Amoxicillin for Acute Rhinosinusitis: A Randomized Controlled Trial

In Review

Garbutt JM, et al. "Amoxicillin for acute rhinosinusitis: a randomized controlled trial". JAMA. 2012. 307(7):685-692.
PubMed • Full text

Clinical Question

In adult populations with acute rhinosinusitis, does the addition of amoxicillin antibiotic treatment on top of symptomatic treatment compared to symptomatic treatment alone increase patient quality of life?

Bottom Line

Treatment of uncomplicated acute rhinosinusitis with amoxicillin offers little improvement in the disease-specific quality of life for patients by day 10 of treatment. Symptomatic treatment alone was found to be sufficient in the improvement of quality of life in most patients.

Major Points

Acute rhinosinusitis impacts a large population which causes them to lose time at work and decreases quality of life. Over prescribing of antibiotics to this population has led to an increase in antibiotic resistance, which is a huge problem for public health. Multiple studies have been completed on whether antibiotics are beneficial or not in acute rhinosinusitis. Many have shown that treatment does show a benefit to the patient, but meta-analyses have shown that there is little benefit in prescribing antibiotics in this situation. This information is very important to consider because 1 in 5 antibiotic prescriptions are for adult sinusitis. The overall purpose of this study was to determine if antibiotics have clinically significant evidence to show benefit in acute rhinosinusitis in adult patients.

This study used a randomized, placebo controlled, blinded trial design in ten primary care physician offices in St. Louis, MO. Their study design/protocol was approved by the institutional review board at Washington University. The study enrolled 166 adults ( 36% males, 78% caucasian) who were randomized into a placebo (81) or amoxicillin (85) group. The data collected showed no difference between the placebo and amoxicillin groups by day 3. That being said, 74% of the amoxicillin group reported symptom improvement by day 7, which compared to only 54% of the placebo group. However, these are secondary outcomes of the study and do not reflect the main purpose of this study. Overall, there was no difference in symptoms for the first 3 days but after that mark the amoxicillin group showed more improvement than the placebo group.

Internal criticisms which gave this study validity were questioning if all patients had acute rhinosinusitis and the concurrent use of symptomatic treatment. An example of external criticisms showed data at Day 7 were not statistically significant in improving quality of life. The criticisms showed some possible weaknesses of the study, but provided reasons why they did not greatly impact the study. The study also reviewed other meta-analyses that showed little benefit in antibiotic treatment. This shows that their data has some validity, and as more studies are conducted which show that antibiotics do not provide great benefits in acute rhinosinusitis the more validity this study will have. Overall, the study showed little difference in symptoms by day 3 in the experimental versus control groups. This provides evidence which is applicable to a large population and could possibly be used in prescribing guidelines in the future.

Guidelines

According to the Infectious Disease Society of America’s guidelines for treatment of acute rhinosinusitis, patients with persistent symptoms lasting for more than 10 days without clinical improvement, onset with severe symptoms such as fever, purulent nasal discharge, or facial pain lasting 3-4 days, or worsening symptoms of fever, headache, or nasal discharge, recommend treatment with antibiotic therapy. Amoxicillin-clavulanate is preferred over amoxicillin. Respiratory fluoroquinolones, macrolides, sulfamethoxazole-trimethoprim, and 2nd and 3rd generation cephalosporins are not recommended. An alternative agent to amoxicillin-clavulanate is doxycycline.

Design

• Randomized placebo-controlled trial
• N= 166 adults
  • Experimental arm: n=85
  • Standard: n=81
• Setting: 10 primary care practices in St. Louis, MO
• Enrollment Period: 2006 to 2009
• Mean follow-up: 3-28 days
• Analysis: intention-to-treat
• Primary outcome: improvement in the disease-specific quality of life (SNOT-16 score)

Population

Inclusion Criteria

• Adult patients (18-70 years old)
• Acute bacterial rhinosinusitis
  • “Moderate, severe, very severe” per CDC Expert Panel’s diagnostic criteria
• Maxillary pain/tenderness of face or teeth AND purulent nasal secretions
• Rhinosinusitis symptoms for more than 7 days and less than 28 days or rhinosinusitis symptoms for less than 7 days that had significantly worsened from the start of symptoms

Exclusion Criteria

• Allergy to penicillin or amoxicillin
• Antibiotic treatment within the past 4 weeks
• Complications of sinusitis
• Comorbidity that impairs the immune response
• Pregnancy
• Cystic fibrosis
• Antibiotic use required for a concurrent condition
• Reported symptoms as very mild to mild

Baseline Characteristics

From the Intervention Group

• Sociodemographics
  • Median age: 32
  • Male gender: 36%

• Sinus Symptoms
  • SNOT-16 score: Mean 1.71
  • Symptom severity:
    • Moderate: 48%
    • Severe: 44%
    • Very severe: 8%
  • Days of symptoms: Mean 11.2
  • Days missed from work before visit: Mean 1.1
  • Days unable to do usual non-work activities before visit: Mean 3.2
  • Used symptomatic treatment before visit: 96%
  • Flu shot this winter: 27%

Interventions

Participants were given amoxicillin at 500 mg per dose three times a day (1500 mg daily) for a duration of 10 days, or a placebo similar in appearance and taste. All participants were given the following medications for symptomatic control as needed unless deemed contraindicated by the primary care physician:

• Acetaminophen 500 mg every 6 hours for fever and pain
• Guaifenesin 600 mg every 6 hours to thin mucous secretions
• Dextromethorphan (10 mg/5 mL) with guaifenesin (100 mg/5 mL) 10 mL every 4 to 6 hours for cough
• Pseudoephedrine 120 mg every 12 hours for nasal congestion
• Saline spray (0.65%) 2 sprays in each nostril as needed

Outcomes

Comparisons are treatment vs. placebo.

Primary Outcome

Improvement in the disease-specific quality of life (SNOT-16 score)

Day 3: amoxicillin, 0.59 (CI 0.47-0.71); control, 0.54 (CI 0.41-0.67); p=0.69

Day 7: amoxicillin 1.06 (CI 0.93-1.20); control, 0.86 (CI 0.71-1.02); p=0.0247

Day 10: amoxicillin 1.23 (CI 1.08-1.37); control, 1.20 (CI 1.07-1.32); p=0.85

Secondary Outcomes

Self-reported symptom improvement

Day 3: amoxicillin, 37% (27-48%); control, 34% (23-45%); p=0.67

Day 7: amoxicillin, 74% (64-83%); control, 56% (45-67%): p=0.0205

Day 10: amoxicillin, 78% (64-83%); control, 80% (71-90%): p=0.71

Patient’s retrospective assessment of change in sinus symptoms and functional status

• Days missed from work

Amoxicillin, 0.55 (0.28-0.82); control, 0.55 (0.22-0.87); p=0.99

• Days unable to perform usual activities

Amoxicillin, 1.15 (0.76-1.54); control, 1.67 (1.08-2.26); p=0.14

• Relapse rate

Amoxicillin, 9% (3-16%); control, 6% (1-11%): p=0.57

• Recurrence rate

Amoxicillin, 6% (1-11%); control, 2% (0-6%); p=0.44

• Satisfaction with treatment

Amoxicillin, 53% (42-64%); control, 41% (29-52%); p=0.13

Subgroup Analysis

There were no subgroup analyses conducted in this study.

Adverse Events

No serious adverse reactions occurred. Reported side effects for the intervention group was 16% (8-24%), and 14% (6-22%) for the control group with p=0.74. Participants who answered yes to one or more specific symptom question for amoxicillin was 48% (37-59%) and 52% (39-62%) for the control with p=0.75. Headache (22% amoxicillin/ 23% control/ p=0.96) and excessive tiredness (11% amoxicillin/ 21% control/ p=0.12) were the only two common adverse events. Nausea, diarrhea, abdominal pain, and vaginitis were also seen, but with no significant difference between intervention and control.

Criticisms

• Internal
  • There is a question of whether all the patients included in the study actually had acute rhinosinusitis.
  • Regarding concurrent use of symptomatic treatments - they were similar and unlikely to bias study findings.

• External
  • Many findings were insignificant; therefore, the statistically significant benefit at Day 7 wasn’t large enough to represent a clinically important change in improvement of quality of life, which the study focused on at day 3.
  • Retrospective measurement by the participants (recollection) could have contributed to a larger percentage of effect observed.

Funding

The funding for this study was attained by grant U01-AI064655-01A1 from the National Institute of Allergy and Infectious Disease.