Doxycycline versus azithromycin in combination with beta-lactams for hospitalized community-acquired pneumonia: A...

Azithromycin plus a beta-lactam is a commonly used empiric regimen for hospitalized community-acquired pneumonia (CAP). Concerns about azithromycin resistance and patient-specific safety considerations have increased interest in doxycycline as an alternative; however, comparative effectiveness data for these two regimens remain scarce.

Using the TriNetX Global Collaborative Network (240 healthcare organizations; data accessed June 14, 2026), we conducted a retrospective cohort study of adults hospitalized with CAP between January 2016 and December 2023. Doxycycline plus beta-lactam recipients were compared with azithromycin plus beta-lactam recipients following 1:1 nearest-neighbor propensity score matching (11,906 patients per group).

Thirty-day and 90-day all-cause mortality did not differ significantly between groups (HR: 1.03, 95% CI: 0.95-1.12; and HR: 1.06, 95% CI: 0.98-1.14, respectively), whereas 180-day mortality was modestly but significantly higher in the doxycycline cohort (HR: 1.08, 95% CI: 1.02-1.16; p = 0.014). Doxycycline-based therapy was associated with a consistently lower risk of antibiotic escalation at all time points assessed (RR: 0.59-0.65; p < 0.001). The 30-day risk of incident sepsis was significantly higher with doxycycline (RR: 1.29, 95% CI: 1.03-1.61; p = 0.024). ICU admission, mechanical ventilation, vasopressor use, and Clostridioides difficile infection did not differ significantly between the two groups.

No statistically significant difference in 30-day mortality was detected between doxycycline plus beta-lactams and azithromycin plus beta-lactams. This finding does not establish equivalence or noninferiority. Secondary findings, including 30-day sepsis and 180-day mortality, were exploratory and require confirmation in prospective randomized studies.