Photodynamic and antibiotic combination therapy against multidrug-resistant Pseudomonas aeruginosa wound infections in diabetic rats.

In our previous study, 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) promoted chronic diabetic wound healing by reducing the microbial burden. However, the anti-bacterial efficacy of ALA-PDT is often compromised by limited light penetration into tissues. To increase the efficacy of ALA-PDT, this study assessed its combined use with the antibiotic ceftazidime in treating chronic diabetic wounds and examined the potential mechanism of action. The results indicated that the combination of ALA-PDT and ceftazidime synergistically inhibited the growth of multidrug-resistant Pseudomonas aeruginosa. The treatment also prevented the formation of bacterial biofilm, delayed the development of antibiotic resistance, inactivated pyocyanin, and exerted a prolonged post-antibiotic effect. The mechanism supporting the synergistic antibacterial effect might involve ALA-PDT-mediated reactive oxygen species generation, leading to bacterial cell structure destruction, increased membrane permeability, and cellular ceftazidime uptake. In a full-thickness skin defect infection model in rats with diabetes, the bactericidal and wound closure rates were highest in the combination therapy group. Transcriptomics analysis of wound tissues revealed that the differentially expressed genes between the combination therapy and model groups were mainly enriched in the IL-17, AKT-STAT, and VEGF signaling pathways. Molecular biology experiments illustrated that the combination therapy might regulate the expression of IL-17, activate the JAK-STAT axis, increase p-JAK2 and p-STAT3 expression, and decrease SOCS3 expression, ultimately leading to Ki-67, CD31, and VEGF upregulation and exerting beneficial effects on angiogenesis, collagen deposition, and tissue regeneration. Overall, PDT and antibiotic combination therapy offers an efficient approach to treat infections in diabetic wounds.