Timothy J. Savage, MD, MPH, MSc; Anne M. Butler, PhD, MS; Matthew P. Kronman, MD, MSCE;
Michael J. Durkin, MD, MPH; Sushama Kattinakere Sreedhara, MBBS, MSPH; Sarah Kabbani, MD, MSc;
Lauri A. Hicks, DO; Krista F. Huybrechts, MS, PhD
IMPORTANCE Acute sinusitis has the highest rate of antibiotic prescribing in adults younger 
than 65 years. There is no consensus regarding whether amoxicillin-clavulanate or amoxicillin
should be first-line treatment for uncomplicated acute sinusitis in adults.
OBJECTIVE To compare the risk of treatment failure and adverse events between
standard-dose amoxicillin-clavulanate vs standard-dose amoxicillin for acute sinusitis
in adults.
DESIGN, SETTING, AND PARTICIPANTS New-user, active comparator retrospective cohort study
using a nationwide health care utilization database comparing amoxicillin-clavulanate vs
amoxicillin for adults aged 18 to 64 years with outpatient acute sinusitis. Patients with a new
acute sinusitis diagnosis between January 1, 2018, and December 1, 2023, were eligible.
Statistical analysis was conducted between July and November 2025. Propensity score
matching was used to help mitigate confounding.
EXPOSURES Standard-dose amoxicillin-clavulanate (875mg-125mg twice daily) or
standard-dose amoxicillin (875mg twice daily or 500mg 3 times daily).
MAIN OUTCOMES AND MEASURES The primary outcomewas treatment failure, defined as the
first occurrence of a new antibiotic dispensation (with or without an outpatient visit),
emergency department or inpatient encounter for acute sinusitis, or inpatient encounter for
a sinusitis complication assessed 1 to 14 days after treatment initiation. Antibiotic-associated
adverse events and secondary infections were also assessed.
RESULTS The full cohort included 521 244 eligible patients. After propensity score matching,
there were 234 608 patients (117 304 patients per group; 65.5%female; median [IQR] age,
43 [31-54] years). Treatment failure occurred in 3.1% of patients overall, with 0.03%
requiring an emergency department or inpatient encounter. There was no observed
difference in the risk of treatment failure between the amoxicillin-clavulanate vs amoxicillin
groups (3.0%vs 3.1%; risk ratio [RR], 0.96 [95%CI, 0.92-1.01]), which was consistent
across sensitivity analyses. There was no difference in antibiotic-associated adverse events
(1.3%vs 1.2%; RR, 1.04 [95%CI, 0.97-1.12]). The risk of secondary infections was higher for
amoxicillin-clavulanate vs amoxicillin, including yeast infections (1.1%vs 0.8%; RR, 1.40
[95%CI, 1.29-1.53]) and Clostridioides difficile infections (0.04%vs 0.02%; RR, 2.14 [95%CI,
1.29-3.54]).
CONCLUSIONS AND RELEVANCE In this observational study of patients aged 18 to 64 years
with acute sinusitis treated in the outpatient setting with standard-dose amoxicillinclavulanate
or standard-dose amoxicillin, there was no observed difference in treatment
failure. Amoxicillin-clavulanate was associated with a higher, albeit rare, risk of adverse
events. These findings suggest standard-dose amoxicillin may be a preferred first-line
treatment for adults with uncomplicated acute sinusitis.
