Antimicrobial photodynamic therapy

These ROS lead to the oxidation of cellular components of a wide array of microbes, including pathogenic bacteria, fungi, protozoa, algae, and viruses.

[5] In the early 20th century, decades before the first chemical antibiotics were developed, Dr. Niels Finsen discovered that blue light could be used to treat skin infections.

[7] In 1903, the Nobel Prize committee awarded him for his work in Physiology/Medicine, "in recognition of his contribution to the treatment of diseases, especially lupus vulgaris, with concentrated light radiation, whereby he has opened a new avenue for medical science".

[8] Similarly, in the beginning of the 20th century, Oscar Raab, a German medical student supervised by Professor Herman Von Tappeiner, accidentally made a scientific observation of the antimicrobial effects of light-activated dyes.

This chance observation highlighted the ability of certain fluorescent compounds, now termed "photosensitizers" (PS), to artificially induce light sensitivity in microorganisms and enhance the known antimicrobial effects of sunlight.

Shortly thereafter, Von Tappeiner and Jodlbauer discovered that oxygen was crucial for light-mediated reactions, leading to the creation of the term "photodynamische wirkung" (photodynamic effect).

[9] Since then, significant progress has been made in understanding the underlying mechanisms and optimizing the efficacy of photodynamic therapy (PDT) for treatment of cancers and age-related macular degeneration.

Today, the branch of PDT focused on killing microbial cells is considered as an option to prevent and treat infectious diseases in a manner that avoids the emergence of antimicrobial drug-resistance.

When the photosensitizer molecule is in an excited triplet state, it can induce local Type 1 photodynamic reactions by direct contact with molecular oxygen, inorganic ions or biological targets.

[15] However, when present in biofilms, microbial populations can exhibit distinct characteristics compared to their planktonic counterparts, including significantly higher tolerance towards antimicrobials (up to 1,000-fold).

[18][19][20] The likelihood of developing resistance in pathogens is higher for antimicrobial strategies that have a specific target structure, following the key-lock principle, embodied in many antibiotics or antiseptics.

In contrast, aPDT acts through a variety of non-specific oxidative mechanisms targeting multiple structures and pathways simultaneously, making the technique far less prone to resistance.

Irradiance is defined as the optical power of the light source in Watts, divided by the area of tissue illumination conventionally described in square meters or centimeters (W/m2 or W/cm2).

The irradiance, as a photodynamic parameter, is limited by the onset of adverse thermal factors in exposed tissue, or by degradative consequences to the sensitizer itself (commonly referred to as "photobleaching").

Fluence is a different physical quantity often used by aPDT practitioners, which considers the backscattering flux of light-tissue interaction causing re-entry of photons back into the treated area.

[26] This promotes electrostatic attraction with negatively charged groups found on microbial cell surfaces (e.g. phosphate, carboxylate, sulfate), thus ensuring that during illumination, production of reactive oxygen species occurs in close contact with the targeted cellular population.

The generation of reactive oxygen species (ROS) in neutrophils, macrophages, and eosinophils is one of the primary means by which the human immune system combats infecting microbes.

[55][56] The ability to inhibit microbial virulence is of particular interest because it could be related to accelerated infection site healing when compared to standard antimicrobial chemotherapy that only relies on bacteriostatic or bactericidal effects.

[57][58] Secreted virulence factors normally contain peptides, and it is well known that some amino acids (e.g. histidine, cysteine, tyrosine, tryptophan and methionine) are highly vulnerable to oxidation.

[46][55][61] The capability to not only eliminate the microbes causing an infection but also to inhibit expression of various molecules that lead to host tissue damage offers a significant benefit over traditional antimicrobial drugs.

[62] Several clinical studies performed using the current standard of care – intranasal mupirocin 2% antibiotic ointment – in surgical patients, concluded that this treatment significantly decreased the rate of hospital-acquired infections.

[74][75][76] One study found a 44% reduction in bloodstream infection rates when universal decolonization was used (e.g. intranasal mupirocin ointment and chlorhexidine body wash) in a trial involving 73,256 hospital patients.

[72] In addition, researchers have demonstrated that eradicating S. aureus from the anterior nares also utilizing intranasal mupirocin ointment reduced surgical site infection rates up to 58% in hospitalized patients who were nasal carriers.

The most clinically used photosensitizers are methylene blue and curcumin, as well as the protoporphyrin IX precursors, aminolevulinic acid (ALA) and methyl-ALA. Fungal infections treated with aPDT have included both Dermatophytosis and Sporotrichosis.

Cutaneous leishmaniasis has been treated with aPDT mediated by either ALA[87] or methylene blue,[88] because the standard treatment using systemic amphotericin B or topical pentavalent antimonial preparations have several drawbacks.

They are classified into three main types, i.e. venous, diabetic, and pressure ulcers and are frequently sites of microbial infection that become a major deterrent to for patient recovery.

[90][91] DFU are frequently infected with a combination of fungi and bacteria including the genera Serratia, Morganella, Proteus, Haemophilus, Acinetobacter, Enterococcus, and Staphylococcus.

[95] In the early 90s, Emeritus Professor Michael Wilson from University College London (UCL), initiated scientific investigations on the potential of aPDT to combat bacteria of interest in dentistry.

[133] Other factors like irradiance, treatment time (or dose), microbial strain, and distance of the product from the light source also play a major role in the microbicidal efficacy of food-based aPDT.

[120][132][133] A recent study demonstrated that appropriate concentrations of a photosensitizer potentially useful for food-based disinfection combined with appropriate peak absorption wavelength light resulted in upwards of 99.999% (5 log10) reduction in MRSA and complete kill in Salmonella cell counts.

Illustrative scheme of photodynamic reactions. The photosensitizer absorbs light and is promoted from its ground singlet state ( 1 PS) to an excited singlet state ( 1 PS*). Alternatively, the photosensitizer can convert to an excited triplet state ( 3 PS*) by intersystem crossing . This is a longer-living state that allow sufficient time for chemical reactions to occur. A photosensitizer in 3 PS* state can return to ground state ( 1 PS) either by emitting phosphorescence , or by photochemical reactions that occur through transfer of charges or energy. These photochemical reactions can locally generate cytotoxic reactive oxygen species (ROS) via the Type I or II photodynamic reactions. In a cellular microenvironment, these ROS have a short lifespan (<10μs), and react with and destroy biomolecules, such as proteins, carbohydrates, nucleic acids, and lipids, very close (<1μm) to the production site. Type I: Charges, such as electrons , are transferred to surrounding substrates (R), forming radicals (R • ) due to the presence of the unpaired electron that was received. Molecular oxygen (O 2 ) participates directly or indirectly in this reaction pathway forming the radical anion known as superoxide (O 2 •– ). The superoxide radical can be further reduced to form hydrogen peroxide (H 2 O 2 ), which can also be reduced to form highly reactive free hydroxyl radicals (HO • ) via Fenton-like reactions . Type II: Energy is transferred to ground state triplet molecular oxygen ( 3 O 2 ), creating singlet oxygen ( 1 O 2 *), an excited form of oxygen that is much more reactive than its ground state triplet counterpart. 1 PS = Ground Singlet State of Photosensitizer; 1 PS* = First Excited Singlet State of Photosensitizer; 3 PS* = First Excited Triplet State of Photosensitizer; ISC = Intersystem Crossing; 3 O 2 = Ground State Triplet Oxygen; 1 O 2 = Excited State Singlet Oxygen.
Molecular frameworks most often used as photosensitizers for antimicrobial photodynamic therapy. The examples listed in this figure include: methylene blue (MB, phenothiazine ), crystal violet (CV, triarylmethane ), porphyrins , phtalocyanines , riboflavin (Vitamin B 2 ), rose bengal (RB, halogenated xanthene ), chlorins and curcumin .