Photodynamic therapy for localized infections--state of the art

Abstract

Photodynamic therapy (PDT) was discovered over 100 years ago by observing the killing of microorganisms when harmless dyes and visible light were combined in vitro. Since then it has primarily been developed as a treatment for cancer, ophthalmologic disorders and in dermatology. However, in recent years interest in the antimicrobial effects of PDT has revived and it has been proposed as a therapy for a large variety of localized infections. This revival of interest has largely been driven by the inexorable increase in drug resistance among many classes of pathogen. Advantages of PDT include equal killing effectiveness regardless of antibiotic resistance, and a lack of induction of PDT resistance. Disadvantages include the cessation of the antimicrobial effect when the light is turned off, and less than perfect selectivity for microbial cells over host tissue. This review will cover the use of PDT to kill or inactivate pathogens in ex vivo tissues and in biological materials such as blood. PDT has been successfully used to kill pathogens and even to save life in several animal models of localized infections such as surface wounds, burns, oral sites, abscesses and the middle ear. A large number of clinical studies of PDT for viral papillomatosis lesions and for acne refer to its antimicrobial effect, but it is unclear how important this microbial killing is to the overall therapeutic outcome. PDT for periodontitis is a rapidly growing clinical application and other dental applications are under investigation. PDT is being clinically studied for other dermatological infections such as leishmaniasis and mycobacteria. Antimicrobial PDT will become more important in the future as antibiotic resistance is only expected to continue to increase.

Figure 1

Problem of antibiotic resistance.

Figure 2

Molecular structures of representative antimicrobial PS

Figure 3

Structures of the cell walls of three different classes of microbial pathogens.

Figure 4

Schematic depiction of the use of ex vivo biological tissues and materials to mimic the use of PDT to kill microbial cells in infections.

Figure 5

Kaplan-Meier plot of survival of mice with excisional wounds infected with Pseudomonas aeruginosa, and given either no treatment, light alone, PS (polylysine-ce6 conjugate) alone, or PDT with conjugate plus light.

Figure 6

Schematic depiction of the steps involved in performing antimicrobial PDT on a burn infection in mice.

Figure 7

Dose response of bacterial luminescence from a representative mouse burn infected with A. baumannii and treated with PEI-ce6 and light (PDT) at 30 minutes after infection; a representative mouse burn infected with A. baumannii and treated with PEI-ce6 only at 30 minutes after infection (dark control); a representative mouse burn infected with A. baumannii and treated with light only at 24 hours after infection (light control).

Figure 8

Real time monitoring accumulation of PS (EtNBS) in subcutaneous granuloma site in BALB/c mice by fluorescence imaging. Fluorescence intensity increased linearly immediately after PS injection up to 60 min, suggesting steady, time dependent delivery of EtNBS to the collagen implants.

Figure 9

Candidate infectious diseases for PDT. A wide variety of localized infections could be clinically treated by antimicrobial PDT.

Figure 10

ALA or MAL-induced PPIX. Schematic illustrating the interaction of the heme biosynthesis pathway with exogenous ALA or MAL to give intracellular PPIX. Abbreviations are ALA-D = ALA dehydratase; ALA-S = ALA synthetase; Coprogen III = coproporphyrinogen III; CPO = coproporphyrinogen oxidase; FCH = ferrochelatase; HMB = hydroxymethylbilane, PBG-D = porphobilinogren deaminase; protogen III = protoporphyrinogen; PPO = protoporphyrinogen oxidase; Urogen III = uroporphyrinogen III; UCS = uroporphyrinogen cosynthase, UGD = uroporphyrinogen decarboxylase.

Figure 11

Schematic depiction of ALA-PDT for acne. The infalammation and the bacteria in the sebaceous gland are destroyed.

Figure 12

Schematic depiction of the advantages of PDT for localized infections compared to antibiotic drugs.