While the use of PDT to treat infections is clearly in its infancy, there may be significant future applications. Multi-antibiotic resistance of pathogens, especially bacteria, is a rapidly growing and alarming phenomenon, and alternative methods of treating localized infections are being urgently sought. In addition, in many localized infections, oral or systemically delivered antibiotics are not particularly effective, either because the bacteria are infecting a tissue that is not well perfused, or because the bacteria are present in the tissue as a biofilm (a state that is known to dramatically reduce antibiotic susceptibility). In addition, the rise in the number of immunosuppressed organ transplant, cancer and AIDS patients has led to the increased occurrence of intractable infections.
We can envisage PDT being used in the future to combat otherwise hard to treat localized infections. The basic premise is that the PS should be capable of local, topical or intracavitary administration into the infected area and, after a suitable time, the appropriate dose (fluence and fluence rate) of the optimum wavelength of light should be delivered into the infected area via a fiber optic, diffusing tip, fiber bundle or implantable light-emitting diode, or by direct illumination of a surgically exposed area.
Surgical wound infections account for 25% of nocosomial infections and frequently display some degree of antibiotic resistance. Species involved include S. aureus, Enterococcus spp. and Gram-(−) enteric bacilli. Patients who have intestinal surgery, who are neutropenic due to cancer chemotherapy or other medication, or who have diabetes or other vascular disease are at increased risk of post-surgical wound infection. It may be possible when these infected wounds need surgical intervention to apply topical PDT, especially for drug-resistant strains.
Acute soft-tissue infections are relatively rare, but they can have devastating consequences to patients. The spread can be rapid, the mortality rate is high (up to 50%) and mutilating surgery is frequently the only means of arresting the unrelenting course of the disease. The group includes such manifestations such as necrotizing fasciitis (S. aureus, Streptococcus spp. or polymicrobial species), gas gangrene (Clostridium spp.), necrotizing cellulitis and Fournier’s gangrene (synergistic mixtures of aerobes and anaerobes). In these infections, repeated excisions of affected tissue are frequently necessary and topical PDT could have a role to play in rapidly reducing the bacterial burden and, hence, reducing the extent of surgical debridement.
An abscess is the common result of an infection in soft tissue and many internal organs, such as liver, lungs, brain and peritoneum. It is the result of a massive influx of neutrophils that kill bacteria but also produce enzymes that lead to local tissue destruction and accumulation of pus (a mixture of living and dead bacteria, dead neutrophils and liquified tissue). An abscess that is successful in limiting the spread of the infection becomes surrounded by a collagen membrane and the contents may be under considerable pressure. The bacteria responsible include S. aureus, Klebsiella spp., enteric bacilli and anaerobes such as Bacteroides spp. Surgical drainage is the normal treatment for abscesses and it could advantageously be followed by topical application of PS followed by illumination to remove residual infection from the abscess bed.
The effect of burns in destroying the cutaneous barrier, rendering the affected tissue non-perfused, and depressing immune defenses, means that they very commonly become infected. In the past, the majority of patients with serious burns died from infections. The introduction of topical antimicrobial treatments and early excision and skin grafting has reduced the death rate significantly. The ubiquitous pathogen P. aeruginosa, together with S. aureus, P. mirabilis, Candida spp. and filamentous fungi are frequently responsible. Burn infections frequently lead to failure of skin grafts. Topical antimicrobials employed include mafenide acetate, mupirocin, silver nitrate and silver sulfadiazine, and topical PDT may also have a role to play.
Chronic and acute sinusitis can present a significant clinical problem as they involve an infected cavity that is sometimes poorly responsive to systemic antibiotics and surgery. The bacteriology can vary among cases, but coagulase-negative Staphylococci, S. pneumoniae, H. influenzae, Moraxella catarrhalis and S. aureus have been shown to be the commonest organisms implicated in chronic sinusitis, and antibiotic resistance is a major problem. Because the sinus is a bony cavity coated by a mucosal layer and is accessible by a catheter or fiber optic for PS and light delivery, it is a possible candidate for antimicrobial PDT. Ear infections such as bacterial otitis media (H. influenzae, Pneumococcus spp., S. pneumoniae and Chlamydia pneumoniae) could also be susceptible.
Periodontal disease is caused by a set of pathogenic bacterial species which, along with a wide range of host-compatible species, form complexes in subgingival biofilms (plaques) and are responsible for clinical inflammation and periodontal destruction. A PS may be injected into the periodontal pocket, followed by illumination with fiber optics inserted into the infected area. This technique keeps the bactericidal effect confined to the disease lesion so that beneficial microflora at other sites in the mouth would remain intact. In a similar manner, tooth surface infections by oral or mutans Streptococci (Fusobacterium nucleatum, Actinomyces viscosus) responsible for dental caries could also be susceptible.
Urinary tract infections (UTI) comprise one of the commonest classes of localized bacterial infections. The majority are caused by E. coli strains (uropathogenic), but Proteus, Staphylococcus, and Klebsiella spp. can also be involved. The bacteria initially adhere to the urothelium of the bladder or urethra, causing cystitis, but can then ascend the urinary tract, leading to pyelonephritis. For anatomical reasons, women are much more likely to contract these infections than men. Although UTIs are usually effectively treated using oral antibiotics that build up to effective concentrations in the urine, recurrence is common and bacterial resistance is becoming increasingly problematic. PDT has been clinically used to treat superficial bladder cancer, wherein the PS is injected systemically and light is delivered intravesically. We hypothesize that intravesical delivery of both PS and light should avoid bladder damage and show utility as a therapy for bacterial cystitis.
As mentioned previously, H. pylori
infection has been shown to be strongly associated with the presence of inflammation in the gastric mucosa (chronic superficial gastritis), and especially with polymorphonuclear cell infiltration (chronic active gastritis). Once acquired, H. pylori
persists, usually for life, unless eradicated by antimicrobial therapy.169 H. pylori
is a major cause of peptic ulcer disease, a human carcinogen and is implicated in the development of gastric cancer (the most important gastrointestinal malignancy in the world). H. pylori
organisms are spiral, microaerophilic, Gram-(−) bacteria that colonize the gastric mucosa and secrete urease and other virulence factors that increase their pathogenicity. Combination antibiotic therapy leads to eradication rates of about 80%, but at the expense of side effects and possible poor patient compliance. Increasing antibiotic resistance and the existence of non-responsive patients suggest that alternative strategies for H. pylori
eradication need to be sought. The clinical trial using ALA referred to previously165
and the discovery in our laboratory that H. pylori
is killed by blue light due to accumulation of endogenous porphyrins81
suggest that light-based therapies may play a role in combating this infection. The relative ease of PS and/or light delivery into the stomach may mean that this is one of the first antibacterial applications of PDT to be used clinically.
Corneal infections such as bacterial keratitis (P. aeruginosa, Capnocytophaga canimorsus, Serratia marcescens, Chlamydia trachomatis or S. aureus) and keratomycosis (fungal infection) could be treated with topical PDT. Dermatophytoses or fungal infections of the skin and nails are a common problem affecting millions of people worldwide, but especially in countries with hot and humid climates. These infections may take the form of ringworm (tinea corporis), athlete’s foot (tinea pedis), onychomycosis (toenail fungus), tinea capitis (scalp), tinea cruris (groin) and tinea barbae (beard). The causative organisms are frequently Trichophyton spp., Epidermophyton floccosum or Microsporum canis. Dermatophytoses are most commonly treated with topical antifungal preparations, although therapeutic success is limited because of the lengthy duration of treatment required, poor patient compliance and high relapse rates at specific body sites. Although at present there are only sporadic reports of dermatophytes developing resistance to antifungals, by analogy with antibiotic resistance in bacteria, it is likely only a matter of time before widespread resistance emerges for dermatophytes. The superficial nature of fungal infections encourages the testing of topical PDT as a therapy.