Background: Treatment guidelines for outpatient community-acquired pneumonia (CAP) include narrow-spectrum (macrolide, doxycycline) and broad-spectrum (fluoroquinolones, β-lactam ± macrolide) antibiotic regimens. Evidence is limited about the real-world comparative safety of antibiotics for outpatient CAP.
Objectives: To estimate the risk of adverse drug events (ADEs) following antibiotic treatment for outpatient CAP among otherwise healthy, non-elderly adults.
Methods: We used the Merative MarketScan Commercial Database (2008–2019) to identify adults 18–64 years diagnosed with outpatient CAP and dispensed a same-day CAP-related oral antibiotic regimen. We excluded patients at risk for multidrug-resistant pathogens (e.g., immunosuppressive disease, recent hospitalization, recent antibiotic therapy) as well as those with chronic lung disease, recent infection, non-standard antibiotic durations, and comorbidities with indications for broad-spectrum antibiotics. To reduce misclassification of CAP, we required a chest x-ray on the CAP diagnosis date and excluded patients coded for viral URI or bronchitis. Follow-up duration of new-onset ADEs ranged from 2–90 days (e.g., anaphylaxis [2 days], Clostridioides difficile infection [90 days]). For each ADE, we used Cox proportional hazards models to estimate unadjusted and standardized mortality ratio-weighted hazard ratios (HRs) of each antibiotic regimen compared to macrolide monotherapy. We used negative control outcomes (ankle/knee sprain, motor vehicle accident, influenza vaccination) to assess the presence of confounding.
Results: Of 145,137 otherwise healthy CAP patients without comorbidities, 52% received narrow-spectrum regimens (44% macrolide, 8% doxycycline) and 48% received broad-spectrum regimens (39% fluoroquinolone, 7% β-lactam, 3% β-lactam + macrolide). Compared to macrolide monotherapy, each broad-spectrum antibiotic regimen was associated with increased risk of several ADEs (e.g., β-lactam: nausea / vomiting / abdominal pain [HR, 1.46; 95% CI, 1.14–1.86]; non-Clostridioides difficile diarrhea [HR, 2.22; 95% CI, 1.68–2.95]; vulvovaginal candidiasis / vaginitis [HR, 1.93; 95% CI, 1.25–2.97]; anaphylaxis / angioedema / laryngeal edema [HR, 1.94; 95% CI, 1.08–3.49]). For each treatment comparison, we observed similar risks of each negative control outcome, indicating minimal confounding, with one exception (macrolide vs β-lactam + macrolide: influenza vaccination [HR, 1.37; 95% CI, 1.09–1.72].
Conclusions: Broad-spectrum antibiotics were associated with increased ADEs among otherwise healthy CAP patients. Antimicrobial stewardship is needed to promote judicious use of broad-spectrum antibiotics, and ultimately decrease antibiotic-related ADEs.
