Effect of local prolonged-release incisional doxycycline on surgical site infection prophylaxis in abdominal colorectal surgery: the SHIELD 1 randomized clinical trial

Introduction: Despite advanced infection control practices including preoperative antibiotic prophylaxis, surgical site infection (SSI) remains a challenge. This study aimed to test whether local administration of a novel prolonged-release doxycycline-polymer-lipid encapsulation matrix (D-PLEX) before wound closure, concomitantly with standard of care (SOC), reduces the incidence of incisional SSI after elective abdominal colorectal surgery.

Materials and methods: This was a phase 3 randomized, controlled, double-blind, multinational study (SHIELD 1) between June 2020 to June 2022. Patients with at least one abdominal incision length greater than 10 cm were randomized 1:1 to the investigational arm (D-PLEX+SOC) or control (SOC) arm. The primary outcome was a composite of incisional SSI, incisional reintervention, and all-cause mortality.

Results: A total of 974 patients were analyzed, of whom 579 (59.4%) were male. The mean age (±SD) was 64.2±13.0 years. The primary outcome occurred in 9.3% of D-PLEX patients versus 12.1% (SOC) [risk difference estimate (RDE), -2.8%; 95% CI (-6.7%, 1.0%), P =0.1520]. In a pre-specified analysis by incision length, a reduction in the primary outcome was observed in the greater than 20 cm subpopulation: 8% (D-PLEX) versus 17.5% (SOC) [RDE, -9.4%; 95% CI (-15.5%, -3.2%), P =0.0032]. In the greater than 10 to less than or equal to 20 cm subgroup, no reduction was observed: 9.9% versus 7.9% [RDE, 2.0%; 95% CI (-2.8%, 6.7%), P =0.4133]. Exploratory post hoc analyses of patients with increased SSI risk (≥1 patient-specific comorbidity) indicated a reduction in the incidence of the primary outcome: 9.0% (D-PLEX) versus 13.7% (SOC) [RDE, -4.8%; 95% CI (-9.5%, -0.1%), P =0.0472]. The D-PLEX safety profile was good (no difference in treatment-emergent adverse events between the groups).

Conclusions: The SHIELD 1 study did not meet its primary outcome of reduced incisional SSI, incisional reinterventions, or all-cause mortality. Pre-specified and post hoc analyses suggested that D-PLEX may reduce the incidence of the primary outcome event in patients with increased SSI risk, including lengthy incisions.