Welcome to this issue’s Diabetes Digest and commentary. I wish you all a very blessed and happy Christmas, wherever you are.
Diabetic foot infections are one of the most damaging wound complications, frequently leading to hospitalisation, surgery, amputation and, sometimes, death. Increasingly worrying and problematic is the rising occurrence of resistance strains to antibiotics. This paper may give some hope to managing this clinical nightmare.
Pravibismane is a novel product that has antimicrobial and antibiofilm activity against a broad range of Gram-positive and Gram- negative bacteria. It is the first in a new class of microbial bioenergetic inhibitor agents that disrupt energy flow in bacterial membranes, essentially stopping bacterial adenosine triphosphate production, which subsequently halts all bacterial downstream biosynthetic activity.
This was a Phase 1b randomised, double blind, placebo-controlled, multicentre trial in the US. It was designed to examine the safety and efficacy of topical pravibismane gel as an adjunct therapy for infected diabetic foot ulcers (DFU). Five study sites were asked to enrol between 12 and 15 subjects with moderate or severely infected DFU, as per Infectious Disease Society of America infection classification.
Inclusion criteria were:
- Treated with antibiotics for ≤36 hours prior to presentation, or failure to antibiotic therapy prior to enrolment.
- Adequate arterial supply determined by palpable pedal pulses; normal Doppler wave forms; toe brachial index ≥0.75; or ankle brachial index >0.9.
- The researchers recruited 53 subjects, with 39 randomised to the pravibismane treatment group (PTG) and 13 to the placebo control group (PCG).
The study duration was 6–7 weeks with thrice weekly visits over 2–3 weeks for application of pravibismane or the placebo gel. There were three dosage levels for pravibismane, which were determined by DFU size (3, 7.5 and 15 μg/cm2). All subjects received standard care, including sharp ulcer debridement, systemic antibiotic therapy and offloading. Tissue samples were collected at baseline and at the end of the study. All wounds were dressed with provided dressings according to exudate levels.
Subjects were evaluated at the end of treatment, which was 3 days after the last dose, at test of cure (2 weeks after the end of treatment) and the end of the study, 4 weeks after the end of treatment.
Recorded data included: adverse events; ulcer area measurement by 3D digital photography, documentation of any lower-extremity amputations, bacterial reinfection or relapse; and serum levels for systemic exposure to pravibismane. Culture results and clinical examination, were used at the end of the study to assess infection status. Safety parameters included clinical observations of tolerability and pharmacokinetics.
The microbiologically evaluable population consisted of 44 (83%) subjects. The most commonly isolated baseline pathogens were: methicillin-susceptible Staphylococcus aureus in 11 (25.0%); methicillin-resistant S aureus in eight (18.2%); Enterococcus faecalis in six (13.6%) and Pseudomonas aeruginosa in five (11.4%). Pravibismane demonstrated in vitro efficacy against all the aerobic and anaerobic species isolated in this study.
The PTG had a threefold ulcer size decrease compared with PCG (85% versus 30%; p=0.27). The incidence of ulcer-related lower-limb amputations was sixfold lower in the pooled PTG 2.6% versus 15.4% in PCG. Pravibismane was well-tolerated and exhibited minimal systemic absorption. In total, 27 (51.9%) subjects experienced an adverse event that required treatment, but none were considered related to the study drug. There were 6 (11.5%) serious adverse events including two subjects in PCG. None of these were considered related to the study drug. Larger studies are needed but these findings suggest that pravibismane is safe and potentially an effective adjunct treatment for infected DFUs.
