C28-16 A Target Trial Emulation of Fluoroquinolone Monotherapy Versus β-lactam Therapy Plus Azithromycin in Hospitalized Adults With Community Acquired Pneumonia

Abstract Rationale Community-acquired pneumonia (CAP) remains a leading cause of morbidity and mortality worldwide; current guidelines recommend either the use of β-lactam therapy with a macrolide (azithromycin; AZM) or monotherapy with a fluoroquinolone for treatment. Limited evidence exists on their comparative effectiveness. To address this gap, we examined the differences in outcomes among CAP patients treated with β-lactam therapy plus AZM or fluoroquinolone monotherapymethods: We emulated a randomized clinical trial that hypothetically assigned patients to β-lactam therapy plus AZM or fluoroquinolone. Eligible patients were all adults hospitalized for nonsevere community-acquired pneumonia (CAP) based on ATS/IDSA criteria; at Mayo Clinic hospitals (3 academic and 16 community) between May 2018 and September 2022 and received one of the two treatments within 12 hours of admission. Ensemble machine learning with augmented inverse probability weighting (AIPW) was used to evaluate “intention to treat” effects on hospital-free days (HFDs), 180-day mortality, use of advanced respiratory support, in-hospital mortality, and the composite of advanced respiratory support and/or in-hospital mortality. We used the E-value and post-discharge systolic blood pressure (SBP) (negative outcome) to evaluate effects of potential unmeasured confounding and alternative “doubly robust” inverse probably weighting with regression adjustment (IPWRA) to evaluate robustness of the findings. Results 2,451 patients (2,142 β-lactam therapy plus AZM and 309 fluoroquinolone) were eligible and included in the analyses: 53.9% were female, 86.8% were White, and mean age was 58.4 years (SD: 17.02). Compared with β-lactam therapy plus AZM, the fluoroquinolone group experienced significantly higher HFD (1.50 days; 95% CI: 1.08, 1.91), lower use of advanced respiratory support (RR: 0.32; 95% CI: 0.09, 0.54), lower in-hospital mortality (RR: 0.14; 95% CI: 0.00, 0.40), and composite of advanced respiratory support and/or in-hospital mortality (RR: 0.29; 95% CI: 0.08, 0.49). Moderate to large e-values (ranging from 3.50 to 4.74) and use of negative outcomes (post-discharge SBP) suggested that unmeasured confounding is unlikely to change the findings. Sensitivity analysis using IPWRA showed very similar results. Conclusion Among hospitalized patients with non-severe CAP, treatment with fluoroquinolone monotherapy was associated with more hospital-free days, lower in-hospital mortality, and reduced need for advanced respiratory support compared with AZM and β-lactam combination. The findings highlight the role of fluoroquinolone as a beneficial alternative CAP patients. However, further studies are needed to explore the underlying mechanisms driving these differences and assess whether specific patient subgroups may benefit most from quinolone-based therapy. This abstract is funded by: none