High-dose versus standard-dose amoxicillin/clavulanate for clinically-diagnosed acute bacterial sinusitis: A randomized clinical trial

Abstract

Background: The recommended treatment for acute bacterial sinusitis in adults, amoxicillin with clavulanate, provides only modest benefit.

Objective: To see if a higher dose of amoxicillin will lead to more rapid improvement.

Design, setting, and participants: Double-blind randomized trial in which, from November 2014 through February 2017, we enrolled 315 adult outpatients diagnosed with acute sinusitis in accordance with Infectious Disease Society of America guidelines.

Interventions: Standard-dose (SD) immediate-release (IR) amoxicillin/clavulanate 875 /125 mg (n = 159) vs. high-dose (HD) (n = 156). The original HD formulation, 2000 mg of extended-release (ER) amoxicillin with 125 mg of IR clavulanate twice a day, became unavailable half way through the study. The IRB then approved a revised protocol after patient 180 to provide 1750 mg of IR amoxicillin twice a day in the HD formulation and to compare Time Period 1 (ER) with Time Period 2 (IR).

Main measure: The primary outcome was the percentage in each group reporting a major improvement-defined as a global assessment of sinusitis symptoms as "a lot better" or "no symptoms"-after 3 days of treatment.

Key results: Major improvement after 3 days was reported during Period 1 by 38.8% of ER HD versus 37.9% of SD patients (P = 0.91) and during Period 2 by 52.4% of IR HD versus 34.4% of SD patients, an effect size of 18% (95% CI 0.75 to 35%, P = 0.04). No significant differences in efficacy were seen at Day 10. The major side effect, severe diarrhea at Day 3, was reported during Period 1 by 7.4% of HD and 5.7% of SD patients (P = 0.66) and during Period 2 by 15.8% of HD and 4.8% of SD patients (P = 0.048).

Conclusions: Adults with clinically diagnosed acute bacterial sinusitis were more likely to improve rapidly when treated with IR HD than with SD but not when treated with ER HD. They were also more likely to suffer severe diarrhea. Further study is needed to confirm these findings.

Trial registration: ClinicalTrials.gov Identifier: NCT02340000.

Fig 1. CONSORT flowchart of study participants.

Reasons for exclusion before randomization were mostly inferred from chart review. We had 30 dropouts during the course of the study. Reason for dropping out included failure to improve or worsening illness (12), adverse reaction (10), allergic reaction (2), fear of side effects (2), misplaced medication bottle (1), switched to different antibiotic for another infection (1), tablet size too large (1), self-discontinuation because of marked symptom improvement (1), and unknown (1). Some participants had multiple reasons for exclusion or for dropping out.