Background/Objectives: Klebsiella pneumoniae is a major pathogen involved in both acute and chronic infections, characterized by high incidence and significant clinical severity. Over the past decade, resistance to traditional antimicrobial treatments has risen rapidly, highlighting the urgent need for innovative approaches. Light-based antimicrobial strategies, including antimicrobial photodynamic therapy (aPDT), offer a promising approach for addressing drug-resistant bacteria. Combining two photosensitizers (PSs) with antibiotics synergistically enhances ROS generation and multi-target bacterial damage, achieving superior antimicrobial efficacy at reduced PS, light and antibiotic doses while limiting resistance development. We evaluated the efficacy of aPDT using the photosensitizers (PSs) methylene blue (MB) and Photodithazine (PDZ), either alone or in combination with the antibiotic ciprofloxacin (CIP), gentamicin (GEN), or ceftriaxone (CEF), against K. pneumoniae. Methods: Bacterial suspensions were treated with PDZ (25–200 μg/mL) and/or MB (5–20 μg/mL) in the presence of CIP (0.005–4 μg/mL), GEN (0.5–16 μg/mL), or CEF (0.5–16 μg/mL), followed by irradiation at either 15 J/cm2 or 30 J/cm2. Bacterial survival was assessed by colony-forming unit (CFU/mL) quantification. Results: The combined application of photosensitizers and antibiotics demonstrated a synergistic bactericidal effect against planktonic K. pneumoniae. The combined use of two PSs with antibiotics markedly reduced the antibiotic dose required to achieve a comparable bactericidal effect. Conclusions: This study highlights the potential of combining aPDT with conventional antibiotics as a promising strategy to combat drug-resistant infections, offering enhanced antimicrobial efficacy while allowing for reduced antibiotic dosages to achieve comparable therapeutic outcomes.
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