Because antimicrobial resistance is accelerating and the antibiotic development pipeline remains limited, an in vitro study suggested that antimicrobial photodynamic therapy (PDT) may enhance the activity of established antibiotics against Klebsiella pneumoniae, a major cause of healthcare-associated infections in hospitals worldwide, especially in cases of hospital-acquired pneumonia or ventilator-associated pneumonia. By combining red light and methylene blue with commonly used agents, researchers have achieved substantial bacterial reduction while lowering the required antibiotic concentrations.

In a study published in Antibiotics, researchers assessed whether pairing widely prescribed antibiotics with PDT could restore or amplify antibacterial efficacy. Under several experimental conditions, this combination achieved complete eradication of K pneumoniae, an outcome not observed with antibiotics alone at comparable doses.

Vanderlei Salvador Bagnato, PhD, one of the study authors, said in an interview with USP Journal that “light acts as a pathway opener. It weakens the bacteria and allows the antibiotic to do its job better.”

The study was conducted by researchers at the São Carlos Institute of Physics, University of São Paulo, São Carlos, Brazil, in collaboration with Texas A&M University, Texas. K pneumoniae was selected because it is a leading cause of ventilator-associated pneumonia and other serious hospital-acquired infections, associated with high mortality rates and increasing resistance to multiple classes of antibiotics.

Because antibiotic susceptibility is declining, therapeutic options are limited, often necessitating higher doses, potentially more toxic regimens, and prolonged hospitalization. This study aimed to enhance the performance of existing antibiotics, which may be as clinically relevant as the development of new agents.

Experimental Approach

Instead of introducing new molecules, researchers have evaluated the integration of antibiotics with PDT. This method combines three components: a photosensitizing dye, light at a specific wavelength, and oxygen. When activated by light, the dye generates reactive oxygen species that damage essential bacterial components.

The study compared methylene blue and photodithazine, both activated by a red light-emitting diode (LED)-based device. Antibiotics were administered at progressively lower concentrations, either alone or in combination with PDT. When methylene blue was combined with light, K pneumoniae became substantially more susceptible to antibiotics, with bacterial reductions of up to six orders of magnitude compared with antibiotics alone.

In addition to its direct bactericidal effects, PDT appears to function as a sensitizing factor. Disruption of the outer membrane of these Gram-negative bacteria may facilitate the entry of antibiotics and interfere with classic resistance mechanisms, including efflux pumps and molecular target alterations.

Mechanistic Rationale

PDT has long been explored as an antimicrobial strategy, although it is often considered an alternative rather than a complementary strategy to antibiotics. Experimental evidence indicates that this technique can inactivate Gram-positive and Gram-negative bacteria, fungi, viruses, and protozoa without inducing resistance because it causes simultaneous oxidative damage to multiple cellular targets. However, most of these studies evaluated the technique in isolation in controlled experimental settings, which limits its application in clinical practice.

A 2024 review identified PDT as a promising approach for multidrug-resistant strains but highlighted the heterogeneity in study design and limited data on combination therapy. The current study systematically evaluated PDT as a bacterial sensitizer, demonstrating the enhanced activity of ciprofloxacin, gentamicin, and ceftriaxone when used with light and methylene blue.

Mechanistically, these findings support the growing evidence that photodynamic therapy enhances antibiotic efficacy by disrupting bacterial membranes and resistance-related structures.

In Gram-negative bacteria, such as Klebsiella, the lipopolysaccharide-rich outer membrane serves as a physical barrier that restricts the entry of many antimicrobial agents. Oxidative damage triggered by photodynamic therapy can compromise this barrier, increase membrane permeability, and facilitate the intracellular penetration of antibiotics that target the internal structures.

The degree of synergy varied according to the photosensitizer and the class of antibiotics involved. Previous studies have reported synergistic effects between methylene blue-mediated PDT and aminoglycosides, such as gentamicin, against Staphylococcus aureus and Pseudomonas aeruginosa. These studies indicate that oxidative damage to the membrane potentiates the effects of antibiotics that act on protein synthesis by facilitating their access to bacterial ribosomes.

Published findings on fluoroquinolones, such as ciprofloxacin, have been inconsistent. The application sequence — PDT before or after the antibiotic — can significantly alter the outcome, with differences of 4-6 orders of magnitude in bacterial reduction, as described in other reports. By showing consistent synergy with concomitant use, this study suggests that the design of the therapy may be as important as the choice of antibiotics.

For antibiotics that act on cell wall synthesis, such as ceftriaxone, the literature indicates that photodynamic therapy can intensify the bactericidal effect by weakening external structures, making the interruption of peptidoglycan production more lethal. The results of this study align with this model, reinforcing the biological plausibility of this strategy.

Taken together, these results provide a clearer picture of the previously scattered findings. PDT is not a substitute for antibiotic therapy. Instead, it reshapes the conditions in which bacteria work, weakens their defenses, and improves drug performance. This shift in perspective helps explain why this strategy is drawing attention at a time when progress in developing new antibiotic classes has slowed.

Clinical Implications

The authors emphasized that the findings were limited to in vitro experiments using standard laboratory strains. The efficacy in animal models or human infections remains unknown, particularly in deep-seated infections where light penetration may be limited.

Standardization challenges remain, including the optimal light dose, photosensitizer selection, timing of application, and antibiotic pairing. The interactions between these variables are likely to be pathogen- and site-specific.

Researchers have suggested that this strategy may be most applicable to localized infections accessible to illumination, such as chronic wounds, ulcers, device-associated infections, and selected respiratory conditions. Because methylene blue and LED devices are already used in clinical practice, the translational barrier may be lower than that associated with the development of new antimicrobial agents.

“It’s a smart way to repurpose safe and well-known technologies to tackle one of the biggest public health challenges,” Bagnato concluded.

Daniela Barros is a journalist from Brazil, specializing in social journalism at the Pontifical Catholic University of São Paulo, and a master’s student in the Department of Social Medicine at the Ribeirão Preto Medical School in Ribeirão Preto, Brazil. She has been involved in medicine for 23 years and has contributed to several specialized publications.

This story was translated from Medscape’s Portuguese edition.