Xinjia Dayuan San for MDR-GN pneumonia: A randomized controlled trial

Multidrug-resistant Gram-negative (MDR-GN) pneumonia presents an urgent global health challenge, characterized by limited therapeutic options and high mortality rates. Traditional Chinese medicine (TCM) offers a rich source of multi-component interventions with potential multi-target effects, demanding rigorous evaluation as an alternative or adjunctive strategy.

This multicenter, randomized, double-blind, head-to-head, placebo-controlled clinical trial was conducted by 4 hospitals in China (June 2022 - March 2025), evaluated Xinjia Dayuan San (XJDS), a standardized TCM formulation, against standard broad-spectrum antibiotics (imipenem/cilastatin [I/C] or cefoperazone/sulbactam [C/S]) in 224 adult patients with confirmed MDR-GN pneumonia. Patients were randomized (1:1) within antibiotic strata to receive either XJDS granules (3 g BID) plus intravenous antibiotic placebo (normal saline) or XJDS placebo plus active antibiotic for 7 days. Primary endpoints were 28-day all-cause mortality and 7-day reduction in sputum bacterial load score (Day 0 minus Day 7, 0-3 scale). Key secondary endpoints included changes in Clinical Pulmonary Infection Score (CPIS) and inflammatory markers. Safety was assessed throughout.

In this trial of 224 critically ill patients, XJDS did not meet the primary endpoint of non-inferiority for 28-day all-cause mortality compared to standard antibiotics. However, XJDS demonstrated superiority in key secondary endpoints reflecting disease control. Specifically, XJDS resulted in a significantly greater reduction in the 7-day sputum bacterial load score versus both comparators (median reduction 1.0 vs 0.0, p < 0.001). This microbiological improvement was paralleled by a more rapid clinical stabilization; XJDS significantly accelerated the reduction in both the Clinical Pulmonary Infection Score (CPIS) and the APACHE-II score by Day 7 (p ≤ 0.001 for all comparisons). These clinical benefits were associated with a significant attenuation of key pro-inflammatory cytokines, including TNF-α and IL-1β. The safety profile was comparable between groups.

While not demonstrating definitive non-inferiority for 28-day mortality in this severe cohort, XJDS significantly improved microbiological clearance and clinical scores (CPIS, APACHE-II) in patients with MDR-GN pneumonia. Its benefits in immune modulation and microbial control, coupled with a comparable safety profile and rigorous standardization, suggest XJDS warrants further investigation as a promising adjunctive therapy as an alternative or adjunctive therapeutic option in managing critical drug-resistant infections. Further research into its precise mechanisms and clinical applications is warranted.