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 >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 >20 cm subpopulation: 8% (D-PLEX) versus 17.5% (SOC) (RDE, -9.4%; 95% CI [-15.5%, -3.2%], P=0.0032). In the >10 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.

Preclinical In-Vivo Safety and Toxicokinetics of D-PLEX100 in an Abdominal Surgery Incision Model in Juvenile Miniature Swine.

D-PLEX100 (D-PLEX) is a novel product candidate made of a polymer-lipid-based matrix (PLEX platform) which contains doxycycline that is being released at a constant rate for 30 days. D-PLEX was developed to prevent surgical site infections, which are a major global health challenge. Previous studies have shown its safety in adult humans, adult swine, and adult rabbits. The aim of this study was to assess the toxicity and safety of D-PLEX also in juvenile animals to support future clinical trials in pediatric patients. Yucatan miniature swine were selected as a model, primarily due to their relatively larger mass. D-PLEX or placebo (formulation without doxycycline) was administered locally to abdominal incisions, and the animal's safety parameters were followed for 9 months and compared to sham-control swine. There was no evidence of any systemic safety concern or local toxicity at the incision site in D-PLEX-treated animals. D-PLEX was detected after 1 month and was fully resorbed at the 3-month time point. The surgical incision sites were fully healed at the 6-month time point in all D-PLEX-treated animals. Toxicokinetic (TK) assessments revealed that doxycycline exhibited low Cmax and therefore minimal systemic exposure following a single dose of local administration. This study provides evidence for the safety of D-PLEX and PLEX-based formulation in juvenile miniature swine and supports its further testing in clinical pediatric population. In addition, it can be used as a reference for future preclinical studies aiming to evaluate the safety of other PLEX-based product candidates for the pediatric population.

Potent antibacterial activity in surgical wounds with local administration of D-PLEX100.

Despite significant advances in infection control guidelines and practices, surgical site infections remain a substantial cause of morbidity, prolonged hospitalization, and mortality. The most effective component of SSI reduction strategies is the preoperative administration of intravenous antibiotics; however, systemic antibiotics drug exposure diminishes rapidly and may result in insufficient prophylactic activity against susceptible and resistant SSI pathogens at the wound. D-PLEX100 (D-PLEX) is an antibiotic-releasing drug (doxycycline) that is supplied as a sterile powder for paste reconstitution with sterile saline. D-PLEX paste is administered locally into the incision site along the entire length of soft tissue and sternal bone wound surfaces prior to skin closure. A single D-PLEX administration is intended for 30 days of constant antimicrobial prophylaxis in the prevention of incisional SSIs. We evaluated D-PLEX minimal bactericidal concentration (MBC) against a panel of bacteria that is prevalent in the abdominal wall and sternal surgical procedures including doxycycline susceptible and resistant strains. D-PLEX in vivo efficacy was assessed in incisional infection rabbit models (abdominal wall and sternal) challenged with a similar bacterial panel. The D-PLEX drug exposure profile was determined by in vitro release assay, and in vivo by quantitative pharmacokinetic parameters of local and systemic doxycycline concentrations released from D-PLEX after local administration in incisional rabbit models. Analyses of pathogens and variations in antibiotic resistance from wound isolates were determined from patients who participated in a previously reported prospective randomized trial that assessed the SSI rate in D-PLEX plus standard of care (SOC) versus SOC alone in colorectal resection surgery. The D-PLEX MBC values demonstrated >3- Log10 reduction in all the organisms tested relative to untreated controls, including doxycycline-resistant bacteria (i.e., Methicillin-resistant Staphylococcus aureus (MRSA), K. pneumoniae, and P. aeruginosa). In vivo, D-PLEX significantly reduced the bacterial loads in all the bacteria tested in both animal models (p=0.0001) with a marked impact observed in E. Coli (>6.5 Log10 reduction). D-PLEX exhibited a zero-order release kinetics profile in vitro for 30 days (R2 = 0.971) and the matched in vivo release profile indicated a constant local release of protein-unbound doxycycline for 30 days at 3-5 mcg/mL with significantly lower (>3 orders of magnitudes) systemic levels. In colorectal surgery patients, where significant SSI reduction was observed, analysis of the positive cultures in the overall population indicated similar pathogen diversity and antibiotic resistance rates in both treatment arms. However, almost all the patients with positive culture in the SOC arm were adjudicated as SSI (94%) compared to only 28% in the D-PLEX arm. The SSI-adjudicated D-PLEX patients also exhibited lower resistance rates to the SOC antibiotics and to MDRs compared to patients in the SOC arm. Thus, D-PLEX provides safe and effective prophylaxis activity against the most prevalent SSI pathogens including doxycycline-susceptible and resistant bacteria. Our findings suggest that D-PLEX is a promising addition to SSI prophylactic bundles and may address the gaps in current SSI prophylaxis. D-PLEX is now evaluated in Phase 3 clinical trial.

Reduction in surgical site infections by localized administration with D-PLEX100 in patients with multiple risk factors undergoing colorectal surgery.

BACKGROUND: D-PLEX100 is a novel drug-eluting lipid polymer matrix that supplies a high, local concentration of doxycycline for approximately 30 days. The objective of this post-hoc analysis was to assess the efficacy of D-PLEX100 in preventing superficial and deep SSIs in patients with ≥2 risk factors. PATIENTS AND METHODS: A post-hoc analysis of a previously reported prospective randomized trial assessing D-PLEX100 plus Standard of Care (SOC) versus SOC alone in colorectal surgery was performed to assess SSI rate in patients with ≥2 risk factors. RESULTS: The overall incidence of SSI was significantly lower for the D-PLEX100 arm (9.9%) versus SOC (21%), p = 0.033. Patients with ≥2 risk factors, SSI incidence was 37.5% for SOC and 15.8% in D-PLEX100 treated patients. CONCLUSIONS: D-PLEX100 reduces the incidence of SSIs beyond benefits associated with SOC treatment alone and including patients with ≥2 risk factors. D-PLEX100 may be a promising addition to established SSI prophylaxis bundles.

Local prolonged release of antibiotic for prevention of sternal wound infections postcardiac surgery-A novel technology.

INTRODUCTION: Sternal wound infection (SWI) is a devastating postcardiac surgical complication. D-PLEX100 (D-PLEX) is a localized prolonged release compound applied as a prophylactic at the completion of surgery to prevent SWI. The D-PLEX technology platform is built as a matrix of alternating layers of polymers and lipids, entrapping an antibiotic (doxycycline). The objective of this study was to assess the safety profile and pharmacokinetics of D-PLEX in reducing SWI rates postcardiac surgery. METHOD: Eighty-one patients were enrolled in a prospective single-blind randomized controlled multicenter study. Sixty patients were treated with both D-PLEX and standard of care (SOC) and 21 with SOC alone. Both groups were followed 6 months for safety endpoints. SWI was assessed at 90 days. RESULTS: No SWI-related serious adverse events (SAEs) occurred in either group. The mean plasma Cmax in patients treated with D-PLEX was about 10 times lower than the value detected following the oral administration of doxycycline hyclate with an equivalent overall dose, and followed by a very low plasma concentration over the next 30 days. There were no sternal infections in the D-PLEX group (0/60) while there was one patient with a sternal infection in the control group (1/21, 4.8%). CONCLUSION: D-PLEX was found to be safe for use in cardiac surgery patients. By providing localized prophylactic prolonged release of broad-spectrum antibiotics, D-PLEX has the potential to prevent SWI postcardiac surgery and long-term postoperative hospitalization, reducing high-treatment costs, morbidity, and mortality.

D-PLEX100 in an Abdominal Surgery Incision Model in Miniature Swine: Safety Study.

Surgical site infections (SSIs) are a common surgical-related complication. To avoid these complications, a new biodegradable polymer-lipid encapsulation matrix that provides controlled release of doxycycline (doxycycline/polymer-lipid encapsulation matrix [D-PLEX]) has been developed. The aim of this comprehensive study was to evaluate the potential safety of D-PLEX100 in abdominal surgical site. D-PLEX100 was administered into incisions of abdominal surgical site in Yucatan miniature swine, which were followed for up to 6 months and compared to sham-control swine. The D-PLEX100 mass did not migrate from the incisional site, and there was no evidence for systemic toxicity or other safety concerns. Surgical incision sites, including the peritoneal surface, were fully healed at 6 months in all animals. Most of the D-PLEX100 mass was absorbed during the first 3 months, and by 6 months, D-PLEX100 was fully absorbed. Toxicokinetic evaluation revealed that doxycycline concentrations were evident at 30 minutes and persisted to 8 days (71 mg/kg) or at least 15 days (284 mg/kg) and were no longer present in plasma by day 29. This study supports the safety of D-PLEX100 and its favorable degradability profile. A clinical study is being performed to assess the safety and the efficacy of D-PLEX100 to prevent human abdominal SSIs.

D-PLEX500: a local biodegradable prolonged release doxycycline-formulated bone graft for the treatment for peri-implantitis. A randomized controlled clinical study.

OBJECTIVES: In the present pilot, multicenter, randomized, single-blinded, controlled study, surgical treatment with or without the administration of D-PLEX500 (a biodegradable prolonged release local doxycycline formulated with ß-tricalcium phosphate bone graft) was accessed for the treatment of peri-implantitis. METHOD AND MATERIALS: Subjects undergoing surgical treatment for intrabony peri-implantitis defects after flap elevation were randomly assigned, to adjunct D-PLEX500 placement group or to control group. Clinical and radiographic parameters were measured at 6 and 12 months. RESULTS: Twenty-seven subjects (average age: 64.81 ± 7.61 years) were enrolled; 14 patients (18 implants) were randomized to the test group and 13 (14 implants) to the control group. There was no difference in plaque scores between the groups. There was no difference in the changes of mean periodontal probing depth between the test and control groups between baseline and the 6-month follow-up, whereas statistically significant difference was observed after 12 months' follow-up when analyzed for all sites averaged. There was a statistically significant difference in the changes of clinical attachment levels and radiographic bone levels between the groups between baseline and 12 months. These improvements were demonstrated when analyzed at both implant and subject levels. Only D-PLEX500 treatment led to improved bone levels at both time points. The improvement in bone levels was significant in the D-PLEX500 treatment group already after 6 months, and further improved over the 12-month follow-up. Implants were lost only in the control group (14%). CONCLUSIONS: D-PLEX500 sustained release local antibiotic formulated with bone filler showed promising results in enabling healing of peri-implantitis lesions. The antibacterial component of the bone graft material might create favorable conditions that enable implant surface decontamination and soft and hard tissue healing over a prolonged period.

Toxicity and Safety Study of D-PLEX100 in a Sternal Surgical Defect in New Zealand White Rabbits.

Bacterial infections are a common complication after surgical procedures. Therefore, local delivery of antibiotics has been developed, including the use of biodegradable polymers. A newly developed product for prevention of surgical site infections is a polymer-lipid encapsulation matrix loaded with doxycycline, named D-PLEX100 (D-PLEX). We evaluated the toxicity and safety of D-PLEX using a sternal surgical defect model in rabbits. D-PLEX was tested with three different concentrations of doxycycline in comparison to sham-operated control after administration into the sternal surgical defect and on the ventral side of the sternum in New Zealand White (NZW) rabbits, following 15 months of exposure. No mortality or abnormal clinical findings were attributed to D-PLEX, and clinical pathology assays were normal. Histological examinations revealed no treatment-related adverse findings in any of the examined tissues, including the osseous and surrounding soft tissues. It has been shown that D-PLEX gradually degraded until complete disappearance after 9 months, and mainly during the first 3 months, in parallel to normal bone formation. In addition, the administration of D-PLEX did not affect sternal bone strength. This study adds to the growing data on preclinical safety studies utilizing biodegradable materials and provides information on the expected normal reaction to biodegradable materials in the sternum of NZW rabbits.

A doxycycline-loaded polymer-lipid encapsulation matrix coating for the prevention of implant-related osteomyelitis due to doxycycline-resistant methicillin-resistant Staphylococcus aureus.

Implant-associated bone infections caused by antibiotic-resistant pathogens pose significant clinical challenges to treating physicians. Prophylactic strategies that act against resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are urgently required. In the present study, we investigated the efficacy of a biodegradable Polymer-Lipid Encapsulation MatriX (PLEX) loaded with the antibiotic doxycycline as a local prophylactic strategy against implant-associated osteomyelitis. Activity was tested against both a doxycycline-susceptible (doxy(S)) methicillin-susceptible S. aureus (MSSA) as well as a doxycycline-resistant (doxy(R)) methicillin-resistant S. aureus (MRSA). In vitro elution studies revealed that 25% of the doxycycline was released from the PLEX-coated implants within the first day, followed by a 3% release per day up to day 28. The released doxycycline was highly effective against doxy(S) MSSA for at least 14days in vitro. A bolus injection of doxycycline mimicking a one day release from the PLEX-coating reduced, but did not eliminate, mouse subcutaneous implant-associated infection (doxy(S) MSSA). In a rabbit intramedullary nail-related infection model, all rabbits receiving a PLEX-doxycycline-coated nail were culture negative in the doxy(S) MSSA-group and the surrounding bone displayed a normal physiological appearance in both histological sections and radiographs. In the doxy(R) MRSA inoculated rabbits, a statistically significant reduction in the number of culture-positive samples was observed for the PLEX-doxycycline-coated group when compared to the animals that had received an uncoated nail, although the reduction in bacterial burden did not reach statistical significance. In conclusion, the PLEX-doxycycline coating on titanium alloy implants provided complete protection against implant-associated MSSA osteomyelitis, and resulted in a significant reduction in the number of culture positive samples when challenged with a doxycycline-resistant MRSA.

A lipid-and-polymer-based novel local drug delivery system--BonyPid™: from physicochemical aspects to therapy of bacterially infected bones.

Bacterial infection of bone may result in bone destruction and is difficult to cure due to poor accessibility to bone of systemically-administrated antibiotic and poor performance of currently available local antibacterial treatments. We developed a novel local drug delivery system based on self-assembly of specific familiar lipids and polymers that encapsulate the desired drug (exemplified by doxycycline). The entrapped doxycycline present in the anhydrous environment of the formulation is fully protected from long-term water-exposure-related degradation. The fine coating of the tricalcium phosphate bone filler by this doxycycline-containing formulation (BonyPid™) is capable of releasing intact and active drug at a steady, zero-order rate for a predetermined period of up to 30 days and in amount sufficient to achieve therapy potentially capable of eliminating the contaminating bacteria. Therefore a clinical evaluation is proposed for testing the efficacy and toxicity of BonyPid for therapy of bacterial bone infections.