Antimicrobial Blue Light: An Emerging Alternative to Antibiotics

B acterial resistance to drugs poses a major healthcare problem, causing widespread epidemic of diseases that hitherto were susceptible to antibiotics. Since penicillin was introduced in the 1940s, the pharmaceutical industry has countered this trend with periodic development and deployment of “stronger” antibiotics; however, bacteria in general, and methicillin-resistant Staphylococcus aureus (MRSA) in particular, have continually evolved a repertoire of evasive mechanisms that frequently defy antibiotic treatment. More than two billion people now carry some strain of S. aureus; 53 million of whom have MRSA. ¹ Estimates indicate that the United States alone spends 3.2–4.2 billion dollars on hospitalized patients with MRSA every year, ^2,3 and this does not include the human costs associated with lost labor, and lost lives, which now exceed that caused by HIV/AIDS. ⁴

Deadly outbreaks of MRSA have been reported in every region of the world, with air travel and sociopolitical ties speeding the spread and resulting in the emergence of similar strains in countries with historical ties. ³ Whereas infections were once confined to hospitals, that is, hospital-associated MRSA (HA-MRSA), the ongoing spread of community-associated MRSA (CA-MRSA) and livestock associated MRSA (LA-MRSA), and the reported jump of strains from animal to human and vice versa, ^{5 –9} now present a larger clinical conundrum. Pandemic strains of CA-MRSA have been found on beaches, computer keyboards, locker rooms, schools, athletic fields, and other common locations. ^{10 –13} It is now estimated that MRSA infection accounts for 44% of all hospital-associated infections in the United States; of these, as many as 92% are CA-MRSA. ¹⁴

The continuing resistance of MRSA and other bacteria to antibiotics calls for a paradigm shift in the quest for therapies capable of stemming their spread. Alternative modalities currently under investigation include hyperbaric oxygen, ¹⁵ photodynamic therapy (PDT), ¹⁶ antibacterial clays, ¹⁷ and blue light phototherapy. ^{18 –20} Interest in hyperbaric oxygen has waned, because of its moderate bactericidal effect compared with other emerging alternatives, such as PDT, antibacterial clay, and blue light. As shown in this issue of the journal, PDT, when used as an adjunct to conventional oral disinfection protocols, significantly reduces infection caused by ontopathogenic bacteria, including Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia. ²¹ Moreover, the report shows that PDT kills cariogenic bacteria, including Streptococcus mutans and Streptococcus sanguis, as well as bacteria associated with infected root canals and peri-implantitis. ²¹

This finding is supported by the work of Gacez et al. ²² (in this issue), who showed that PDT, using 660 nm diode laser and methylene blue, significantly reduced infection in human root canals inoculated with Pseudomonas aeruginosa or Enterococcus faecalis. Similarly, PDT has been shown to be beneficial in treating dermatologic and ophthalmologic disorders. ^23,24 However, serious concerns remain for its acute side effects and the non-targeted nature of available photosensitizers. ²⁴ This situation calls for other alternatives to PDT, in spite of its beneficial antimicrobial effect. The Ebers Papyrus, published circa 1600 BCE, ²⁵ and the 5000-year-old tablets of Nippur ²⁶ identified clay and sunlight as therapies used by humans to treat a wide range of diseases, including infections caused by bacteria. Emerging reports now show that certain types of clay and light in the ultraviolet (UV), violet, and blue spectra have antibacterial properties. ^{18 –20,27}

In this issue of the journal, we focus on articles that indicate that certain wavelengths of light are bactericidal and can eradicate recalcitrant bacteria in vitro and in vivo. First, a connection between light therapy and the antimicrobial action of clay may be seen in the work of Lipovsky et al. ²⁸ (in this issue) who showed that doping nanoparticles such as ZnO, CuO, and TiO_2, with transition metals ions, or attaching the metal oxides nanoparticles to an organic molecule, enhances their antimicrobial reactive oxygen species (ROS) generation activity when irradiated with light in the visible and near infrared ranges. Furthermore, they found that ZnO and TiO₂ nanoparticles had notable absorption in the blue spectrum, indicating that visible light could be used to trigger ROS production, and, hence, the antimicrobial effect of metal oxides. Studies of clay treatment similarly show that mineral leachates, including ions of copper, iron, cobalt, nickel, and zinc, from certain varieties of clay, are responsible for the antibacterial action of clay against Escherichia coli and MRSA. ¹⁷ That light may be equally involved in clay treatment remains unexplored, but a potential role cannot be ruled out entirely.

Similarly, encouraging data from Dai et al., ²⁹ (in this issue) indicate that the bacteria- eradicating effect of blue light, long reported in a multitude of in vitro studies, ^{18 –20,27} is achievable in vivo. They found that irradiation with 415±10 nm blue light reduced bacterial burden in abrasive skin wounds of laboratory rats inoculated with CA-MRSA. Furthermore, bacterial clearance was achieved without significant adverse effect on keratinocytes co-cultured with CA-MRSA. And electron microscopy revealed that irradiation of the bacteria caused extrusions of cytoplasmic content, cell wall damage, and cell debris, providing an insight into the potential mechanisms involved in photo-eradication of MRSA. However, these results are achievable only with certain parameters, as suggested by the preliminary findings of Lanzafame et al., ³⁰ (in this issue) who found significant reduction of bacteria with photo-activated collagen-embedded flavins (PCF) treatment, but not with 455±5 nm blue light irradiation alone, when treating pressure ulcers in mice inoculated with MRSA. The implication is that experimental model and mode of treatment can significantly affect the results obtained in these types of studies.

Further evidence that experimental parameters influence outcomes can be seen in the work of Bumah et al. ³¹ and Kim et al. ³² For example, Bumah et al. ³¹ showed that irradiation with either 405 or 470 nm blue light cleared MRSA progressively as fluence increased, and also as bacterial density increased, even though the proportion of bacterial colonies cleared decreased inversely as bacterial density. Whereas both wavelengths had similar effects on less dense cultures, that is, 3×10⁶ colony-forming units (CFU)/mL and 5×10⁶ CFU/mL cultures, 405 nm light cleared more bacteria in the denser 7×10⁶ CFU/mL culture. And regardless of wavelength, more bacteria were cleared when the culture plates were irradiated from above and below instead of being irradiated from one direction at the same corresponding total dose. The latter finding suggests that the bactericidal effect of light-emitting diode (LED) blue light is limited more by the ability of blue light to penetrate the layers of bacteria than by bacterial density alone. That wavelength affects the outcome of LED photo-irradiation of bacteria is corroborated by Kim et al. ³² They showed that, even though P. gingivalis and E. coli are killed with 425 nm blue light, 525 nm green light only induces bacteriostatic effect. Also, 625 nm red light did not kill any of the bacteria tested.

Collectively, these reports present further evidence that light, in particular, blue light in the range of 405–470 nm wavelength is bactericidal, and has the potential to help stem the ongoing pandemic of MRSA and other bacterial infections.