Study Group 3

Using light to treat infections：Research on photodynamic therapy (PDT) to treat infections

Team leader: Toshiyuki Ozawa

In recent years, with the increase in lifestyle-related diseases, the number of patients with diabetic skin ulcers and gangrene of the lower leg has increased rapidly. When gangrene of the lower leg is untreatable, there is no choice but to carry out amputation, which significantly decreases the patient’s quality of life. A major factor that makes treatment difficult is bacterial infection of ulcers, especially by methicillin-resistant Staphylococcus aureus (MRSA) and other multidrug-resistant organisms. This applies not only to gangrene but also to systemic burns; if the wound is infected with MRSA and the infection cannot be controlled, this may cause sepsis and result in death. Normal bacterial infections can be controlled by antibiotics, but with MRSA the usual antibiotics do not work because the bacteria have acquired resistance to multiple drugs. At present, there are several kinds of antibiotics in Japan that are effective against MRSA. However, if they are abused, MRSA may acquire resistance to these antibiotics as well, so they must be used with great caution. We are faced with a dilemma: administration of antibiotics to treat patients with MRSA infection now will lead to increased risk for future patients with MRSA infection.

In order to solve these problems, we are conducting research with the aim of treating infections with photodynamic therapy (PDT).

PDT is a general term for procedures in which photosensitizers are injected into the body and light of a specific wavelength is applied to the target body tissue, causing the photosensitizers to produce active oxygen to treat cancerous and infected lesions.

We are performing PDT against MRSA using 5-aminolevulinic acid (ALA) as a photosensitizer and a 410-nm wavelength LED as a light source. ALA is now covered by insurance as an orphan drug for use in intraoperative fluorescence diagnosis during the removal of brain tumors in neurosurgery; the safety of this amino acid is established, and it is also used in health food and cosmetics. When ALA is taken up by malignant tumors and bacteria, it is metabolized and accumulates as protoporphyrin IX (PpIX). ALA is characterized by its high specificity for malignant tumors and bacteria because PpIX does not accumulate in normal cells. When light of a specific wavelength (410-nm in this case) is applied to PpIX, active oxygen is generated, which kills cells and bacteria. In antimicrobial PDT, bacteria are killed by a completely different mechanism from that associated with antibiotics, so it is thought that resistant organisms will not develop (see Figure 1).

In most cases of antimicrobial PDT that have been reported, direct application of ALA as an ointment has been used against bacteria. However, it was anticipated that application of ointments in patients with large areas of ulcers or systemic burns would be difficult and make the treatment complex. We therefore designed PDT in which ALA is administered systemically, as is the case with systemic antibiotics, and found that administering intraperitoneal injections of ALA to mice with ulcers brings positive results (Figure 2). (This study received the Meeting Award at the 2013 Annual Meeting of the Japan Society for Laser Surgery and Medicine.)

In the future, we plan to advance our research on PDT against multidrug-resistant Pseudomonas aeruginosa (currently applying for a patent) and further our studies of the use of light in treating infected ulcers in general.