A large cohort study finds no reduction in treatment failure with broader-spectrum therapy but increased risk of secondary infections.
Standard-dose amoxicillin provides comparable effectiveness to amoxicillin-clavulanate for adults with acute sinusitis, with a more favourable safety profile, according to a large nationwide cohort study.
Acute sinusitis has the highest rate of antibiotic prescribing in adults younger than 65 years, the US researchers wrote in JAMA.
“There is no consensus regarding whether amoxicillin-clavulanate or amoxicillin should be first-line treatment for uncomplicated acute sinusitis in adults,” they said.
The retrospective analysis included 521,244 adults aged 18 to 64 years treated in outpatient settings across the United States between 2018 and 2023.
After propensity score matching, 234,608 patients were analysed, with balanced baseline characteristics including comorbidities, prior antibiotic exposure and markers of disease severity.
Treatment failure, defined as antibiotic switching, repeat outpatient encounters or escalation to emergency or inpatient care within 14 days, was uncommon at 3.1% overall and did not differ between treatment groups (3.0% for amoxicillin-clavulanate vs 3.1% for amoxicillin; RR 0.96, 95% CI 0.92–1.01).
The most frequent component was a new antibiotic dispensation without a visit, followed by a return consultation with a change in therapy, while hospital-level care was rare.
Subgroup analyses showed no clinically meaningful differences by age group, sex, immunocompromised status or amoxicillin dosing strategy.
Although a small relative reduction in treatment failure was observed with amoxicillin-clavulanate among younger adults, the absolute benefit was minimal, with hundreds of patients needing treatment to prevent a single failure event.
Sensitivity analyses incorporating high-dimensional propensity scoring, extended washout periods for prior antibiotic use, and longer outcome windows up to 30 days all confirmed the robustness of the findings, the researchers said.
Overall antibiotic-associated adverse events were similar between groups (1.3% vs 1.2%), predominantly gastrointestinal effects.
However, secondary infections were more frequent with amoxicillin-clavulanate, including yeast infections (1.1% vs 0.8%; RR 1.40) and Clostridioides difficile infection (0.04% vs 0.02%; RR 2.14), albeit with small absolute risk differences.
The researchers said the findings were clinically notable given the high burden of antibiotic prescribing for acute sinusitis and ongoing variability in guideline recommendations.
While clavulanate extended activity against β-lactamase–producing organisms such as Haemophilus influenzae and Moraxella catarrhalis, this theoretical microbiological advantage did not translate into improved patient outcomes in routine care, they said.
By contrast, the broader spectrum was associated with measurable downstream harms, reinforcing concerns around antimicrobial resistance and avoidable adverse effects.
The study’s scale and inclusion of outpatient care, where most sinusitis was managed, addressed a key evidence gap in adult populations, the researchers wrote.
They noted several limitations that tempered interpretation. As an observational study, residual confounding could not be excluded, although advanced propensity score methods incorporating a large number of covariates and proxies yielded results consistent with the primary analysis.
Medication dispensing rather than adherence was measured, meaning nonadherence could not be directly assessed, although treatment changes related to intolerance or poor response were captured within the failure definition.
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Use of adjunctive therapies such as saline irrigation and over-the-counter medications was not fully captured, although analyses of negative control outcomes suggested similar healthcare-seeking behaviour between groups, reducing concern for systematic bias. Microbiological data were unavailable, preventing pathogen-level analysis, though this reflects real-world practice where treatment is typically empiric.
Despite these constraints, the scale, consistency and real-world setting of the findings supported standard-dose amoxicillin as the preferred empiric option for uncomplicated acute sinusitis when antibiotics are indicated, reserving broader-spectrum therapy for selected higher-risk scenarios, they said.
“For adults with acute sinusitis treated with standard-dose amoxicillin-clavulanate or standard-dose amoxicillin in the outpatient setting, there was no difference in treatment failure and a slightly elevated risk of yeast and C difficile infections observed among patients treated with amoxicillin-clavulanate,” the researchers concluded.
“These findings support standard-dose amoxicillin as a preferred empiric treatment for adults with uncomplicated acute sinusitis without recent antibiotic exposure when antibiotics are indicated.”
