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Antimicrobial Blue Light: An Emerging Alternative to Antibiotics

Authors:
Editorial
Antimicrobial Blue Light:
An Emerging Alternative to Antibiotics
Chukuka S. Enwemeka, PhD, FACSM
Bacterial 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 de-
ployment 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
Esti-
mates 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 com-
pared with other emerging alternatives, such as PDT, anti-
bacterial 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 actino-
mycetemcomitans, Porphyromonas gingivalis, and Prevotella in-
termedia.
21
Moreover, the report shows that PDT kills
cariogenic bacteria, including Streptococcus mutans and
Streptococcus sanguis, as well as bacteria associated with in-
fected 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 hu-
man root canals inoculated with Pseudomonas aeruginosa or
Enterococcus faecalis. Similarly, PDT has been shown to be
beneficial in treating dermatologic and ophthalmologic dis-
orders.
23,24
However, serious concerns remain for its acute
side effects and the non-targeted nature of available photo-
sensitizers.
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 TiO
2
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 ox-
ides. 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
College of Health Sciences. University of Wisconsin—Milwaukee, Milwaukee, Wisconsin.
Photomedicine and Laser Surgery
Volume 31, Number 11, 2013
ªMary Ann Liebert, Inc.
Pp. 1–3
DOI: 10.1089/pho.2013.9871
1
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. How-
ever, these results are achievable only with certain parame-
ters, 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 irradia-
tion 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 ob-
tained 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 pro-
gressively 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 ·10
6
colony-forming units (CFU)/mL and 5 ·10
6
CFU/mL cultures, 405 nm light cleared more bacteria in the
denser 7 ·10
6
CFU/mL culture. And regardless of wave-
length, more bacteria were cleared when the culture plates
were irradiated from above and below instead of being ir-
radiated 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.
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Address correspondence to:
Chukuka S. Enwemeka
College of Health Sciences
University of Wisconsin—Milwaukee
2400 E. Hartford Avenue
Milwaukee, WI 53211
E-mail: Enwemeka@uwm.edu
ANTIMICROBIAL BLUE LIGHT 3
... It appears that, similar to aPDT, pathogens treated by aBL are less able to develop resistance than the ones treated with traditional antibiotics due to the multitargeted characteristics of aBL. Although the mechanism of action of aBL is still not fully understood, there is evidence that blue light excites the naturally occurring endogenous porphyrins and/or flavins of microbial cells leading to the formation of ROS in situ [ 107,108,109 ]. ...
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The emergence of microbial resistance to antimicrobials among several common pathogenic microbial strains is an increasing problem worldwide. Thus, it is urgent to develop not only new antimicrobial therapeutics to fight microbial infections, but also new effective, rapid, and inexpensive methods to monitor the efficacy of these new therapeutics. Antimicrobial photodynamic therapy (aPDT) and antimicrobial blue light (aBL) therapy are receiving considerable attention for their antimicrobial potential and represent realistic alternatives to antibiotics. To monitor the photoinactivation process provided by aPDT and aBL, faster and more effective methods are required instead of laborious conventional plating and overnight incubation procedures. Bioluminescent microbial models are very interesting in this context. Light emission from bioluminescent microorganisms is a highly sensitive indication of their metabolic activity and can be used to monitor, in real time, the effects of antimicrobial agents and therapeutics. This chapter reviews the efforts of the scientific community concerning the development of in vitro, ex vivo, and in vivo bioluminescent bacterial models and their potential to evaluate the efficiency of aPDT and aBL in the inactivation of bacteria.
... Over the last decade, an innovative light-based approach, antimicrobial blue light therapy (aBL), has emerged as a potent microbicide that does not require the application of exogenous photosensitizers [19,[25][26][27][28][29][30]. Notably, aBL has been found to be far less damaging to human cells when compared to UVC [31,32]. ...
... Over the last decade, an innovative light-based approach, antimicrobial blue light therapy (aBL), has emerged as a potent microbicide that does not require the application of exogenous photosensitizers [19,[25][26][27][28][29][30]. Notably, aBL has been found to be far less damaging to human cells when compared to UVC [31,32]. ...
... In the past, several microbial species were studied for blue light antimicrobial activity in the spectral range of 400-470 nm, including Gram-positive and Gram-negative bacteria, mycobacteria and fungi. These studies were performed both in vitro and in vivo (preclinical studies and clinical trials) [3][4][5][6][7][8][9][10][11][12][13][14]. ...
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Blue LED light has proven to have a powerful bacteria-killing ability; however, little is known about its mechanism of virucidal activity. Therefore, we analyzed the effect of blue light on different respiratory viruses, such as adenovirus, respiratory syncytial virus and SARS-CoV-2. The exposure of samples to a blue LED light with a wavelength of 420 nm (i.e., in the visible range) at 20 mW/cm2 of irradiance for 15 min appeared optimal and resulted in the complete inactivation of the viral load. These results were similar for all the three viruses, demonstrating that both enveloped and naked viruses could be efficiently inactivated with blue LED light, regardless of the presence of envelope and of the viral genome nature (DNA or RNA). Moreover, we provided some explanations to the mechanisms by which the blue LED light could exert its antiviral activity. The development of such safe and low-cost light-based devices appears to be of fundamental utility for limiting viral spread and for sanitizing small environments, objects and surfaces, especially in the pandemic era.
... Indeed, the antimicrobial effects of blue light therapy have differed among studies and the target microorganism species, possibly owing to environmental conditions, blue light wavelength spectrum, and time of light exposure. Based on the reported blue light effects on the elimination of resistant bacteria and/or fungi (Enwemeka, 2013;Rapacka-Zdonczyk et al., 2019), we investigated the action of blue light on the protozoan T. cruzi. ...
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... Pioneers of this development which has made LEDs the light source of choice for microbial inactivation today include and the duo of J. Stephen Guffey and Jay Wilborn of Arkansas State University in the US [156,157], Chukuka S. Enwemeka and his research team, then at the New York Institute of Technology, Old Westbury, New York, USA, and currently at San Diego State University, San Diego, California, USA [17,18,158], and the team of Michelle MacClean, Scott J. MacGregor, John G. Anderson, Gerry Woolsey and others at the University of Strathclyde, Glasgow, Scotland, UK [159]. Their studies [17,18,[156][157][158][159] have been widely corroborated [19][20][21][24][25][26][27][29][30][31][160][161][162][163], and this has prompted the bourgeoning use of violet-blue LEDs for microbial inactivation and disinfection [3,[164][165][166][167][168][169][170], and the ongoing effort to improve the technology [19][20][21]. ...
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Objective: The aim of this study was to test photodynamic therapy (PDT) as an alternative approach to biofilm disruption on dental hard tissue, We evaluated the effect of methylene blue and a 660 nm diode laser on the viability and architecture of Gram-positive and Gram-negative bacterial biofilms. Materials and methods: Ten human teeth were inoculated with bioluminescent Pseudomonas aeruginosa or Enterococcus faecalis to form 3 day biofilms in prepared root canals. Bioluminescence imaging was used to serially quantify and evaluate the bacterial viability, and scanning electron microscopic (SEM) imaging was used to assess architecture and morphology of bacterial biofilm before and after PDT employing methylene blue and 40 mW, 660 nm diode laser light delivered into the root canal via a 300 μm fiber for 240 sec, resulting in a total energy of 9.6 J. The data were statistically analyzed with analysis of variance (ANOVA) followed by Tukey test. Results: The bacterial reduction showed a dose dependence; as the light energy increased, the bioluminescence decreased in both planktonic suspension and in biofilms. The SEM analysis showed a significant reduction of biofilm on the surface. PDT promoted disruption of the biofilm and the number of adherent bacteria was reduced. Conclusions: The photodynamic effect seems to disrupt the biofilm by acting both on bacterial cells and on the extracellular matrix.
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We have identified a natural clay mixture that exhibits in vitro antibacterial activity against a broad spectrum of bacterial pathogens. We collected four samples from the same source and demonstrated through antibacterial susceptibility testing that these clay mixtures have markedly different antibacterial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Here, we used X-ray diffraction (XRD) and inductively coupled plasma - optical emission spectroscopy (ICP-OES) and - mass spectrometry (ICP-MS) to characterize the mineralogical and chemical features of the four clay mixture samples. XRD analyses of the clay mixtures revealed minor mineralogical differences between the four samples. However, ICP analyses demonstrated that the concentrations of many elements, Fe, Co, Cu, Ni, and Zn, in particular, vary greatly across the four clay mixture leachates. Supplementation of a non-antibacterial leachate containing lower concentrations of Fe, Co, Ni, Cu, and Zn to final ion concentrations and a pH equivalent to that of the antibacterial leachate generated antibacterial activity against E. coli and MRSA, confirming the role of these ions in the antibacterial clay mixture leachates. Speciation modeling revealed increased concentrations of soluble Cu(2+) and Fe(2+) in the antibacterial leachates, compared to the non-antibacterial leachates, suggesting these ionic species specifically are modulating the antibacterial activity of the leachates. Finally, linear regression analyses comparing the log10 reduction in bacterial viability to the concentration of individual ion species revealed positive correlations with Zn(2+) and Cu(2+) and antibacterial activity, a negative correlation with Fe(3+), and no correlation with pH. Together, these analyses further indicate that the ion concentration of specific species (Fe(2+), Cu(2+), and Zn(2+)) are responsible for antibacterial activity and that killing activity is not solely attributed to pH.
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Objective: The purpose of this study was to investigate the effect of wavelength and methicillin-resistant Staphylococcus aureus (MRSA) density on the bactericidal effect of 405 and 470 nm light. Background data: It is recognized that 405 and 470 nm light-emitting diode (LED) light kill MRSA in standard 5 × 10(6) colony-forming units (CFU)/mL cultures; however, the effect of bacterial density on the bactericidal effect of each wavelength is not known. Methods: In three experiments, we cultured and plated US300 MRSA at four densities. Then, we irradiated each plate once with either wavelength at 0, 1, 3, 45, 50, 55, 60, and 220 J/cm(2). Results: Irradiation with either wavelength reduced bacterial colonies at each density (p<0.05). More bacteria were cleared as density increased; however, the proportion of colonies cleared, inversely decreased as density increased--the maximum being 100%, 96%, and 78% for 3 × 10(6), 5 × 10(6), and 7 × 10(6) CFU/mL cultures, respectively. Both wavelengths had similar effects on the sparser 3 × 10(6) and 5 × 10(6) CFU/mL cultures, but in the denser 7 × 10(6) CFU/mL culture, 405 nm light cleared more bacteria at each fluence (p<0.001). To determine the effect of beam penetration, denser 8 × 10(6) and 12 × 10(6) CFU/mL culture plates were irradiated either from the top, the bottom, or both directions. More colonies were eradicated from plates irradiated from top and bottom, than from plates irradiated from top or bottom at the same sum total fluences (p<0.001). Conclusions: The bactericidal effect of LED blue light is limited more by light penetration of bacterial layers than by bacterial density per se.
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Objective: The purpose of this article was to review studies that use visible light instead of dangerous ultraviolet (UV) radiation, for inducing antibacterial properties in metal oxide nanoparticles (NPs). Background data: Metal oxide NPs such as ZnO, CuO, and TiO2 are frequently studied for their antibacterial effects, based on their capability to generate reactive oxygen species (ROS) in their water suspensions, following UV light absorption. Methods: Research articles on shifting metal oxide NPs absorption into the visible light region, published up to 2011, were retrieved from library sources, as well as PubMed and MEDLINE(®) databases. Results: The studies indicated that doping metaloxide NPs with transition metals ions, or attaching the metal oxide nanoparticles to an organic molecule, enhanced their activity in the visible and near infrared (NIR) range. Moreover, ZnO and TiO2 nanoparticles were found to have an absorption peak in UV-A, with a marked absorption in the blue region. Conclusions: It is possible to extend the absorption region of metal oxide NPs to the red/NIR, increasing their antibacterial activity without inducing damage to tissues and cells.
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Background and objective: Bacterial skin and soft tissue infections (SSTI) affect millions of individuals annually in the United States. Treatment of SSTI has been significantly complicated by the increasing emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strains. The objective of this study was to demonstrate the efficacy of blue light (415 ± 10 nm) therapy for eliminating CA-MRSA infections in skin abrasions of mice. Methods: The susceptibilities of a CA-MRSA strain (USA300LAC) and human keratinocytes (HaCaT) to blue light inactivation were compared by in vitro culture studies. A mouse model of skin abrasion infection was developed using bioluminescent USA300LAC::lux. Blue light was delivered to the infected mouse skin abrasions at 30 min (acute) and 24 h (established) after the bacterial inoculation. Bioluminescence imaging was used to monitor in real time the extent of infection in mice. Results: USA300LAC was much more susceptible to blue light inactivation than HaCaT cells (p=0.038). Approximately 4.75-log10 bacterial inactivation was achieved after 170 J/cm(2) blue light had been delivered, but only 0.29 log10 loss of viability in HaCaT cells was observed. Transmission electron microscopy imaging of USA300LAC cells exposed to blue light exhibited disruption of the cytoplasmic content, disruption of cell walls, and cell debris. In vivo studies showed that blue light rapidly reduced the bacterial burden in both acute and established CA-MRSA infections. More than 2-log10 reduction of bacterial luminescence in the mouse skin abrasions was achieved when 41.4 (day 0) and 108 J/cm(2) (day 1) blue light had been delivered. Bacterial regrowth was observed in the mouse wounds at 24 h after the blue light therapy. Conclusions: There exists a therapeutic window of blue light for bacterial infections where bacteria are selectively inactivated by blue light while host tissue cells are preserved. Blue light therapy has the potential to rapidly reduce the bacterial load in SSTI.
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Objective: The purpose of this study was to evaluate the relationship of 625, 525, and 425 nm wavelengths, providing average power output and effects on three common pathogenic bacteria. Background data: Ultraviolet (UV) light kills bacteria, but the bactericidal effects of UV may not be unique, as 425 nm produces a similar effect. The bactericidal effects of light-emitting diode (LED) wavelengths such as 625 and 525 nm have not been described. Before conducting clinical trials, the appropriate wavelength with reasonable dose and exposure time should be established. Materials and methods: The bactericidal effects of 625, 525, and 425 nm wavelength LED irradiation were investigated in vitro for the anaerobic bacterium Porphyromonas gingivalis and two aerobes (Staphylococcus aureus and Escherichia coli DH5α). Average power output was 6 mW/cm(2) for 1 h. The bacteria were exposed to LED irradiation for 1, 2, 4, and 8 h (21.6, 43.2, 86.4, and 172.8 J/cm(2), respectively). LED irradiation was performed during growth on agar and in broth. Control bacteria were incubated without LED irradiation. Bacterial growth was expressed in colony-forming units (CFU) and at an optical density at 600 nm in agar and broth. Results: The bactericidal effect of LED phototherapy depended upon wavelength, power density, bacterial viable number, and bacteria species. The bactericidal effect of 425 and 525 nm irradiation varied depending upon the bacterial inoculation, compared with unirradiated samples and samples irradiated with red light. Especially, P. gingivalis and E. coli DH5α were killed by 425 nm, and S. aureus growth was inhibited by 525 nm. However, the wavelength of 625 nm was not bactericidal for P. gingivalis, E. coli DH5α, or S. aureus. Conclusions: Irradiation at 625 nm light was not bactericidal to S. aureus, E. coli, and P. gingivalis, whereas wavelengths of 425 and 525 nm had bactericidal effects. S. aureus was also killed at 525 nm.
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Objective: The aim of this study was to assess whether or not photodynamic therapy enhanced standard antibacterial therapy in dentistry. Background data: Photodynamic therapy when used as an adjunct to conventional periodontal therapy kills more bacteria than when conventional periodontal therapy is used alone. Materials and methods: To address the focused question, "Does photodynamic therapy enhance killing of oral bacteria?" PubMed/MEDLINE(®) and Google Scholar databases were explored. Original human and experimental studies and studies using photodynamic therapy for killing oral bacteria were included. Letters to the Editor, historic reviews, and unpublished data were excluded. Results: Photodynamic therapy significantly reduces periodontopathogenic bacteria including Aggregatibacter actinomycetemcomitans, Prevotella intermedia, and Porphyromonas gingivalis. Photodynamic therapy kills cariogenic bacteria (such as Streptococcus mutans and Streptococcus sanguis), bacteria associated with infected root canals, and those associated with periimplantitis. Conclusions: Photodynamic therapy, when used as an adjunct to conventional oral disinfection protocols, enhances standard antibacterial therapy in dentistry.
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Objective: The aim of this study was to evaluate the occluding effects of a combination of dentifrice containing nano-carbonate apatite (n-CAP) and a CO2 laser on dentinal tubules, and to assess the acid resistance of the occluded dentinal tubules produced. Background data: A number of experiments have been conducted recently to relieve the symptoms of dentin hypersensitivity (DH) using a laser in combination with desensitizing products. Materials and methods: One hundred and twenty specimens with exposed dentinal tubules were divided into four groups: the control, n-CAP, laser, and combined groups. Thirty specimens in each group were reassigned into three different conditions: baseline, treatment for occluding dentinal tubules, and acid challenge (pH 4.0 acetate buffer solution for 3 min). At the end of each phase, all specimen surfaces were evaluated by scanning electron microscope (SEM). Results: The combined group had a significantly smaller mean dentinal tubule area than the control group, and the fewest reopened dentinal tubules after acid challenge. Conclusions: The combined therapy is a promising means of treating DH patients in the clinic.