Cellulitis is a painful bacterial skin infection commonly seen in Canadian emergency departments. Cellulitis has a negative impact on patients' quality of life and productivity. While this is a bacterial infection, there is evidence inflammation also contributes to the disabling symptoms of pain, redness and swelling. Some studies have suggested that a nonsteroidal anti-inflammatory drug (NSAID) such as naproxen in addition to antibiotics may control inflammation and speed recovery. However, these studies have had too few patients to tell if there is a true benefit.

The investigators are proposing a randomized controlled trial of patients with cellulitis to compare oral naproxen (500 mg twice daily) plus oral antibiotics versus placebo plus oral antibiotics. The investigators will compare the proportion of patients who have an early clinical response (reduction in area of redness ≥20% at 72 hours), cure, treatment failure, adverse events, and hospital admission.

If naproxen proves to be superior to placebo, this simple, low-cost intervention will speed time to recovery with less pain for patients, and may potentially reduce treatment failure and time missed from activities. The results of this trial will help inform future cellulitis treatment guidelines.

Cellulitis is a common bacterial skin infection and a frequent cause of emergency department visits in Canada. Standard management involves antibiotic therapy; however, patients often experience significant pain, erythema, and swelling that can impair quality of life and productivity. There is increasing evidence that inflammation contributes to these symptoms, suggesting that adjunct anti-inflammatory therapy may improve recovery.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen, may reduce inflammation and improve symptom resolution when used alongside antibiotics. Prior randomized trials and meta-analyses have suggested a potential benefit in early clinical response; however, these studies were limited by small sample sizes and methodological constraints. As a result, there remains uncertainty regarding the effectiveness and safety of NSAIDs as adjunct therapy for cellulitis.

This study is a multicentre, double-blind, randomized controlled trial designed to evaluate the impact of adjunct naproxen on clinical outcomes in adult patients with cellulitis receiving standard antibiotic therapy. Participants will be randomly assigned in a 1:1 ratio to receive either naproxen or placebo in addition to oral antibiotics for 7 days. The trial will be conducted at multiple tertiary care emergency departments in Canada.

Participants will be followed longitudinally with assessments at prespecified time points to evaluate clinical response, patient-reported outcomes, healthcare utilization, and safety. Data will be collected through a combination of in-person, virtual, and telephone follow-up assessments.

The study is powered to detect a clinically meaningful difference in early response between treatment groups. Analyses will be conducted using an intention-to-treat approach, with regression-based methods used to compare outcomes between groups.

Findings from this study are expected to provide high-quality evidence regarding the role of NSAIDs as adjunct therapy for cellulitis and may inform future clinical practice guidelines and decision-making in emergency and outpatient care settings.

Inclusion Criteria:

• adults (age ≥18 years)
• diagnosed with cellulitis and
• determined by the treating physician to be eligible for outpatient treatment with oral cephalexin

Exclusion Criteria:

These are appropriate exclusions according to eligibility for treatment with naproxen in clinical practice, and the investigators believe that relatively few patients will be excluded.

The investigators will exclude participants for any of the following reasons:

1. Age <18 years;
2. Patient already taking oral antibiotics or NSAIDs;
3. Treating physician decides IV antibiotics are required;
4. Skin abscess requiring incision and drainage;
5. Known prior skin or soft tissue infection secondary to methicillin-resistant Staphylococcus aureus (MRSA);
6. Cellulitis secondary to a human or animal bite;
7. Penetrating wound or water exposure resulting in cellulitis;
8. Surgical site infection;
9. Pregnancy or breastfeeding;
10. Prior gastric bypass surgery;
11. Patients on dual antiplatelet therapy;
12. Patients on warfarin, low molecular weight heparin, or direct oral anticoagulant therapy;
13. Severe uncontrolled heart failure, or coronary artery bypass grafting (CABG) surgery within 14 days prior to the index visit, or planned CABG surgery within 21 days following the index visit.;
14. History of gastric/duodenal ulcer or gastrointestinal bleeding in the past 12 months;
15. Known kidney impairment with an estimated glomerular filtration rate <30 mL/min documented on the electronic health record at any time within the past three months;
16. Known hyperkalemia documented on the electronic health record at any time within the past three months;
17. Liver cirrhosis;
18. Inflammatory bowel disease;
19. History of asthma, urticaria or allergic reactions after taking NSAIDs or aspirin;
20. Allergy to cephalosporins or history of anaphylaxis to penicillin; (u) Inability to provide informed consent.

Exclusion criteria (i) through (s) are known contraindications to NSAIDs.

IPD requests can be submitted to the Investigator and will be reviewed on a case by case basis.

Patients will be randomized (1:1) to naproxen versus placebo arms. The randomization sequence will be computer-generated by a statistician