Outpatient management of moderate cellulitis in children using high-dose oral cephalexin

Abstract

Objectives

To evaluate the effectiveness of a high-dose (HD) oral cephalexin treatment guideline for children with moderate cellulitis treated as outpatients.

Methods

In this retrospective cohort study, we included children who presented to the emergency department (ED) with moderate cellulitis and treated according to the institution’s HD oral cephalexin guideline over a 2-year period. All children had standardized follow-up at a medical day hospital (MDH). Treatment was considered effective in the absence of treatment failure, defined as admission, switch to IV treatment or ED visit within 2 weeks of discharge from the MDH. Safety was ascertained by recording adverse events and severe complications at follow-up.

Results

A total of 123 children were treated as outlined in the guideline, including 117 treated with HD oral cephalexin. The success rate was 89.7% (105/117). Among 12 (10.3%) children who had treatment failure, 10 (8.5%) required admission, 1 (0.9%) received IV antibiotics at the MDH and 1 (0.9%) had a return visit to the ED without admission. No severe complications were reported; four abscesses required drainage and one patient had a rash. The mean number of visits per child at the MDH was 1.6 (SD 1.0).

Conclusions

With a success rate of 89.7%, HD oral cephalexin seems effective and safe for the treatment of children with moderate cellulitis. Its use potentially reduces hospitalization rates for this condition and decreases the need for IV insertion.

Graphical Abstract

What is known on this subject:

Children with mild cellulitis typically receive a standard dose of oral antibiotics, whereas those with severe cellulitis are usually admitted with IV antibiotics. Children with moderate cellulitis are commonly treated with IV antibiotics.

What this study adds:

Treatment with high-dose oral cephalexin and follow-up for children with moderate cellulitis appears safe and effective. This approach potentially reduces the number of hospitalizations, of painful procedures and the use of health care resources.

Cellulitis is common amongst children seen in the Emergency Department (ED) (1–3). Most children with cellulitis have localized signs and symptoms, including erythema, swelling, warmth and pain, while some will present with systemic symptoms (4). Common causative agents include group A β-haemolytic Streptococci (GAS) and Staphylococcus aureus (S. aureus) (4–8). Typically, children with mild cellulitis receive oral (PO) treatment, whereas those with rapidly progressing or with severe systemic symptoms are hospitalized with intravenous (IV) antibiotics and surveillance (9–11). There is a grey zone for children with moderate cellulitis; children with moderate-to-severe cellulitis are frequently treated with IV antibiotics in hospital or in an outpatient medical setting until significant clinical improvement is observed (12,13).

Drawbacks to inpatient care following an ED visit for cellulitis include high treatment costs, resource utilization, and exposure to hospital-acquired infections (13,14). Outpatient management is preferred when it is feasible and when no contraindications are present, including hospital-in-the-home programs (treatment at home), return to the ED, or to a Medical Day Hospital (MDH) for ongoing IV antibiotics and keeping patients in the ED or in a short-stay unit for the administration of multiple doses of IV antibiotics prior to discharge, with the goal of avoiding hospitalization (3,9,15–17). At our institution, a MDH is available 7 days a week and allows close clinical follow-up by general paediatricians. In 2003, a multidisciplinary group developed an institutional treatment guideline for children presenting with moderate-to-severe cellulitis in the ED, using IV ceftriaxone (50–75 mg/kg/day; max 2 g/day) with daily follow-up at the MDH. A prospective observational study of children who were treated with this regimen concluded that ambulatory treatment of moderate-to-severe cellulitis with daily IV ceftriaxone was safe and effective with a success rate of about 80% (9). Similar findings were also reported in other studies in children, using IV ceftriaxone (18,19), and in adults, using either daily IV ceftriaxone or IV cefazolin twice daily or daily with probenecid (20–22). Despite its attractiveness, outpatient parenteral antibiotic therapy requires an IV access or repeated IM injections, which are painful procedures (23–26). Moreover, ceftriaxone is an overly broad-spectrum antibiotic, with potentially suboptimal efficacy against S. aureus. Ceftriaxone pharmacokinetic-pharmacodynamic simulations have shown that once daily dosing achieved suboptimal efficacy target for methicillin-susceptible S. aureus (time plasma concentrations exceed minimal inhibitory concentrations) (27). Oral antibiotics for the treatment of moderate cellulitis may be more appropriate for children, as reported in the adult literature (28,29). A study of outpatient parenteral antimicrobial therapy for infectious conditions, including patients with cellulitis, highlighted the importance of closer alignment with the best available evidence, reporting that parenteral antibiotics could be avoided in some children (15,16).

One study on the pharmacokinetics and pharmacodynamics of PO cephalexin in children with osteoarticular infections reported that high dose (HD) of PO cephalexin allowed achievement of optimal plasma concentrations and was well tolerated by children (30). Treatment of cellulitis using HD PO cephalexin is an attractive alternative to ceftriaxone with respect to its narrower spectrum of action against GAS and S. aureus, without requiring IV access. Based on these premises, a new treatment guideline for the management of moderate cellulitis was introduced at our institution in 2013, using HD PO cephalexin (90 mg/kg per day, a dose aimed at treating non-osteoarticular infections) instead of IV ceftriaxone in an outpatient setting (31). We aimed to evaluate the effectiveness of this treatment guideline.

METHODS

Study design and setting

This is a single center retrospective cohort study of children presenting to the ED with moderate cellulitis between January 1 2014 and January 1 2016 at a university-affiliated paediatric tertiary hospital with more than 80,000 ED visits annually. The study period was chosen to allow a period of adjustment to the treatment guideline, implanted in April 2013.

Population

All children aged <18 years old with a diagnosis of moderate cellulitis, deemed sufficiently severe by the treating physician in the ED to be followed at the MDH and to be treated with the HD PO cephalexin treatment guideline, were included (31). According to the treatment guideline, treatment with HD PO cephalexin and MDH follow-up could be offered by ED physicians for children with cellulitis (with or without lymphangitis) deemed severe enough to otherwise warrant admission; physicians used their clinical judgement to establish whether cellulitis was moderate. Children presenting the following criteria were not eligible for treatment with HD PO cephalexin: clinical signs of toxicity, immunosuppression, <3 months old, significant comorbidity, orbital/periorbital cellulitis, retropharyngeal/peritonsillar abscess, varicella, suspected fasciitis/tenosynovitis/chondritis, animal bites, puncture wounds, or rapidly progressing cellulitis (doubling every 4 h).

All patients with cellulitis who received IV antibiotics at the initial visit for severe cellulitis or who were discharged directly from the ED on standard doses of oral antibiotics for mild cellulitis were excluded from the analysis.

Intervention: HD PO cephalexin treatment guideline

All children treated for moderate cellulitis using the guideline received HD PO cephalexin at 90 mg/kg/day (a dose aimed at non-osteoarticular infections) divided in three doses (max 1.5 g/dose, 4.5 g/day). Children with documented or suspected penicillin allergy and known carriers of methicillin-resistant staphylococcus aureus (MRSA) were treated with PO clindamycin (30 mg/kg/day divided in three doses; max 600 mg/dose, 1.8 g/day). Referral to the MDH was planned 24 to 48 h after the initial ED visit for reassessment. Treatment was standardized by using a pre-written order form summarizing the moderate cellulitis treatment guideline.

Children were reassessed clinically at the MDH by a general paediatrician. According to the guideline, admission to hospital for IV treatment was recommended if the patient’s clinical condition was worsening (i.e., significant progression of the cellulitis, severe systemic symptoms, or bacteremia). The guideline suggested continued follow-up at the MDH until resolution of fever and 75% improvement of the cellulitis.

Outcomes

Our primary outcome of interest was effectiveness of the outpatient PO treatment guideline as defined by the absence of treatment failure. Treatment failure was defined as need for hospital admission at follow-up, switch to IV treatment, or ED visit within 2 weeks after discharge from the MDH. We also compared the success rate of this HD oral cephalexin treatment guideline to the one described by Gouin et al., using daily IV ceftriaxone in a historical cohort study within the same institution (9).

Secondary outcomes included the guideline’s safety as ascertained by recording adverse events and severe complications such as invasive infections including necrotizing fasciitis, septic shock, or bacteremia. The need for abscess drainage was also assessed. Resource utilization was reported, including number of visits at the MDH, use of laboratory tests, radiologic investigations, and specialist consultations.

Data collection and analysis

All cases of cellulitis diagnosed in the ED and followed at the MDH during the 2-year study period were reviewed by a single data collector. Data about demographic and clinical variables, including clinical characteristics at outset and treatment in the ED and at the MDH, were ascertained through chart review using a standardized collection form.

Mean, standard deviation (SD), and 95% confidence intervals were calculated for estimates reported.

This retrospective cohort study was approved by our local Institutional Review Board. Parental consent was waived since the study was retrospective.

RESULTS

During the 2-year study period, 682 cases of cellulitis were diagnosed in the ED. From these, 320 (46.9%) were discharged from the ED, 186 (27.3%) were hospitalized, and 176 (25.8%) were followed up at the MDH. Of children followed at the MDH, 53 were excluded as they were not treated according to the outpatient PO treatment guideline for moderate cellulitis (23 patients received IV antibiotics, mainly IV ceftriaxone [16 patients, 6 admitted later] and 30 patients received PO antibiotic, mainly standard doses of cephalexin [20 patients]). One hundred and twenty-three children were treated according to the outpatient PO treatment guideline for moderate cellulitis; 117 (95.1%) were treated with HD PO cephalexin and 6 (4.9%) with PO clindamycin (Figure 1). Patients’ demographics and clinical characteristics are reported in Table 1.

Figure 1.

Patients consulting for cellulitis between January 1, 2014 and January 1, 2016. Abbreviations: ATB antibiotic; ED, Emergency Department; HD, High Dose; IV, intravenous; MDH, Medical Day Hospital; n, number; PO, oral.

*IV ATB in the ED for 23 patients: 16 treated with previous IV ceftriaxone guideline (6 later admitted), 1 treated with IV cefazolin, and 6 with IV cefotaxime followed by HD oral cephalexin guideline (0 admitted).

^ΩOther PO ATB prescribed (outside of pre-written order) in 30 patients: 20 treated with standard PO doses of cephalexin, 1 PO cefadroxil, 1 PO azithromycin, 6 PO amoxicillin clavulanate, and 1 PO Trimethoprim/sulfamethoxazole.

Table 1.

Characteristics of patients treated with an outpatient PO treatment guideline for moderate cellulitis

Variables	Patients(n = 123)
Male—n (%)	71(57.7)
Age—median [range] in years	5 [0.3–17]
Use of antibiotics prior to ED consultation—n (%)	9 (7.3)
Patient suspected with allergies—n (%)	10 (8.1)
◦ Cephalosporin allergies	1 (0.8)
◦ Penicillin allergies	9 (7.3)
Previous episode of cellulitis reported—n (%)	16 (13.0)
Patient known for chronic illness*—n (%)	11 (8.9)
Fever† at presentation—n (%)	32 (26.0)
Location—n (%)
◦ Lower limbs	61 (49.5)
◦ Upper limbs	31 (25.2)
◦ Head and neck	26 (21.1)
◦ Trunk and abdomen	5 (4.1)
Risk factors for cellulitis—n (%)
◦ No risk factor reported	46 (37.4)
◦ Laceration/trauma	42 (34.1)
◦ Insect bite suspected	24 (19.5)
◦ Vaccine	5 (4.1)
◦ Other‡	6 (4.9)

Abbreviations: ED Emergency Department; n number.

Chronic illness: autism, Down syndrome, congenital heart malformation, deletion syndrome, prematurity, encephalopathy, vascular malformation, extrahepatic biliary atresia, type 1 diabetes.

Fever defined as temperature ≥ 38°C.

Postoperative wound, venous access

The guideline had a success rate of 110/123 (89.4%, 95% CI [84.0–95.0]) (Table 2). Specifically, treatment with HD PO cephalexin was successful in 105/117 (89.7%) children. Among the 12 children who had treatment failure with HD PO cephalexin, 10 (8.5%) required admission (8 from the MDH, 2 after a return visit to the ED), 1 (0.9%) received a single dose of IV antibiotic (ceftriaxone) at the MDH, and 1 (0.9%) visited the ED upon discharge from the MDH but was not admitted. Amongst the 10 admitted patients, none had invasive infection such as sepsis, necrotizing fasciitis, or septic arthritis but one had tenosynovitis; five patients were admitted less than 24 h after their ED visit (one patient had not taken the antibiotic at home) and the remaining five patients were admitted 2 to 6 days after their initial visit. Amongst children treated with PO clindamycin, treatment was successful in 5/6 (83.3%) patients and one patient re-visited the ED in between two visits at the MDH but was not admitted.

Table 2.

Success and failure rates of the outpatient PO treatment guideline for moderate cellulitis

Outcomes	Patients—n (%)
Success rate
◦ All patients with cellulitis treated in ED with pre-written order n = 123	110 (89.4)
	% [95%CI] [84–95]
◦ Patients treated with HD PO cephalexin—n = 117	105 (89.7)
◦ Patients treated with PO clindamycin—n = 6	5 (83.3)
Failure rate of treatment with HD PO cephalexin—n = 117
◦ All patients with cellulitis treated with HD PO cephalexin	12 (10.3)
Hospitalization*	10 (8.5)
Change to IV ATB	1 (0.9)
2nd consultation in ED without admission	1 (0.9)
Other pertinent outcomes n = 123
◦ Abscess drainage required	4 (3.4)
◦ Side effect†	1 (0.9)

Abbreviations: ATB antibiotic; ED Emergency Department; HD High Dose; IV intravenous; n number; PO oral

Reasons for admissions: 9 because of deteriorations of cellulitis, 1 falsely positive blood culture (contaminant).

Rash

An adverse event was reported in one patient (rash). There were no severe complications. Abscess drainage was required in four (3.4%) patients (two of whom were admitted).

The mean number of visits at the MDH was 1.6 visits (SD 1.0) (Table 3). Five (4.1%) children did not come to the MDH despite their appointment but had a favourable outcome on telephone follow-up. One patient was lost to follow up. Of 115 patients followed at MDH, 65.2% were clinically improved at their first MDH visit. Blood culture and other blood tests were done in the ED in respectively 31 (25.2%) and 45 (36.6%) patients. Skin cultures were performed in 35 (28.5%) patients; 68.6% were positive, mainly with methicillin susceptible S. aureus (MSSA) (19/35) or with MRSA (5/35). MRSA nose carrier screening was done in 12 (9.8%) patients and was positive in three cases.

Table 3.

Healthcare resources utilization for patients treated as outpatient with the PO treatment guideline for moderate cellulitis

Follow-up of patients with cellulitis treated in ED with pre-written order	Patients
Number of visits at the MDH—mean [range] (SD)	1.6 [0–5] (1.0)
Number of cellulitis followed in the MDH—n (%) n = 123
Did not present at follow-up*	8 (6.5)
1 visit at the MDH	57 (46.3)
2 visits at the MDH	43 (35.0)
3 and more visits at the MDH	15 (12.2)
Time lapse between ED visit and the first MDH visit—n (%) n = 115
24 h after their ED visit	83 (72.2)
48 h after their ED visit	30 (26.1)
72 h after their ED visit	2 (1.7)
Timing of significant improvement at follow-up—n (%) n = 115
Significant improvement at first visit	75 (65.2)
Significant improvement at 2nd visit (58 patient seen at least 2 time in MDH)	23 (20.0)
Number of patients with investigations—n 123 (%)
Skin culture†	35 (28.5)
MRSA nose carrier screening‡	12 (9.8)
Blood culture in ED‖	31 (25.2)
Other blood tests in ED$	45 (36.6)
Blood tests in MDH	8 (6.9)
Imaging test in ED and MDH	43 (35.0)
X-rays	21 (17.1)
Ultrasound	25 (20.3)
Bone scan	4 (3.3)
Consultations to another specialist§	32 (26)

Abbreviations: ED Emergency Department; MDH Medical Day Hospital; MRSA Methicillin-resistant Staphylococcus aureus; n number; SD standard deviation.

No follow-up: 2 patients already admitted after re-consultation in the ED prior to follow-up, 5 patients reached by phone who were improved, 1 patient lost at follow-up.

From them, 24/35 (68%) positive skin culture (19 Staphylococcus aureus (5 MRSA), 3 group A β-haemolytic Streptococci, 1 coagulase-negative staphylococci, 1 Enterococcus faecalis).

From them, 3/12 positive MRSA.

From them, 1/31 falsely positive blood culture: considered contamination with coagulase-negative staphylococci, 30/31 negative.

Including, CBC, CRP, ESR, as proposed as prn in prewritten order.

Thirty-two patients were reviewed by 38 specialists.

Most patients (72%) were prescribed a total of 10 days of antibiotics. Antibiotics were stopped at the MDH for three (2.4%) patients due to a change in diagnosis (panniculitis, erythema nodosum, and localized vaccine reaction). Deviation from guideline while at the MDH was noted for 18 (14.6%) children (i.e., 11 patients had a change for another PO antibiotic because of MRSA or ear/mouth involvement and 7 had a dose reduction), but this did not affect the treatment success rate in this subgroup, which was 94%. These patients were included in the overall success rate since they were treated initially with HD PO cephalexin.

DISCUSSION

Oral HD cephalexin for the outpatient treatment of children with moderate cellulitis with follow-up at a MDH was effective in almost 90% of cases in this study. There were no serious adverse events or complications, even amongst admitted patients, showing the safety of this treatment option. To the best of our knowledge, it is the first study to follow a cohort of children treated with HD PO cephalexin and to demonstrate its effectiveness and safety when treating moderate cellulitis in the paediatric population.

Other studies have demonstrated the effectiveness and safety of outpatient treatment of moderate/severe cellulitis but they were limited to IV treatment either in children (9,18,19) or in adults (14,20–22). In adult studies assessing outpatient management with IV cefazolin twice daily (or daily ceftriaxone), investigators reported favourable outcomes in 85% to 90% of patients, with IV treatment of 6 days or less (20–22). Paediatric studies also reported favourable outcomes using outpatient IV ceftriaxone: Ibrahim et al., in a paediatric cohort study, reported no treatment failure using a mean of 2.3 IV antibiotic days (18). In a recent RCT, home treatment of children with moderate-to-severe cellulitis with IV ceftriaxone was not inferior to hospital treatment with IV flucloxacillin, with treatment failure of 2% in the home group compared to 7% in the hospital group (risk difference −5.2%, 95% CI −11.3 to 0.8, P = 0.088). Gouin et al. reported a success rate of 80% with a mean of 2.2 days of IV ceftriaxone given at a MDH (9). Interestingly, results for the HD PO cephalexin treatment guideline we used compare favourably to these studies, with about 90% success rate, a mean of 1.6 days of follow-up at the MDH and without the need for an IV access. Outpatient treatment with PO HD cephalexin with follow-up is an attractive option when cellulitis is too severe for treatment with a standard oral antibiotic, but not severe enough to warrant IV antibiotics and hospital admission.

Oral outpatient treatment of moderate cellulitis in children has many advantages: avoiding needle puncture (therefore reducing pain/distress related to this procedure), gaining nursing staff time, and reducing hospital costs related to prolonged ED/hospital stays (26,32). Moreover, children treated at home do better psychologically and physically, with a decreased risk of hospital-acquired infections (18,33), and most patients/parents are satisfied with treatment at an MDH (9,34).

In addition, using PO cephalexin narrows the spectrum of antimicrobial activity compared to the use of IV ceftriaxone. A recent study reported that half of patients with uncomplicated skin and soft tissue infections received avoidable antibiotic exposure, including patients treated with unnecessarily large spectrum antibiotics or unnecessarily prolonged treatment (35). Narrow spectrum antibiotics may reduce emergence of antibiotic resistance, a very real threat (36–39). At the time of the guideline creation, local clindamycin susceptibility rate of MRSA was 80%.

To further reduce needle-stick pain, the clinical relevance of blood tests needs to be addressed since bacteremia in children with uncomplicated skin infection is infrequent (<1%) (40,41). Also, the use of MRSA screening can be questioned in our population because of the low rate of MRSA carriage found in this cohort compared to American studies (36–38,40) and the recent evidence showing that the addition of trimethoprim sulfamethoxazole, the most frequently used antibiotic against MRSA (42), to cephalexin showed no difference in success rate in two adult randomized clinical trials (28,29).

There are several limitations to this study. First, it was a retrospective cohort study and chart review was performed by a single reviewer; some of the details about adverse events or complications could have been missed. However, since oral treatment was continued in most patients, if adverse events were present, they were probably mild. Our study may also be limited in terms of external validity because our study is in a single centre. Moreover, there were no standardized criteria to define the severity of cellulitis at that time in the medical literature. However, we assumed that cellulitis that was considered severe enough by experienced clinicians to require treatment with HD PO cephalexin and MDH follow-up was likely to be at least moderate. Indeed, 50% of patients with cellulitis, assumed to be mild, were discharged directly from the ED without follow-up during the same study period. Moreover, similar patients were previously treated with IV ceftriaxone using a previous IV guideline at our institution. Future studies evaluating HD PO cephalexin treatment for moderate cellulitis should assess its use prospectively, using new validated scores for the severity of cellulitis to guide treatment (43). Some patients followed at the MDH were not included in this study since they were not treated with the PO treatment guideline for moderate cellulitis; this can be partly explained by the difficulty in changing physicians’ practice. Finally, in the group treated successfully with the PO guideline, antibiotic therapy was modified in about 15% of patients in the course of MDH follow-up, mostly to adapt to skin culture results or improvement of infection.

CONCLUSION

Oral outpatient treatment of moderate cellulitis in children seems to be a safe and effective option, with a success rate of about 90%. With a reduction in painful IV access, a narrower spectrum of antibiotics, and an expected reduction of costs, its success compares favourably with previous studies using ambulatory IV antibiotics for this condition. Further prospective studies would be necessary to determine the safety and effectiveness of different PO treatment regimens for moderate cellulitis, using specific diagnosis criteria.

Authors’ Contributions: Dr. D. Trottier conceptualized the study design, drafted the protocol and the manuscript, and reviewed, revised, and adapted the manuscript for publication. Dr. Farley St-Amand conceptualized the study design, collected and analyzed the data, and drafted the protocol and the manuscript. Dr. Gouin conceptualized the study design, helped draft the protocol and the initial manuscript, and reviewed and revised the manuscript. Drs. Chevalier, Autmizguine, Vincent, and Mrs. Tremblay contributed to the conception of the study design and critically reviewed the manuscript for important intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding: There are no funders to declare for this manuscript.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.