Acute Sinusitis: Amoxicillin Equals Broader Therapy, Lowers Infection Risk in New Study

Standard-dose amoxicillin demonstrated similar effectiveness to amoxicillin-clavulanate for the treatment of uncomplicated acute sinusitis in adults, with a lower risk of certain adverse outcomes, according to a large observational study published in JAMA.

In a propensity score–matched cohort of 234 608 adults aged 18 to 64 years, investigators found no significant difference in treatment failure between the 2 regimens (3.0% with amoxicillin-clavulanate vs 3.1% with amoxicillin; risk ratio [RR], 0.96; 95% CI, 0.92-1.01). Treatment failure events requiring emergency department or inpatient care were rare, occurring in approximately 0.03% of cases.

The nationwide retrospective cohort study included 521 244 adults diagnosed with acute sinusitis between 2018 and 2023. After matching, both treatment groups comprised 117 304 patients, with a median age of 43 years and 65.5% female. Patients received standard-dose regimens of either amoxicillin-clavulanate (875 mg/125 mg twice daily) or amoxicillin (875 mg twice daily or 500 mg 3 times daily).

Overall treatment failure was uncommon (3.1%) and most frequently reflected outpatient antibiotic changes rather than severe complications. Rates of antibiotic-associated adverse events were similar between groups (1.3% vs 1.2%; RR, 1.04; 95% CI, 0.97-1.12).

However, secondary infections occurred more often in patients treated with amoxicillin-clavulanate. Yeast infections were reported in 1.1% of these patients compared with 0.8% in the amoxicillin group (RR, 1.40; 95% CI, 1.29-1.53), and Clostridioides difficile infection occurred in 0.04% vs 0.02%, respectively (RR, 2.14; 95% CI, 1.29-3.54), although absolute differences were small.

Subgroup and sensitivity analyses, including extended follow-up and alternative outcome definitions, consistently showed no meaningful difference in treatment failure across age groups, sex, immune status, or dosing strategies.

Acute sinusitis is among the most common indications for outpatient antibiotic prescribing in US adults, contributing to millions of prescriptions annually. Although some clinical guidelines favor broader-spectrum therapy, these findings suggest no added benefit from amoxicillin-clavulanate in most cases of uncomplicated disease.

Patient Care Online sat down with lead investigator, Timothy J. Savage, MD, MPH, MSc, an instructor in medicine at Mass General Brigham in Boston, MA, to discuss the study in more detail and clinical implications for primary care physicians.

Reference: Savage TJ, Butler AM, Kronman MP, Durkin MJ, Sreedhara SK, Kabbani S, Hicks LA, Huybrechts KF. Amoxicillin-Clavulanate vs Amoxicillin for Acute Sinusitis in Adults. JAMA. Published online April 18, 2026. doi:10.1001/jama.2025.26902