Steps Toward Prevention and Treatment of Female UTI Using PDT

Introduction

Recent research on skin infection and its treatment with PDT identified combinations of photosensitisers and light for eradication of specific pathogens [1]. It has also been discovered that both the Photosensitiser Drug (PS) and the action of Reactive Oxygen Species (ROS) are subject to microbial tolerance gradually over time [2]. However, this resistance is likely to develop more slowly than antibiotic resistance, which is a serious issue for those with recurrent infections caused by ESKAPE pathogens [3]. Using multidisciplinary knowledge of physics, urology and microbiology, a logical next step would be to apply PDT to the treatment of UTI [4], identification of the pathogen in-situ as a guide for the choice of PS and light wavelength by imaging is an aspirational and longerterm endpoint. The aim of this study is to collate information on the incidence and nature of Urinary Tract Infection (UTI) in females, and to consider treatments based on clinical, translational and lab research.

Study Design, Materials and Methods

Literature Review.

Results

Epidemiology

The opening chapter of the seventh International Consultation on Incontinence [5] describes the incidence of Urinary Incontinence (UI) and Faecal Incontinence (FI) as a function of health, maternal, and social factors. However Urinary Tract Infection (UTI) was omitted. Women are significantly more likely to experience UTI than men [6], and their lifetime incidence of UTIs is reported to be 50-60%, with prevalence increasing with age [7]. Among a cohort of 113 young women with UTI, 27% percent experienced at least one recurrence (rUTI) within six months [8]. Catheter-associated UTI is the most common nosocomial infection, accounting for over a million cases at any one time in US hospitals and nursing homes [9].

Microbiology

Uncomplicated Human Urinary Tract Infection (uUTI) is caused by Escherichia coli [10], however E. Faecalis and Staphylococcus saprophyticus have also been found [11]. In catheter users, the Klebsiella and Proteus genera are present in the urine. In those with diabetes mellitus, Klebsiella, Enterobacter and candida genera are likely, with Enterococcus spp and candida spp also reported in complicated human UTI.

Technology

GaniteTM is a Gallium Nitrate preparation proven to destroy biofilm-forming urinary pathogens in the lab [12] including a variety of E. Coli and P. Aeruginosa Strains. This research group have a patent for the intravesical instillation of the drug in humans and so clinical trial data is imminent. In rats a Foley catheter with an embedded fibre optic light guide delivered a photosensitiser and laser irradiation synergistically [13] demonstrating that the technology works, even at a small scale. More realistically for an ambulant animal, a wireless LED device was implanted in a mouse given oral 5-Aminovulenic acid. This treated lab-induced cancer over several days and is known as metronomic Photodynamic Therapy (PDT)[14].

The optimal light and photosensitiser combinations for PDT of a variety of human infections have been published [1]. For example, methylene blue and 660nm light is thought to kill Covid-19. PDT can kill microbes even if they are resistant to antibiotics, and any tolerance that the pathogens develop is likely to happen slowly. The technique was recently employed in conjunction with antibiotics to treat UTI caused by e-coli [15]. Lothar Lilge at al. [16] describe the intravesical instillation of a photosensitiser and fibre-optic delivery of green light during PDT for bladder cancer. The shape of the bladder, optical properties of the mucosal layer, and the geometry of illumination all influenced treatment efficacy. Castle and co-authors [17] describe the use of PDT, infrared laser therapy and bacterial interference in a cohort of patients with Neurogenic bladders and rUTI.

Interpretation of Results

The technology to deliver PDT to bladders already exists but should be evaluated for human females with symptomatic UTI. Effective parameters are known for skin infection [10]; however, they may require alteration for intravesical use necessitating further clinical research.

The simple treatment method of instilling a drug into to bladder is protected by at least one patent and so alternative versions may have to be researched. However, the use of antibiotics with adjunctive pharmacy is emerging could halt the development of microbial resistance, suggesting they will remain a useful method of treatment in some situations.

The research chapter of ICI consultation seven outlines the need for prevention and early intervention in UTI [18]. The Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium aims to expand research beyond the detection and treatment of Lower Urinary Tract Symptoms (LUTS) to the promotion and preservation of bladder health and prevention of LUTS in girls and women [19]. PDT has successfully prevented skin cancers [20] , and so over time an application for rUTI and related LUTs may emerge.

Concluding Message

Several techniques are being developed for the treatment of infection to avoid overuse of antibiotics and the emergence of resistant microbes. PDT appears close to being ready for clinical use in UTI and may have roles in treatment and prevention.

Acknowledgement

None.

Conflict of Interest

None.

References

• Mackay AM (2022) Antimicrobial Photodynamic Therapy of Human Skin. J Dermatol & Skin Sci 4(2): 20-23.
• Mackay AM (2022) Microbial Resistance to Photodynamic Therapy. J Cell Immunol 4(3): 117-120.
• Murray CJ, Ikuta KS, Sharara F, Swetschinski L, Aguilar GR, et al. (2022) Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. The Lancet 399(10325): 629-655.
• Mackay AM (2022) Sustainable Treatment of Female UTI. International Continence Society.
• Cardozo, Wagg, Wein. International Consultation on Incontinence 7. Chapter 1 Epidemiology.
• Foxman B (2003) Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Dis Mon 49(2): 53-70.
• Medina M, Castillo Pino E (2019) An introduction to the epidemiology and burden of urinary tract infections. Ther Adv Urol 11: 1756287219832172.
• Foxman B (1990) Recurring urinary tract infection: incidence and risk factors. Am J Public Health 80(3): 331-333.
• Kaye KS, Gupta V, Mulgirigama A, Ashish V Joshi, Nicole E Scangarella Oman, et al. (2021) Antimicrobial Resistance Trends in Urine Escherichia coli Isolates from Adult and Adolescent Females in the United States From 2011 to 2019: Rising ESBL Strains and Impact on Patient Management. Clin Infect Dis 73(11): 1992-1999.
• Lamb LE, Dhar N, Timar R, Wills M, Dhar S, et al. (2020) COVID-19 inflammation results in urine cytokine elevation and causes COVID-19 associated cystitis (CAC). Med Hypotheses 145: 110375.
• Abrams P, Andersson KE, Apostolidis A, Lori Birder, Donna Bliss, et al. (2018) 6th International Consultation on Incontinence. Recommendations of the International Scientific Committee: EVALUATION AND TREATMENT OF URINARY INCONTINENCE, PELVIC ORGAN PROLAPSE AND FAECAL INCONTINENCE. Neurourol Urodyn 37(7): 2271-2272.
• Sarir S, Thomas C, Rajagopath A, Zimmern P (2016) Antimicrobial Properties of Gallium Nitrate against established biofilm-forming Urinary pathogens in older women with recurrent urinary tract infections.
• Huang YY, Wintner A, Seed PC, Brauns T, Gelfand JA, et al. (2018) Antimicrobial photodynamic therapy mediated by methylene blue and potassium iodide to treat urinary tract infection in a female rat model. Sci Rep 8(1): 7257.
• Kirino I, Fujita K, Sakanoue K, Rin Sugita, Kento Yamagishi, et al. (2020) Metronomic photodynamic therapy using an implantable LED device and orally administered 5-aminolevulinic acid. Sci Rep 10: 22017.
• Tichaczek Goska D, Wojnicz D, Symonowicz K, Ziółkowski P, Hendrich AB (2019) Photodynamic enhancement of the activity of antibiotics used in urinary tract infections. Lasers Med Sci 34(8):1547-1553.
• Lilge L, Wu J, Xu Y, Angelica Manalac, Daniel Molenhuis, et al. (2020) Minimal required PDT light dosimetry for non-muscle invasive bladder cancer. J Biomed Opt 25(6): 1-13.
• Castle AC, Albert Park, Alissa J Mitchell, Donna Z Bliss, Jeffrey A Gelfand, et al. (2018) Neurogenic Bladder: Recurrent Urinary Tract Infections-Beyond Antibiotics. Current Bladder Dysfunction Reports 13(4): 191-200.
• Cardozo, Wagg, Wein. International Consultation on Incontinence 7. Chapter 22 Research.
• Brady SS, Bavendam TG, Berry A, Cynthia S Fok, Sheila Gahagan, et al. (2018) The Prevention of Lower Urinary Tract Symptoms (PLUS) in girls and women: Developing a conceptual framework for a prevention research agenda. Neurourol Urodyn 37(8): 2951-2964.
• Liew YCC, De Souza NNA, Sultana RG, Oh CC (2020) Photodynamic therapy for the prevention and treatment of actinic keratosis/squamous cell carcinoma in solid organ transplant recipients: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol 34(2): 251-259.