cellulitis directly from the ED for ambulatory intravenous antibiotics.

The main limitation of this study is that the data for the comparison group were collected retrospectively, although we followed guidelines for high-quality medical record review in that the abstractors were trained and study materials were piloted.27 Numbers were relatively low to detect complications, although rates were similar to other studies.11,13,15 The study was conducted at a tertiary center with pediatricians available to review patient progress as necessary. With the introduction of this pathway, medical review was incorporated to assess for complications. Lack of available medical review may limit the generalizability of our findings, although during the study it became clear that complication rates were low and that the main role of medical staff was in the decision to stop IV antibiotics.

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Keywords:

antibiotics; intravenous; hospital-in-the-home; ambulatory; cellulitis

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