Antimicrobial photodynamic therapy mediated by methylene blue and potassium iodide to treat urinary tract infection in a female rat model

Abstract

Drug-resistant urinary tract infections (UTIs) are difficult and sometimes impossible to treat. Many UTIs are caused by uropathogenic Escherichia coli (UPEC). We developed an intact rat model of UTI, by catheterizing female rats and introducing a bioluminescent UPEC strain into the female rat bladder which lasted for up to six days. We recently showed that antimicrobial photodynamic inactivation (aPDI) of a bacterial infection mediated by the well-known phenothiazinium salt, methylene blue (MB) could be strongly potentiated by addition of the non-toxic salt potassium iodide (KI). In the intact rat model we introduced MB into the bladder by catheter, followed by KI solution and delivered intravesicular illumination with a diffusing fiber connected to a 1 W 660 nm laser. Bioluminescent imaging of the bacterial burden was carried out during the procedure and for 6 days afterwards. Light-dose dependent loss of bioluminescence was observed with the combination of MB followed by KI, but recurrence of infection was seen the next day in some cases. aPDT with MB + KI gave a significantly shorter duration of infection compared to untreated controls. aPDT with MB alone was the least effective. No signs of aPDT damage to the bladder lining were detected. This procedure to treat urinary tract infections without antibiotics by using already approved pharmaceutical substances (MB and KI) may have clinical applicability, either initially as a stand-alone therapy, or as an adjunct to antibiotic therapy by a rapid and substantial reduction of the bacterial burden.

Photodynamic enhancement of the activity of antibiotics used in urinary tract infections

“…This method is also successfully used against gram-positive and gram-negative bacteria in in vitro studies [25][26][27][28][29][30][31]. However, it should be underlined that there are only a few reports describing the use of aPDT in urological infection [13,14]. To our knowledge, current work is the first report focused on the modulatory effect of the aPDT on antibacterial activity of antibiotics possessing different mechanisms of action against UPEC rods.…”

“…It has been reported to possess noteworthy advantages, e.g., short photosensitizing period, selective accumulation in the target tissue and cell's parts, relatively good absorption of red light, and minimal side effects [11,12]. The combination of the aPDT and conventionally used antibiotics to treat severe bacterial infections shows significant potential, being a chance for more effective therapies also in UTIs [7,13,14].…”

Can light‐based approaches overcome antimicrobial resistance?

“…This may be difficult as a high concentration of KI (100 s of mM) is required to obtain the best potentiation effect. The use for treating a bladder infection was attractive, as the bladder is ideally suited to contain an aqueous solution at the same time as light is delivered (Huang et al, ). However, the urothelial lining of the bladder may be more sensitive to the damaging effects of PDT compared to skin and soft tissue.…”

“…A mouse model of oral candidiasis caused by bioluminescent C. albicans was treated by MB‐mediated aPDT combined with KI (Freire, Ferraresi, Jorge, & Hamblin, ). A model of urinary tract infection in the female rat bladder caused by a bioluminescent strain of uropathogenic E. coli was treated by instillation of MB solution followed by a KI solution and then intravesicular delivery of red light using a fiber optic (Huang et al, ).…”

Oxygen-Independent Antimicrobial Photoinactivation: Type III Photochemical Mechanism?

“…MB is considered to have a significant contribution of the Type I photochemical mechanism in its aPDI activity, especially when compared to porphyrins [67]. We also reported that the aPDI activity of intravesicular MB plus red light was potentiated by addition of KI in a female rat model of bladder infection caused by bioluminescent uropathogenic E. coli [68]. In a recent study we investigated the potentiation of MB-mediated aPDI by addition of KI [69].…”