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

BACKGROUND

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.

METHODS

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.

FINDINGS: 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.

INTERPRETATION: 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.