Beta-Lactam plus Azithromycin or Doxycycline versus Fluoroquinolones in Hospitalized Adult Patients with Community-Acquired Pneumonia: A Systematic Review and Network Meta-Analysis

Abstract Background Community-acquired pneumonia (CAP) is a significant public health concern associated with increased rates of hospital admissions and mortality. Purpose To compare beta-lactam plus azithromycin or doxycycline versus fluoroquinolones in hospitalized adults with CAP. Methods We searched several databases from inception to June 10, 2024. Two reviewers independently screened, selected and extracted data. Disagreements were resolved by consensus or a third reviewer. Study quality was assessed in duplicate using the Cochrane Risk of Bias 2 for randomized studies, and the Newcastle-Ottawa scale for nonrandomized studies. Meta-analysis was conducted using a random-effect model when feasible. Network meta-analysis (NMA) was performed to compare direct and indirect evidence. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was followed to rate the certainty of evidence. Results 20 studies (20 beta-lactam + azithromycin, 7 beta-lactam + doxycycline, 12 levofloxacin, and 4 moxifloxacin) were included, of which 6 were randomized, enrolling 861 participants, mean age 61.8 years, 43.2% women, and 14 non-randomized studies enrolling 185928 participants, mean age 65.2 years, 42.9% women. Both direct comparison and NMA results showed no statistically significant differences and likely equal effectiveness between the beta-lactam + azithromycin and beta-lactam + doxycycline in terms of in-hospital mortality, need for ICU admission or invasive mechanical ventilation, or safety outcomes including Clostridioides difficile infection and QT-prolongation. Conclusion The current evidence demonstrated likely no difference in outcomes between azithromycin and doxycycline in hospitalized adults with CAP receiving beta-lactam. Head-to-head randomized clinical trials are needed to validate these results.